Rituximab

Number: 0314

Brand Selection for Medically Necessary Indications

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Truxima (rituximab-abbs) and Riabni (rituximab arrx) are more costly to Aetna than other CD20-directed cytolytic antibody agents for certain indications. There is a lack of reliable evidence that Truxima and Riabni are superior to other lower cost CD20-directed cytolytic antibody agents for moderately to severely active rheumatoid arthritis. Therefore, Aetna considers Truxima and Riabni to be medically necessary only for members who have a contraindication, intolerance, or ineffective response to the available equivalent alternative CD20-directed cytolytic antibody agents per criteria below.

Moderately to severely active rheumatoid arthritis (RA)

Member has failed treatment with Rituxan and Ruxience due to a documented intolerable adverse event (e.g., rash, nausea, vomiting) and the adverse event was not an expected adverse event attributed to the active ingredient as described in the prescribing information (i.e., known adverse reaction for both the brand and biosimilar medication).

Policy

Note: Requires Precertification.

Precertification of Rituxan (rituximab), Rituxan Hycela (rituximab and hyaluronidase), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), and Riabni (rituximab-arrx) is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Treatment of Hematologic and Oncologic Conditions

Criteria for Initial Approval

Aetna considers Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) as medically necessary for the following indications:
1. Oncologic indications
  
  - for treatment of any of the following oncologic disorders that are CD20-positive as confirmed by testing or analysis:
  1. B-cell acute lymphoblastic leukemia (ALL)
  2. B-cell lymphomas with any of the following subtypes:
    1. Acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma
    2. B-cell lymphoblastic lymphoma
    3. Burkitt lymphoma
    4. Castleman’s disease
    5. Diffuse large B-cell lymphoma (DLBCL)
    6. Follicular lymphoma
    7. High-grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified)
    8. Histological transformation from follicular lymphoma to diffuse large B-cell lymphoma
    9. Histological transformation from nodal marginal zone lymphoma to diffuse large B-cell lymphoma
    10. Mantle cell lymphoma
    11. Marginal zone lymphomas:
      1. Nodal marginal zone lymphoma
      2. Gastric mucosa associated lymphoid tissue (MALT) lymphoma
      3. Nongastric MALT lymphoma
      4. Splenic marginal zone lymphoma
    12. Post-transplant lymphoproliferative disorder (PTLD)
    13. Pediatric aggressive mature B-cell lymphomas;
  3. Central nervous system (CNS) cancers with either of the following:
    1. Leptomeningeal metastases from lymphomas; or
    2. Primary CNS lymphoma
  4. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
  5. Hairy cell leukemia
  6. Hodgkin’s lymphoma, nodular lymphocyte-predominant
  7. Primary cutaneous B-cell lymphoma
  8. Rosai-Dorfman disease
  9. Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (LPL);
2. Hematologic indications
3. Myasthenia gravis
  
  - for treatment of refractory myasthenia gravis;
4. Immune checkpoint inhibitor-related toxicities.
Aetna considers all other hematologic and oncologic indications as experimental and investigational (for additional information, see Experimental and Investigational or Not Medically Necessary, and Background sections).
Continuation of Therapy

Aetna considers continuation of Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) therapy medically necessary for the following indications:
1. Oncologic indications
  
  - for members requesting reauthorization for an oncologic indication listed in Section I.A. when there is no evidence of unacceptable toxicity;
2. Immune checkpoint inhibitor-related toxicities
  
  - for members requesting reauthorization for treatment of immune checkpoint inhibitor-related toxicities who are experiencing benefit from therapy;
3. All other indications
  
  - for members requesting reauthorization for an indication listed in Section I.B-C. who are experiencing benefit from therapy.

Treatment of Rheumatoid Arthritis and Other Conditions

Criteria for Initial Approval

Aetna considers Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) as medically necessary for the following indications:
1. Rheumatoid arthritis (RA)
  1. For the treatment of moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate (MTX) unless the member has a contraindication (see Appendix) or intolerance to MTX and either of the following criteria are met:
    1. The member has previously received any biologic disease-modifying antirheumatic drug (DMARD) or targeted synthetic DMARD (e.g., Xeljanz) indicated for the treatment of moderately to severely active rheumatoid arthritis; or
    2. The member has received at least two full doses of Rituxan, Ruxience, Truxima or Riabni for the treatment of RA, where the most recent dose was given within 6 months of the request; or
  2. For treatment of moderately to severely active RA in combination with MTX unless the member has a contraindication (see Appendix) or intolerance to MTX when all of the following criteria are met:
    1. The member meets either of the following criteria:
      1. The member has been tested for either of the following biomarkers and the test was positive:
        
        Rheumatoid factor (RF); or
        
        Anti-cyclic citrullinated peptide (anti-CCP); or
      2. The member has been tested for all of the following biomarkers:
        
        RF; and
        
        Anti-CCP; and
        
        C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR); and
    2. The member meets either of the following criteria:
      1. The member has experienced an inadequate response to at least a 3-month trial of MTX despite adequate dosing (i.e., titrated to 20 mg/week); or
      2. The member had an intolerable adverse effect or contraindication to MTX (see Appendix), and an inadequate response to another conventional DMARD (e.g., hydroxychloroquine, leflunomide, sulfasalazine);
2. Granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis), microscopic polyangiitis (MPA), Churg-Strauss, or pauci-immune glomerulonephritis;
3. Sjögren’s syndrome
  
  - when corticosteroids and other immunosuppressive agents were ineffective;
4. Relapsing remitting multiple sclerosis (MS);
5. Neuromyelitis optica (i.e., neuromyelitis optica spectrum disorder (NMOSD), Devic disease)
  
  - when both of the following criteria are met:
  1. At least one other immunotherapy was ineffective; and
  2. The member will not receive the requested drug concomitantly with other biologics for the treatment of NMOSD;
6. Autoimmune blistering disease
  
  - for treatment of autoimmune blistering diseases (e.g., pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita and paraneoplastic pemphigus);
7. Cryoglobulinemia
  
  - when corticosteroids and other immunosuppressive agents were ineffective;
8. Solid organ transplant treatment and prevention of antibody mediated rejection in solid organ transplant;
9. Opsoclonus-myoclonus-ataxia associated with neuroblastoma
  
  - when the member is refractory to steroids and chemotherapy;
10. Systemic lupus erythematosus (SLE) that is refractory to immunosuppressive therapy.
Aetna considers all other indications (except for hematologic and oncologic indications considered medically necessary) as experimental and investigational (for additional information, see Experimental and Investigational or Not Medically Necessary, and Background sections).
Continuation of Therapy

Aetna considers continuation of Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) therapy medically necessary for the following indications:
1. Rheumatoid arthritis in all members (including new members) requesting reauthorization who meet all initial authorization criteria and achieve or maintain positive clinical response after at least two doses of therapy with Rituxan, Ruxience, Truxima, or Riabni as evidenced by low disease activity improvement of at least 20% from baseline in tender joint count, swollen joint count, pain, or disability;
2. Multiple sclerosis in members requesting reauthorization for relapsing remitting MS who are experiencing disease stability or improvement while receiving Rituxan, Ruxience, Truxima, or Riabni;
3. Other indications in all members (including new members) requesting reauthorization who meet all initial authorization criteria and are receiving benefit from therapy.

Rituximab and Hyaluronidase (Rituxan Hycela)

Criteria for Initial Approval

Aetna considers rituximab and hyaluronidase (Rituxan Hycela) medically necessary for treatment of the following oncologic disorders that are CD20-positive as confirmed by testing or analysis, in a member who has received at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions:
1. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
2. Hairy cell leukemia (HCL)
3. B-cell lymphomas:
  1. Castleman’s disease (CD)
  2. Diffuse large B-cell lymphoma (DLBCL)
  3. Follicular lymphoma
  4. High grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified)
  5. Histologic transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma
  6. Mantle cell lymphoma
  7. Post-transplant lymphoproliferative disorder (PTLD)
  8. Marginal zone lymphomas:
    1. Nodal marginal zone lymphoma
    2. Gastric mucosa associated lymphoid tissue (MALT) lymphoma
    3. Nongastric MALT lymphoma
    4. Splenic marginal zone lymphoma
4. Primary cutaneous B-cell lymphoma (e.g., cutaneous marginal zone lymphoma or cutaneous follicle center lymphomas)
5. Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continuation of rituximab and hyaluronidase (Rituxan Hycela) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity.

Dosage and Administration

Rituxan

Rituxan is available as (10 MG/ML) in 100mg/10 mL and 500 mg/50 mL single‐dose vials. Administer only as an intravenous infusion. Do not administer as an intravenous push or bolus. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion.

Chronic Lymphocytic Leukemia (CLL)

The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m² in cycles 2-6, in combination with fludarabine and cyclophosphamide, administered every 28 days.

Component of Zevalin (ibritumomab tiuxetan) Therapeutic Regimen for NHL

Infuse rituximab 250 mg/m² within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin. Administer Rituxan and In-111-Zevalin 7- 9 days prior to Rituxan and Y-90- Zevalin. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

The induction dose for adults with active Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. The follow up dose for persons with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.

The induction dose for pediatrics with GPA and MPA in combination with glucocorticoids is 375 mg/m² once weekly for 4 weeks. The follow up dose for pediatrics with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 250 mg/m² intravenous infusions separated by two weeks, followed by a 250 mg/m² intravenous infusion every 6 months thereafter based on clinical evaluation.

Non-Hodgkin’s Lymphoma (NHL)

The dose for NHL is 375 mg/m² as an intravenous infusion according to the schedules listed in the prescribing information:

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: Administer once weekly for 4 or 8 doses.
Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses.
Previously Untreated, Follicular, CD20-Positive, B-Cell NHL: Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In persons with complete or partial response, initiate maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer as a single-agent every 8 weeks for 12 doses.
Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy: Following completion of 6-8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
Diffuse Large B-Cell NHL: Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.

Pemphigus Vulgaris (PV)

Two-1000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion.

Rheumatoid Arthritis (RA)

The dose for RA in combination with methotrexate is two-1000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion.

Source: Genentech, 2020

Ruxience

Rituximab-pvvr is available as Ruxience and supplied as 100 mg/10 mL (10 mg/mL) and 500 mg/50 mL (10 mg/mL) solution in single-dose vials for intravenous infusions only.

NHL: 375 mg/m²

CLL: 375 mg/m² in the first cycle and 500 mg/m² in cycles 2- 6, in combination with FC, administered every 28 days.

The dose as a component of Zevalin (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m².

The induction dose for adults with active GPA and MPA in combination with glucocorticoids is 375 mg/m² once weekly for 4 weeks. The follow up dose for adults with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.

Source: Pfizer Biosimilars, 2020

Truxima

NHL: 375 mg/m²

CLL: 375 mg/m² in the first cycle and 500 mg/m² in cycles 2- 6, in combination with FC, administered every 28 days.

The dose as a component of Zevalin (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m².

Source: Teva, 2020

Riabni

Riabni (rituximab-arrx) is supplied as 100 mg/10 mL (10 mg/mL) and 500 mg/50 mL (10mg/mL) solution in single-dose vials for intravenous infusion only, not to be administered as an intravenous push or bolus. Riabni should only be administered by a healthcare professional.

The dose for NHL is 375 mg/m².

The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m² in cycles 2-6, in combination with fludarabine and cyclophosphamide (FC), administered every 28 days.

The dose as a component of Zevalin (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m².

Source: Amgen, 2020b

Rituxan Hycela

Rituximab and hyaluronidase human is available as Rituxan Hycela supplied in the following dosage forms and strengths for subcutaneous injection:

1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) solution in a single-dose vial
1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) solution in a single-dose vial

Per FDA-approved labeling, initiate treatment with Rituxan Hycela only after patients have received at least one full dose of a rituximab product by intravenous infusion.

Follicular lymphoma / diffuse large B-cell lymphoma (FL/DLBCL): Administer 1,400 mg / 23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously according to recommended schedule.

Chronic lymphocytic leukemia (CLL): Administer 1,600 mg / 26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously according to recommended schedule.

Premedicate with acetaminophen and antihistamine before each dose; In addition, consider premedication with glucocorticoids.

Administer specified volume into subcutaneous tissue of abdomen:

11.7 mL from 1,400 mg / 23,400 Units vial over approximately 5 minutes
13.4 mL from 1,600 mg / 26,800 Units vial over approximately 7 minutes
Observe 15 minutes following administration.

Source: Genentech, 2021

Experimental and Investigational or Not Medically Necessary

Aetna considers Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) therapy in combination with other biologics (e.g., Arzerra, Cosentyx, Enbrel, Humira, Cimzia Simponi, Remicade, Orencia, Stelara, or Kineret) to be experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) therapy in combination with other multiple sclerosis drugs (excluding Ampyra) to be experimental and investigational because the clinical value has not been established.

Aetna considers Rituxan, Ruxience, Truxima or Riabni uproven and not medically necessary for the treatment of rheumatoid arthritis (RA) when planned date of administration is less than 16 weeks since date of last dose received.

Aetna considers anti-chimeric antibody testing and/or chimeric anti-TNF antibody testing for Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) therapy experimental and investigational because of insufficient evidence in the peer-reviewed literature.

Aetna considers intrathecal rituximab for the treatment of progressive multiple sclerosis experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers Rituxan (rituximab), Ruxience (rituximab-pvvr), Truxima (rituximab-abbs), or Riabni (rituximab-arrx) experimental and investigational for all other indications because its effectiveness for these indications has not been established, including (not an all-inclusive list):

Acute disseminated encephalomyelitis
Acute myeloid leukemia
Acute zonal occult outer retinopathy (AZOOR)
Adrenal gland neoplasm
Amyopathic dermatomyositis
Ankylosing spondylitis
Anterior nodular scleritis
Anti-MAG neuropathy
Anti-myelin-associated glycoprotein neuropathy
Anti-phospholipid syndrome
Aplastic anemia
Arthritis associated with inflammatory bowel disease
Autoimmune encephalitis (e.g., limbic autoimmune encephalitis, NMDA-receptor antibody encephalitis)
Autoimmune epilepsy
Autoimmune hepatitis
Autoimmune neutropenia
Autoimmune pancreatitis/atrophy of the pancreas
Autoimmune polyendocrine syndrome type 1 (APS-1) [also known as autoimmune polyendocrinopathy candidiasis and ectodermal Dysplasia (APECD)]
Autoimmune retinopathy
Axial spondyloarthritis
Behcet's disease
Bile salt export pump deficiency after liver transplantation
Birdshot retinochoroidopathy
Bronchiolitis obliterans
Cerebral folate deficiency
Chronic inflammatory demyelinating polyneuropathy (CIDP)/IgM-associated polyneuropathy
Chronic urticaria
Cogan's syndrome
Collagenous gastritis
Complex regional pain syndrome (reflex sympathetic dystrophy)
Crescentic IgA nephropathy
CREST syndrome
Dermatomyositis
Dermatopolymyositis
Fibrosing mediastinitis
GALOP syndrome (Gait disorder_ataxia; Autoantibodies_IgM against central myelin antigen; Late age of Onset; Polyneuropathy)
Generic (idiopathic) interstitial lung disease
Goodpasture's syndrome
Granulomatous lymphocytic interstitial lung disease (GLILD)
Graves ophthalmopathy
Factor VIII and IX inhibitors in persons with hemophilia
Hashimoto's encephalitis
Hemophagocytic lymphohistiocytosis
Hypersensitivity pneumonitis
Idiopathic nephrotic syndrome
Idiopathic pulmonary fibrosis
Immune complex vasculitis
IgG4 related sclerosing disease
Juvenile dermatomyositis
Juvenile rheumatoid arthritis (juvenile idiopathic arthritis)
Kawasaki disease
Langerhans cell histiocytosis
Lupus cerebritis
Lupus nephritis
Membrano-proliferative nephrosis
Membranous glomerulopathy
Minimal change nephrosis/minimal change disease
Monoclonal gammopathy of undetermined significance (MGUS) neuropathy
Morvan’s syndrome
Multiple myeloma
Myelodysplastic syndromes
Necrotizing myopathy
Neuroblastoma
Neuropsychiatric lupus
Neurosarcoidosis
Non-autoimmune hemolytic
Optic neuropathy
Orbital apex sphenoid syndrome
Orbital pseudolymphoma
Orbital pseudotumor
Orbital xanthogranuloma
PANDAS syndrome
Paraneoplastic myelopathy
Paraneoplastic neurologic syndromes
Parry-Romberg syndrome
Plasma cell dyscrasia
Plasma cell leukemia
POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes) syndrome
Polyarteritis nodosa
Polymyositis
Posterior scleritis
Primary angiitis of the central nervous system
Psoriatic arthritis
Radiation retinopathy
Red call aplasia in thymoma
Retroperitoneal fibrosis
Rhabdomyosarcoma
Sarcoidosis
Scleritis
Scleroderma
Segmental glomerulosclerosis
Sinus histocytosis with massive lymphadenopathy disease (SHML)
Sneddon syndrome
Steroid-dependent nephrotic syndrome
Stiff man/stiff person syndrome
Thyroid-associated ophthalmopathy
Tolosa-Hunt syndrome
Transverse myelitis
Uveitis
Viral meningitis
Xanthogranuloma.

Background

Rituximab (Rituxan), Rituximab-pvvr (Ruxience), Rituximab-abbs (Truxima), and Rituxmab-arrx (Riabni)

U.S. Food and Drug Administration (FDA)-Approved Indications

Non-Hodgkin’s lymphoma (NHL) in adult patients with:
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy
- Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent after first-line CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens
Chronic lymphocytic leukemia (CLL), in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in combination with glucocorticoids

FDA-Approved Rituxan and Truxima are also indicated for the following:

Rheumatoid Arthritis (RA)
Rituxan or Truxima, in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

FDA-Approved Rituxan is also indicated for the following:

Pemphigus Vulgaris (PV)

Compendial Uses for Rituxan, Ruxience, Truxima and Riabni

Autoimmune hemolytic anemia
B-cell acute lymphoblastic leukemia (ALL)
B-cell lymphomas
- Acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma
- B-cell lymphoblastic lymphoma
- Burkitt lymphoma
- Castleman’s disease
- High-grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified)
- Histological transformation from follicular lymphoma to diffuse large B-cell lymphoma
- Histological transformation from nodal marginal zone lymphoma to diffuse large B-cell lymphoma
- Mantle cell lymphoma
- Marginal zone lymphomas
  - Nodal marginal zone lymphoma
  - Gastric mucosa associated lymphoid tissue (MALT) lymphoma
  - Nongastric MALT lymphoma
  - Splenic marginal zone lymphoma
- Post-transplant lymphoproliferative disorder (PTLD)
- Pediatric aggressive mature B-cell lymphomas
Central nervous system (CNS) cancers
- Leptomeningeal metastases from lymphomas
- Primary CNS lymphomas
Chronic graft-versus-host disease (GVHD)
CLL/Small lymphocytic lymphoma (SLL)
Hairy cell leukemia
Hodgkin’s lymphoma, nodular lymphocyte-predominant
Immune checkpoint inhibitor-related toxicities
Myasthenia gravis, refractory
Prevention of Epstein-Barr virus (EBV)-related PTLD in high risk patients
Primary cutaneous B-cell lymphoma
Relapsed/refractory immune or idiopathic thrombocytopenic purpura (ITP)
Rosai-Dorfman disease
Thrombotic thrombocytopenic purpura
Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (LPL)
Sjögren’s syndrome
Multiple sclerosis, relapsing remitting
Neuromyelitis optica (i.e. neuromyelitis optica spectrum disorder, NMOSD, Devic disease)
Autoimmune blistering disease
Cryoglobulinemia
Solid organ transplant
Opsoclonus-myoclonus ataxia
Systemic lupus erythematosus

Rituximab and hyaluronidase human (Rituxan Hycela)

U.S. Food and Drug Administration (FDA)-Approved Indications

Adult patients with follicular lymphoma (FL):
- Relapsed or refractory, follicular lymphoma as a single agent
- Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
- Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy.
Adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens
Adult patients with previously untreated and previously treated chronic lymphocytic leukemia (CLL), in combination with fludarabine and cyclophosphamide (FC).

Limitations of Use:

Initiate treatment with Rituxan Hycela only after patients have received at least one full dose of a rituximab product by intravenous infusion.

Rituxan Hycela is not indicated for the treatment of non-malignant conditions.

Compendial Uses

B-cell lymphomas:
- Castleman’s disease (CD)
- High grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified)
- Histologic transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma
- Marginal zone lymphomas
  - Nodal marginal zone lymphoma
  - Gastric mucosa associated lymphoid tissue (MALT) lymphoma
  - Nongastric MALT lymphoma
  - Splenic marginal zone lymphoma
- Mantle cell lymphoma
- Post-transplant lymphoproliferative disorder (PTLD)
Hairy cell leukemia
Primary cutaneous B-cell lymphoma (e.g., cutaneous marginal zone lymphoma or cutaneous follicle center lymphomas)
Small lymphocytic lymphoma (SLL)
Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma.

Rituximab is available as Rituxan (Genentech, Inc.), Ruxience (Pfizer Biosimilars), Truxima (Teva Pharmaceuticals USA, Inc.), and Riabni (Amgen, Inc.).

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Rituximab binds to the antigen CD20 (human B‐lymphocyte–restricted differentiation antigen, Bp35). This antigen is a hydrophobic transmembrane protein that is located on pre‐B and mature B lymphocytes. It is also expressed on more than 90% of B‐cell non‐Hodgkin’ lymphomas but not expressed on hematopoietic stem cells, pro‐B cells, normal plasma cells, or other normal tissues. CD20 regulates an early step or steps in the activation process for cell cycle initiation and differentiation and may also function as a calcium ion channel. It is not shed from the cell surface and does not internalize upon antibody binding. No free CD20 antigen is found in the circulation. The mechanism of antineoplastic action may involve mediation of B cell lysis by means of binding of the Fab domain of rituximab to the CD20 antigen on B lymphocytes and by recruitment of immune effector functions by the Fc domain. Cell lysis may be the result of complement‐dependent cytotoxicity (CDC) and antibody‐dependent cellular cytotoxicity (ADCC). In addition, the antibody has been shown to induce apoptosis in the DHL‐4 human B‐cell lymphoma line.

B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production (Genentech, 2020).

Rituxan carries a black box warning for fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy (PML). Labeled warnings and precautions include tumor lysis syndrome, infections, cardiac adverse reactions, renal toxicity, bowel obstruction and perforation, and embryo-fetal toxicity. In addition, live virus vaccinations prior to or during Rituxan treatment is not recommended.

The most common adverse reactions in clinical trials include:

NHL (25% or more): infusion-related reactions, fever, lymphopenia, chills, infection and asthenia;
CLL (25% or more): infusion-related reactions and neutropenia;
RA (10% or more): upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events);
GPA and MPA (15% or more): infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions;
PV (15% or more): infusion-related reactions, depression, upper respiratory tract infection/ nasopharyngitis, headache (other important adverse reactions include infections).

Rituximab and hyalurondisase human is available as Rituxan Hycela (Genentech, Inc).

Rituxan Hycela carries a black box warning for severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoenephalopathy (PML). Labeled warnings and precautions include hypersensitivity and other administration reactions, tumor lysis syndrome, infections, renal toxicity, bowel obstruction and perforation, and embryo-fetal toxicity. Live virus vaccinations prior to or during treatment are not recommended. The most common adverse reactions (incidence of 20% or more) include for follicular lymphoma (infections, neutropenia, nausea, constipation, cough, and fatigue), for DLBCL (infections, neutropenia, alopecia, nausea, and anemia), and for CLL (infections, neutropenia, nausea, thrombo, pyrexia, vomiting, and injection site erythema) (Genentech, 2021).

Rituximab-abbs (Truxima, a Biosimilar to Rituxan)

On November 28, 2018, the FDA approved rituximab-abbs (Truxima, Celltrion Inc.; the first biosimilar to Rituxan (Genentech Inc.) for patients with CD20-positive, B-cell NHL to be used as a single-agent or in combination with chemotherapy. Rituximab-abbs was approved for the treatment of adult patients with:

Non-Hodgkin’s Lymphoma (NHL)
- Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single-agent;
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with 1st-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy;
- Non-progressing (including stable disease), low-grade, CD20positive, B-cell NHL as a single-agent after 1st-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens.
Chronic Lymphocytic Leukemia (CLL): Previously untreated and previously treated CD20-positive CLL in ombination with fludarabine and cyclophosphamide (FC).
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids.
Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies.

The FDA approval of Truxima was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity, and other clinical safety and effectiveness data demonstrating that Truxima is biosimilar to US Rituxan. Truxima has been approved as a biosimilar, not as an interchangeable product. The most common AEs of Truxima are infusion reactions, fever, lymphopenia, chills, infection, and asthenia.

Rituximab-arrx (Riabni, a Biosimilar to Rituxan)

In December 2020, the FDA approved rituximab-arrx (Riabni, Amgen Inc), a biosimilar to Rituxan (rituximab), for the treatment of adult patients with Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), and Microscopic Polyangiitis (MPA) (Amgen, 2020a).

FDA approval was based on a randomized, double-blind, comparative clinical study which evaluated the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability and immunogenicity of Riabni compared to Rituxan in subjects with grade 1, 2, or 3a follicular B-cell NHL and low tumor burden. There were 256 patients enrolled and randomized (1:1) to receive 375 mg/m² intravenous infusion of either Riabni or Rituxan, once weekly for 4 weeks followed by dosing at weeks 12 and 20. The primary endpoint, an assessment of overall response rate (ORR) by week 28, was within the prespecified margin for Riabni compared to Rituxan, showing clinical equivalence. PK, PD, safety and immunogenicity of Riabni were found to be similar to Rituxan (Amgen, 2020a, 2020b).

Riabni also has the same strength as Rituxan, and the dosage form and route of administration are identical to the intravenous formulation of Rituxan (Amgen, 2020a).

Rituximab-pvvr (Ruxience, a Biosimilar to Rituxan)

On July 23, 2019, the FDA approved rituximab-pvvr (Ruxience, Pfizer Inc.; the second biosimilar to Rituxan (Genentech Inc.) for the treatment of adult patients with:

Non-Hodgkin’s Lymphoma (NHL)
- Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single-agent;
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with 1st-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy;
- Non-progressing (including stable disease), low-grade, CD20positive, B-cell NHL as a single-agent after 1st-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens.
Chronic Lymphocytic Leukemia (CLL): Previously untreated and previously treated CD20-positive CLL in ombination with fludarabine and cyclophosphamide (FC).
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids.

The FDA approval of Ruxience was based on the review of a comprehensive data package, which demonstrated biosimilarity of Ruxience to the reference product. This includes results from the REFLECTIONS B3281006 clinical comparative study, which evaluated the efficacy, safety and immunogenicity, pharmacokinetics and pharmacodynamics of Ruxience and found no clinically meaningful differences in safety or efficacy compared to the reference product in patients with CD20-positive, low tumor burden follicular lymphoma.

Hematologic and Oncologic Conditions

Non-Hodgkin's lymphoma (NHL) is a neoplasm of the lymphoid tissue which can originate from B-cell or T-cell precursors, mature B-cells or T-cells, or (rarely) natural killer cells (Freedman et al., 2020; Sapkota and Shaikh, 2020). NHL is comprised of various subtypes,"each with different epidemiologies, etiologies, immunophenotypic, genetic, clinical features, and response to therapy". NHL neoplasms can be considered either 'indolent', slow-growing, or 'aggressive,' fast-growing, based on the disease's prognosis. "The most common mature B cell neoplasms are Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Mantle cell lymphoma, marginal zone lymphoma, primary CNS lymphoma. The most common mature T cell lymphomas are Adult T cell lymphoma, Mycosis fungoides. The treatment of NHL varies greatly, depending on tumor stage, grade, and type of lymphoma, and various patient factors (e.g., symptoms, age, performance status)" (Sapkota and Shaikh, 2020).

A pivotal study (Linch, 2001) demonstrated a response rate of 56 % in relapsed or refractory low-grade NHL.

Published evidence from Phase I and Phase II trials have shown that rituximab has activity against CLL with acceptable toxicity. Perry and Rasool (2001) stated that "[t]herapy with monoclonal antibodies has been evaluated in patients with CLL. The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future." The National Cancer Institute's PDQ on Chronic Lymphocytic Leukemia (January 2002) states that "CAMPATH-1H and rituximab (monoclonal antibodies) are under clinical evaluation. Higher doses of rituximab than those used for other non- Hodgkin lymphomas are required."

There are several published phase II studies of rituximab for lymphocyte predominance Hodgkin's disease (LPHD) (Younes et al, 2003; Ekstrand et al, 2003; Rehwald et al, 2003). Additional studies of rituximab for LPHD are currently ongoing. Younes et al (2003) examined the potential role of infiltrating benign B cells in classic HD lesions in supporting the survival of malignant Hodgkin and Reed-Sternberg (H/RS) cells. The authors initiated a pilot study of rituximab, which is used to primarily deplete normal B cells from HD lesions. Patients with recurrent, classic HD who had received a minimum of 2 prior treatment regimens, regardless of whether H/RS cells expressed CD20, were treated with 6 weekly doses of 375 mg/m² rituximab to selectively deplete infiltrating benign B cells. Objective tumor response was determined 3 weeks after completion of the last dose of rituximab and every 3 months thereafter. Serum samples were collected from patients before they started rituximab therapy and 3 weeks after the final course of rituximab. Serum cytokine levels of interleukin 6 (IL-6), IL-10, IL-12, IL-13, and interferon gamma were determined using commercially available enzyme-linked immunosorbent assay kits. Twenty-two patients with nodular sclerosis histology were evaluable for treatment response. Five patients (22 %) achieved partial or complete remission that lasted for a median of 7.8 months (range of 3.3 to 14.9 months). Remissions were observed in patients only at lymph node and splenic sites, but not at extra-nodal sites, and were irrespective of CD20 expression by H/RS cells. Furthermore, systemic (B) symptoms resolved in 6 of 7 patients after therapy. In 2 patients, partial remissions were associated with a decline in serum IL-6 levels. The authors concluded that current data suggest that rituximab therapy in patients with recurrent, classic HD can alter serum IL-6 cytokine levels, can improve B symptoms, and may result in clinical remissions.

Ekstrand et al (2003) stated that lymphocyte predominance Hodgkin's disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m². Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100 %) with complete response (CR) in 9 (41 %), unconfirmed complete response in 1 (5 %), and partial response in 12 (54 %). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in the trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are needed to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.

In a phase 2 study, Rehwald et al (2003) evaluated the safety and efficacy of rituximab in patients with relapsed lymphocyte predominance Hodgkin's disease (LPHD )or other CD20(+) subtypes of Hodgkin disease (HD). Eligibility criteria required expression of the CD20 antigen on more than 30 % of malignant cells. A total of 14 patients were treated with 4 weekly intravenous infusions of rituximab (375 mg/m²). All patients had at least 1 prior chemotherapy (median, 2). The median time from first diagnosis was 9 years. Adverse events, such as rhinitis, fever, chills, and nausea, were usually transient and of mild to moderate grade, allowing outpatient treatment in most cases. All patients completed treatment and were eligible for a response. The overall response in 14 assessable patients was 86 %, with 8 complete remissions and 4 partial remissions, and 2 patients with progressive disease. At a median follow-up of 12 months, 9 of 12 responders were in remission. The median duration of response has not been reached yet (20+ months). The authors concluded that rituximab is both safe and effective in a subgroup of CD20(+) patients with HD.

The U.S. Pharmacopoeial Convention has concluded that rituximab is indicated for treatment of Waldenström’s macroglobulinemia. Dimopolous et al (2002) reported on 27 patients with symptomatic Waldenström’s macroglobulinemia who were treated with rituximab. Twelve patients (44 %; 95 % confidence interval [CI]: 25.5 % to 64.7 %) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range of 2.2 to 7.1 months). The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, 9 of 12 responding patients remain free of progression. The investigators reported that approximately 25 % of patients experienced some mild form of infusion-related toxicity, usually fever and chills.

Rituximab may be considered for persons with relapsed or refractory hairy cell leukemia who have failed at least two courses of cladribine. The National Cancer Institute information on hairy cell leukemia (NCI, 2007) states that rituximab can be used for relapsed or refractory hairy cell leukemia after failure of purine analog therapy (i.e., cladribine). "Rituximab can induce durable complete remissions with minimal toxic effects in the majority of patients with relapsing or refractory disease after purine analog therapy. The lack of subsequent immunosuppression with rituximab has made this treatment the first choice among relapsing patients in the absence of a clinical trial." The largest clinical trial of rituximab for hairy cell leukemia reported to date (Nieva et al, 2003) reported that rituximab "has only modest single-agent activity in cladribine-failed HCL patients when compared with other agents active in this disease."

An uncontrolled, 3-month study of rituximab in 19 subjects with multiple myeloma has shown promising results in a subgroup of subjects who expressed CD20 on their bone marrow plasma cells (Treon et al, 2002).

There is evidence for the effectiveness of rituximab for post-transplant lymphoproliferative disorders (PTLD) (Cincinatti Hospital Children's Medical Center, 2003). PTLD is a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Oertel et al (2005) reported on the results of a multi-center phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with 4 weekly doses of 375 mg/m² of rituximab. The mean follow-up time was 24.2 months. The investigators reported that rituximab therapy was well-tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living at the time of the report. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. The investigators concluded that rituximab proved to be well-tolerated and effective in the treatment of PTLD.

There is emerging evidence for the effectiveness of rituximab in Castleman's disease (CD). Two clinical classifications of CD have been described: unicentric (unifocal or localized) and multi-centric (multi-focal or generalized) (Dispenzieri and Gertz, 2005). The uni-centric presentation responds well to surgical resection and is associated with a benign course. The multi-centric presentation requires systemic therapy and prognosis is guarded. Associated systemic symptoms are common. There is an increased incidence of CD in patients with HIV. The human herpes virus-8 is associated with nearly all of the HIV-associated CD cases and nearly 50 % of non-HIV cases. Interleukin (IL)-6 has also been shown to play a significant role in the pathogenesis of the disease. Paraneoplastic and autoimmune entities are not uncommon in the disorder. Variable benefit has been achieved with rituximab (Dispenzieri and Gertz, 2005; Ide et al, 2006; Casquero et al, 2006; Marcelin et al, 2003). Patients with CD are at increased risk for developing frank malignant lymphoma.

Ferreri and co-workers (2011) noted that systemic administration of rituximab has varying response rates with different types of lymphoma, generally with a mild toxicity level. Intralesional administration of this drug has increased local disease control in cases of cutaneous mucosa-associated lymphoid tissue (MALT) lymphoma. In a pilot study, these researchers evaluated the tolerability and activity of the intralesional administration of rituximab in patients with conjunctival B-cell lymphoma. Two patients with conjunctival MALT lymphoma refractory to previous systemic treatment with rituximab and 1 patient with relapsed follicular lymphoma of the eyelid were included in the study. Patients received 4 weekly intralesional injections followed by 6 monthly injections of undiluted rituximab together with xylocaine 2 %. Side effects and tumor response were assessed before each intralesional injection and at 3-month intervals after treatment conclusion. The 2 conjunctival MALT lymphoma patients achieved complete remission after intra-conjunctival rituximab treatment, which shows that this method of administration can overcome the primary resistance to this monoclonal antibody. The patient with the eyelid follicular lymphoma did not achieve tumor regression after the first intralesional injections of rituximab. In this patient, the addition of autologous serum resulted in lymphoma remission at the end of treatment, suggesting that drug inefficacy can be related to the low bioavailability of effectors in the tumor tissue. The authors concluded that although follow-up is still short, these preliminary findings suggest that intralesional rituximab is a well-tolerated strategy in marginal-zone and follicular lymphomas of the conjunctiva. An increased bioavailability of effectors in the tumor tissue, by means of the addition of autologous serum, may improve rituximab activity. This strategy could be used in other extranodal CD20+ indolent lymphomas to improve local control, even in patients who are initially refractory to systemic rituximab treatment. They stated that response duration and potential late effects remain to be defined, and a large, prospective, clinical trial to address this promising therapeutic technique, both in ocular adnexal lymphoma and other extra-nodal lymphomas, is needed.

Salles and colleagues (2011) assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. The randomized, open-label PRIMA (Primary Rituxan and Maintenance) study was undertaken in 223 centers in 25 countries. A total of 1,217 patients with previously untreated follicular lymphoma needing systemic therapy received 1 of 3 non-randomized immunochemotherapy induction regimens used in routine practice. A total of 1,019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m² every 8 weeks) or observation. Treatment was assigned equally by centralized block randomization, stratified by induction regimen, response, region, and center. Neither the participants nor those giving the interventions, assessing outcomes, and analyzing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention-to-treat. A total of 505 patients were assigned to rituximab maintenance and 513 to observation (1 patient died during randomization). With a median follow-up of 36 months (inter-quartile range [IQR] 30 to 42), PFS was 74·9 % (95 % CI: 70·9 to 78·9) in the rituximab maintenance group (130 patients progressed) and 57·6 % (53·2 to 62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95 %: CI 0·44 to 0·68, p < 0·0001). Two years after randomization, 361 patients (71·5 %) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2 %) in the observation group (p = 0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95 % CI: 0·51 to1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24 %) in the rituximab maintenance group and 84 (17 %) in the observation group (risk ratio 1·46, 95 % CI: 1·14 to 1·87; p = 0·0026). Infections (grades 2 to 4) were the most common adverse event, occurring in 197 (39 %) and 123 (24 %) patients, respectively (risk ratio 1·62, 95 % CI: 1·35 to 1·96; p < 0·0001). The authors concluded that 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS.

In January 2011, the FDA approved the use of rituximab as maintenance therapy for advanced follicular lymphoma in patients with an initial response to induction therapy with the drug plus chemotherapy. The approval was based on results of the afore-mentioned PRIMA study, which showed that showed continuing rituximab administration every 2 months for 2 years in patients who responded to initial treatment with rituximab plus chemotherapy, nearly doubled the likelihood of them living without the disease worsening (PFS) compared to those who stopped treatment (based on a HR of 0.54, 95 % CI: 0.42 to 0.70; p < 0.0001).

Arampatzis et al (2011) presented a rare case of chronic lymphocytic leukemia (CLL)-associated focal segmental glomerulosclerosis (FSGS) with nephrotic-range proteinuria. A 53-year old Caucasian man, previously healthy, with no history of hypertension, alcohol use or smoking presented with rapid weight gain, massive peripheral edema, and hypertension. Laboratory findings included a white blood cell count of 49,800 cells/mm³ with an absolute lymphocyte count of 47,000 cells/mm³, serum albumin of 2.3 g/dL, urea 65 mg/dL, and creatinine 1.5 mg/dL. A 24-hour urine collection contained 7.1 g protein and significant hematuria. A peripheral blood smear showed mature lymphocytosis and smudge cells. Diagnostic imaging showed mild para-aortic lymphadenopathy with no renal abnormalities. Bone marrow aspiration and trephine biopsy showed diffuse and focal infiltration with B-CLL lymphocytes. Percutaneous renal biopsy revealed total sclerosis in 3/21(14 %) of the glomeruli and focal and segmental solidification and sclerosis in 4/21 (19 %) glomeruli. A regimen of fludarabine, cyclophosphamide and rituximab was successful in inducing remission of the CLL and clinical resolution of the nephritic-range proteinuria. The authors concluded that a multi-disciplinary approach to monitor both the malignancy and the glomerular lesions is crucial for the optimal management of paraneoplastic glomerulonephritis. They noted that although chemotherapy with fludarabine, cyclophosphamide and rituximab successfully treated CLL-associated nephrotic syndrome in this patient, further studies are required to confirm efficacy in this setting.

In a systematic review, Araya and Dharnidharka (2011) stated that recurrence of FSGS occurs in 30 to 40 % of allografts. Therapies for recurrence are not well established. These researchers retrieved all published reports depicting kidney transplant recipients with FSGS recurrence, treated with rituximab, to determine factors associated with treatment response. They found 18 reports of 39 transplant recipients who received rituximab. By uni-variate analysis for 2 outcomes (no response versus any response), fewer rituximab infusions and normal serum albumin at recurrence were associated with treatment response. For 3 outcomes (no response, partial and complete remission), male gender, fewer rituximab infusions, shorter time to rituximab treatment, and normal serum albumin were associated with remission. Multi-variate analysis for both models revealed that normal serum albumin at FSGS recurrence and lower age at transplant were associated with response. The authors noted that rituximab for recurrence of FSGS may be beneficial for only some patients. A younger age at transplant and normal serum albumin level at recurrence diagnosis may predict response.

The National Institutes of Health (NIH) Office of Rare Diseases Research states that Rosai-Dorfman disease is a benign disease which is characterized by over-production and accumulation of a specific type of white blood cell (histiocyte) in the lymph nodes of the body, most often those of the neck. Other lymph node groups may also be involved and, in some cases, abnormal accumulation of histiocytes may occur in other areas of the body. The cause of this condition, which was first described by Rosai and Dorfman in 1969, remains unknown. It has been hypothesized that altered immune responses and infectious agents may play a role. Sinus histocytosis with massive lymphadenopathy disease (SHML) is a self-limited and seldom life-threatening disease which commonly does not require therapy.

The NIH Office of Rare Diseases Research further reports that in many cases the signs and symptoms of Rosai-Dorfman disease resolve without any treatment (spontaneous remission) and that this generally occurs within months to a few years. The preferred course of management is continuous observation without treatment when possible. Many individuals will not require therapy, but in some cases, various treatment options may become necessary and are typically directed toward the affected individual’s specific symptoms. Some individuals may need surgical removal of histiocytic lesions.[4] In more serious cases, treatment options have included therapy with certain drugs including steroids (e.g., prednisone), alfa-interferon (a man-made copy of a protein that is normally made by the body in response to infection), chemotherapy and radiation therapy. However, these treatments have improved symptoms in some individuals, but in others they have not been effective.

The British Society for Haematology’s guidelines on thrombotic thrombocytopenic purpura (TTP) (Scully et al, 2012) recommend use of rituximab in patients with refractory or relapsing immune-mediated TTP. The guidelines also stated that rituximab should be considered on admission, in conjunction with steroids and plasmapheresis, in acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality. An UpToDate review on “Treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults” (Kaplan and George, 2013) recommended the use of rituximab or cyclosporine in patients with a severe course of refractory or recurrent TTP-HUS who do not rapidly respond to plasma exchange, worsen with neurologic abnormalities despite plasma exchange plus corticosteroids, or have relapsing disease.

UpToDate reviews on “Treatment protocols for multiple myeloma” (Brenner et al, 2013), “Treatment of relapsed or refractory multiple myeloma” (Rajkumar, 2013a), “Determination of initial therapy in patients with multiple myeloma” (Rajkumar, 2013b), and “Treatment of kidney disease in multiple myeloma” (Rajkumar et al, 2013) do not mention the use of rituximab (Rituxan). Also, the 2012 NCCN Drugs and Biologics Compendium does not list other forms of multiple myeloma as a recommended indication of rituximab.

An UpToDate review on “Plasma cell leukemia” (Rajkumar, 2013) states that “There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with multiple myeloma. In general, patients younger than 65 in good performance status are treated with aggressive induction therapy, such as VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) followed by hematopoietic cell transplantation (HCT) …. Chemotherapy alone is the principal option for those ineligible for HCT”. Rituximab is not mentioned as a therapeutic option.

The anti-CD20 monoclonal antibody rituximab produced a clinical response rate of 70 % mainly for musculoskeletal and cutaneous chronic GVHD (Cutler et al, 2006). These responses were durable through 1 year after initiation of therapy and allowed a 75 % reduction in steroid doses.

A review on immunosuppressive agents for graft versus host disease in UpToDate commented: “Prospective studies are investigating the use of the anti-CD20 monoclonal antibody, rituximab, in an attempt to decrease allogeneic donor B cell immunity and, potentially, associated chronic GVHD. While initial results demonstrate decreased B cell immunity and low rates of chronic GVHD, this approach remains experimental. Randomized trials are needed to determine the efficacy and toxicity of rituximab in this setting, including the effect on long-term B cell function.”

British Society of Haematology guidelines on acute graft versus host disease recommends against the use of rituximab. British Society of Haematology guidelines on chronic graft versus host disease suggest rituximab as a second line treatment option in refractory cutaneous or musculoskeletal chronic graft versus host disease. This is a weak recommendation based upon moderate quality evidence (2B).

Rheumatoid Arthritis and Other Conditions

Rituximab has been approved for use in rheumatoid arthritis. An assessment of targeted immune modulators by the Drug Evaluation Research Project (DERP0 (Thaler, et al., 2012) found insufficient evidence to reach conclusions of the comparative efficacy of rituximab with other targeted immune modulators, because of heterogeneity of studies.

Edwards et al (2004) reported on the results of an multi-center randomized controlled clinical trial of rituximab in rheumatoid arthritis, which found that a single course of 2 infusions of rituximab alone or in combination provided significant improvement in disease symptoms for 48 weeks. The investigators randomly assigned 161 adults who had active rheumatoid arthritis despite treatment with methotrexate to receive 1 of 4 treatments: oral methotrexate; rituximab; rituximab plus cyclophosphamide; or rituximab plus methotrexate. Eligible patients had active disease despite treatment with at least 10 mg of methotrexate per week. Active disease was defined by the presence of at least 8 swollen and 8 tender joints and at least 2 of the following: a serum C-reactive protein level of at least 15 mg per liter, an erythrocyte sedimentation rate of at least 28 mm per hour, or morning stiffness lasting longer than 45 minutes. In addition, eligible patients were seropositive for rheumatoid factor. At 24 weeks, the proportion of patients with 50 % improvement in disease symptoms according to American College of Rheumatology (ACR) criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 %, p = 0.005) and the rituximab-cyclophosphamide combination (41 %, p = 0.005) than with methotrexate alone (13 %). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 % improvement in disease symptoms according to the ACR criteria (65 to 76 % versus 38 %, p < 0.025) or had EULAR responses (83 to 85 % versus 50 %, p < 0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The investigators reported that the majority of adverse events occurred with the first rituximab infusion. At 24 weeks, serious infections occurred in one patient (2.5 %) in the control group and in 4 patients (3.3 %) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. The investigators concluded that in patients with active rheumatoid arthritis despite methotrexate treatment, a single course of 2 infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in diseases symptoms at both 24 and 48 weeks.

The American College of Rheumatology (ACR) conducted a systematic review to synthesize the evidence for the benefits and harms of various treatment options. Their goal was to develop evidence-based, pharmacologic treatment guideline for rheumatoid arthritis. The 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis provided “strong” recommendations for established RA and symptomatic early RA.

For established RA, the guidelines state “if the disease activity is low, in patients who have never taken a DMARD, the recommendation is to use DMARD monotherapy (methotrexate preferred) over TNFi”. “If disease activity remains moderate or high despite DMARD monotherapy, the recommendation is to use combination traditional [conventional] DMARDs or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. Recommendations for patients with symptomatic early RA state that “if disease activity is low, in patients who have never taken a DMARD, use DMARD monotherapy (methotrexate preferred) over double or triple therapy”. “If disease activity remains moderate or high despite DMARD monotherapy (with our without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with our without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. A strong recommendation means that the panel was confident that the desirable effects of following the recommendation outweigh the undesirable effects (or vice versa), so the course of action would apply to most patients, and only a small proportion would not want to follow the recommendation (Singh et al., 2016).

A number of reports have indicated the usefulness of rituximab in the treatment of subjects with warm agglutinin autoimmune hemolytic anemia not responding to conventional treatment including corticosteroids and splenectomy (Zecca et al, 2001; D'Arena et al, 2006; Gupta et al, 2002; Shanafelt et al, 2003; Mantadakis et al, 2004) and to cold agglutinin disease not responding to conventional treatments (Schollkopf et al, 2006; Berentsen et al, 2004).

A Cochrane systematic evidence review (Hughes et al, 2003) concluded that there is inadequate evidence of the effectiveness of rituximab in the treatment of chronic inflammatory polyneuropathy.

Ahmed and Wong (2007) noted that mixed cryoglobulinemia (CG) is a systemic immune complex-mediated disease that involves small-to-medium vessel vasculitis, provoked by the CG containing immune complexes that precipitate in cold. It is associated with hepatitis C virus (HCV) infection in 80 % of patients. Mixed CG-mediated vasculitis can affect the kidney, liver and heart. Laboratory parameters show presence of cryoglobulin, and in most cases of mixed CG, rheumatoid factor IgM kappa. The current treatment strategy of HCV-associated CG includes targeting the viral trigger HCV with a combination of anti-viral medication, interferon-alpha and ribavirin, or the downstream pathogenic events by means of plasmapheresis, steroids or immunosuppression. With multi-organ involvement, the anti-viral therapy may be limited due to severity of renal disease, treatment failure, side effects or contraindications. On the other hand, immunosuppressive therapy may be poorly tolerated or ineffective. Thus, new treatment options such as rituximab have been proposed as a rescue therapy. These researchers reviewed the literature to evaluate the current evidence in treating HCV-related refractory mixed CG. There have been many published case series and case reports on the use of rituximab in the treatment of HCV-related CG. However, there has been no randomized controlled trial. In the literature, there have been 60 patients with CG treated with rituximab. The male to female ratio was 14:46. A total of 53 patients were HCV-positive; 46 had mixed type II CG, 7 had type III CG, and for 7 the type was not specified. Twenty-five patients had renal involvement ranging from proteinuria, to nephrotic syndrome, to nephritic syndrome, to chronic kidney disease. Eight patients had had a renal transplant and were on immunosuppression. Most patients responded to rituximab, with only 17 of 60 patients relapsing, and 8 of 17 of those were re-challenged with rituximab with a good response. Total follow-up period varied between 3 and 31 months. The authors concluded that rituximab is a suitable rescue therapy in refractory CG associated with HCV. There is evidence supporting the use of rituximab as first-line therapy, as opposed to the proposals of others who would strongly recommend anti-viral therapy. However, a prospective, randomized, controlled trial is needed to assess the safety and effectiveness of rituximab compared with current standard therapy, which includes anti-viral therapy, immunosuppression, as well as plasmapheresis.

Interest in rituximab for minimal change disease is based upon the hypothesis that the disease has an underlying immune mediated basis. Peters et al (2008) stated that minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) are the main causes of the idiopathic nephrotic syndrome. The former usually responds to steroids and the long-term prognosis is generally good. However, some patients require prolonged treatment with immunosuppressive agents. The latter generally follows a less favorable course: patients do not always respond to steroids and may progress to end-stage renal disease. Recurrence of FSGS after renal transplantation is frequently observed and may result in graft loss. Recently, anecdotal case reports have described long-term resolution of nephrotic syndrome due to MCNS or FSGS after treatment with rituximab. These investigators presented 4 patients with nephrotic syndrome due to MCNS, FSGS or recurrence of FSGS following kidney transplantation, who were treated with rituximab with variable success. A review of the recent literature suggests that anti-CD20 antibodies may be a promising therapy, especially for patients with MCNS or idiopathic FSGS. The authors concluded that controlled studies are needed to determine the effectiveness of rituximab and to define which patients will benefit. Furthermore, in a review of treatment of MCNS in adults, Meyrier (2009) stated that despite these preliminary exciting results, these findings can not yet lead to treatment recommendations.

The development of human anti-chimeric antibodies (HACA) against rituximab may have potential clinical consequences (e.g., reduced duration of response to treatment, and requirements for higher doses or more frequent dosing intervals). However, the full clinical impact of HACA is unknown. Leandro and Edwards (2009) noted that the clinical significance of HACA development in patients with rheumatoid arthritis is unclear. Furthermore, FDA-approved labeling for Rituxan does not include recommendation for HACA testing.

Gartlehner and associates (2008) noted that biologics are an important therapeutic option for treating patients with juvenile idiopathic arthritis (JIA). In adults, they are associated with rare but severe adverse events such as serious infections and malignancies. These investigators reviewed systematically the evidence on the safety and effectiveness of biologics for the treatment of JIA. They searched electronic databases up to August 2006. They limited evidence to prospective studies for effectiveness but included retrospective observational evidence for safety. Outcomes of interest were clinical response, radiographical progression, quality of life, and adverse events. One randomized controlled trial (RCT) and 11 uncontrolled prospective studies provided data on effectiveness; 3 additional studies assessed safety. The only RCT and 6 uncontrolled trials support the general effectiveness of etanercept for the treatment of JIA. Internal and external validity of these studies were limited. The evidence on other biologic agents such as adalimumab, abatacept, anakinra, infliximab, rituximab, and tocilizumab was sparse or entirely missing. Because of the lack of sound long-term safety data, evidence is insufficient to draw firm conclusions about the balance of risks and benefits of any biologic agent for the treatment of JIA. Clinicians have to be aware of the lack of evidence supporting a long-term net benefit when considering biologics for patients with JIA.

In a multi-center, retrospective descriptive case series, Eleftheriou et al (2009) reported the safety and effectiveness of biologic therapies in children with primary systemic vasculitis (PSV). Primary retrospective outcome assessment measures were: daily corticosteroid dose; Birmingham Vasculitis Activity Score (BVAS); and adverse events (including infection rate). A total of 25 patients median age 8.8 (range of 2.4 to 16) years; 11 males with active PSV (n = 6 with anti-neutrophil cytoplasmic antibody associated vasculitides, n = 11 with polyarteritis nodosa, n = 7 with unclassified vasculitis, and n = 1 with Behçet's disease) were treated with biologic agents including infliximab (n = 7), rituximab (n = 6), etanercept (n = 4), adalimumab (n = 1) or multiple biologics sequentially (n = 7). Overall, there was a significant reduction in BVAS from a median of 8.5 (range of 5 to 32) at start of therapy to 4 (range of 0 to 19) at median 32 months follow-up (p = 0.003) accompanied by significant reduction in median daily prednisolone requirement from 1 (range of 0.2 to 2) to 0.25 (range of 0 to 1) mg/kg/day, p = 0.000. For those receiving multiple biologic agents sequentially, a similar clinical improvement was observed with corticosteroid sparing. Infections occurred in 24 %, the most severe in those receiving infliximab. The authors concluded that these findings provided retrospective evidence of efficacy of these agents, and high-lighted the associated infectious complications. They stated that further multi-center standardization of treatment protocols and data collection to inform clinical trials of biologic therapy in systemic vasculitis of the young is needed.

Sprangers and colleagues (2010) stated that recurrence of the original kidney disease after renal transplantation is an increasingly recognized cause of allograft loss. Idiopathic membranous nephropathy (iMN) is a common cause of proteinuria that may progress to end-stage renal disease. It is known that iMN may recur after kidney transplantation, causing proteinuria, allograft dysfunction, and allograft loss. Limited data regarding the frequency and treatment of recurrent iMN are available. In this single-center study, all patients who had iMN and were receiving a first kidney transplant were included. These investigators retrospectively assessed the incidence of biopsy-confirmed recurrent iMN and compared clinical characteristics of patients with and without recurrence. In addition, the effect of treatment with rituximab on proteinuria and renal allograft function in patients with recurrent iMN was examined. The incidence of recurrent iMN was 44 %, and recurrences occurred at a median time of 13.6 months after transplantation. Two patterns of recurrence were identified -- early and late. No predictors of recurrence or disease progression could be identified. Treatment with rituximab was effective in 4 of 4 patients in stabilizing or reducing proteinuria and stabilizing renal function. The authors concluded that recurrence of iMN is common even in the era of modern immunosuppression. They stated that rituximab seems to be a valuable treatment option for these patients, although lager studies are needed to confirm these data.

Cavailhes et al (2009) note that epidermolysis bullosa acquisita (EBA) is a rare autoimmune sub-epidermal blistering disease; it is potentially serious and is often refractory to conventional treatments, including corticosteroids. The authors reported a new case of successful treatment of EBA using rituximab without relapse after 1 year of follow-up. A 76-year old man was seen for blisters of the skin and mucosa, atrophic scars and milia on areas of friction. The diagnosis of EBA was made on the basis of histological and immunohistochemical criteria. The patient was unsuccessfully treated with topical steroids, dapsone, topical tacrolimus, systemic steroids, mycophenolate mofetil, doxycycline and methotrexate. Four weekly infusions of rituximab of 375 mg/m(2) body area were performed, combined with systemic steroids: they proved beneficial within 3 weeks, with a noticeable improvement and no further blisters at 7 months. After 1 year of follow-up, the skin disease is still stable with 5 mg/day of prednisone alone being given. The authors concluded that this was the 8th reported case of treatment of EBA with rituximab and the 6th successful therapeutic outcome, with good steroid sparing effect and undeniable improvement in quality of life within several months and good tolerability at 12 months of follow-up. This treatment may be proposed early in cases of EBA refractory to conventional treatments. Moreover, the authors stated that clinical observation is necessary to study potential long-term adverse effects.

In a retrospective, comparative, interventional case series, Foster et al (2010) compared the safety and effectiveness of the combination therapy of rituximab (RTX) and intravenous immunoglobulin (IVIG) to other immunosuppressive regimens in the treatment of ocular cicatricial pemphigoid (OCP; n = 12). These investigators reviewed medical records of 12 patients with OCP. Ten of the 12 patients were blind in 1 eye after initial systemic immunosuppressive therapies (phase I treatment). Patients were then divided into 2 groups based on treatments received during phase II. The study group consisted of 6 patients who received the combination of RTX and IVIG during phase II of their treatment. For comparison purposes, the control group consisted of 6 patients who during phase II of their treatment received more aggressive immunosuppressive therapies, but not RTX and IVIG. Main outcome measures included blindness (best-corrected visual acuity [BCVA] less than or equal to 20/200) and OCP staging (Foster). The median total follow-up periods were 57.5 and 55.5 months in the control group and the study group, respectively. After phase I treatment, all 6 patients in the control group were blind in 1 eye. Similarly, 4 of the patients in the study group were blind in 1 eye, whereas 2 had good BCVA bilaterally but experienced persistent conjunctival inflammation despite phase I treatment. After phase II treatment, all 6 patients in the control group had OCP progression and became blind in both eyes. In contrast, BCVA was stable and no further progression of OCP staging was observed in all 6 patients in the study group. In the study group, the median follow-up from completion of the RTX and IVIG treatment protocol was 11 months. No adverse events, immediate or delayed, were reported in any of the patients who received the combination therapy of RTX and IVIG. The authors concluded that in this preliminary study, the combination therapy of RTX and IVIG arrested disease progression and prevented total blindness in patients with recalcitrant OCP. They noted that a larger cohort of patients needs to be studied before definitive conclusions can be made.

Pranzatelli et al (2010) reported the findings of 12 immunotherapy-naïve children with opsoclonus-myoclonus syndrome (OMS) and cerebrospinal fluid (CSF) B cell expansion who received rituximab, adrenocorticotropic hormone (ACTH), and Iintravenous immunoglobulin. Motor severity lessened 73 % by 6 months and 81 % at 1 year (p < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. Dosage of ACTH was tapered by 87 %. Reduction in total CSF B cells was profound at 6 months (-93 %). By study end, peripheral B cells returned to 53 % of baseline and serum IgM levels to 63 %. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but 1 non-ambulatory subject became ambulatory without additional chemotherapy; 2 relapsed and remitted; 4 had rituximab-related or possibly related adverse events; and 2 had low-titer human anti-chimeric antibody. The authors concluded that combination of rituximab with conventional agents as initial therapy was effective and safe. They stated that a controlled trial with long-term safety monitoring is indicated.

Gorman et al (2010) stated that opsoclonus-myoclonus syndrome (OMS) is a severe autoimmune central nervous system disorder, which predominantly affects young children and causes lifelong neurological disability. Early recognition and treatment may yield better outcomes. Appreciation of the spectrum of clinical presentations of OMS, awareness of common mis-diagnoses, and utilization of diagnostic criteria may facilitate the timely diagnosis of OMS. Approximately 50 % of patients have an associated neuroblastoma, which may escape detection by traditional methods and require MRI or computed tomography of the torso for diagnosis. In non-paraneoplastic cases, many associated infections have been reported. Although there has been progress in autoantibody identification and CSF B cell expansion is a common finding, there is no diagnostic biomarker for OMS currently. Approximately 80 % of reported patients, typically treated with conventional therapies such as ACTH, corticosteroids, and/or intravenous immunoglobulin, develop long-term neurological morbidity. Newer treatment approaches using early, aggressive therapy with cyclophosphamide or rituximab are promising. The authors concluded that the diagnosis of OMS requires a high level of suspicion and a systematic approach for diagnostic testing, particularly for neuroblastoma. They stated that future collaborative studies are needed to determine if early, aggressive therapy will improve the typically poor long-term neurological outcome.

In a retrospective, interventional case series study, Khanna et al (2010) examined the effectiveness of rituximab therapy in patients (n = 6) with severe, corticosteroid (CS)-resistant thyroid-associated ophthalmopathy (TAO). Electronic medical record of consecutive patients receiving rituximab during the previous 18 months was reviewed. Responses to therapy were graded using standard clinical assessment and flow cytometric analysis of peripheral lymphocytes. Main outcome measures included clinical activity score (CAS), proptosis, strabismus, treatment side effects, and quantification of regulatory T cells. Systemic CS failed to alter clinical activity in all patients (mean CAS +/- standard deviation, 5.3 +/- 1.0 before versus 5.5 +/- 0.8 during therapy for 7.5 +/- 6.4 months; p = 1.0). However, after rituximab treatment, CAS improved from 5.5 +/- 0.8 to 1.3 +/- 0.5 at 2 months after treatment (p < 0.03) and remained quiescent in all patients (CAS, 0.7 +/- 0.8; p < 0.0001) at a mean follow-up of 6.2 +/- 4.5 months. Vision improved bilaterally in all 4 patients with dysthyroid optic neuropathy. None of the 6 patients experienced disease relapse after rituximab infusion, and proptosis remained stable (Hertel measurement, 24 +/- 3.7 mm before therapy and 23.6 +/- 3.7 mm after therapy; p = 0.17). The abundance of T regulatory cells, assessed in 1 patient, increased within 1 week of rituximab therapy and remained elevated at 18 months of follow-up. The authors stated that prospective studies are needed to establish if rituximab is a therapeutic option in these patients.

In a prospective, open-label, interventional clinical trial, Silkiss et al (2010) evaluated the safety and effectiveness of rituximab-mediated B-lymphocyte depletion as treatment for thyroid eye disease (TED; n = 12). Patients with CAS (VISA [vision, inflammation, strabismus and appearance/exposure] classification) of 4 or greater were followed for 1 year after rituximab (1000 mg) treatment, administered intravenously on days 1 and 15. Clinical activity scores, peripheral B-lymphocyte levels, thyroid autoantibody levels, and thyroid function tests were recorded at baseline, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 52 weeks after the second infusion. The primary endpoint was a change from baseline in CAS. Thyroid-stimulating immunoglobulin and thyroid-stimulating hormone levels were also monitored over the 12-month post-infusion observation period. Clinical activity scores demonstrated a statistically significant decrease from baseline at each of the follow-up visits. Thyroid-stimulating immunoglobulin and thyroid-stimulating hormone levels demonstrated no statistically significant change from baseline. B-cell depletion was observed within 1 month after rituximab treatment, and peripheral B-lymphocyte counts started to increase 36 weeks after the infusion. B-cell depletion was well-tolerated, and there were no adverse effects of the rituximab infusions. The authors concluded that CAS were significantly reduced over time in this group of 12 patients and appeared to be associated with rituximab infusion. However, the variable natural history of TED makes it difficult to definitively assign efficacy. The results support the continued investigation of rituximab for TED in a larger placebo-controlled trial.

Bartalena (2010) noted that treatment of Graves' orbitopathy (GO) is a major challenge, and the outcome of medical therapy is unsatisfactory in about 1/3 of cases. Glucocorticoids are the first-line therapy for moderate-to-severe and active GO, more commonly given through the intravenous route. Uncertainty remains as to the best therapeutic approach when the initial glucocorticoid treatment provides an incomplete response or no response. The choice largely depends on personal experience because of the limited evidence in this field. In the author's view, if a first course of glucocorticoids provides a suboptimal response, a second course of intravenous (or oral) glucocorticoids associated with orbital radiotherapy should be given. An alternative might be represented by oral glucocorticoids associated with cyclosporine. The use of biological agents, the most promising being rituximab, is for the time being experimental and warrants support from randomized clinical trials.

McMillan et al (2011) commented that newer steroid-sparing immunomodulatory agents, such as rituximab, have not been studied extensively in children. They show promising results from case reports and retrospective cohort studies, but there is a need for comparative studies looking at their relative efficacy, tolerability, and long-term adverse effects (including secondary malignancy) in children.

Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity (Trebst, et al., 2014). Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. The Neuromyelitis Optica Study Group (NEMOS) stated that NMO Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. The NEMOS stated that it is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. The NEMOS suggested azathioprine and rituximab as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.

In an open label study, Cree et al (2005) reported their findings of 8 patients with worsening neuromyelitis optica who were treated with rituximab. Treatment was well- tolerated; 6 of 8 patients were relapse free and median attack rate declined from 2.6 attacks/patient/year to 0 attacks/patient/year (p = 0.0078). Seven of 8 patients experienced substantial recovery of neurological function over 1 year of average follow-up. The pre-treatment median Expanded Disability Status Scale score was 7.5, and at follow-up examination was 5.5 (p = 0.013). These investigators noted that the apparently robust effects of rituximab deserve further investigation through controlled trials.

In a prospective, open-label study, Kim and colleagues (2011) evaluated the safety and effectiveness of repeated rituximab treatment based on the assessment of peripheral circulating memory B cells over 24 months in patients with relapsing neuromyelitis optica (NMO). A total of 30 patients with relapsing NMO or NMO spectrum disorder were included in this study. Treatment protocol of rituximab consisted of an induction therapy (375 mg/m² once-weekly for 4 weeks or 1,000 mg infused twice, with a 2-week interval between the infusions) followed by maintenance therapy. The maintenance therapy was repeated treatment with rituximab (375 mg/m², once) whenever the frequency of reemerging CD27+ memory B cells was more than 0.05 % in peripheral blood mononuclear cells by flow cytometric analysis. Main outcome measures included annualized relapse rate, disability (Expanded Disability Status Scale score), anti-aquaporin 4 antibody level, and safety of rituximab treatment. Of 30 patients, 28 showed a marked reduction in relapse rate while taking rituximab over 24 months. The relapse rate was reduced significantly, by 88 %, and 70 % of patients became relapse-free over 24 months. Disability either improved or stabilized in 97 % of patients. Anti-aquaporin 4 antibody levels declined significantly following treatment with rituximab, consistent with the clinical response and the effect on CD27+ memory B cells. Repeated treatment with rituximab was generally well-tolerated, and no clinically relevant adverse event leading to discontinuation of treatment was observed. The authors concluded that repeated treatment with rituximab appeared to produce consistent and sustained efficacy over 24 months with good tolerability in patients with NMO.

Pellkofer et al (2011) performed a prospective long-term cohort study of 10 patients with neuromyelitis optica (NMO) who were treated up to 5 times with rituximab as a second-line therapy. Clinical examinations, B-cell counts, and serum concentrations of BAFF (B-cell activating factor of the TNF family; also called TNFSF13b), APRIL (a proliferation-inducing ligand; also called TNFSF13), AQP4-ab, and immunoglobulin levels were measured every 3 months. Repeated treatment with rituximab led to sustained clinical stabilization in most patients with NMO. Disease activity correlated with B-cell depletion, but not clearly with AQP4-ab or levels of APRIL. BAFF levels increased after application of rituximab and indicated persisting efficacy of the drug but did not correlate with disease activity. Overall, rituximab was well-tolerated even after up to 5 consecutive treatment courses; however, several severe adverse reactions were observed. The authors concluded that these data indicated that long-term therapy with rituximab is effective in NMO as a second-line therapy and has an acceptable safety profile. Re-treatment with rituximab should be applied before re-appearance of circulating B cells.

The Ameriacn Academy of Neurology's guideline on "Clinical evaluation and treatment of transverse myelitis" (Scott et al, 2011) assessed the evidence for diagnostic tests and therapies for transverse myelitis (TM) and made evidence-based recommendations. A review of the published literature from 1966 to March 2009 was performed, with evidence-based classification of relevant articles. Level B recommendations: NMO-immunoglobulin G (IgG) antibodies should be considered useful to determine TM cause in patients presenting with clinical acute complete transverse myelitis (ACTM) features. The presence of NMO-IgG antibodies (aquaporin-4-specific antibodies) should be considered useful in determining increased TM recurrence risk. Level C recommendations: in suspected TM, distinction between ACTM or acute partial transverse myelitis may be considered useful to determine TM etiology and risk for relapse (more common with APTM). Age and gender may be considered useful to determine etiology in patients presenting with TM syndrome, with spinal infarcts seen more often in older patients and more female than male patients having TM due to multiple sclerosis (MS). Brain MRI characteristics consistent with those of MS may be considered useful to predict conversion to MS after a first partial TM episode. Longer spinal lesions extending over greater than 3 vertebral segments may be considered useful in determining NMO versus MS. CSF examination for cells and oligoclonal bands may be considered useful to determine the cause of the TM syndrome. Plasma exchange may be considered in patients with TM who fail to improve after corticosteroid treatment. Rituximab may be considered in patients with TM due to NMO to decrease the number of relapses. Level U recommendations: there is insufficient evidence to support or refute the efficacy of other TM therapies or the usefulness of ethnicity to determine the cause of a subacute myelopathy.

Tracy and Dyck (2010) examined the data for treatment of inflammatory demyelinating peripheral neuropathies, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). A large clinical trial showed short and long-term efficacy of IVIG for the treatment of CIDP and the U.S. Food and Drug Administration approved the use of IVIG (Gamunex) as a treatment for CIDP. Recent trials for other agents for CIDP treatment have not proved as promising, with a large study of methotrexate failing to show significant benefit. There are recent cases of monoclonal antibodies (e.g., rituximab, alemtuzumab) showing benefit in patients with CIDP, but the side effect profiles can be worrisome. Clinical history, neurological examination, spinal fluid examination, and electrophysiological evaluation remain mainstays for the diagnosis of demyelinating inflammatory polyradiculoneuropathy. Genetic testing and nerve biopsy are important diagnostic tools in some patients. Potential treatments for immune-mediated demyelinating polyradiculoneuropathies are varied, with the authors generally favoring IVIG and/or corticosteroids as first-line agents. Plasma exchange can be helpful in selected patients. Data for efficacy of other oral immunomodulatory agents are based primarily on case reports and case series, and have not been uniformly positive. The use of monoclonal antibodies (particularly rituximab) may have promise, but further research needs to be done, and the risks need to be carefully considered.

Nobile-Orazio et al (2010) stated that chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) usually respond to immune therapies including steroids and plasma exchange for CIDP and high-dose IVIGs for both diseases. Other immune therapies have been used to reduce the costs or the side-effects of these therapies, but their efficacy was only recently assessed in randomized controlled trials (RCTs). The prolonged efficacy of IVIG in CIDP has been confirmed in a 48-week RCT. Two other RCTs showed that oral methotrexate or intramuscular interferon beta were not more effective than placebo in improving the efficacy or reducing the dose of IVIG or steroids. In MMN, a RCT showed that oral mycophenolate mofetil was not more effective than placebo in increasing the efficacy or reducing the dose of IVIG. Other immune therapies were assessed in open trials in both diseases, but their efficacy remains unclear, even if in some patients a possible efficacy of rituximab was reported. Some preliminary studies suggest that subcutaneous immunoglobulin may be as effective as IVIG in the maintenance therapy of CIDP and MMN. The authors concluded that after several years of anecdotal reports, a number of RCT have now appeared in CIDP and MMN, but their results are still insufficient to support the use of new therapies in these diseases.

In a retrospective, observational and multi-center study, Benedetti et al (2011) analyzed the efficacy of rituximab in a large chronic inflammatory demyelinating polyneuropathy (CIDP) cohort. A total of 13 CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring hematological diseases. Patients who improved by at least 2 points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders. Nine patients (7 with hematological diseases) responded to rituximab: 6 of them, who were non-responders to conventional therapies, improved clinically, and the other 3 maintained the improvement that they usually achieved with IVIG or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range of 1 to 6) and lasted for a median period of 1 year (range of 1 to 5). The authors concluded that rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring hematological diseases.

In a Cochrane review, Mahdi-Rogers (2010) systematically reviewed the evidence from RCTs of cytotoxic drugs and interferons other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyneuropathy (CIDP). These researchers sought RCTs and quasi-randomized trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, ciclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as interferon alfa and interferon beta in participants fulfilling standard diagnostic criteria for CIDP. Two authors independently selected trials, judged their methodological quality and extracted data. They wanted to measure the change in disability after 1 year as the primary outcome. Secondary outcomes were change in disability after 4 or more weeks (from randomization), change in impairment after at least 1 year, change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after 1 year and for those participants who were receiving corticosteroids or IVIG, the amount of this medication given during at least 1 year after randomization. Participants with one or more serious adverse events during the first year was also a secondary outcome. Four trials fulfilled the selection criteria, one of azathioprine (27 participants), 2 of interferon beta-1a (77 participants in total) and 1 of methotrexate (60 participants). None of these trials showed significant benefit in the primary outcome or secondary outcomes selected for this review. The evidence from RCTs does not show significant benefit from azathioprine, interferon beta-1a or methotrexate but none of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for RCTs to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures and longer durations.

Arce-Salinas et al (2012) reported the findings of 8 patients with refractory lupus nephritis (LN) who received rituximab after failing standard sequential therapy and were followed for 104 weeks after the infusion. One patient died secondary to a complicated pregnancy but had stable renal function; 3 patients received a re-infusion of rituximab approximately 12 months apart due to a renal flare; and during the 2nd year of follow-up, those patients progressed toward end-stage renal disease. The 4 remaining patients demonstrated improvements in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, creatinine clearance, and proteinuria with maintenance of their standard immunosuppressive therapy and did not require a re-infusion of rituximab. The authors concluded that although rituximab as induction therapy for refractory LN has been shown to have a good response, its effectiveness in long-term assessments demonstrated disappointing results.

In a randomized, double-blind, placebo-controlled phase 3 trial (LUNAR study), Rovin et al (2012) evaluated the safety and effectiveness of rituximab in LN patients treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. Patients (n = 144) with Class III or IV LN were randomized 1:1 to rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary endpoint was renal response status at week 52. Rituximab depleted peripheral CD19+ B cells in 71/72 patients. Complete and partial renal responses were achieved in 33/72 (45.8 %) placebo- and 41/72 (56.9 %) rituximab-treated patients (p = 0.55), the difference mostly accounted for by partial responses. The primary endpoint (superior response rate with rituximab) was not achieved. Eight placebo patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti-dsDNA antibody levels were observed with rituximab. In both treatment groups, a reduction in anti-dsDNA greater than the median reduction was associated with improvement in proteinuria. Rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. The authors concluded that although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

Wink et al (2011) noted that cryoglobulinemia associated with systemic vasculitis mediated by immune complexes is a rare combination. These immune complexes are composed of immunoglobulins and precipitate when exposed to cold temperature. Cryoglobulinemic vasculitis, treated or untreated, may lead to substantial morbidity and even mortality. Novel targeted therapies may well provide new therapeutic options following or perhaps even prior to the classical cytotoxic therapies. Systemic B cell depletion with rituximab, a chimeric monoclonal antibody against CD20 antigen, is commonly applied in patients with non-Hodgkin's lymphoma or in refractory rheumatoid factor-positive rheumatoid arthritis. Since B cell clones are the source of cryoglobulins, therapeutic effectiveness of rituximab in cryoglobulinemic vasculitis may be expected. These researchers described a 72-year old woman with mixed cryoglobulinemia type 2, who has successfully been treated with rituximab infusions after failing on prednisone and azathioprine. They reviewed the literature and found 142 cases of cryoglobulinemic vasculitis, 138 mixed (type 2 or 3) and 4, type 1. Rituximab was applied mostly after failure on other treatments. Significant reduction in levels of rheumatoid factor, cryoglobulins and IgM were reported after rituximab therapy. Of the total 142, cases 119 could be evaluated for the response on rituximab therapy, the other 23 cases only regarding side effects. Of the 119 evaluated patients, 71 (60 %) had complete response; 28 (23 %), partial response and 20 patients (17 %), no response. Data were not blinded or placebo-controlled. Side effects were seen in 27 of the 142 patients. Occurrence of the side effects was associated with high baseline levels of cryoglobulins, with a high-dose of rituximab infusion of 1,000 mg and with a high level of complement activation. Death was reported four times and was related with the disease.

Pietrogrande et al (2011) defined a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. The authors concluded that although there are few controlled randomized trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

De Vita et al (2012) conducted a long-term, prospective, randomized controlled trial evaluating RTX therapy for severe mixed cryoglobulinemia (MC) or cryoglobulinemic vasculitis (CV). A total of 59 patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had HCV infection, treatment of the HCV infection with anti-viral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 g each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3 % versus 3.5 % [p < 0.0001]), as well as at 3 months (92.9 % versus 13.8 % [p < 0.0001]), 6 months (71.4 % versus 3.5 % [p < 0.0001]), and 24 months (60.7 % versus 3.5 % [p < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean +/- SD of 11.9 +/- 5.4 at baseline to 7.1 +/- 5.7 at month 2; p < 0.001) up to month 24 (4.4 +/- 4.6; p < 0.0001). Rituximab appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well-tolerated. The authors concluded that rituximab monotherapy represents a very good option for severe CV and can be maintained over the long-term in most patients.

Sneller et al (2012) conducted a single-center, open-label, randomized controlled trial of rituximab (375 mg/m(2)/week for 4 weeks) compared to the best available therapy (maintenance or increase in immunosuppressive therapy) for HCV-associated CV in patients in whom anti-viral therapy had failed to induce remission. The primary end point was disease remission at 6 months from study entry. A total of 24 patients were enrolled (12 in each treatment group). Baseline disease activity and organ involvement were similar in the two groups. Ten patients in the rituximab group (83 %) were in remission at study month 6, as compared with 1 patient in the control group (8 %), a result that met the criterion for stopping the study (p < 0.001). The median duration of remission for rituximab-treated patients who reached the primary end point was 7 months. No adverse effects of rituximab on HCV plasma viremia or on hepatic transaminase levels were observed. The authors concluded that rituximab was a well-tolerated and effective treatment in patients with HCV-associated CV in whom anti-viral therapy failed to induce remission.

Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of disease prognosis (Carubbi, et al., 2013). Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX.

A systematic evidence review concluded that further clinical trials are necessary to establish the efficacy of rituximab in primary Sjogren syndrome. Ramos-Casals, et al (2010) searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. The search strategy yielded 37 trials. The authors repored that a placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. The authors concluded that, in primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab. An accompanying editorial by Vissink, et al. (2010) stated that "larger trials are needed before the role of rituximab in the treatment of primary Sjögren syndrome can be settled, not only with respect to its effect on salivary flow rate and xerostomia but also with regard to the effect of rituximab treatment on general symptoms, extraglandular involvement, and life-threatening situations in primary Sjögren syndrome."

Carubbi et al (2013) conducted a study to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients. Forty-one patients with early pSS and active disease (EULAR Sjogren's syndrome disease activity index, ESSDAI ≥ 6) were enrolled in the study. Patients were treated with either RTX or DMARDs in two different rheumatology centers and followed up for 120 weeks. Clinical assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-reported global disease activity pain, sicca symptoms and fatigue on visual analogic scales, unstimulated saliva flow and Schirmer's I test at week 12, 24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to week 120. Two labial minor salivary gland (MSG) biopsies were obtained from all patients at the time of inclusion in the study and at week 120. The investigators concluded that their study demonstrated that RTX treatment results in a faster and more pronounced decrease of ESSDAI and other clinical parameters compared to DMARDs treatment. No adverse events were reported in the two groups. The investigators also observed that RTX is able to reduce glandular infiltrate, interfere with B/T compartmentalization and consequently with the formation of ectopic lymphoid structures and germinal center-like structures in pSS-MSGs. The investigators reported that this is the first study performed in a large cohort of early active pSS patients for a period of 120 weeks. The investigators stated that the study showed that RTX is a safe and effective agent to be employed in pSS patients with systemic, extra-glandular involvement. Furthermore, they noted that their data on pSS-MSGs provide additional biological basis to employ RTX in this disease.

In a double-blind, randomized, placebo-controlled trial, Meijer et al (2010) examined the safety and effectiveness of rituximab in patients with primary Sjogren's syndrome (pSS). Patients with active pSS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of greater than or equal to 0.15 ml/min were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Follow-up was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. A total of 30 patients with pSS (29 females) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (p = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extra-glandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (p = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short-Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. The authors concluded that these results indicated that rituximab is an effective and safe treatment strategy for patients with pSS.

Mekinian et al (2012) evaluated RTX in pSS with peripheral nervous system (PNS) involvement. Patients with pSS and PNS involvement who were included in the French AIR registry were analyzed. A total of 17 patients (aged 60 years (44 to 78 years); 14 were female) were included in this analysis. Neurological improvement was noted in 11 patients (65 %) at 3 months. Rankin scale decreased from 3 (1 to 5) to 2 (1 to 5), 2 (1 to 5) and 2 (1 to 6) after 3, 6 and 9 months (p = 0.02). European Sjogren's Syndrome Disease Activity Index (ESSDAI) decreased from 18 (10 to 44) to 11 (5 to 20), 11 (5 to 29) and 12 (5 to 30) after 3, 6 and 9 months (p < 0.05). Rituximab was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinemia (90 %) (group 1) at 3 months and in 2/7 cases (29 %) without cryoglobulinemia and vasculitis (p = 0.03). Rankin and European Sjogren's Syndrome Disease Activity Index scales decreased significantly in group 1. The authors concluded that RTX seems effective in cryoglobulinemia or vasculitis-related PNS involvement in pSS.

Gottenberg et al (2013) evaluated the safety and effectiveness of rituximab in patients with progressive systemic sclerosis (pSS). The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectively followed-up every 6 months for 5 years. A total of 78 patients with pSS (11 men, 67 women), who already had at least 1 follow-up visit, were analyzed. Median age was 59.8 years (29 to 83), median duration of disease was 11.9 years (3 to 32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in 4 patients. The median ESSDAI was 11 (2 to 31); 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6 to 81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60 %) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2 to 31) to 7.5 (0 to 26) (p < 0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3 to 60) to 10.8 mg/day (p = 0.1). A total of 41 patients were retreated with rituximab; 4 infusion reactions and 1 delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and 2 cancer-related deaths occurred. The authors concluded that in common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study showed good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

An UpToDate review on “Treatment of the antiphospholipid syndrome” (Bermas et al, 2013) states that “Investigational therapies for the APS include autologous stem cell transplantation and rituximab. To date, insufficient data on the use of these approaches exist to guide therapeutic recommendations”. Furthermore, the British Committee for Standards in Haematology’s guidelines on “The investigation and management of antiphospholipid syndrome” (Keeling et al, 2012) does not mention rituximab as a therapeutic option.

Khattri et al (2012) reviewed the literature on B cell directed therapies in human and experimental antiphospholipid syndrome (APS). The clinical data are limited to B cell depletion with rituximab and comprises case reports and case series. Murine studies included use of modulators of B cell function such as belimumab and abatacept. In both human and murine studies, B cell directed therapies appeared to have clinical and serologic beneficial effects including a decrease in the antiphospholipid antibody titers after treatment. The authors stated that randomized controlled clinical trials are needed to determine whether B cell depletors and/or B cell modulators can be effective agents for treating patients with APS.

In a pilot, phase II study, Erkan et al (2013) evaluated the safety of rituximab in antiphospholipid antibody (aPL)-positive patients with non-criteria manifestations of APS. The secondary objectives were to evaluate the effect of rituximab on the aPL profile and to evaluate the efficacy of rituximab treatment for non-criteria manifestations of APS. In this 12-month study, adult aPL-positive patients with thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and/or cognitive dysfunction received 2 doses of rituximab (1,000 mg) on days 1 and 15. Antiphospholipid antibody profiles and clinical outcome measures, which were categorized as complete response, partial response, no response, or recurrence, were analyzed at preset time points. Two of 19 patients experienced infusion reactions, resulting in early termination; 12 serious adverse events and 49 non-serious adverse events were recorded. All patients who had positive results of lupus anticoagulant, anti-cardiolipin, and anti-β(2)-glycoprotein I antibody tests at baseline had positive results at 24 weeks and 52 weeks. The numbers of patients with a complete response, a partial response, no response, and recurrence for the clinical outcome measures at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively. The authors concluded that the findings of this uncontrolled and non-randomized pilot study suggested that the safety of rituximab in aPL-positive patients is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

Uhlving et al (2012) stated that bronchiolitis obliterans (BO) following allogeneic hematopoietic SCT (HSCT) is a serious complication affecting 1.7 to 26.0 % of the patients, with a reported mortality rate of 21 to 100 %. It is considered a manifestation of chronic graft-versus-host disease (GVHD), but the knowledge of etiology and pathogenesis is still limited. The authors noted that no convincing effect of rituximab on bronchiolitis obliterans has been established.

In a Cochrane review, Lunn and Nobile-Orazio (2012) assessed the effects of immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy. These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. They also checked bibliographies and contacted authors and experts in the field. They included randomized or quasi-randomized controlled trials involving participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity. The primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomization. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomization; 10-meter walk time, subjective clinical scores and electrophysiological parameters at 6 and 12 months after randomization; IgM paraprotein levels and anti-myelin-associated glycoprotein antibody titers at six months after randomization; and adverse effects of treatments. The 2 authors independently selected studies. Two authors independently assessed the risk of bias in included studies. They identified 7 eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials. There were no clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at 2 weeks and 10-meter walk time at 4 weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high-risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. The authors concluded that there is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well-designed randomized trials of at least 6 to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive and valid outcome measures.

Sauvaget et al (2012) reported the case of a 6-year old boy who had Kawasaki disease resistant to intravenous immunoglobulin and systemic steroids. Because of an uncontrolled disease course, with significant lesions of the coronary arteries, anti-CD20 treatment was used. Rapid clinical, biological, and cardiac improvement was observed. The patient tolerated the treatment well. Also, an UpToDate review on “Treatment of refractory Kawasaki disease” (Sundel, 2013) states that “New antiinflammatory agents, including biologic response modifiers, become available regularly. Rituximab, a B cell depleting monoclonal anti-CD20 antibody, was reported effective in a single case involving a child with KD refractory to IVIG and glucocorticoids”.

Leger et al (2013) examined if rituximab 375 mg/m2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). A total of 44 patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) greater than or equal to 4 and VAS greater than 4 or ataxia score greater than or equal to 2. The primary outcome was mean change in ISS at 12 months. Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per-protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form-36 questionnaire. The authors concluded that although primary outcome measures provided no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per-protocol analysis. This study provided Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.

Miya et al (2014) noted that the NMDAR is involved in normal physiological and pathological states in the brain. Anti-NMDAR encephalitis is characterized by memory deficits, seizures, confusion, and psychological disturbances in males and females of all ages. This type of encephalitis is often associated with ovarian teratoma in young women, but children are less likely to have tumors. Anti-NMDAR encephalitis is a neuroimmune syndrome in patients with autoantibodies recognizing extracellular epitopes of NMDAR, and the autoantibodies attenuate NMDAR function through the internalization of NMDAR. Following the initial symptoms of inflammation, the patients show the various symptoms such as memory loss, confusion, emotional disturbances, psychosis, dyskinesis, decrease in speech intelligibility, and seizures. About 50 % of these patients improved with immunotherapy including high-dose intravenous corticosteroids and IVIG is administrated to these patients, but the patients who had no improvement with these therapies require further treatments with rituximab or cyclophosphamide. It is necessary to detect anti-NMDAR antibodies at early stages, because the prognosis of these patients may be improved by early treatment. Recovery is slow, and the patients may have some disturbances in their motor function and cognition. The authors concluded that the pathologic mechanism underlying the development of anti-NMDAR encephalitis has been elucidated gradually, but the optimal treatment has not yet been clarified. They stated that further studies are required to clarify in detail the mechanism underlying anti-NMDA encephalitis and to develop effective treatments.

In a multi-center retrospective study, Dale et al (2014) evaluated the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. A total of 144 children and adolescents (median age of 8 years, range of 0.7 to 17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range of 0.05 to 9.5 years). Infusion adverse events were recorded in 18/144 (12.5 %), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6 %) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range of 0.1 to 8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87 %) patients. A total of 17.4 % of patients had a modified Rankin Scale (mRS) score of 0 to 2 at rituximab initiation, compared to 73.9 % at outcome. The change in mRS 0 to 2 was greater in patients given rituximab early in their disease course compared to those treated later. The authors concluded that while limited by the retrospective nature of this analysis, these findings supported an off-label use of rituximab, although the significant risk of infectious complications suggested rituximab should be restricted to disorders with significant morbidity and mortality. This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6 % risk of adverse infections.

Ikeguchi et al (2012) reported the case of a young woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, without tumor, who was successfully treated with rituximab. Because conventional immunotherapy, including corticosteroids, immunoglobulin (IVIG), and plasma exchange showed little improvement in this patient, these researchers introduced another treatment using rituximab. A week after the first administration of rituximab, her symptoms improved gradually and significantly. The authors concluded that this case provided in-vivo evidence that rituximab is an effective agent for treating anti-NMDAR encephalitis, even in those cases where conventional immunotherapies have been ineffective. They stated that rituximab should be regarded as a beneficial therapeutic agent for this disease. This is a single case study.

In a multi-institutional observational study, Titulaer et al (2013) tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, IVIG, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumor removal. Predictors of outcome were determined at the Universities of Pennsylvania and Barcelona (Spain) by use of a generalized linear mixed model with binary distribution. These researchers enrolled 577 patients (median age of 21 years, range of 8 months to 85 years); 211 of whom were children (less than 18 years). Treatment effects and outcome were assessable in 501 (median follow-up of 24 months, range of 4 to 186): 472 (94 %) underwent first-line immunotherapy or tumor removal, resulting in improvement within 4 weeks in 251 (53 %). Of 221 patients who did not improve with first-line treatment, 125 (57 %) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not (odds ratio [OR] 2.69, CI: 1.24 to 5.80; p = 0.012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0-2; median 6 months, IQR 2 to 12) and 30 died. At 24 months' follow-up, 203 (81 %) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0.62, 0.50 to 0.76; p < 0.0001) and no admission to an intensive care unit (0.12, 0.06 to 0.22; p < 0.0001). Moreover, 45 patients had one or multiple relapses (representing a 12 % risk within 2 years); 46 (67 %) of 69 relapses were less severe than initial episodes (p < 0.0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. The authors concluded that most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. It is unclear how many patients received rituximab as 2nd line therapy in this observational study. The main drawback of the study by Titulaer et al (2013) was that the study was not randomized, but it is precursory to future trials to establish the efficacy of each individual treatment (e.g., steroids, intravenous immunoglobulins, plasmapheresis, rituximab, and cyclophosphamide) and duration of immunotherapy.

Hachiya et al (2013) measured anti- NMDAR autoantibody levels and assessed B cell subsets using multi-color flow cytometry of peripheral blood mononuclear cells (PBMCs) from a recurrent anti-NMDAR encephalitis case to evaluate the effectiveness of rituximab treatment. Rituximab depleted CD20(+) fractions of naïve and memory B cell subsets and reduced the number of CD20(-) plasmablasts. The authors concluded that the findings of this study suggested that short-lived plasmablasts are removed by rituximab-induced depletion of the CD20(+) B cell population. Increased numbers of plasmablasts in PBMCs may be a candidate predictive factor for unfavorable prognosis of anti-NMDAR encephalitis and an indication of when to commence second-line immunotherapy. This was an in-vitro study.

Brown et al (2014) stated that autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. Two case reports were presented. Both cases had facio-brachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months, respectively. Rituximab use allowed withdrawal of corticosteroids and was well-tolerated. The authors concluded that randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides.

In an observational study, Irani et al (2014) described the safety and effectiveness of rituximab in 5 patients with voltage-gated potassium channel (VGKC)-complex/leucine-rich, glioma-inactivated 1 (LGI1) antibody-associated encephalopathy. This case series reported sequential seizure frequencies, modified Rankin Scale scores, and VGKC-complex antibody titers in 5 adult patients (median age of 65 years; range of 48 to 73 years) treated with rituximab. Median time from symptom onset to rituximab initiation was 414 days (range of 312 to 851 days). One patient showed a rapid clinical improvement after treatment with rituximab alone and experienced a rituximab-responsive clinical relapse. Another showed possible improvement on neuropsychometric memory indexes after rituximab therapy. In contrast, all patients showed robust responses to treatment with glucocorticoids, intravenous immunoglobulins, and/or plasma exchange at some point in their illness. Treatment with glucocorticoids-less so with intravenous immunoglobulins and plasma exchange-was associated with the most marked reductions in VGKC-complex antibodies. The only patient who did not receive glucocorticoids showed the poorest clinical and serologic responses. The authors concluded that rituximab was well-tolerated in this predominantly older adult patient population and may be an effective option for some patients with LGI1 antibody-associated encephalopathy. They stated that glucocorticoid therapy appears particularly efficacious; earlier rituximab administration and randomized trials are needed to formally evaluate effectiveness.

Benitah et al (2011) noted that Behcet's disease (BD) is a multi-system inflammatory disorder of uncertain etiology with a variety of potential manifestations throughout the body, and its ocular complications are some of its most devastating. Treatment with immunosuppressive agents has improved outcomes, but many patients suffer from disease that responds poorly to conventional therapies. Because of this, therapy with a variety of biological response modifiers has been employed. The earliest was interferon-alpha, and a multitude of reports have described its benefits for the uveitis associated with BD. Many patients enjoy durable remissions of their ocular inflammatory disease even after discontinuation of therapy, but side-effects are almost universal and some can be dangerous. Of the newer biological response modifiers, infliximab, a monoclonal antibody to TNF-alpha, has been most extensively studied. It is reported to be rapidly effective in many cases of BD uveitis, though with conflicting data as to the ability to induce durable remission after cessation of treatment. Side-effects are relatively rare, but may be serious. Several reports have been published on the use of other biologic agents, including adalimumab, etanercept, and rituximab. Of the 3 of these, adalimumab has the most promising initial evidence, etanercept has very few positive reports in patients with BD uveitis (and is likely ineffective in uveitis in general), and rituximab is lacking data. The authors concluded that although RCTs are almost completely lacking, currently available evidence is promising that biologic agents can prove an invaluable addition to the armamentarium of the practitioner treating patients with BD uveitis.

Lin et al (2013) stated that progressive familial intrahepatic cholestasis type 2 (PFIC2) results from recessive mutations in the adenosine triphosphate-binding cassette B11 gene, which encodes for bile salt export pump (BSEP). Liver transplantation (LT) is offered to PFIC2 patients with end-stage liver disease. Reports have described recurrent cholestasis in PFIC2 patients after transplantation, and this has been associated with immunoglobulin G antibodies to BSEP. High-titer anti-BSEP antibodies appeared to correlate with episodes of cholestatic graft dysfunction. There is no established paradigm for treating antibody-mediated post-transplant BSEP disease. It appeared to be refractory to changes in immunosuppressant medications that would typically be effective in treating allograft rejection. Taking what is known about its pathophysiology, these researchers designed a treatment consisting of rituximab in combination with intravenous immunoglobulin (IVIG) and plasmapheresis. Using this approach, the authors reported the successful management of 2 patients with antibody-mediated recurrence of PFIC2 after LT. The main drawback of this study was its limited sample size (n = 2). Furthermore, the findings were confounded by the combinational use of rituximab, IVIG, and plasmapheresis.

Rodriguez-Porcel et al (2014) stated that acute disseminated encephalo-myelitis (ADEM) is characterized by its rapid progression with variable symptoms and severity in adults and children. Multiple therapeutic options have been proposed, but solid evidence is yet to be gathered. These researchers described an adult man with a fulminant form of ADEM unresponsive to numerous treatment modalities. Furthermore, an UpToDate review on “Acute disseminated encephalomyelitis in adults” (Waldman and Jacobs, 2015) does not mention rituximab as a therapeutic option.

Pandey et al (2014) reported on the case of a 45-year old woman with pulmonary sarcoidosis diagnosed 5 years previously; she was on treatment with prednisone and methotrexate for 1 year, developed partial seizure with secondary generalization. MRI showed 3 non-cavitary enhancing lesions in the cerebello-occipital region. These lesions were presumed to be neurosarcoidosis. Methotrexate was discontinued, prednisone dose was increased and azathiopurine and levetiracetam were added. While the patient was on treatment, follow-up imaging showed enlarging brain lesions. Biopsy of the lesions showed Epstein Barr virus (EBV) positive diffuse B cell lymphoma. Immunosuppressants were tapered off and she started on rituximab. Because of lack of improvement after 4 cycles of rituximab, she was then treated with high-dose methotrexate and temozolamide.

An UpToDate review on “Infliximab (Remicade) is a chimeric human-murine antihuman antibody that specifically blocks the effect of tumor necrosis factor-alpha (TNF-alpha). Preliminary results indicate that infliximab may be useful in selected patients with pulmonary and extrapulmonary sarcoidosis refractory to corticosteroid therapy. In one series of seven patients with corticosteroid-refractory neurosarcoidosis, treatment with infliximab (with mycophenolate mofetil in six patients) was associated with symptom relief, regression of neurologic deficits, and a decrease in disease activity on MRI. Another series reported stabilization and improvement in four patients with central nervous system manifestations of neurosarcoidosis. A single case report describes the successful use of rituximab (monoclonal antibody directed against B cells) in a patient with CNS neurosarcoidosis. Use of infliximab requires an intravenous infusion (5 mg/kg of ideal body weight) initially, and periodically thereafter as the clinical course is monitored”.

In a prospective, dose-ranging, randomized, double-masked phase I/II clinical trial, Suhler et al (2014) examined if rituximab is effective in the treatment of refractory non-infectious scleritis. A total of 12 patients with non-infectious scleritis refractory to systemic corticosteroid and greater than or equal to 1 other systemic immunosuppressive agents were enrolled from January 2007 to March 2010. Subjects were randomly assigned to 500 (n = 5) or 1,000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1,000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1,000 mg infusions. Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by greater than or equal to 50 %. Patients were characterized as responders to study therapy if greater than or equal to 1 of these end-points showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment. Of 12 enrolled patients, 9 met the SGS end-point at or before week 24, and 4 additionally were able to reduce corticosteroid dose by greater than or equal to 50 %. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of re-treatment were noted between the dosing arms. The authors concluded that rituximab was effective treatment for 9 of 12 enrolled patients with refractory, non-infectious scleritis at 24 weeks, although 7 required re-infusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. They stated that further long-term studies are needed to determine the safety and effectiveness of rituximab in treating non-infectious scleritis and other ocular inflammatory diseases.

Acute Zonal Occult Outer Retinopathy (AZOOR)

Kitakawa et al [2012] reported a case of a 42-year old woman patient diagnosed with acute zonal occult outer retinopathy (AZOOR) receiving 2 courses of steroid pulse therapy (methylprednisolone 1 g/day for 3 consecutive days) followed by 30 mg of prednisolone tapered over 1 month; 14 months later the patient presented improvements in visual acuity (VA), perimetry, optical coherence tomography (OCT), and electroretinography (ERG) testing.

Nakao et al [2015] presented the case of a 3- year old man diagnosed with AZOOR. He received no treatment and after 2 months presented spontaneous remission. The patient was closely monitored with spectral-domain OCT, multi-focal ERG and imaging with prototype adaptive optics scanning laser ophthalmoscopy (AO-SLO). Subject was tested at the initial visit and at 1 month intervals for 2 months, showing gradual improvement until the parameters were nearly normalized.

Chen et al [2015] demonstrated the favorable outcome of systemic steroids in a retrospective study involving 9 patients who had a mean follow-up duration of 47 months; 3 patients received intravenous pulse therapy (methylprednisolone 250 mg every 6 hours for 3 days) as initial treatment followed by oral prednisolone with gradual tapering for 3 months; 5 patients received a standard dosage of oral prednisolone (1 mg/kg/day) with gradual tapering for 3 months; 1 patient initiated with oral prednisolone, but couldn’t be tapered due to reactivation of the disease. She was maintained on 10 mg/day and mycophenolate (immunosuppressant) 360 mg twice-daily. At the final follow-up visit all patients had improvements in visual field and OCT testing.

The American Academy of Ophthalmology (AAO) EyeWiki on “Acute Zonal Occult Outer Retinopathy (AZOOR)” (Salcedo et al, 2016) noted that “No proven treatment exists. Systemic corticosteroids, immunosuppressive drugs (cyclophosphamide, methotrexate, azathioprine, etc.), anti-viral (acyclovir and valacyclovir) and antibacterial (sulfadiazine and trimethoprim) medications have been tried with no consensus on the success of said therapies”.

Adrenal Gland Neoplasm

Yun and colleagues (2010) stated that the involvement of certain organs such as the adrenal gland and ovaries is rare in NHL. There are few studies comparing clinical features and prognosis based on the extra-nodal organ involved. These researchers elected patients presenting with predominantly extra-nodal involvement among patients diagnosed with NHL from 1998 to 2009. A total of 48 patients with NHL involving rare extra-nodal sites were analyzed. The extra-nodal sites were as follows: adrenal gland (n = 14), ovary (n = 13), pancreas (n = 11), uterus (n = 4), esophagus (n = 4) and prostate (n = 2). Diffuse large B-cell lymphoma (DLBCL) was the most common (n = 39), and the median overall survival (OS) was 16.63 months. There was no significant difference in OS according to the involved sites. Rituximab plus CHOP failed to provide an additive survival benefit over CHOP alone in 39 DLBCL patients. The OS of DLBCL in rare extra-nodal sites was worse than that in common sites when compared based on tumor stage. The authors concluded that NHL involving rare extra-nodal sites had a poor prognosis, and the impact of rituximab on survival was negligible.

Amyopathic Dermatomyositis

Yosipovitch et al (2013) stated that no study has compared the clinical characteristics, malignancy associations, and treatment of dermatomyositis in predominantly Caucasian versus Asian populations. This prospective study was conducted to compare clinical characteristics of dermatomyositis, its relationship to malignancy, and treatment between 2 tertiary medical centers in the USA and Singapore. A total of 19 newly-diagnosed patients in the USA and 15 patients in Singapore were enrolled. Dermatomyositis or amyopathic dermatomyositis (ADM) were diagnosed based on clinical assessment, skin and muscle biopsies, and muscle testing; 95 % of patients in the USA group were of Caucasian descent, while 93 % of patients in the Singapore group were of Chinese descent. Both groups were predominantly female. Pruritus was the most common initial symptom reported in both groups, while peri-ungual erythema and Gottron's papules were the most common skin presentations. Heliotrope eruption was more common in the Singapore group, occurring in 80 % of patients versus 32 % of patients in the USA group (p = 0.007); 3 patients in the Singapore group developed a malignancy, with 2 of these patients having nasopharyngeal carcinoma. None of the USA patients developed malignancies in a follow-up period of 2 to 5 years. Immunosuppressive steroid-sparing therapy with hydroxychloroquine was more frequently used in Singapore, while topical tacrolimus was more frequently used in the USA. The authors concluded that the clinical presentations of dermatomyositis varied among different ethnic populations; Chinese patients with dermatomyositis had a significant risk for nasopharyngeal carcinoma. Rituximab was not mentioned as a therapeutic option.

Koichi et al (2017) noted that rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically ADM (CADM) associated with antibodies to melanoma differentiation-associated gene5 (MDA5) resulted in a high mortality rate. These investigators experienced a case of anti-MDA5-positive RP-ILD of CADM that showed a response to rituximab, although there was no significant effect due to standard immunosuppressive treatment. The authors concluded that this case suggested that rituximab has the potential to offer an effective agent for the treatment of anti-MDA5-positive RP-ILD of CADM.

Garcia et al (2017) stated that the inflammatory myopathies are a heterogeneous group of muscle diseases and comprise polymyositis, DM, myopathies associated with cancers, necrotizing myositis and inclusion body myositis. DM occasionally exhibits few or no muscular signs: i.e., hypomyopathic/amyopathic DM. Anti-MDA5 DM is a rare form of dermatomyositis that is frequently amyopathic; the prognosis is linked mainly to pulmonary involvement. These researchers reported the case of a 69-year old woman who was treated for mucosa-associated lymphoid tissue (MALT) gastric lymphoma and was referred for a bullous eruption. Based on the investigations performed, a diagnosis was made of bullous pemphigoid. At the same time, ADM was discovered together with ILD. Systemic steroids were introduced in combination with rituximab. A favorable outcome was achieved. The authors concluded that anti-MDA5 dermatomyositis must be considered systematically in all cases of pulmonary involvement associated with cutaneous signs of DM, in which no muscular involvement is generally seen. This condition accounts for up to 7 % of DM and carried a severe prognosis due to pulmonary involvement.

Anti-Neutrophil Cytoplasmic Antibody-Associated (ANCA-associated) Vasculitides

Two randomized, controlled clinical trials found rituximab to be non-inferior to cyclophosphamide-containing regimens in the induction of remission in persons with ANCA-associated vasculitis. In the RAVE trial (Stone et al, 2010), investigators compared intravenous rituximab and oral cyclophosphamide in 197 patients. The investigators found rituximab to be non-inferior to cyclophosphamide, with 64 % in the rituximab group reaching the primary end point of remission without need for prednisone at 6-month follow-up, compared with 53 % of the cyclophosphamide group. In the 101 patients with relapsing disease, rituximab was significantly more effective.

The European Vasculitis Study group (Jones et al, 2010) compared 4 weeks of intravenous rituximab plus 2 doses of cyclophosphamide to intravenous cyclophosphamide followed by azathioprine in patients with ANCA-associated renal vasculitis. Of 44 patients, 76 % of rituximab recipients and 82 % of cyclophosphamide recipients experienced the primary end point of sustained remission at 12 months. Rates of adverse effects were similar in both groups; 18 % of patients in each group died.

These findings are consistent with an earlier case series report (Eriksson et al, 2005), which reported the results of rituximab treatment 2 women with refractory myeloperoxidase-ANCA-positive microscopic polyangiitis and 7 patients (5 men and 2 women) with refractory proteinase 3-ANCA-positive Wegener's granulomatosis. All patients were resistant to conventional therapy or had relapsed repeatedly after cessation of cyclophosphamide (Cyc). The cases were treated with intravenous infusions of rituximab once a week 2 times (3 cases) or 4 times (6 cases). To prevent formation of antibodies to rituximab, mycophenolate mofetil (5 patients), azathioprine (1 patient), or a short course of Cyc (2 patients) were added or allowed to continue. Main outcome measures were remission at 6 months assessed with Birmingham vasculitis activity score. The cases were followed 6 to 24 months and relapse rate was also noted. Eight of 9 patients responded completely and 1 case responded partially. Pulmonary X-ray improved (4 cases), progress of lower extremity gangrene stopped (1 case), remission of neuropathy was stable (1 patient), renal vasculitis went into remission (2 cases), and severe musculoskeletal pain improved (1 case). Minor relapse in the nose occurred in 2 cases. No adverse events or major infections were noted.

Guillevin et al (2014) stated that the combination of cyclophosphamide and glucocorticoids leads to remission in most patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission. Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end-point at month 28 was the rate of major relapse (the re-appearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score greater than 0, and involvement of 1 or more major organs, disease-related life-threatening events, or both). The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29 %) and in 3 patients in the rituximab group (5 %) (hazard ratio [HR] for relapse, 6.61; 95 % confidence interval [CI]: 1.56 to 27.96; p = 0.002). The frequencies of severe adverse events (AEs) were similar in the 2 groups; 25 patients in each group (p = 0.92) had severe AEs; there were 44 events in the azathioprine group and 45 in the rituximab group; 8 patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group; 2 patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer). The authors concluded that more patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine.

Zand et al (2014) stated that ANCA-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. The authors concluded that there is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. The BSR and BHPR guideline for “The management of adults with ANCA-associated vasculitis” (Ntatsaki et al, 2014) stated that “Rituximab is as effective as cyclophosphamide for remission induction of previously untreated patients and is preferable when cyclophosphamide avoidance is desirable, such as in young people at risk of infertility and those at high risk of infection (B)”.

According to the European League Against Rheumatism (EULAR)/ERA-EDTA recommendations for the management of ANCA-associated vasculitis (Yates et al, 2016) -- more specific items related to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary hemorrhage.

Taha et al (2017) stated that rituximab (RTX) is established for the treatment of rheumatoid arthritis. This systematic review of the literature since 2006 summarized evidence for the use of RTX in the treatment of additional rheumatologic diseases: ANCA-vasculitis (AAV), hepatitis C virus-related cryoglobulinemic vasculitis, Henoch-Schonlein purpura, ankylosing spondylitis, and Raynaud's phenomenon. Data from randomized controlled trials (RCTs) are available only for AAV, confirming efficacy for remission induction, including in disease resistant to conventional treatment, and maintenance of remission. Further studies are required to confirm optimal maintenance regimens in AAV, important questions needing to be addressed including protocol administration versus treatment in response to clinical relapse and the importance of maintaining B-cell depletion. Sufficient data are available in other diseases to suggest RTX to be useful and that randomized controlled trials should be conducted.

Ayan et al (2018) noted that RTX is becoming a standard treatment for patients with AAV; but heterogeneity exists regarding its use. These investigators presented their uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. They retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, 4 unclassified) treated with RTX (median 2, IQR 1 to 3 courses; median follow-up 24, IQR 17 to 50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72 % at month 6 and 88 % at month 12. Two patients had died and 3 serious adverse events (SAEs) occurred. The systematic review included 56 studies on 1,422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported greater than 80 % complete or partial remission rates with the lowest response (37.5 %) for granulomatous lesions. The relapse rate was 30 %. Infections and infusion reactions were the main AEs. The authors concluded that their experience with RTX in refractory AAV was in line with the literature in terms of safety and efficacy.

On behalf of the French Vasculitis Study Group, Terrier et al (2018) compared long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing ANCA-associated vasculitides. The 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary end-point was the major-relapse rate at month 60. Relapse and SAE-free survival were also assessed. Among the 115 enrolled patients, only 1 was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4 % (95 % CI: 38.0 % to 64.3 %) and 71.9 % (95 % CI: 61.2 % to 84.6 %) (p = 0.003); minor and major relapse-free survival rates were 37.2 % (95 % CI: 26.5 % to 52.2 %) and 57.9 % (95 % CI: 46.4 % to 72.2 %) (p = 0.012); overall survival rates were 93.0 % (95 % CI: 86.7 % to 99.9 %) and 100 % (p = 0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p < 0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse; HRs of positive ANCA to predict relapse increased over time. The authors concluded that the rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival.

Ankylosing Spondylitis and Axial Spondyloarthritis

In a review on “Ankylosing spondylitis and axial spondyloarthritis”, Taurog and colleagues (2016) stated that “It is unclear at present whether there may be a role for the anti-CD20 monoclonal antibody rituximab”.

Furthermore, an UpToDate review on “Assessment and treatment of ankylosing spondylitis in adults” (Yu, 2018) stated that “Rituximab, a monoclonal antibody that depletes B cells, has undergone preliminary study in 20 patients with active AS, based in part upon previous findings of dense B cell infiltration in subchondral bone of inflamed sacroiliac joints of patients with AS. Significant efficacy at week 24 following initial intravenous administration of rituximab was observed in patients who were naive to TNF inhibitor therapy, but not in those who had already failed to respond to a TNF inhibitor (ASAS20 response 50 versus 30 %, BASDAI50 response 50 versus 0 %). Further study, including randomized trials, will be required to determine whether there is a role for rituximab in the treatment of AS”.

Anterior Nodular Scleritis

Rogue (2017) stated that the initial therapy for diffuse scleritis or nodular scleritis consists of an NSAID; in case of therapeutic failure, 2 additional successive different NSAIDs should be tried following the first drug. In high-risk patients, consider appropriate gastro-intestinal (GI) protection with misoprostol or omeprazole. If NSAIDs are not effective or have untoward complications, oral corticosteroids can be substituted. Remission may be maintained with continued NSAIDs. Periorbital and subconjunctival steroid injections have been reported to be efficacious as adjunctive therapy. Caution should be observed, particularly when a co-morbid infectious etiology such as toxoplasmosis or syphilis cannot be completely ruled out. In case of therapeutic failure of systemic corticosteroids, immunosuppressive drugs should be added or substituted. Methotrexate (MTX) can be the 1st choice, but azathioprine, mycophenolate mofetil, cyclophosphamide, or cyclosporine may also be helpful. Cyclophosphamide should be the 1st choice in treating patients with associated potentially lethal vasculitic diseases, such as granulomatosis with polyangiitis or polyarteritis nodosa. In case of therapeutic failure, biologic response modifiers, such as infliximab or adalimumab, may be effective. Other alternatives include golimumab, certolizumab, tocilizumab, and rituximab, although further investigation is needed.

Antibody Mediated Rejection

Current guidelines (Costanzo et al, 2010) recommend the use of rituximab for antibody mediated rejection in heart transplant recipients, with steroids, plasmapheresis and/or IVIG, to reduce the risk of recurrent rejection. Initial therapy of antibody-mediated rejection can include immunoadsorption and corticosteroid or plasmapheresis/low dose of IVIG and corticosteroid. The guidelines state that rituximab can be added to reduce the risk of recurrent rejection. Changes in therapy, which can be considered for maintenance immunosuppression in patients who experience antibody mediated rejection, can include switch to tacrolimus in patients receiving cyclosporine-based immunosuppression, increased doses of mycophenolate mofetil, and corticosteroids.

Macklin et al (2017) conducted a systematic reviewto evaluate the evidence for use of rituximab in the treatment of acute and chronic antibody-mediated renal transplant rejection (AAMR; CAMR). A systematic search of four databases and three trial registries was conducted. The small number and heterogeneous nature of included studies precluded meta-analysis and thus a narrative review was conducted. A total of 28 records met the inclusion criteria (AAMR, 18 records relating to 9 studies; CAMR, 10 records relating to 7 studies). Two systematic reviews were identified that had differing inclusion criteria to this current review. Of seven primary studies in the setting of AAMR, four reported increased graft survival and one reported improved graft function with rituximab. This contrasts with CAMR in which only one of seven studies reported improved graft outcomes with a rituximab-based regimen; three studies reported inferior outcomes and three reported no difference. Only one study reported that rituximab was associated with an increase in adverse effects. The included studies suggest that rituximab may be of some benefit in the setting of AAMR but a lack of high quality evidence precludes firm conclusions from being drawn. Rituximab does not appear to reliably improve outcomes in CAMR. Further well-conducted studies are required to better define the effects and long-term safety profile of rituximab in the treatment of antibody-mediated renal transplant rejection.

Hychko et al (2011) conducted a systematic review and meta-analysis of studies of rituximab in AMR of renal allografts. Combining two comprehensive search themes (AMR and rituximab), the authors searched electronic databases from 1969 through 2010, supplemented by a manual review of abstracts from nephrology and transplant meetings, and reference lists of review articles. All studies evaluating explicit response of patients with AMR to rituximab were included. The outcome was pooled odds ratio (OR) of response to rituximab. A total of 114 studies were identified, 94 of which were excluded on initial screening. Analysis of the 10 studies (249 patients) showed an OR of 3.16 (95% CI: 1.75-5.70) for response to rituximab. Reported adverse effects included BK virus nephropathy, cytomegalovirus (CMV) viremia, pneumonia, herpes zoster, and septic shock. The authors concluded that this reviewsuggests that rituximab is a reasonable therapeutic option in the treatment of AMR. Further randomized studies are necessary to establish its efficacy and safety.

Anti-MAG Neuropathy

On behalf of the Rituximab versus Placebo in Polyneuropathy Associated with Anti-MAG IgM Monoclonal Gammopathy (RIMAG) Study Group (France and Switzerland), Leger et al (2013) examined if rituximab (375 mg/m2) was effective in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). A total of 54 patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) greater than or equal to 4 and visual analog pain scale greater than 4 or ataxia score greater than or equal to 2. The primary outcome was mean change in ISS at 12 months; 26 patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 sub-scores of the Short Form-36 questionnaire. The authors concluded that although primary outcome measures provided no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. This study provided Class I evidence that rituximab was ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.

Iancu Ferfoglia et al (2016) noted that the RIMAG Trial showed no improvement using the ISS as primary outcome in patients with IgM anti-MAG neuropathy treated with rituximab, when compared with placebo. However, some secondary outcomes appeared to improve in the per protocol analysis. Patients from 1 participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (IQR 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in 7rituximab-treated patients (group 1) and in 8 placebo-treated patients (group 2). In group 2, 6 of 8 patients received immunotherapy during follow-up, while only 2 of 7 did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The authors concluded that the RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. These investigators stated that this study emphasized the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy.

In a Cochrane review, Lunn and Nobile-Orazio (2016) examined the effects of immunotherapy for IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy. The authors concluded that there was inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinemic neuropathy to form an evidence base supporting any particular immunotherapy treatment; IVIG has a statistically but probably not clinically significant benefit in the short-term. The meta-analysis of 2 trials of rituximab provided, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis awaited confirmation, as 1 of the 2 included studies was of very low quality. These investigators stated that large, well-designed randomized trials of at least 12 months' duration are needed to evaluate existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.

Anti-Synthetase Syndrome

Witt and colleagues (2016) stated that anti-synthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include arthritis, interstitial lung disease (ILD), myositis, and Raynaud's phenomenon. There is a higher prevalence and increased severity of ILD in patients with anti-synthetase syndrome, as compared to dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. Diagnosis is made by a multi-disciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with anti-synthetase syndrome often require multi-modality immunosuppressive therapy to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, as well as disease-related sequelae that can include pulmonary hypertension, progressive ILD necessitating lung transplantation, malignancy and decreased survival. The authors concluded that it is hoped that greater awareness of the clinical features of this syndrome will allow for earlier diagnosis and appropriate treatment to improve outcomes in patients with anti-synthetase syndrome.

The NIH’s Genetics and Rare Diseases Information Center’s webpage on “Antisynthetase syndrome” (GARD, 2017) stated that anti-synthetase syndrome is a chronic autoimmune disorder afflicting the muscles and various parts of the body. The signs and symptoms can vary but may include ILD, myositis, polyarthritis, thickening and cracking of the hands, and Raynaud phenomenon. The exact underlying cause is unknown; however, the production of auto-antibodies that attack certain enzymes in the body called “aminoacyl-tRNA synthetases” appeared to be linked to the cause of the syndrome. These auto-antibodies may arise after viral infections, or patients may have a genetic predisposition. Treatment is based on the signs and symptoms present in each person; and may include corticosteroids, immunosuppressive medications, and/or physical therapy.

Furthermore, an UpToDate review on “Interstitial lung disease in dermatomyositis and polymyositis: Treatment” (Dellaripa and Miller, 2018) stated that “When the ILD is refractory to glucocorticoids plus another immunosuppressive agent, rituximab can be substituted for the immunosuppressive agent or a third agent can be added. If the disease remains refractory after rituximab or combination therapy, the opposite therapy can be substituted”.

Aplastic Anemia

A review on “Clinical management of aplastic anemia” (DeZern and Brodsky, 2011) did not mention rituximab as a therapeutic option.

A Medscape review on “Aplastic Anemia Treatment & Management” (Bakhshi, 2015) did not mention rituximab as a therapeutic option.

Liu et al (2015) evaluated the safety and effectiveness of rituximab in treatment of immune platelet transfusion refractoriness (PR). These investigators retrospective analyzed 7 patients (5 aplastic anemia, 2 myelodysplastic syndrome) with immune PR who received at least 3 weekly infusions of rituximab (375 mg/m(2)). All enrolled patients acquired improvement of platelets transfusion more than 2 months (CCI greater than or equal to 4.5 × 10(9)/L). These researchers first found that there were 2 patterns of response to rituximab treatment in patients with immune PR, which the early but transient after the first rituximab administration and the late but continuous beginning to appear at 3 weeks from the start of treatment. The authors concluded that rituximab is a promising treatment in patients with immune PR and giving the opportunity and time for cure the disease.

Furthermore, an UpToDate review on “Treatment of aplastic anemia in adults” (Schrier, 2016) does not mention rituximab as a therapeutic option.

Autoimmune Blistering Dermatoses

Rituximab has been increasingly used in autoimmune blistering dermatoses, mainly in pemphigus. Joly et al (2007) found that a single cycle of rituximab is an effective treatment for pemphigus vulgaris of pemphigus foliaceus. The investigators studied 21 patients with pemphigus vulgaris or pemphigus foliaceus whose disease had not responded to an 8-week course of 1.5 mg of prednisone per kilogram of body weight per day (corticosteroid-refractory disease), who had had at least 2 relapses despite doses of prednisone higher than 20 mg per day (corticosteroid-dependent disease), or who had severe contraindications to corticosteroids. Patients were treated with 4 weekly infusions of 375 mg of rituximab per square meter of body-surface area. Eighteen of 21 patients had a complete remission at 3 months after the end of treatment. In 8 of the 18 patients, this remission was maintained without corticosteroid or immunosuppressive therapy after a median follow-up of almost 3 years. One patient developed pyelonephritis and another died of septicemia. The investigators concluded that a single cycle of rituximab is an effective treatment for pemphigus (Joly et al, 2007). The investigators warned that, because of its potentially severe side effects, its use should be limited to the most severe types of the disease. An editorialist noted that this study demonstrated the value of a multi-center approach to accomplish relevant clinical research in orphan diseases such as pemphigus (Diaz, 2007).

Kasperkiewicz et al (2011) concluded that adjuvant rituximab is effective and well- tolerated not only in patients with pemphigus but also with pemphigoid. A total of 17 patients with refractory autoimmune blistering dermatoses (pemphigus vulgaris, n = 8; pemphigus foliaceus, n = 2; bullous pemphigoid, n = 2; mucous membrane pemphigoid, n = 5) were treated 4 times with rituximab at weekly or bi-weekly intervals. Six of 8 patients with a relapse after this regimen received rituximab again twice in a 2-week interval. The investigators reported that all lesions cleared in 14 patients (7 pemphigus vulgaris, 2 pemphigus foliaceus, 2 bullous pemphigoid, 3 mucous membrane pemphigoid), whereas partial healing was found in 3 others (1 pemphigus vulgaris, 2 mucous membrane pemphigoid). Relapses occurred in 8 patients (5 pemphigus vulgaris, 2 pemphigus foliaceus, 1 bullous pemphigoid). Re-treatment with rituximab again resulted in complete (2 pemphigus vulgaris, 1 pemphigus foliaceus, 1 bullous pemphigoid) or partial (2 pemphigus vulgaris) remission.

Peterson and Chan (2009) performed a survey of 71 consecutive patients with autoimmune blistering diseases treated with rituximab from initial use up to 2007, using the PubMed database. The authors stated that a heterogeneous group of patients, including 51 patients with pemphigus vulgaris, 1 with pemphigus vegetans, 9 with pemphigus foliaceus, 5 with paraneoplastic pemphigus, 4 with epidermolysis bullosa acquisita, and 1 with both bullous pemphigoid and graft-versus-host disease was included in this survey. The authors reported that, overall, the monoclonal antibody seems to be effective in that 69 % of patients showed complete response, 25 % of patients showed partial response, whereas 6 % of patients showed progressive disease. Six deaths occurred in association with the treatment, with 4 of these deaths in patients with paraneoplastic pemphigus, a disease characteristically resistant to conventional medication and with a high mortality rate.

Autoimmune Epilepsy

Dubey et al (2014) evaluated the outcome of multi-modality treatment in autoimmune limbic epilepsy in 3 consecutive patients (2 male and 1 female; age of 33 to 55 years) presenting with a combination of focal non-convulsive status epilepticus, memory impairment, and psychosis. MRI showed right or bi-temporal T2 or FLAIR hyper-intensity. Video-EEG showed seizures of right temporo-occipital or bi-temporal independent onset. Extensive work-up failed to reveal infectious etiology or an underlying tumor. However, the autoantibody panel was positive for 1 or more of these antibodies: anti-VGKC, anti-GABAB, anti-VGCC (P/Q, N types), and anti-GAD65. All patients received:

conventional anti-epileptic drugs (AEDs) including levetiracetam, lacosamide, phenobarbital, lamotrigine, and valproate;
immunomodulatory therapy including methylprednisolone, plasmapheresis, and intravenous immunoglobulin (IVIG); and
rituximab. After a 4- to 6-week in-hospital course, the seizures resolved in all patients; but 2 had persistent memory impairment.

Autoimmune Hepatitis

Barth and Clawson (2010) stated that autoimmune hepatitis (AIH) is a form of chronic hepatitis of unknown etiology. It was first described in the 1950s as a form of chronic hepatitis noted in younger women. It was later termed lupoid hepatitis due to its association with autoantibodies before being named AIH in 1965. Corticosteroids and azathioprine have been the standard therapy for AIH, but due to treatment failures and toxicities from these medications, new medications are being examined as possible therapeutic options. Rituximab has been used in various autoimmune disorders with good success. These investigators reported the case of a 34-year old woman with a history of B cell lymphoma and concurrent AIH treated with rituximab. The diagnosis of AIH was made by classic serological and histological features. The patient was initially treated with steroids but had a progression of her disease as well as suffering toxicities from the steroids. She was then given 8 weeks of rituximab with good improvement in both laboratory and histological findings. The authors concluded that more studies are needed to further elicit the role of rituximab in AIH.

In an open-label, single-center, pilot study, Burak et al (2013) examined the safety and efficacy of rituximab in patients with refractory AIH. A total of 6 patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received 2 infusions of rituximab 1,000 mg 2 weeks apart and were followed for 72 weeks. Rituximab was well-tolerated with no serious AEs. By week 24, mean (± SD) aspartate amino-transferase (AST) levels had significantly improved (90.0 ± 23.3 U⁄L versus 31.3 ± 4.2 U⁄L; p = 0.03) and mean immunoglobulin G levels had fallen (16.4 ± 2.0 g⁄L versus 11.5 ± 1.1 g⁄L; p = 0.056). The prednisone dose was weaned in 3 of 4 subjects, with 1 subject flaring after steroid withdrawal. Inflammation grade improved in all 4 subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n = 5), although interferon-gamma-induced protein 10 levels improved in 3 of 5 subjects. The authors concluded that rituximab was safe, well-tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results supported further investigation of rituximab as a treatment for AIH.

The authors stated that this study was limited by its small sample size (n = 6) and open-label design. Unfortunately, complete data were not available for all patients to carefully examine the pharmacokinetics of rituximab in this population of patients with chronic liver disease. The steroid-sparing effects demonstrated must be viewed with caution because these investigators did not have a standardized protocol for tapering prednisone once patients entered remission. Similarly, the impact of rituximab on liver histology remained uncertain due to lack of paired biopsies in all patients. Despite these limitations, these researchers believed that these preliminary observations supported the further investigation of rituximab as a potential therapy in AIH. Specifically, rituximab appeared to be a safe and effective 2nd-line therapy for AIH patients who experience treatment failure following prednisone and azathioprine (AZA).

Gautam et al (2014) evaluated the safety and efficacy of rituximab in the treatment of refractory AIH. A retrospective case note review of well-defined and biopsy proven type-1 AIH (simplified scoring greater than 6). A total of 5 patients out of 200 who were intolerant/refractory to standard therapy were given rituximab and the responses were followed-up for 72 weeks. Efficacy was measured by biochemical and immunological parameters (bilirubin, AST, ALT and immunoglobulin) every 12 weeks. The dose of prednisolone as well as UKELD/MELD score pre- and post-treatment was also evaluated. All 5 patients were women and mean age was 45 years (range of 35 to 66). The rituximab dose used was 1,000 mg and the total number of doses received varied between 2 and 4 (mean of 3.2); 3 patients had other concomitant autoimmune conditions (endocrine, rheumatologic and renal related autoimmune diseases). The mean dose of prednisolone used pre-rituximab was 19 mg (± SD 12.57) and this was reduced to 12.5 mg (± SD 5.0) post-treatment (statistically not significant = NS). There was a slight improvement of IgG pre- and post-rituximab treatment (NS), with no improvement in UKELD score. There was an improvement in biochemical profile but this was not statistically significant throughout the observation period. All 5 patients were alive and rituximab was well-tolerated without any serious AEs. The authors concluded that rituximab was well-tolerated and safe to use in resistant AIH. It could cause some biochemical and immunological improvement. Moreover, these researchers stated that current evidence for its use in AIH patients is not well proven. The study numbers were too small (n = 5) to detect the actual outcome of the therapy. They stated that a prospective, larger cohort, multi-center study with longitudinal immunological, biochemical and histological profile assessment is needed to examine its efficacy in resistant AIH patients.

Terziroli Beretta-Piccoli et al (2017) noted that AIH is a rare chronic inflammatory liver disease, affecting all ages, characterized by elevated transaminase and immunoglobulin G levels, positive auto-antibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. These investigators summarized the evidence for standard treatment and provided a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and AZA, and led to disease remission in 80 % to 90 % of patients. Alternative 1st-line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated; 2nd-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials (RCTs) have been performed for 2nd-line options. Mycophenolate mofetil is the most widely used 2nd-line drug, and has good efficacy particularly for patients intolerant to AZA, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumor necrosis factor (TNF)-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centers. These researchers noted that clinical trials with new therapeutic options are ongoing.

Autoimmune Limbic Encephalitis

Lee and colleagues (2016) examined the safety and effectiveness of rituximab treatment as a 2nd-line immunotherapy treatment for autoimmune limbic encephalitis (ALE) and determined factors associated with functional improvement and favorable outcome following rituximab treatment. These investigators recruited 80 patients with ALE who were treated with rituximab as a 2nd-line immunotherapy from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry and reviewed 81 patients without rituximab as a control. They grouped patients according to the detection or type of antibodies; in addition, these researchers evaluated clinical, laboratory, 1st-line immunotherapy, and rituximab treatment profiles and defined main outcomes as improvements on the modified Rankin Scale (mRS) score and a favorable mRS score (0 to 2) at the last follow-up. Functional improvement occurred more frequently in the rituximab group compared to the control group. In the rituximab group, 30 (37.5 %) patients had synaptic autoantibodies, 15 (18.8 %) in the paraneoplastic autoantibodies, and 35 (43.8 %) were antibody-negative. The effect of rituximab was the same regardless of autoantibody status. Additional monthly rituximab therapy and partial response to 1st-line immunotherapies were associated with mRS score improvements, as well as favorable mRS scores; mRS scores of 4 to 6 as the worst neurologic status predicted an unfavorable mRS score. There were no reported serious infusion-related or infectious AEs of rituximab. The authors concluded that rituximab is safe and effective as a 2nd-line immunotherapy for ALE, regardless of autoantibody status. Moreover, they stated that additional monthly rituximab therapy might potentiate the efficacy of rituximab. This study provides Class IV evidence that rituximab improves mRS scores for patients with ALE who fail 1st-line therapy. The main drawbacks of this study were: (i) the lack of standardized treatment and follow-up protocols, and (ii) the absence of follow-up of serum immunoglobulin levels or autoantibody titers, which might have been a good indicator of response to rituximab. They stated that prospective controlled studies are needed to establish the effectiveness of rituximab as a 1st-line immunotherapy.

In an editorial that accompanied the afore-mentioned study, Vollmer and McCarthy (2016) stated that “The study is a retrospective study …. Clearly, more controlled studies are necessary to identify optimal treatment of the various forms of ALE”.

Hallowell et al (2017) stated that anti-N-methyl d-aspartate receptor (anti-NMDAR) encephalitis is a devastating disease that is increasingly being identified in both children and adults with psychosis, language disturbances, behavioral changes, and motor deficits. Currently no consensus guidelines exist for the optimal management of patients with this disease, although intravenous immune globulin (IVIG) therapy is often considered 1st-line pharmacotherapy. These researchers presented a case of an otherwise healthy 4-year old child who presented with seizures, loss of age-appropriate language skills, and behavioral changes, in whom anti-NMDAR was subsequently diagnosed. After marked intolerance to corticosteroid therapy and inadequate clinical response to IVIG, immunotherapy with rituximab was initiated. The patient had rapid return of language skills and complete resolution of dyskinesia after a single rituximab infusion, with no residual deficits at her 6-month follow-up visit. Early intervention in patients with anti-NMDAR encephalitis is of paramount importance for successful outcomes and baseline recovery. Only approximately 50 % of patients respond to 1st-line immunotherapy, necessitating further evaluation of alternative therapies and the development of a treatment algorithm for practitioners. The authors concluded that this case report built upon previous findings illustrating rapid symptom resolution after rituximab infusion and added to the available body of evidence for management of pediatric patients with anti-NMDAR. Moreover, they stated that further research is needed to elucidate the potential benefits of using rituximab sooner in the treatment course to improve symptom resolution and return to baseline in patients with anti-NMDAR encephalitis.

Autoimmune Myopathy Associated with Anti-Signal Recognition Particle Antibodies

Valiyil et al (2010) noted that the myopathy associated with anti-signal recognition particle (anti-SRP) is a severe necrotizing immune-mediated disease characterized by rapidly progressive proximal muscle weakness, markedly elevated serum creatine kinase (CK) levels, and poor responsiveness to traditional immunosuppressive therapies. Reports on the efficacy of B cell depletion therapy for anti-SRP-associated myopathy are mixed. In a case-series study, these researchers described 8 patients with anti-SRP-associated myopathy and their response to treatment with the anti-CD20 monoclonal antibody rituximab. These investigators identified 8 patients with myopathy who tested positive for anti-SRP antibodies by immunoprecipitation and were treated with rituximab as part of clinical care. They reviewed their medical records to assess clinical, serologic, and histologic characteristics and response to therapy. In 5 patients, serum was collected before and after rituximab therapy. Autoantibodies were detected by immunoprecipitation and quantitated by densitometry, and the percent decreases in anti-SRP autoantibody levels were calculated; 6 of 8 patients who had been refractory to standard immunosuppressive therapy demonstrated improved manual muscle strength and/or decline in CK levels as early as 2 months after rituximab treatment; 3 patients sustained the response for 12 to 18 months after initial dosing. All of the patients were continued on adjunctive corticosteroids, but doses were substantially reduced after rituximab. Quantitative levels of serum anti-SRP antibodies also decreased after rituximab treatment. The authors concluded that B cell depletion therapy with rituximab was effective for patients with myopathy associated with anti-SRP. The substantial decrease in anti-SRP antibody levels after rituximab treatment also suggested that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy. Moreover, they stated that further studies are needed to elucidate the underlying disease pathogenesis and the precise role of anti-SRP antibodies in this unique subset of myopathies.

Fasano et al (2017) noted that several uncontrolled studies have encouraged the use of rituximab (RTX) in patients with myositis. Unfortunately, the first placebo-phase trial to assess the efficacy of RTX in refractory myositis did not show a significant difference between the 2 treatment groups, and doubts have been expressed about its study design. In this review, these investigators presented an up-to-date overview of the reported experiences of RTX therapy in myositis. A PubMed search was performed to find all the available cases of refractory myositis patients treated with RTX up to July 2015. The following terms were assessed: inflammatory myopathies, or anti-synthetase syndrome, or polymyositis, or dermatomyositis and RTX. A total of 48 studies were included. These researchers identified 458 patients with myositis treated with RTX. Dermatomyositis (DM) was the most frequent disease reported [151 cases (32.9 %)]. The response to RTX in refractory polymyositis (PM) has been analyzed in 144 patients (31.4 %), including 19 subjects with anti-signal recognition particle antibody positivity. In addition, RTX was administered to 79 patients with anti-synthetase syndrome (ASS) (17.2 %) and to 72 patients with juvenile DM (15.7 %); 1 patient each was affected with Inclusion-body myositis (IBM) and undifferentiated inflammatory myositis (UI). In 10 cases, the idiopathic inflammatory myopathies (IIM) subtype was not specified. The authors found a rate of response to RTX of 78.3 %; RTX could play a role in the management of patients with myositis, at least in those with positive myositis-specific autoantibodies. Moreover, they stated that the lack of validated criteria for evaluating clinical response and the concomitant use of immunosuppressive drugs limit their ability to determine the specific role of B cell–depletion therapy. They stated that further studies of RTX in myositis are needed, particularly in treatment-naive patients.

Autoimmune Retinopathy

Maleki et al (2017) examined the efficacy of rituximab as a monotherapy or in combination therapy for the treatment of patients with non-paraneoplastic autoimmune retinopathy (AIR). A total of 12 eyes of 6 patients with non-paraneoplastic AIR who were treated with rituximab and had at least 6 months of follow-up were included. Demographic data, clinical data, visual field (VF) parameters, electroretinography (ERG) parameters, and anti-retinal and anti-optic nerve autoantibody bands were collected from the Massachusetts Eye Research and Surgery Institution database between September 2010 and January 2015. Changes in visual acuity (VA), VF parameters, ERG parameters, and anti-retinal and anti-optic nerve autoantibody bands from the initial visit to the most recent visit were examined. From the initial visit to the last visit, VA was stable in 8 (66.7 %) eyes; VF was stable in 6 (50 %) eyes and improved in 2 (16.7 %) eyes; ERG was stable or improved in 8 (66.7 %) eyes. The average number of anti-retinal and anti-optic nerve antibody bands was reduced. The authors concluded that stabilization and/or improvement of VA, VF parameters, and ERG parameters were observed in a high number of patients (75 %) on rituximab, as a monotherapy (1 patient) or in combination therapy. Moreover, they stated that a prospective multi-center study with a large population and longer follow-up is needed standardize the use of VF, ERG parameters, and evaluation of anti-retinal and anti-optic nerve antibody bands and titers so that criteria can be established for a proper response to treatment with rituximab, alone or in combination therapy.

The authors stated that this study was limited by its retrospective nature and small sample size (n = 6 patients). Not having optical coherence tomography (OCT) data for all patients was another limitation of this trial. These researchers were also dependent on a commercially available laboratory for anti-retina and anti-optic nerve antibodies, and they did not include the antibodies’ titers in their reports. Moreover, the patient population in their tertiary referral center was skewed toward patients with very severe intra-ocular disease. Thus, it was difficult to predict from these data, the outcomes of treatment in patients with a milder disease course. Notwithstanding these limitations, this article described the only cohort to-date of patients with non-paraneoplastic AIR who were treated with rituximab as a monotherapy or in combination with cyclophosphamide and/or bortezomib with a comprehensive analysis of the static VF, ERG, and anti-retinal and anti-optic nerve antibodies.

In a retrospective, interventional, case-series studies, Davoudi et al (2017) evaluated clinical and ancillary testing, including adaptive optics, outcomes in AIR patients (n = 16) treated with rituximab. All patients were treated with a loading and maintenance dose schedule of intravenous rituximab; VA, ERG, and spectral-domain OCT (SDOCT) and VF results were recorded. A subset of patients was also imaged using adaptive optics scanning laser ophthalmoscopy (AO-SLO). Main outcome measures were rates of VA change before versus after rituximab initiation were compared with mixed-model linear regression. The rate of visual decline was significantly less after rituximab initiation compared with the rate of visual decline prior to rituximab initiation (p = 0.005); 77 % of eyes had stable or improved VA 6 months after rituximab initiation. Amplitudes and implicit times on ERG, mean deviation on VF, central subfield mean thickness, and total macular volume did not decrease to a significant degree over the rituximab treatment period; 6 eyes had serial AO-SLO imaging. Cone densities did not change significantly over the treatment period. The authors concluded that VA was stable or improved in a majority of AIR patients while they were being treated with rituximab; OCT and ERG parameters, as well as AO-SLO cone densities, were stable during treatment. Moreover, they stated that studies with additional patients and longer follow-up periods are needed to further explore the utility of rituximab in the management of AIR.

Boudreault et al (2017) stated that AIR is a rare but potentially blinding condition that is often under-diagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies (ARA). AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. These researchers evaluated the effects of rituximab infusions on ERG responses and visual function outcomes in patients with non-paraneoplastic AIR (npAIR). Following infusion(s), 3 out of 5 patients showed no evidence of disease progression or improved, while 2 patients continued to progress on ERG; 1 patient demonstrated improvement in VA (2 lines) in both eyes; ERG responses provided objective monitoring of patients' visual function and response to immunosuppression over time. The authors concluded that these findings suggested that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in this case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients' progression during treatment. The recommended interval for ARA testing following rituximab administration, as well as the use of this measure to drive decision-making in isolation from other tests, remains an important consideration for future studies. They also noted that in future studies, it would be valuable to examine if earlier administration after diagnosis may enable greater improvements in patient outcomes.

The authors stated that this study had several drawbacks. While 1 of the patients was under 10 years of age and 1 older than 60, the typical npAIR diagnosis is made between the ages of 20 and 25 years of age. Also, the regiment of rituximab was not standardized across patients. Some patients followed the rituximab protocol that was developed for B-cell lymphoma, while some were prescribed a regiment that was originally designed for rheumatoid arthritis patients, and yet others used non-standard protocols. Additional experience with other patients with autoimmune disorders and retinal atrophies may guide dosing of rituximab in the future. Additionally, the time-point of assessment and ARA testing following rituximab infusions were also different for each patient, and the optimal follow-up time after infusion cannot be determined from these data. Testing blood before and at varying intervals after each rituximab infusion is one strategy that could determine the ideal timing for ARA testing in future studies, which in turn may enable better delineation of the drug’s effects on ARAs. Finally, ratio analysis for ERG was used in this series in order to obtain an efficient comparison strategy of responses at different points for each patient, although actual voltage numbers could also have been used.

Chronic Urticaria

Steinweg and Gaspari (2015) noted that rituximab is a chimeric murine/human monoclonal antibody directed against CD20, traditionally used to treat non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA) in combination with methotrexate, granulomatosis with polyangiitis, and microscopic polyangiitis. Rituximab depletes memory B-lymphocytes that are necessary for autoantibody production, which is the proposed mechanism by which it may alleviate the symptoms of chronic urticaria (CU). There are few case reports published demonstrating the successful use of rituximab in patients with CU. These investigators described 3 cases of recalcitrant CU that attained benefits following the use of rituximab. Moreover, the authors stated that no randomized, blinded trials have been conducted to support the use of rituximab in CU, though a small number of case reports reveal remission of recalcitrant CU following the use of rituximab. They stated that further studies are needed to determine the exact efficacy and optimal dosing of rituximab in the treatment of CU.

Combalia et al (2018) stated that chronic spontaneous urticaria (CSU) is a frequent mast cell-driven disease that affects approximately 0.5 to 1 % of the population. Anti-histamines are currently the drugs of choice in patients with CSU. Omalizumab has been shown to be very effective in CSU and has been recently approved as 2nd-line therapy. However, although its introduction has markedly improved the therapeutic possibilities for CSU, there is still a hard core of patients who do not respond and require effective treatment. These investigators reported the case of a patient who achieved an 8-month remission of refractory CSU following the use of rituximab, and performed a review of the literature regarding the use of rituximab in CSU. There was a remarkable improvement in her CSU after the administration of rituximab maintained over time. The authors concluded that rituximab is a chimeric murine/human monoclonal antibody directed against CD20, which depletes memory B-lymphocytes that are necessary for autoantibody production. The abrogation of the autoantibody production is the proposed mechanism by which it may alleviate the symptoms of CSU. Moreover, they stated that these findings are encouraging; there are, however, still no randomized blinded trials. They stated that further studies should be performed to determine the role of rituximab and other B-cell therapeutics in patients with severe CSU.

Furthermore, an UpToDate review on “Chronic urticaria: Treatment of refractory symptoms” (Khan, 2018) does not mention rituximab as a therapeutic option.

Collagenous Gastritis

Le Clech et al (2013) stated that cytomegalovirus (CMV) encephalitis is a rare infection that immuno-deficient patients, mainly where HIV-positive, may suffer from. Several cases were described when complications with the treatment with monoclonal antibodies, like rituximab, for malignant lymphomas. The authors described the case of a patient, who developed CMV gastritis, then CMV encephalitis after the treatment of a CLL with a chemotherapy and maintenance therapy with rituximab.

Tariq et al (2017) noted that follicular B cell lymphomas account for a significant portion of all newly diagnosed non-Hodgkin's lymphomas (NHLs). While involvement can be varied, the most common extra-nodal presentation is within the gastro-intestinal (GI) tract beyond the stomach. In addition, the stomach has a diffuse multi-vessel vascular supply, which decreases the likelihood of developing ischemic gastritis. These researchers reported on the case of an 89-year old woman with history of diabetes, deep venous thromboembolism, and hypertension who was referred due to a newly diagnosed retroperitoneal mass. Biopsy of a left para-aortic node was consistent with low-grade follicular B cell lymphoma. Following mainstream treatment guidelines, rituximab was administered. Approximately 12 hours later, the patient presented to the Emergency Department with intractable vomiting and nausea. After admission, an esophagogastroduodenoscopy (EGD) revealed extensive ischemic gastritis. Due to recurrent ascites requiring frequent paracenteses, and the clinical aggressiveness of the patient's underlying lymphoma, a 2nd dose of rituximab was administered with concurrent initiation of total parenteral nutrition. Approximately 1 week later, the patient underwent a repeat EGD for quality of life planning while in hospice. The repeat EGD revealed resolved ischemic gastritis. Her diet was advanced and she was subsequently discharged home. The authors concluded that rituximab alone showed promise in treating extensive follicular B cell lymphoma complicated by ischemic gastritis, which has not been previously reported in the literature.

Crescentic IgA Nephropathy

The Kidney Disease: Improving Global Outcomes (KDIGO)’s clinical practice guideline on “Glomerulonephritis” (2012) did not mention rituximab as a therapeutic option for crescentic IgA nephropathy.

The Japanese Society for Pediatric Nephrology’s clinical guideline on “IgA Nephropathy” (2015) did not mention rituximab as a therapeutic option.

Furthermore, an UpToDate review on “Treatment and prognosis of IgA nephropathy” (Cattran and Appel, 2016) does not mention rituximab as a therapeutic option.

CREST Syndrome

William et al (2011) reported a case of a 61-year old man with a history of CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) who presented for evaluation of thrombocytopenia. He had evident cervical adenopathy and lymph node biopsy showed small lymphocytic lymphoma (SLL) with evident systemic adenopathy and bone marrow involvement. The patient achieved a complete remission with FCR (fludarabine/cyclophosphamide/rituximab) chemotherapy. About 30 cases of lymphomas were reported in the literature in association with systemic sclerosis. To the authors’ knowledge, there are no reports of a small lymphocytic lymphoma (SLL) in association with limited cutaneous systemic sclerosis with classic features of the CREST syndrome. This was a single-case study and its findings were confounded by the combined use of fludarabine, cyclophosphamide, and rituximab.

Dermatomyositis / Polymyositis

In an open-label uncontrolled pilot study (n = 7), Levine (2005) reported their findings of 7 adult patients with dermatomyositis (DM), 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents. All patients received 4 intravenous infusions of rituximab given at weekly intervals. Patients were followed up for up to 1 year without further treatment with rituximab. One patient was lost to follow-up. The principal effectiveness outcome was muscle strength, measured by quantitative dynomometry. All 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by 36 to 113 %. Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM (e.g., rash, alopecia, and reduced forced vital capacity) improved markedly in patients with these symptoms. Rituximab was well-tolerated, with no treatment-related severe or serious adverse events during the observation period of this study. The authors concluded that the results of this small open-label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM. Furthermore, in a review on "B cell-targeted therapy in diseases other than rheumatoid arthritis", Looney (2005) stated that "depletion of B cells during rituximab therapy was associated with improvement in global disease activity …. further controlled studies are warranted to optimize rituximab as monotherapy and to develop combination therapies in patients with refractory autoimmune diseases".

In an open-label study, Mok and colleagues (2007) reported the effectiveness and toxicity of rituximab in the treatment of refractory polymyositis. Adult patients with active polymyositis as evidenced by persistent proximal muscle weakness, elevated creatine kinase (CK) level, and features of active myositis on electromyography who were refractory to corticosteroids and at least 2 other immunosuppressive agents were recruited. While immunosuppressive agents were continued, rituximab (375 mg/m2) was given by intravenous infusion weekly for 4 consecutive weeks. Patients were followed-up 4-weekly for serial assessment of muscle power, serum muscle enzymes, physician's and patient's global impression of disease activity, disability, and quality of life scores. Four patients (3 women, 1 man) were studied. The mean age was 53 +/- 11 years and the mean duration of polymyositis was 4.8 +/- 3.3 years. All had persistently active myositis for at least 2 years. At Week 28, significant improvement in the mean proximal muscle power scores and reduction in CK levels in comparison to baseline were observed. Two patients had return of full muscle power with significant drop in CK level. There was a trend of improvement in disability scores as well as both the mental and physical components of the Medical Outcomes Study Short Form-36 Health Survey scores. Rituximab was well-tolerated. The authors concluded that rituximab is an option to be considered in refractory polymyositis, however, further controlled trials are needed to confirm its effectiveness.

In a multi-center prospective study, Bader-Meunier and associates (2011) evaluated the safety and effectiveness of rituximab in juvenile dermatomyositis (JDM) in off-trial patients. A total of 9 patients with severe JDM were studied. The main indication for rituximab treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). Rituximab was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with rituximab for muscle involvement. In these responders steroid therapy was stopped or tapered to less than 15 % of the baseline dosage, with no relapse, with a follow-up ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients. The authors concluded that this small series suggested that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Moreover, they stated that further studies are needed to identify predictive factors of response to rituximab in patients with severe JDM.

The largest trial of rituximab in inflammatory myositis, the Rituximab in Myositis (RIM) trial, involved 195 patients, all of whom were treated with rituximab either at baseline or after an 8-week delay, including 76 patients with adult DM and polymyositis (PM) and 48 patients with juvenile DM; all patients had disease refractory to glucocorticoids and at least 1 immunosuppressive or immunomodulatory agent (mean of 3.1 agents in addition to the glucocorticoid) (Oddis et al, 2013). No differences in response to rituximab were seen between the 2 groups to which the patients were allocated. Patients were randomly assigned to receive rituximab (750 mg/m2 up to 1 g, administered intravenously once-weekly for 2 weeks) either on weeks zero and 1 (“early arm”) or on weeks 8 and 9 (“late arm”), and were assigned to receive placebo at the time-point during which they did not receive rituximab. There were no differences between the early and late treatment arms in the time from baseline to achieve the composite response criteria (both at about 20 weeks) or 20 % improvement in strength, nor were there differences between the 2 arms in the frequency with which the response criteria or 20 % improvement in strength were achieved or in the rate of glucocorticoid taper. The disease groups (DM, PM, and juvenile DM) did not differ in outcome. Despite the failure to demonstrate differences based upon the 8-week treatment delay, results of secondary end-points suggested potential benefit, indicating the need for further study. The composite response criterion was achieved by 83 % of the patients receiving rituximab during the 44-week trial, and the mean dose of prednisone in the 160 patients on it at baseline was significantly reduced, from 20.8 to 14.4 mg daily. Response criteria were also met after a second course of therapy by 8 of 9 patients eligible for re-treatment after an initial response and later recurrence; 26 serious adverse effects attributed to the rituximab were observed, most of which were infections. These included pneumonia and cellulitis (6 patients each), as well as urosepsis and herpes zoster (2 patients each), and 1 patient each had septic arthritis, histoplasmosis, urinary tract infection, respiratory failure, heart failure, dysrhythmia, venous thrombosis, syncope, rash, and neurologic symptoms. One patient withdrew from the trial due to adverse effects, and 1 patient died during the trial from a suspected malignancy and stroke. Infusion reactions were more common with the administration of rituximab compared with placebo (15.4 versus 5.3 %).

An accompanying editorial (de Visser et al, 2013) stated that several reasons may explain why the RIM Study failed to achieve its primary efficacy end-point. The investigators mention the following issues:

the power calculation based on the postulated effect of rituximab by 8 weeks
the selection of a placebo phase of 8 weeks and
the core set of measures and the definition of improvement.

Rider and colleagues (2014) evaluated changes in myositis core set measures and ancillary clinical and laboratory data from the NIH’s subset of patients enrolled in the RIM trial. A total of 18 patients (5 dermatomyositis, 8 polymyositis, 5 juvenile dermatomyositis) completed more in-depth testing of muscle strength and cutaneous assessments, patient-reported outcomes, and laboratory tests before and after administration of rituximab. Percentage change in individual measures and in the definitions of improvement (DOIs) and standardized response means were examined over 44 weeks. Core set activity measures improved by 18 to 70 % from weeks 0 to 44 and were sensitive to change; 15 patients met the DOI at week 44, 9 patients met a DOI 50 % response, and 4 met a DOI 70 % response. Muscle strength and function measures were more sensitive to change than cutaneous assessments. Constitutional, gastro-intestinal, and pulmonary systems improved 44 to 70 %. Patient-reported outcomes improved up to 28 %. CD20+ B cells were depleted in the periphery, but B cell depletion was not associated with clinical improvement at week 16. The authors concluded that this subset of patients had high rates of clinical response to rituximab, similar to patients in the overall trial. Most measures were responsive, and muscle strength had a greater degree of change than cutaneous assessments. Several novel assessment tools, including measures of strength and function, extra-muscular organ activity, fatigue, and health-related quality of life, are promising for use in future myositis trials. The authors stated that further study of B cell-depleting therapies in myositis, particularly in treatment-naïve patients, is warranted.

Vermaak et al (2015) stated that dermatomyositis (DM) and polymyositis (PM) are rare chronic inflammatory disorders with significant associated morbidity and mortality despite treatment. High-dose corticosteroids in addition to other interventions such as immunosuppressants, immunomodulators, and more recently, biologics are commonly used in clinical practice; however, there are no clear guidelines directing their use. These investigators reviewed the evidence for immunotherapy in the treatment of DM and PM. Relevant studies were identified through Embase and PubMed database searches. Trials were selected using pre-determined selection criteria and then assessed for quality; RCTs and experimental studies without true randomization and including adult patients with definite or probable DM or PM were evaluated. Any type of immunotherapy was considered. Clinical improvement, judged by assessment of muscle strength after 6 months, was the primary outcome. Secondary outcomes included IMACS definition of improvement, improvements in patient and physician global scores, physical function, and muscle enzymes. A total of 12 studies met eligibility criteria. Differences in trial design, quality, and variable reporting of baseline characteristics and outcomes made direct comparison impossible. Although no treatment can be recommended on the basis of this review, improved outcomes were demonstrated with a number of agents including methotrexate, azathioprine, cyclosporine, rituximab, and IVIG. Plasmapheresis and leukapheresis were of no apparent benefit. The authors concluded that more high-quality RCTs are needed to establish the role of immunosuppressive agents in the treatment of these conditions and the clinical context in which they are most likely to be beneficial.

Sunderkotter et al (2016) stated that the present guidelines on DM represent an excerpt from the inter-disciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30 % of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic work-up. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5 to 20 % of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30 % of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1 to 2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of (IVIGs is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for 1 to 3 years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include anti-malarial agents (also in combination), methotrexate, and corticosteroids; IVIGs or rituximab may also be helpful; UV protection is an important prophylactic measure.

Oddis (2016) noted that the management of patients with idiopathic inflammatory myopathy (IIM) remains a challenge given the systemic features beyond active myositis. That is, recognizing the inflammatory arthropathy, varying DM rashes, and overt and occult features of interstitial lung disease in addition to myositis adds to the complexity of diagnosis and treatment of IIM. However, clinicians now have available many more immunosuppressive drugs as well as biologic agents for use in patients with myositis and other autoimmune diseases. In this study, the use of these agents was reviewed and support based on available published literature was provided even though many studies have been small and results somewhat anecdotal. Glucocorticoids remain the initial treatment of choice in most instances and methotrexate and azathioprine are often used early in the treatment course. These agents are followed by other immunosuppressive drugs (e.g., mycophenolate mofetil, tacrolimus, cyclosporine and cyclophosphamide), some of which are used alone while combinations of these agents also provide an effective option. The author stated that there is more rationale for the use of biologic agents such as rituximab from a mechanistic perspective and, given the incorporation of validated core set measures in assessing myositis patients, can look forward to better designed clinical trials in the future.

Factor VIII and Factor IX Inhibitors in People with Inherited Severe Hemophilia

In a Cochrane review, Liu and colleagues (2015) stated that hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU)/ml. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the effectiveness of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide “off-label” use of rituximab for treating people with hemophilia and inhibitors, its safety and effectiveness need to be evaluated. These investigators evaluated the safety and effectiveness of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. They searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and hand-searching of journals and conference abstract books. They searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. Date of last search: January 27, 2015. Randomized controlled trials and controlled clinical trials investigating the safety and effectiveness of rituximab for treating inhibitors in people with hemophilia were selected for analysis No RCTs matching the selection criteria were eligible for inclusion. No RCTs on rituximab for treating inhibitors in people with hemophilia were identified. The authors concluded that they were unable to identify any relevant trials on the safety and effectiveness of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. They stated that RCTs are needed to evaluate the safety and effectiveness of rituximab for this condition.

D'arena et al (2016) stated that acquired hemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about 50 % of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as hematological malignancies, such as chronic lymphocytic leukemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. These investigators provided a systematic description of data available in the literature on the use of rituximab for the treatment of AHA. They performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words "rituximab" and "acquired h(a)emophilia". Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. The review of the literature confirmed that rituximab may be a safe and useful treatment for AHA. The authors concluded that although rituximab is not a standard therapy for AHA, it may be useful in resistant cases. However, the definitive place of this monoclonal antibody in the therapeutic strategy for AHA (1st or 2nd-line, alone or in combination with other drugs) remains to be determined more precisely and warrants further investigation.

Janbain et al (2015) reviewed the data on rituximab for acquired hemophilia a. The authors observed that rituximab is increasingly used first- and second-line for inhibitor eradication in AHA. The authors found no data to support the contention that rituximab used alone or in combination with other immunosuppressants results in higher remission rates or more rapid remissions. In the European Acquired Haemophilia Registry (EACH2) (citing Collins, et al., 2012), a stable CR was achieved by 59% of patients (30 of 51) treated with any rituximab – a success rate halfway between that achieved with steroids alone (48%) and steroids plus cyclophosphamide (70%). The authors concluded that, nevertheless, some patients resistant to standard first-line immunosuppression respond to second-line rituximab. In the EACH2, seven of 14 patients (50%) achieved a stable CR with rituximab-based regimens used after the failure of first-line drug(s) or relapse.

Fibrosing Mediastinitis

Hennigan et al (2008) stated that pulmonary hypertension is a common but under-diagnosed complication of systemic lupus erythematosus, which can be associated with significant morbidity and early mortality. Although often associated with anti-phospholipid antibodies, the etiology remains poorly understood. In case reports and small open trials, the anti-CD20, B-cell targeted therapeutic antibody, rituximab, has been reported to provide benefits for systemic lupus erythematosus patients with glomerulonephritis, anti-phospholipid antibody syndrome, vasculitis, arthritis, and refractory skin disease. However, the outcome of rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus has not been described. These researchers, therefore, presented a case of a young systemic lupus erythematosus patient with early onset of pulmonary arterial hypertension during the disease course, refractory to multiple treatment modalities, who had significant improvement with rituximab therapy.

Peikert et al (2012) stated that fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are 2 fibro-inflammatory disorders with potentially overlapping clinical and radiological features. These investigators examined histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. They identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4; 3 samples met the pre-defined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases). The authors concluded that up to 1/3 of histoplasmosis or granulomatous-disease-associated FM cases demonstrated histopathological features of IgG4-RD spectrum. Whether these changes occurred as the host immune response against Histoplasma or represented a manifestation of IgG4-RD remained to be determined. They stated that studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are needed.

Westerly et al (2014) conducted a series of 3 case reports evaluating the rituximab in progressive FM. These investigators hypothesized that tissue B lymphocytes play a pathogenic role in progressive FM, and that the off-label use of rituximab therapy can prevent disease progression. Patient 1 was treated with 4 weekly rituximab infusions of 375 mg/m². Both patient 2 and patient 3 received an infusion of rituximab 1,000 mg on Days 0 and 14. Prednisone was prescribed at the time of the infusion and tapered off entirely in all 3 patients over the following 3 to 4 months. All patients received pneumocystis prophylaxis, and patients 2 and 3 also received itraconazole to prevent histoplasmosis reactivation. Circulating B lymphocytes, measured by flow cytometry, were completely depleted in all patients. Patient 2 experienced a pleural space infection during the period of B-lymphocyte depletion, which was attributed to a previously inserted intra-pleural catheter. There were no other serious AEs. All patients had a favorable therapeutic response. The authors concluded that depletion of B lymphocytes resulted not only in reduced metabolic activity of the FM lesions but also in a significant reduction of the size of the FM lesions and improvements in clinical symptoms; however, this novel mechanism-based treatment approach deserves further investigation.

Furthermore, an UpToDate review on “Fibrosing mediastinitis” (Weinberger, 2018) states that “There is no curative therapy for fibrosing mediastinitis. Antifungal agents are generally ineffective, although several case reports have suggested a potential benefit. Glucocorticoids do not appear to be beneficial in typical cases of fibrosing mediastinitis, although controlled trials have not been performed. However, in fibrosing mediastinitis due to sarcoidosis, improvement may sometimes be seen. Another possible exception is autoimmune fibrosing mediastinitis, which may respond more favorably to glucocorticoid therapy, although these cases are difficult to identify prospectively. Based upon the finding of CD20-positive B lymphocytes in tissue samples from patients with fibrosing mediastinitis, a preliminary report of off-label treatment with rituximab reported a therapeutic response and reduction of both lesion size and metabolic activity in 3 patients with progressive and refractory disease”.

Furthermore, an UpToDate review on “Treatment of pulmonary hypertension in adults” (Hopkins and Rubin, 2018) does not mention rituximab as a therapeutic option.

Hypersensitivity Pneumonitis

In a review on “Hypersensitivity pneumonitis” (Sforza and Marinou, 2017), rituximab is not mentioned as a therapeutic option.

Immune Thrombocytopenic Purpura

The U.S. Pharmacopoeial Convention (2002) concluded that rituximab is indicated for treatment of idiopathic thrombocytopenic purpura. This conclusion is based on the results of several single-institution cohort studies that have reported on response rates exceeding 50 %, and only minor adverse events. Stasi et al (2001) stated that "[I]n view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted."

Tamary and colleagues (2010) stated that the rarity of severe complications of immune thrombocytopenia (ITP) in children makes randomized clinical trials in this disease infeasible. Thus, the current management recommendations for ITP are largely dependent on clinical expertise and observations. As part of its discussions during the Intercontinental Cooperative ITP Study Group Expert Meeting in Basel, the Management working group recommended that the decision to treat an ITP patient be individualized and based mainly on bleeding symptoms and not on the actual platelet count number and should be supported by bleeding scores using a validated assessment tool. The group stressed the need to develop a uniform validated bleeding score system and to explore new measures to evaluate bleeding risk in thrombocytopenic patients -- the role of rituximab as a splenectomy-sparing agent in resistant disease was also discussed. Given the apparently high recurrence rate to rituximab therapy in children and the drug's possible toxicity, the group felt that until more data are available, a conservative approach may be considered, reserving rituximab for patients who failed splenectomy. More studies of the effectiveness and side effects of drugs to treat refractory patients, such as TPO mimetics, cyclosporine, mycophenolate mofetil, and cytotoxic agents are needed, as are long-term data on post-splenectomy complications. In the patient with either acute or chronic ITP, using a more personalized approach to treatment based on bleeding symptoms rather than platelet count should result in less toxicity and empower both physicians and families to focus on quality-of-life.

Liang et al (2012) noted that rituximab has been widely used off-label as a second line treatment for children with ITP. However, its role in the management of pediatric ITP requires clarification. To understand and interpret the available evidence, these researchers conducted a systematic review to assess the safety and effectiveness of rituximab for children with ITP. They searched Medline, Embase, Cochrane Library, CBM, CNKI, abstract databases of American Society of Hematology, American Society of Clinical Oncology and Pediatric Academic Society. Clinical studies published in full text or abstract only in any language that met pre-defined inclusion criteria were eligible. Efficacy analysis was restricted to studies enrolling 5 or more patients. Safety was evaluated from all studies that reported data of toxicity. A total of 14 studies (323 patients) were included for efficacy assessment in children with primary ITP. The pooled complete response (platelet count ≥ 100 × 10(9)/L) and response (platelet count ≥ 30 × 10(9)/L) rate after rituximab treatment were 39 % (95 % confidence interval [CI]: 30 % to 49 %) and 68 % (95 % CI: 58 % to 77 %), respectively, with median response duration of 12.8 month. A total of 4 studies (29 patients) were included for efficacy assessment in children with secondary ITP; 11 (64.7 %) of 17 patients associated with Evans syndrome achieved response. All 6 patients with systemic lupus erythematosus associated ITP and all 6 patients with autoimmune lymphoproliferative syndrome associated ITP achieved response. A total of 91 patients experienced 108 adverse events associated with rituximab, among that, 91 (84.3 %) were mild-to-moderate, and no death was reported. The authors concluded that RCTs on effect of rituximab for children with ITP are urgently needed, although a series of uncontrolled studies found that rituximab resulted in a good platelet count response both in children with primary and children secondary ITP. Most adverse events associated with rituximab were mild-to-moderate, and no death was reported.

Chugh and associates (2015) stated that rituximab is commonly used as a treatment for primary ITP to induce and maintain remission. The benefit of adding rituximab to standard-of-care treatment is uncertain. These investigators performed a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the safety and effectiveness of rituximab for treatment of adults with primary ITP. They searched Medline, Embase, and the Cochrane database in duplicate and independently from inception up to July 31, 2014, for relevant studies. Primary outcomes were the proportion of patients achieving a complete platelet count response and a partial platelet count response (as defined in primary studies) that was maintained until the end of follow-up. They also assessed bleeding, infection, and infusion reactions. The database search returned 468 abstracts, of which 5 trials (with total of 463 patients) were eligible for analysis. No patients had splenectomy at the time of enrolment. Median follow-up was 6 months (IQR 6 to 12). Complete response (> 100 × 10(9) platelets per L without rescue therapy) was more common with rituximab than with standard of care (weighted proportions: 46.8 % versus 32.5 %; relative risk [RR] 1.42, 95 % CI: 1.13 to 1.77; p = 0.0020). Partial response was not significantly different between groups (57.6 % versus 46.7 %; RR 1.26, 95 % CI: 0.95 to 1.67; p = 0.11). Rituximab was not associated with a reduction in bleeding (9.2 % versus 5.2 %; RR 1.34, 95 % CI: 0.63 to 2.87; p = 0.44) or an increase in infections (20.1 % versus 12.1 %; RR 1.40, 95 % CI: 0.87 to 2.26; p = 0.17). The authors concluded that rituximab can improve complete platelet count responses by 6 months in patients with ITP. Evidence for sustained responses beyond 6 to 12 months is limited. Clinicians must consider the goals of treatment before prescribing rituximab.

Langerhans Cell Histiocytosis

Terrier et al (2005) stated that intravascular lymphoma (IVL) is a rare and aggressive disorder, characterized by frequent cutaneous and neurological involvement and medullary infiltration. In rare cases particularly in Asia, IVL can be associated with hemophagocytic syndrome (IVL-HS). These investigators reported the case of a 61-year old Caucasian female who presented with IVL-HS. Bone marrow biopsy showed hemophagocytic features and medullary localization of a diffuse large B-cell lymphoma. Liver biopsy showed exclusive sinusoidal infiltration by large B cells. Treatment by poly-chemotherapy associated with rituximab induced a rapid complete remission. Unfortunately, death occurred as a consequence of septic shock. Early recognition of IVL-HS by performing bone marrow biopsy is critical to start rapidly appropriate treatment. The authors stated that the role of rituximab in the management of IVL-HS remains to be established.

Lucine-Rich, Glioma-Inactivated 1 Antibody Associated Encephalopathy

In an observational study, Irani et al (2014) described the safety and efficacy of rituximab in 5 patients with voltage-gated potassium channel (VGKC)-complex/leucine-rich, glioma-inactivated 1 (LGI1) antibody-associated encephalopathy. This case series reported sequential seizure frequencies, modified Rankin Scale scores, and VGKC-complex antibody titers in 5 adult patients (median age of 65 years; range of 48 to 73 years) treated with rituximab. Median time from symptom onset to rituximab initiation was 414 days (range of 312 to 851 days). One patient showed a rapid clinical improvement after treatment with rituximab alone and experienced a rituximab-responsive clinical relapse. Another showed possible improvement on neuropsychometric memory indexes after rituximab therapy. In contrast, all patients showed robust responses to treatment with glucocorticoids, intravenous immunoglobulins (IVIGs), and/or plasma exchange (PE) at some point in their illness. Treatment with glucocorticoids -- less so with IVIGs and PE -- was associated with the most marked reductions in VGKC-complex antibodies. The only patient who did not receive glucocorticoids showed the poorest clinical and serologic responses. The authors concluded that rituximab was well- tolerated in this predominantly older adult patient population and may be an effective option for some patients with LGI1 antibody-associated encephalopathy. Glucocorticoid therapy appeared particularly effective. These researchers stated that earlier rituximab administration and randomized trials are needed to formally assess efficacy.

Brown et al (2014) noted that autoimmune encephalitis associated with antibodies to LGI1 is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. These investigators reported provided 2 case reports. Both cases had facio-brachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months, respectively. The authors concluded that rituximab use allowed withdrawal of corticosteroids and was well-tolerated. Moreover, they stated that randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides.

Nosadini et al (2015) reviewed the literature of immune therapy in autoimmune encephalitis associated with antibodies to cell surface antigens including N-methyl-D-aspartate receptor (NMDAR), LGI1, contactin-associated protein-2 (Caspr2), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid-A receptor (GABAAR), γ-aminobutyric acid-B receptor (GABABR), glycine R and other rarer antigens. Most studies are retrospective cohorts, and there are no randomized controlled trials. Most clinicians use 1st-line therapy (steroids, IVIG, PE), and if severe or refractory, 2nd-line therapy (rituximab, cyclophosphamide). When present, tumors should be removed. There are common therapeutic themes emerging. Firstly, patients given immune therapy do better and relapse less than patients given no treatment. Secondly, patients given early treatment do better. And thirdly, when patients fail 1st-line therapy, 2nd-line therapy improves outcomes and reduces relapses. The authors noted that given the retrospective uncontrolled data, the literature has inherent bias, including severity and reporting bias.

Dubey et al (2017) conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville-FL) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014 to 06/30/2016). An Antibody Prevalence in Epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as greater than 50 % reduction of seizure frequency at the first follow-up. Serum and CSF from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation; 387 of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)-specific antibodies were detected in 44 patients. Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral prodrome, FBDS/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody-positive patients had an APE score of greater than or equal to 4 (97.7 % versus 21.6 %, p < 0.01). Sensitivity and specificity of an APE score of greater than or equal to 4 to predict presence of specific neural auto-antibody were 97.7 % and 77.9 %, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, FBDS/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score of greater than or equal to 7 to predict favorable seizure outcome were 87.5 % and 83.8 %, respectively. The authors concluded that APE and RITE scores could aid diagnosis, treatment, and prognostication of autoimmune epilepsy.

Lupus

In an open study, Leandro et al (2005) reported their findings of 24 patients with severe SLE treated with rituximab and followed for a minimum of 3 months. In the majority of patients (19 out of 24), 6 months follow-up data were described. The authors concluded that for patients who had failed conventional immunosuppressive therapy, considerable utility in the use of B-cell depletion has been demonstrated. They noted that the data obtained in this open study provided strong support for the performance of a full double-blind control trial. This is in agreement with the observation of Sfikakis et al (2005) who stated that double-blind studies comparing rituximab with existing immunosuppressive therapies are needed.

Guidelines from the European League Against Rheumatism (EULAR, 2008) stated that in the absence of randomized controlled clinical trials, rituximab is recommended for selected patients with disease refractory to standard treatments with mycophenolate mofetil and cyclophosphamide. Established treatments for SLE include corticosteroids and the immunosuppressives cyclophosphamide and azathioprine. There is some evidence that oral mycophenolate may be an effective alternative to cyclophosphamide treatment in patients with lupus nephritis.

A study of rituximab for SLE (Ng et al, 2007) examined its efficacy in combination with cyclophosphamide and glucocorticoids in 90 patients with systemic lupus erythematosus refractory to conventional treatment. Following rituximab infusion patients were followed for from 3 to 40 months; a "meaningful" decrease in disease activity was noted in 80 %, infusions were well-tolerated in 90 % of patients, but adverse events (ascribed to hypersensitivity to the chimeric antibody) occurred in 10 %.

In December 2006, the FDA learned that 2 patients who were treated with rituximab for systemic lupus erythematosus developed progressive multifocal leukoencephalopathy (PML), a fatal viral infection of the central nervous system (FDA, 2007). This side effect has been reported in patients as late as 12 months after their last dose of rituximab. The FDA stated that SLE is not an approved indication for rituximab. A black box warning was added to the labeling of rituximab stating that JC virus infection resulting in PML and death has been reported in patients treated with rituximab.

Genentech, Inc. reported that the EXPLORER study, a phase II/III randomized, double-blind, placebo-controlled, multi-center study of rituximab for SLE, did not meet its primary endpoint defined as the proportion of rituximab treated patients who achieved a major clinical response or partial clinical response measured by BILAG, a lupus activity response index, compared to placebo at 52 weeks. A total of 257 patients were randomized 2:1 to receive rituximab plus prednisone or placebo plus prednisone in 2 infusions 15 days apart. Patients were retreated 6 months later with the same regimen. Patients were evaluated for efficacy every four weeks for 52 weeks. The majority of patients are being monitored to week 78. The study also did not meet any of the 6 secondary endpoints, including: time adjusted area-under-the-curve minus baseline of BILAG score over 52 weeks; proportion of patients who achieve a major clinical response, and proportion of patients who achieve a partial clinical response (including major clinical response) at week 52; proportion of patients who achieve BILAG C or better in all domains at week 24; time to moderate or severe flare over 52 weeks; change in SLE Expanded Health Survey physical function score from baseline at week 52; and proportion of subjects who achieve a major clinical response with 10 mg prednisone per day from weeks 24 to 52 (Genentech, 2008; Merrill, et al., 2010).

Rovin et al (2012) evaluated the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end-point was renal response status at week 52. Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8 % among the 72 patients receiving placebo and 56.9 % among the 72 patients receiving rituximab (p = 0.18); partial responses accounted for most of the difference. The primary end-point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti-double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. The authors concluded that, although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The authors also found that the combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

A systematic evidence review and metaanalysis by Borba et al (2014) of biologic therapies for systemic lupus erythematosus (SLE) found that rituximab showed no superiority over placebo in terms of efficacy, despite an acceptable safety profile.

Morvan’s Syndrome

Diaz-Manera and associates (2007) reported on the case of a 46-yearold woman presented to a local hospital with acute respiratory failure and a 2-year progressive history of fatigue, personality changes, increased sweating, dysphagia with substantial weight loss, dysarthria, and intermittent ptosis and diplopia. Neurological examination showed facial weakness, lingual atrophy and bulbar palsy, which necessitated the use of a feeding tube and ventilatory support. Mild limb weakness with severe muscle atrophy and diffuse muscle twitches were observed. The patient had also developed visual hallucinations and persecutory delusions. Her personal and family medical histories were unremarkable. Sensory and motor nerve conduction studies, repetitive nerve stimulation, electromyogram, blood-cell counts, general chemistry and metabolic function tests, a computed tomography (CT) scan, an [(18)F]fluorodeoxyglucose-PET scan, and tests for serum antibodies to acetylcholine receptors, muscle-specific tyrosine kinase, voltage-gated potassium channels, P/Q-type voltage-gated calcium channels, and paraneoplastic antigens, were carried out. Diagnosis was myasthenia gravis (MG) associated with antibodies to acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK), and Morvan's syndrome associated with antibodies to voltage-gated potassium channels in the absence of thymoma. The patient received combined treatment with prednisone, intravenous immunoglobulin (IVIG), cyclosporine, and rituximab. This was a single-case study and its findings were confounded by the use of combinational therapies.

van Sonderen et al (2013) noted that MG, Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia are neuromuscular transmission disorders occurring with or without associated malignancy. Due to the common antibody-mediated pathophysiology, immunosuppression has an important role in the treatment of each of these disorders. Symptomatic treatment is more variable. Pyridostigmine is first-line treatment in generalized MG. Response appeared to be better in patients with AChR antibodies than in patients with antibodies against MuSK. Pyridostigmine can be sufficient in mild MG, although most patients need additional immunosuppressive therapy. If so, prednisolone is efficient in the majority of the patients, with a relatively early onset of clinical effect. High drug dosage and treatment duration should be limited as much as possible because of serious corticosteroid-related side effects. As long-term treatment is needed in most patients for sustainable remission, adding non-steroid immunosuppressive drugs should be considered. Their therapeutic response is usually delayed and often takes a period of several months. In the meantime, corticosteroids are continued and doses are tapered down over a period of several months. There are no trials comparing different immunosuppressive drugs. Choice is mainly based on the clinician's familiarity with certain drugs and their side effects, combined with patients' characteristics. Most commonly used is azathioprine. Alternatively, tacrolimus, cyclosporine A, mycophenolate mofetil or rituximab can be used. The use of cyclophosphamide is limited to refractory cases, due to serious side effects. Plasma exchange and IVIG induce rapid but temporary improvement, and are reserved for severe disease exacerbations because of high costs of treatment. It is recommended that CT of the thorax is performed in every AChR-positive MG patient, and that patients are referred for thymectomy in case of thymoma. In patients without thymoma, thymectomy can be considered as well, especially in younger, AChR-positive patients with severe disease. However, definite proof of benefit is lacking and an international randomized trial to clarify this topic is currently ongoing. When LEMS is suspected, always search for malignancy, especially small cell lung carcinoma with continued screening up to 2 years. In paraneoplastic LEMS, cancer treatment usually results in clinical improvement of the myasthenic symptoms. 3,4-diaminopyridine is 1st-line symptomatic treatment in LEMS. It is usually well-tolerated and effective. When immunosuppressive therapy is needed, the same considerations apply to LEMS as described for MG. Peripheral nerve hyper-excitability in neuromyotonia can be treated with anti-convulsant drugs such as phenytoin, valproic acid or carbamazepine. When response in insufficient, start prednisolone in mild disease and consider the addition of azathioprine. Plasma exchange or IVIG is indicated in severe neuromyotonia and in patients with neuromyotonia combined with central nervous system symptoms, a clinical picture known as Morvan's syndrome.

Multiple Sclerosis

More than 80 % of individuals with multiple sclerosis (MS) experience a relapsing-remitting disease course (He et a., 2013). Approximately 10 years after disease onset, an estimated 50 % of individuals with relapsing-remitting MS (RRMS) convert to secondary progressive MS. Multiple sclerosis causes a major socioeconomic burden for the individual patient and for society. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and help to reduce the socioeconomic burden of MS. Alternative and more effective MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire. It has been shown that B lymphocytes are involved in the pathophysiology of MS and rituximab lyses B-cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Current clinical trials are evaluating the role of rituximab as a B-cell depletion therapy in the treatment of RRMS.

He et al (2013) completed an update of the Cochrane review of rituximab for RRMS. The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (interferon-β (IFN-β), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed. The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register. The authors checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. They also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche. The systematic review included all randomised, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than 1 year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS without restrictions regarding dosage, administration frequency and duration of treatment. The authors used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. Principal investigators of included studies were contacted for additional data or confirmation of data. One trial involving 104 adult RRMS patients with an entry score less than or equal to 5.0 on the Expanded Disability Status Scale (EDSS) and at least 1relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1,000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0 %). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91 %) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3 % versus 40.0 %), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6 %). The most common infection-associated adverse events (greater than 10 % in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5 % versus 8.6 %) and sinusitis (13.0 % versus 8.6 %) were more common in the rituximab group. One ongoing trial was identified. The authors concluded that there is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only 1 randomized controlled trial (RCT) was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The authors concluded that the beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.

In a phase II, double-blind, 48-week clinical trial involving 104 patients with relapsing-remitting multiple sclerosis, Hauser et al (2008) assigned 69 patients to receive 1,000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse. As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (p < 0.001) and of total new gadolinium-enhancing lesions over the same period (p < 0.001); and these results were sustained for 48 weeks (p < 0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5 % versus 34.3 %, p = 0.02) and week 48 (20.3 % versus 40.0 %, p = 0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the 2 groups. The authors concluded that a single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. However, the authors noted that this phase II study was not designed to evaluate long-term safety or to detect uncommon adverse events. They stated that the safety and effectiveness of rituximab for the treatment of multiple sclerosis need to be validated by larger and longer-term controlled studies. MacFarland (2008) noted that a phase II clinical trial leaves many questions unanswered including the duration of the treatment effect, the effect of progression of disability, and most importantly the types of adverse events that may occur at low frequency. Issues of long-term safety of rituximab must still be addressed, given reports to the Food and Drug Administration (FDA) of progressive multi-focal leukoencephalopathy in patients with lupus who were treated with rituximab.

Genentech, Inc. (South San Francisco, CA) reported that a Phase II/III randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy, safety and tolerability of 4 courses of rituximab for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period. A total of 439 patients were randomized 2:1 to receive either 4 treatment courses of rituximab 6 months apart or placebo. MRI evaluations were conducted at baseline, weeks 6, 48, 96 and 122. The incidence of overall adverse events was comparable between rituximab and placebo treatment groups. Serious adverse events were 16.4 % in the rituximab arm versus 13.6 % in the placebo arm, with an incidence of serious infections of 4.5 % compared with less than 1.0 % respectively. Infectious events (10 %) reported in either group included upper respiratory and urinary tract infections. Most infectious events in the rituximab arm were reported as mild to moderate in severity, though events of greater severity were reported more frequently in patients receiving rituximab. There were more infusion-related reactions with rituximab, the majority of which were mild to moderate in severity (Genentech, 2008).

A randomized controlled trial (Hawker et al, 2009) of rituximab for PPMS found no significant difference between rituximab and placebo in time to confirmed disease progression, the primary study endpoint. Subgroup analysis suggested that rituximab may have a significant effect on time to confirmed disease progression in younger patients; however, this finding would need to be confirmed in clinical trials designed to test this hypothesis. In an accompanying editorial, Hartung and Aktas (2009) stated that "having failed to reach the primary endpoint, rituximab joins the league of drugs that showed disappointing or inconclusive results in therapy trials in PPMS". Regarding the findings of the subgroup analysis, Hartung and Aktas (2009) commented that "[t]hus, these results suggest that, before jumping to conclusions, a note of caution needs to be added to these types of subgroup analyses. They are of a purely exploratory character and definitely should not guide therapeutic decisions in current neurological practice. However, they do offer important insights into the pathobiology of the disease as correctly pointed out by Hawker and colleagues in their discussion of the findings obtained".

Intrathecal Rituximab for Progressive Multiple Sclerosis

In an open-label, phase-I clinical trial, Brown and colleagues (2018) examined the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive MS (PMS) and assessed the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period. Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir; follow-ups were carried out at 1, 3, 6, 9, and 12 months. Mild-to-moderate vertigo and nausea were common but temporary AEs associated with intrathecal rituximab infusion, which was otherwise well-tolerated. The only severe AE was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers. The authors concluded that intrathecal administration of rituximab was well-tolerated. However, it may involve a risk for injection-related infections. These researchers stated that the small scale of the study (n = 23), lack of a control group and the short time window for observing a slowly progressing disease, prevented conclusions regarding efficacy from being made. They stated that a 2-year follow-up study of the present trial is ongoing and will shed more light on the possible long-term effects of intrathecal rituximab. The apparently high-risk of infection should be kept in mind for any future intrathecal studies.

Myasthenia Gravis

Zebardast et al (2010) noted that myasthenia gravis (MG) is an immune-mediated disorder with a variable response to treatment. In this study, patients with refractory MG who were treated with rituximab were identified. Patients with refractory MG who were treated with rituximab were reviewed for response to treatment. Patients who had muscle-specific kinase (MuSK(+)) or acetylcholine receptor (AChR(+)) antibodies were included. A total of 6 patients were identified who met the criteria described. All patients tolerated rituximab without side effects and had a reduced need for immunosuppressants and/or improvement in clinical function. Patients with refractory MG appeared to respond to rituximab in this small, retrospective study. The authors concluded that these findings suggested that a larger, prospective trial is indicated.

Sadnicka et al (2011) reported the case of a 76-year old man with a pre-existing diagnosis of MG who was admitted to an intensive care unit with pneumonia and type II respiratory failure. In addition, muscle weakness, widespread myokymia, neuropsychiatric disturbance and autonomic disturbance were present. Anti-voltage gated potassium channel antibodies, anti-striated muscle antibodies and anti-acetylcholine receptor antibodies were positive. Nerve-conduction studies demonstrated findings consistent with patchy demyelination. Electromyography confirmed widespread myokymia, and there was evidence of diffuse encephalopathy on electroencephalography. Diagnoses of Morvan syndrome and chronic inflammatory demyelinating polyradiculopathy (CIDP) were made. Treatment with intravenous immunoglobulin, plasma exchange and high-dose steroids were ineffective, and the patient remained dependent on mechanical ventilation. The co-existence of possibly 3 humorally-mediated autoimmune diseases led to treatment with rituximab. Rituximab treatment was followed by an improvement in muscle strength, allowing successful weaning from mechanical ventilation, diminution in myokymia and improved cognition. At follow-up, there was reversal of the neuropsychiatric manifestations and normal muscle strength. This case suggested that rituximab may be useful in the treatment of autoimmune neurological disease refractory to other immunosuppressant therapies. Specifically, it adds further evidence for the use of rituximab in CIDP. As indications for rituximab in humorally-mediated disease continue to expand, international multi-center RCTs are needed to prove the effectiveness of this important emerging biological agent.

In a retrospective study, Nowak et al (2011) reported the results of 14 refractory generalized myasthenia gravis patients (6 AChR+; 8 MuSK+) treated with rituximab. Sustained clinical improvement was observed in all patients as well as a reduction of conventional immunotherapies. Prednisone dose decreased a mean of 65.1 %, 85.7 %, and 93.8 % after cycle 1, 2, and 3 of rituximab therapy, respectively. A statistically significant reduction in plasma exchange sessions was seen after cycle 1 with all patients being off of plasma exchange after cycle 3. Acetylcholine receptor antibody titers decreased a mean of 52.1 % (p = 0.0046) post-cycle 2. The authors concluded that these findings supported the hypothesis that rituximab is beneficial and well-tolerated in managing refractory myasthenia gravis and nearly doubles published cases. These investigators proposed that B-cell-directed therapies may become an attractive option and suggested pursuit of a prospective trial.

Evoli et al (2012) stated that rituximab is a promising treatment for refractory MuSK-MG; in uncontrolled studies, nearly all treated patients achieved significant improvement with substantial decrease of medication. The authors noted that it is yet to be clarified whether the early use of rituximab could prevent the permanent bulbar weakness, which constitutes a relevant disability in these patients.

Díaz-Manera et al (2012) noted that rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. These researchers reported the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compared the response between AChR+MG and MuSK+MG patients. Myasthenia Gravis Foundation America post-intervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed re-infusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no re-infusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up, MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80 % in the other 3. The authors concluded that in view of the long-lasting benefit observed in MuSK+MG patients, they recommend rituximab be used as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. This study provided Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

Collongues et al (2012) examined the effect of rituximab (RTX) on refractory (RM) and non-refractory (NRM) myasthenia. This retrospective multi-center study involved 13 RM and 7 NRM patients treated with sequential RTX infusions over 2 years, on average. Rituximab was used as a substitute for corticosteroids in NRM patients. Disability was assessed using the annualized relapse rate (ARR) and Myasthenia Gravis Foundation of America (MGFA) scores. Rituximab induction decreased the ARR from 2.1 to 0.3 (p < 0.001), and lowered MGFA scores from 5-3b to 4b-0 in RM patients, and from 1.9 to 0.1 (p < 0.001) and 4b-2b to 3b-0 in NRM patients. No side effects were reported in either group, except for 1 case of spondylodiscitis 1 year after the last RTX infusion. Within a year after RTX induction, complete corticosteroid withdrawal was obtained in 7 RM and 4 NRM patients. The authors concluded that RTX is efficacious and well-tolerated. Its use allows for dose reduction or withdrawal of corticosteroids.

Konno (2013) stated that evidence of rituximab'si effectiveness in myasthenia gravis is mostly limited to a few case series or open-label trials. Querol and Illa (2013) noted that controlled trials of rituximab for myasthenia gravis are needed to confirm initial results from pilot studies.

In a multi-center, blinded, prospective review, Hehir et al (2017) evaluated the efficacy of RTX in treatment of anti- MuSK MG. These investigators compared anti-MuSK-positive patients with MG treated with RTX to those not treated with RTX. The primary clinical end-point was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level of less than or equal to 2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs; 77 of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was greater than 3.5 years. At last visit, 58 % (14/24) of RTX-treated patients reached the primary outcome compared to 16 % (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome was 2.4. At last visit, 29 % of RTX-treated patients were taking prednisone (mean dose of 4.5 mg/day) compared to 74 % of controls (mean dose of 13 mg/day) (p = 0.001 and p = 0.005). The authors concluded that these findings provided Class IV evidence that for patients with anti-MuSK MG, RTX increased the probability of a favorable outcome. These researchers stated that although a prospective randomized controlled trial (RCT) may not be logistically feasible given the rarity of anti-MuSK MG, this study provided baseline data to design such a study. The observed robust clinical response suggested that a smaller sample size would provide enough power to detect a difference between RTX and other treatments in an RCT.

The authors stated that this study was limited because data were obtained retrospectively. These investigators attempted to reduce bias by utilizing the blinded prospective review. They also normalized time 0 for both groups to allow comparison over time. Finally, these researchers employed a stringent clinical end-point to measure clinical relevance while limiting type 1 error. Although the sample size was small, they observed a robust, strongly statistically significant, clinical benefit from RTX in this cohort. This small (n = 24) study provided only Class IV Evidence.

Behin and Le Panse (2018) noted that acquired MG is a neuromuscular disease caused by autoantibodies against components of the neuromuscular junction. It is a prototype organ-specific autoimmune disease with well-defined antigenic targets mainly the nicotinic acetylcholine receptor (AChR). Patients suffer from fluctuating, fatigable muscle weakness that worsens with activity and improves with rest. Various therapeutic strategies have been used over the years to alleviate MG symptoms. These strategies aim at improving the transmission of the nerve impulse to muscle or at lowering the immune system with steroids or immunosuppressant drugs. Nevertheless, MG remains a chronic disease and symptoms tend to persist in many patients, some being or becoming refractory over time. In this review, based on recent experimental data on MG or based on results from clinical trials for other autoimmune diseases, these researchers explored new potential therapeutic approaches for MG patients, going from non-specific approaches with the use of stem cells with their anti-inflammatory and immunosuppressive properties to targeted therapies using monoclonal antibodies specific for cell-surface antigens or circulating molecules.

These investigators noted that the data obtained on rituximab over the last few years in MG were very heterogeneous in terms of treatment regimen, evaluation and patients’ previous management, and the best therapeutic scheme is not yet determined. A recent meta-analysis has shown that MuSK-MG patients, younger and mild-to-moderate cases appeared to develop a better response to rituximab. Independently of the antibody status, studies showed a variable response rate, ranging from 50 to 100 %. The BeatMG (NCT02110706) and Rinomax (NCT02950155) trials, comparing rituximab with placebo (unfortunately with different treatment schemes) should soon add new data.

MacIsaac and colleagues (2018) stated that the anti-CD20 monoclonal antibody rituximab has immune-modulatory effects similar to intravenous immunoglobulin (IVIG). These investigators performed a systematic review and meta-analysis to determine the safety and efficacy of rituximab in autoimmune diseases that are also treated with IVIG. The most common indications for immune modulation with IVIG, as identified from a 2012 regional audit in Canada, were chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenia (ITP), MG, multi-focal motor neuropathy, Guillain-Barre syndrome (GBS), systemic lupus erythematosus (SLE), Sjogren's syndrome, and pemphigus vulgaris. They searched Medline, Embase, and the Cochrane Library until July 2016 for studies evaluating rituximab in each of these conditions. The primary outcome in this meta-analysis was clinical response at 6 months as defined by disease-specific criteria in randomized trials. They also calculated pooled proportions of responders within disease types from observational studies. A total of 95 rituximab studies were identified: 86 were observational studies in patients with ITP (n = 1,746), SLE (n = 1,047), pemphigus vulgaris (n = 564), Sjogren's syndrome (n = 138), MG (n = 66), and CIDP (n = 31) and 9 were randomized controlled trials (n = 992) in patients with ITP, SLE, and Sjogren's syndrome that compared rituximab with placebo plus standard of care. Among randomized trials, response rates were higher with rituximab (relative risk [RR], 1.38; 95 % confidence interval [CI]: 1.05 to 1.83). The pooled proportion of rituximab responses ranged from 94 % (95 % CI: 88 % to 98 %) for pemphigus vulgaris to 48 % (95 % CI: 30 % to 66 %) for CIDP. Rituximab was generally well-tolerated in observational studies although in the randomized trials, adverse events (AEs) were more common in the rituximab group. The authors concluded that rituximab is an immune-modulating agent with biologic activity across many autoimmune conditions. They stated that these data support the use of comparative trials with broad eligibility criteria to evaluate rituximab as an alternative to IVIG in autoimmune diseases.

Optic Neuropathy / Radiation Retinopathy

Sasaki et al (2015) noted that autoimmune optic neuropathy is optic neuropathy caused by an autoimmune mechanism. As treatment, steroid is usually used. If steroid is ineffective to improve visual function, other immunosuppressive agents are used as needed. Rituximab is one of molecular target agents and is now used as treatment for several types of autoimmune disorders. In a case report, a 77-year old woman presented with vision loss in her left eye. Her past medical history included disturbances of multiple organs. Laboratory tests revealed positive myeloperoxidase-anti-neutrophil cytoplasmic antibody. These researchers assumed that her vision loss was caused by autoimmune optic neuropathy and put her on high-dose glucocorticoid therapy. Her visual function quickly re-deteriorated after high-dose glucocorticoid therapy discontinuation. To achieve vision improvement, these investigators added rituximab to her treatment regimen. Her visual acuity recovered to almost 20/20 within a week later. She received other 3 rituximab-infusions and her visual acuity remained 20/20 while tapering glucocorticoid. The authors concluded that autoimmune optic neuropathy may result in blindness if treatment fails; and rituximab may be a therapeutic option for autoimmune optic neuropathy and may produce immediate response. This was a single-case study and its findings were confounded by the combinational use of glucocorticoid and rituximab.

Furthermore, UpToDate reviews on “Nonarteritic ischemic optic neuropathy: Prognosis and treatment” (Tamhankar and Volpe, 2018a), “Posterior ischemic optic neuropathy” (Tamhankar and Volpe, 2018b) and “Delayed complications of cranial irradiation” (Dietrich et al, 2018) do not mention rituximab as a therapeutic option.

Orbital Apex Sphenoid Syndrome, Orbital Pseudotumor, Orbital Xanthogranuloma and Posterior Scleritis

Escudero Gonzalez et al (2010) stated that ocular manifestations in SLE are relatively frequent, with a major prevalence of the keratoconjunctivitis sicca. Nevertheless, the appearance of unilateral exophthalmos secondary to orbital pseudotumor in patients with SLE is extremely rare, and on occasion it can be refractory to conventional pharmacological treatment (glucocorticoids and immunosuppressants). These researchers presented the case of a patient with SLE and orbital pseudotumor refractory to treatment with cyclophosphamide and an excellent clinical response, with disappearance of the ophthalmological condition after the beginning of therapy with rituximab, continuing after the infusion of 2 complete cycles without incidents.

Garcia et al (2012) noted that corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. The authors stated that this was the 1st report to describe successful treatment with rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy.

In a retrospective analysis of interventional case-series, Recillas-Gispert (2015) evaluated the clinical response to RTX in patients with scleritis due to granulomatosis with polyangiitis (GPA), in patients who had proved refractory to treatment with systemic glucocorticoids and immunosuppressive agents. A total of 8 patients (12 affected eyes) due to scleritis secondary to GPA, refractory to conventional treatment were included to receive RTX as therapy for remission induction. RTX was administered as a 1 g infusion every 2 weeks, for a total of 2 g. Patient follow-up included clinical evaluation (systemic and ophthalmologic), B-cell subset (CD19, CD20, CD22) counts, proteinase-3 anti-neutrophil cytoplasmic antibody (PR-3 ANCA), and Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS-WG). Outcomes were response to treatment and achievement of remission, as well as number of ocular relapses. The main indication for treatment was refractory necrotizing anterior scleritis. Four weeks after completion of treatment with RTX, all patients showed clear clinical improvement, with no further progression. In all patients, an absolute depletion of B cells was confirmed in the first 6 weeks after treatment; 7 patients (87.5 %) achieved remission of inflammatory activity in 7 months or less. However, 3 patients experienced ocular relapse, which comprised reactivation of the anterior scleritis, uveitis, and posterior scleritis, and 2 patients required a 2nd dose of RTX, with immediate improvement. The authors concluded that RTX was useful in the treatment of refractory necrotizing scleritis in patients with GPA. Of note, in those who relapsed after remission, RTX could be successfully used for re-treatment.

Sagiv et al (2018) reported a case of a patient with bilateral orbital necrobiotic xanthogranuloma and no associated systemic paraproteinemia. Orbital biopsy showed strong expression of CD20-positive cells. The patient was treated with systemic rituximab monotherapy, with excellent clinical response and marked regression of the orbital lesions on imaging. At the time of writing, the patient had been treated with bi-monthly rituximab maintenance therapy for 22 months and had stable clinical and imaging findings with sustained response to treatment and no reported side effects. To the authors' knowledge, this was the 1st reported case of orbital necrobiotic xanthogranuloma successfully treated with rituximab monotherapy. They hoped that this well-documented case would encourage clinicians to consider rituximab monotherapy as a possible therapeutic option, albeit one entailing an off-label use of this drug, for patients with necrobiotic xanthogranuloma of the orbit.

Furthermore, an UpToDate review on “Tolosa-Hunt syndrome” (Shindler, 2018) stated that “Orbital pseudotumor is a related condition of idiopathic inflammation involving the orbit. Patients present with painful ophthalmoplegia and orbital signs (proptosis, conjunctival injection, and chemosis). This condition, which is also glucocorticoid responsive, may be identical to Tolosa-Hunt syndrome, distinguished only by a different anatomic localization. Therefore, distinguishing between this syndrome and Tolosa-Hunt syndrome is less important than excluding other causes of painful ophthalmoplegia”. This review did not mention rituximab as a therapeutic option.

PANDAS Syndrome

An UpToDate review on “PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci” (Pichichero, 2018) does not mention rituximab as a therapeutic option.

Prophylaxis for EBV Post-Transplant Lymphoproliferative Disorder

Burns et al (2016) stated that EBV-associated PTLD remains an important complication of allogeneic HSCT (allo-HSCT). These researchers retrospectively analyzed the incidence and risk factors for EBV re-activation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single center. The cumulative incidence of EBV reactivation was 48 % (CI: 41 to 55 %) by 1 year, with an incidence of high-level EBV re-activation of 18 % (CI: 13 to 24 %); 8 patients were concurrently diagnosed with PTLD. Among patients with high-level re-activation 31/38 (82 %) developed this within only 2 weeks of 1st EBV qPCR positivity. In uni-variate analysis age of greater than or equal to 50 years was associated with significantly increased risk of EBV re-activation (HR 1.54, CI: 1.02 to 2.31; p = 0.039). Furthermore, a diagnosis of NHL was associated with greatly reduced risk of re-activation (HR 0.10, CI: 0.03 to 0.33; p = 0.0001) and this was confirmed in multi-variate testing. More importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV re-activation (HR 0.18, CI: 0.07 to 0.48; p = 0.001) although confounding with NHL was apparent. The authors concluded that these findings emphasized the risk of PTLD associated with alemtuzumab. These researchers stated that the findings of this study suggested that peri-transplant rituximab might be effective prophylaxis for PTLD arising after allo-HSCT; the data made a strong case for prospectively evaluating the role of rituximab in allograft conditioning.

Rituximab Maintenance for a Maximum of 5 Years

Taverna and colleagues (2016) stated that rituximab maintenance therapy has been shown to improve PFS in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. In a phase III RCT, a total of 270 patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with 4 doses of rituximab monotherapy in weekly intervals (375 mg/m(2)). Patients achieving at least a partial response (PR) were randomly assigned to receive maintenance therapy with 1 infusion of rituximab every 2 months, either on a short-term schedule (4 administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end-point was event-free survival (EFS); secondary end-points were PFS, overall survival (OS), and toxicity. Comparisons between the 2 arms were performed using the log-rank test for survival end-points. A total of 165 patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95 % CI: 2.1 to 5.3) in the short-term arm and 5.3 years (95 % CI: 3.5 to not available) in the long-term arm (p = 0.14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76 % versus 50 % of patients with at least 1 adverse event (p < 0.001), 5 versus 1 patient with grade 3 and 4 infections, and 3 versus 0 patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the 2 groups. The authors concluded that long-term rituximab maintenance therapy did not improve EFS, which was the primary end-point of this trial, or OS, and was associated with increased toxicity.

Steroid-Dependent Nephrotic Syndrome

In a review on nephrotic syndrome and rituximab, Haffner and Fischer (2009) noted that rituximab (RTX) has recently gained attention as a potentially successful therapy for complicated idiopathic nephrotic syndrome in children. A number of case reports and 1 prospective non-controlled multi-center trial point to the beneficial effects of RTX as a rescue therapy in children with steroid/cyclosporine-dependent or steroid/cyclosporine-resistant nephrotic syndrome. However, publication bias often results in positive outcomes being more likely to be reported than negative ones and, in particular, the safety profile of this drug in this group of patients remains unclear. The authors concluded that controlled randomized studies are needed to assess this issue, to develop treatment guidelines, to evaluate the therapeutic and economical efficacy, and to define criteria for the selection of patients.

In a review of treatment of nephrotic syndrome in children, Niaudet (2009) commented that "However, both the efficacy and safety of this drug in this group of patients remain unclear. Further studies including controlled trials are needed to determine whether there is a role for RTX in the treatment of children with steroid dependent NS". The author commented that "it is too early to recommend such therapy [rituximab] in children with SRNS [steroid-resistant nephrotic syndrome].

Kemper et al (2012) noted that in patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available. These investigators performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m(2) given weekly for 1 to 4courses). Long-term follow-up data (greater than 2 years, median of 36 months, range of 24 to 92.8) are available for 29 patients (12 boys). Twenty-six of 37 (70.3 %) patients remained in remission after 12 months. Relapses occurred in 24 (64.8 %) patients after a median of 9.6 (range of 5.2 to 64.1) months. Time to first relapse was significantly shorter in patients receiving 1 or 2 compared to 3 or 4 initial infusions. In the 29 patients with long-term follow-up for greater than 2 years, 12 (41 %) patients remained in remission after the initial rituximab course for greater than 24 months, 7 (24.1 %) patients without further maintenance immunosuppression. Nineteen children received 2 to 4 repeated courses of rituximab increasing the total number of patients with long-term remission to 20 (69 %), remission including 14 (48 %) patients off immunosuppression. The proportion of patients with long-term remission was not related to the number of initial rituximab applications. No serious side effects were noted. The authors concluded that rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Moreover, they state that further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.

Ravani et al (2015) noted that steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. In an open-label, non-inferiority, randomized controlled trial at 4 sites in Italy, these researchers examined if rituximab is non-inferior to steroids in maintaining remission in juvenile SDNS. They enrolled children aged 1 to 16 years who had developed SDNS in the previous 6 to 12 months and were maintained in remission with high prednisone doses (greater than or equal to 0.7 mg/kg per day). These investigators randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m²; intervention). Prednisone was tapered in both groups after 1 month. For non-inferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m2 per day) within a pre-specified non-inferiority margin of 3 times the levels among controls (primary outcome). These researchers followed participants for greater than or equal to 1 year to compare risk of relapse (secondary outcome). A total of 15 children per group (21 boys; mean age of 7 years [range of 2.6 to 13.5 years]) were enrolled and followed for less than or equal to 60 months (median of 22 months). Three-month proteinuria was 42 % lower in the rituximab group (geometric mean ratio, 0.58; 95 % confidence interval [CI]: 0.18 to 1.95 [i.e., within the non-inferiority margin of 3 times the levels in controls]). All but 1 child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95 % CI: 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in 1 child. The authors concluded that rituximab was non-inferior to steroids for the treatment of juvenile SDNS.

The authors noted that this study had several drawbacks including failure to use placebo among controls, lack of blinding, and small sample size (n = 15 in the rituximab group). They stated that several questions need to be addressed before rituximab use on a large scale can be recommended. Data are not available on long-term benefits and harms or on the optimal frequency of repeated rituximab infusions, particularly in children relapsing within 6 months of the first rituximab infusion (1 of 15 children in this study). These researchers did not know whether SDNS is a progressive disease or a disease that affects some children more severely than others, and therefore they did not know whether the strategy to maximize the benefits of rituximab therapy should be based on the stage of the disease or the patient characteristics. Preliminary data from this study indicated that most children can be maintained in remission using rituximab treatment alone with repeated infusions every 9 to 30 months. Second, the long-term safety of rituximab remains uncertain (median follow-up period in this study was 22 months), including the risk of malignancy and progressive multifocal leukoencephalopathy. According to a recent systematic review, these longer-term adverse events that have been reported in the literature occurred in individuals who had received other immunosuppressive medications before rituximab and in non-renal patients. Finally, most recent reports, including the present trial, have included only white patients, and further studies of patients from different ethnic groups are needed.

Niu et al (2016) examined the therapeutic efficacy of a single dose of RTX in children with steroid-dependent minimal change nephrotic syndrome (SD-MCNS). Patients with biopsy-proven minimal change disease (MCD) and clinical features of SDNS received a single dose of RTX (375 mg/m2). The toxicity and side effects of RTX were also observed. The study included 19 patients (10 males and 9 females). Follow-up of the patients was 1 to 50 months (28.1 ± 16.6 months). B-cell depletion was achieved with RTX infusion (CD20 less than 0.5 %) and lasted 1 to 6 months (mean of 2.92 ± 1.57 months). During follow-up, 10 patients remained in CR and did not relapse without administration of oral steroids or immunosuppressants for 4 to 50 months (mean of 30.1 ± 12.6 months), despite recovery of the B-cell count; 9 patients relapsed in the process of reducing steroids, thus, treatment was maintained at a lower dosage (T = 0, p < 0.05) than prior to use of RTX. The number of relapses also decreased significantly (T = 95, p < 0.05); 5 of the patients relapsed after stopping steroid for several months. At the end of follow-up, the efficacy of a single induction of RTX was 47.4 % (9/19). There were no significant side effects associated with administration of RTX. The authors concluded that RTX was a safe and effective alternative for children with SD-MCNS. They noted that RTX was an effective treatment for the rapid induction of remission and reduced relapse and steroid dependency. A single dose of RTX for children with SD-MCNS was recommended for rapid induction of remission, reduction of long-term steroid dosage, and decrease in the number of relapses, as it had few side effects. This was a small study (n = 19); and the authors concluded that larger samples of RCTs are needed to justify the definite efficacy and safety of RTX in this group of patients.

An UpToDate review on “Steroid-resistant idiopathic nephrotic syndrome in children” (Niaudet, 2018) states that “we do not recommend the routine use of rituximab in treating children with SRNS until there are data demonstrating that it is both effective and safe”.

Transverse Myelitis

American Academy of Neurology’s evidence-based guideline on “Clinical evaluation and treatment of transverse myelitis” (Scott et al, 2011) did not mention rituximab as a therapeutic option.

Kurz et al (2014) stated that clinical complications of Sjoegren's syndrome include myelitis and skin manifestations. There is scarce observational data and a lack of randomized controlled studies regarding the treatment of Sjoegren's syndrome in the presence of such complications. These investigators reported the case of a 41-year old Caucasian woman with biopsy-proven Sjoegren's syndrome who initially presented with generalized exanthema and subsequently developed acute extensive transverse myelitis. In view of the rapid deterioration these researchers opted for an intensive treatment using a combination of corticosteroid pulse therapy, plasmapheresis and cyclophosphamide, which they later changed to rituximab. Under that treatment the skin manifestations resolved entirely whereas transverse myelitis showed incomplete remission. Severe neurological and dermatological complications may occur in Sjoegren's syndrome. This suggested a close yet currently unclear pathogenetic relationship. The authors concluded that intensive immunosuppressant treatment resulted in significant improvement of both symptom clusters. Skin manifestations may precede other severe complications in Sjoegren's syndrome and therefore require particular attention.

Baxter et al (2017) noted that severe longitudinally extensive transverse myelitis (LETM) can cause quadriplegia, marked sensory dysfunction, and respiratory failure. Some patients are unresponsive to conventional immune therapy. These researchers reported 2 cases of severe immune-mediated LETM requiring intensive care admission that failed to respond to high-dose corticosteroids, plasma exchange, IVIG, and rituximab. Disease cessation and significant recovery was achieved after cyclophosphamide induction. In patients with severe acute immune-mediated LETM who failed to respond to corticosteroids and plasma exchange, cyclophosphamide induction should be considered. This agent and regimen provided a robust immunosuppressive response and can be induced rapidly.

Furthermore, an UpToDate review on “Transverse myelitis” (Krishnan and Greenberg, 2018) does not mention rituximab as a therapeutic option.

Viral Meningitis

An UpToDate review on “Viral meningitis: Management, prognosis, and prevention in children” (Di Pentima, 2018) does not mention rituximab as a therapeutic option.

Appendix

Examples of Contraindications to Methotrexate

Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease
Breastfeeding
Blood dyscrasias (e.g., thrombocytopenia, leukopenia, significant anemia)
Elevated liver transaminases
History of intolerance or adverse event
Hypersensitivity
Interstitial pneumonitis or clinically significant pulmonary fibrosis
Myelodysplasia
Pregnancy or currently planning pregnancy
Renal impairment
Significant drug interaction.

Table: Brands of Targeted Immune Modulators and FDA-approved Indications
Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Cytokine release syndrome (CRS) Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
Arcalyst	rilonacept	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA)
Avsola	infliximab-axxq	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthrits Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Adult-onset Still's disease Periodic fever syndromes Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behcet’s Disease Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Rheumatoid arthritis
Rituxan, Truxima, Ruxience, Riabni	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris (Rituxan only) Rheumatoid arthritis (Rituxan and Truxima only) Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis Ulcerative colitis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis Psoriatic arthritis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
*Rituximab (Rituxan), Rituximab-pvvr (Ruxience) and Rituximab-abbs (Truxima), Rituximab (Riabni)* :
CPT codes not covered for indications listed in the CPB:
62350	Implantation, revision or repositioning of tunneled intrathecal or epidural catheter, for long-term medication administration via an external pump or implantable reservoir/infusion pump; without laminectomy
62351	Implantation, revision or repositioning of tunneled intrathecal or epidural catheter, for long-term medication administration via an external pump or implantable reservoir/infusion pump; with laminectomy
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [anti-chimeric antibody testing and/or chimeric anti-TNF antibody testing for Rituxan therapy]
96450	Chemotherapy administration, into CNS (eg, intrathecal), requiring and including spinal puncture
Other CPT codes related to the CPB:
85651	Sedimentation rate, erythrocyte; non-automated
85652	Sedimentation rate, erythrocyte; automated
86140	C-reactive protein
86141	C-reactive protein; high sensitivity (hsCRP)
86200	Cyclic citrullinated peptide (CCP), antibody
86430	Rheumatoid factor; qualitative
86431	Rheumatoid factor; quantitative
96401 - 96446	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9312	Injection, rituximab, 10 mg
Q5115	Injection, rituximab-abbs, biosimilar, (Truxima), 10 mg
Q5119	Injection, rituximab-pvvr, biosimilar, (RUXIENCE), 10 mg
Q5123	Injection, rituximab-arrx, biosimilar, (riabni), 10 mg
Other HCPCS codes related to the CPB:
Inebilizumab-cdon (Uplizna), Interferon Beta Plegridy - no specific code
J0202	Injection, alemtuzumab, 1 mg
J0702	Injection, betamethasone acetate 3 mg and betamethasone sodium phosphate 3 mg
J1300	Injection, eculizumab, 10 mg
J1595	Injection, glatiramer acetate, 20 mg
J1826	Injection, interferon beta-1a, 30 mcg
J1830	Injection interferon beta-1b, 0.25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J2323	Injection, natalizumab, 1 mg
J2350	Injection, ocrelizumab, 1 mg
J3245	Injection, tildrakizumab, 1 mg
J7513	Daclizumab, parenteral, 25 mg
J8530	Cyclophosphamide; oral, 25 mg
J8562	Fludarabine phosphate, oral, 10 mg
J9070	Cyclophosphamide, 100 mg
J9185	Injection, fludarabine phosphate, 50 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
J9293	Injection, mitoxantrone HCI, per 5 mg
J9370	Vincristine sulfate, 1 mg
J9371	Injection, vincristine sulfate liposome, 1 mg
Q3027	Interferon beta-1a, 1 mcg for intramuscular use
ICD-10 codes covered if selection criteria are met:
C81.00 - C81.09	Nodular lymphocyte predominant Hodgkin lymphoma
C81.40 - C81.49	Lymphocyte-rich Hodgkin lymphoma
C82.00 - C82.99	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma
C83.10 - C83.19	Mantle cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.50 - C83.59	Lymphoblastic (diffuse) lymphoma
C83.70 - C83.79	Burkitt lymphoma
C83.80 - C83.89	Other non-follicular lymphoma
C83.90 - C83.99	Non-follicular (diffuse) lymphoma, unspecified
C84.00 - C84.79, C84.A0 - C84.Z9, C84.90 - C84.99	Mature T/NK – cell lymphomas
C85.10 - C85.19	Unspecified B-cell and mediastinal (thymic) large B-cell lymphoma
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma
C85.80 - C85.99	Other specified types of non-Hodgkin lymphoma and non-Hodgkin's lymphoma, unspecified
C86.0 - C86.4	Extranodal NK/T-cell lymphoma, nasal type, Hepatosplenic T-cell lymphoma, Enteropathy-type (intestinal) T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, and Blastic NK-cell lymphoma
C86.5	Angioimmunoblastic T-cell lymphoma
C86.6	Primary cutaneous CD30-positive T-cell proliferations
C88.0	Waldenstrom's macroglobulinemia
C88.4	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]
C91.00 - C91.01	Acute lymphoblastic leukemia [ALL] [Philadelphia chromosome-negative]
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type [small lymphocytic lymphoma]
C91.40 - C91.42	Hairy cell leukemia
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2	Castleman disease
D59.0 - D59.1	Autoimmune hemolytic anemias [refractory]
D69.3	Immune thrombocytopenic purpura [refractory]
D76.3	Other histiocytosis syndromes [Rosai-Dorfman disease]
D89.1	Cryoglobulinemia [refractory to corticosteroids and other immunosuppressive agents]
D89.811	Chronic graft-versus-host disease
G04.81	Other encephalitis and encephalomyelitis [for immune checkpoint inhibitor related encephalitis]
G35	Multiple sclerosis
G36.0	Neuromyelitis optica [Devic]
G70.00 - G70.01	Myasthenia gravis [muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG)]
H55.89	Other irregular eye movements [opsoclonus-myoclonus-ataxia associated with neuroblastoma]
I77.6	Arteritis, unspecified [ anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitides]
L10.0	Pemphigus vulgaris [corticosteroid-refractory]
L10.2	Pemphigus foliaceous [corticosteroid-refractory]
L10.81	Paraneoplastic pemphigus [corticosteroid-refractory]
L12.0	Bullous pemphigoid
L12.1	Citricial pemphigoid
L12.30 - L12.35	Acquired epidermolysis bullosa
L40.1	Generalized pustular psoriasis
M05.00 - M14.89	Rheumatoid arthritis and other inflammatory polyarthropathies
M30.1	Polyarteritis with lung involvement [Churg-Strauss] [medically necessary when rituximab is used in conjunction with glucocorticoids]
M31.1	Thrombotic microangiopathy [refractory thrombotic thrombocytopenic purpura]
M31.30 - M31.31	Wegener's granulomatosis [medically necessary when rituximab is used in conjunction with glucocorticoids]
M31.7	Microscopic polyangiitis [medically necessary when rituximab is used in conjunction with glucocorticoids]
M32.0 - M32.9	Systemic lupus erythematosus
M35.00 - M35.09	Sicca syndrome [Sjogren]
N01.3	Rapidly progressive nephritic syndrome with diffuse mesangial proliferative glomerulonephritis [pauci-immune glomerulonephritis] [in conjunction with glucocorticoids]
T86.00 - T86.99	Complications of transplanted organs and tissue [antibody mediated rejection in heart transplant recipients]
Z94.0 - Z94.9	Transplanted organ and tissue status [prevention (desensitization) of antibody mediated rejection in highly sensitized solid organ transplant recipients]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A87.0 - A87.9	Viral meningitis
C74.00 - C74.92	Malignant neoplasm of adrenal gland
C79.70 - C79.72	Secondary malignant neoplasm of adrenal gland
C90.10 - C90.12	Plasma cell leukemia
C92.60 - C92.62	Acute myeloid leukemia with 11q23-abnormality
C92.A0 - C92.A2	Acute myeloid leukemia with multilineage dysplasia
C94.0 - C94.9	Acute erythroid leukemia
C96.5 - C96.6	Multifocal and unisystemic Langerhans-cell histiocytosis and unifocal Langerhans-cell histiocytosis
D47.2	Monoclonal gammopathy [of undetermined significance (MGUS) neuropathy]
D59.2 - D59.4	Nonautoimmune hemolytic anemias
D60.0 - D60.9	Aquired pure red cell aplasia [erythroblastopenia]
D61.01 - D61.9	Other aplastic anemias and other bone marrow failure syndromes
D66	Hereditary factor VIII deficiency
D67	Hereditary factor IX deficiency
D68.0	Von Willebrand's disease
D68.1	Hereditary factor XI deficiency
D68.311	Acquired hemophilia
D68.61	Anticardiolipin syndrome [anti-phospholipid syndrome]
D70.8	Other neutropenia [autoimmune]
D76.1 - D76.2	Hemophagocytic syndromes [lymphohistiocytosis]
D86.0 - D86.9	Sarcoidosis
D89.1	Cryoglobulinemia
D89.810, D89.812 - D89.813	Graft-versus host disease
D89.89	Other specified disorders involving the immune mechanism, not elsewhere classified
E05.00 - E05.01	Thyrotoxicosis with diffuse goiter [Graves' opthalmopathy] [thyroid-associated ophthalmopathy]
E06.3	Autoimmune thyroiditis [Hashimoto's encephalitis]
E53.8	Deficiency of other specified B group vitamins [folate deficiency (cerebral)]
E88.09	Other disorders of plasma-protein metabolism, not elsewhere classified [plasma cell dyscrasia]
G04.00 - G04.39, G04.89 - G05.4	Encephalitis, myelitis, and encephalomyelitis [autoimmune encephalitis][except immune checkpoint inhibitor related encephalitis]
G11.9	Hereditary ataxia, unspecified [GALOP Syndrome]
G24.1	Genetic torsion dystonia [paraneoplastic]
G25.82	Stiff man syndrome
G37.3	Acute transverse myelitis in demyelinating disease of central nervous system
G40.409	Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus. [autoimmune epilepsy]
G51.8	Other disorders of facial nerve [Parry-Romberg syndrome]
G60.0 - G60.9	Hereditary and idiopathic peripheral neuropathy [anti-myelin-associated glycoprotein]
G61.81	Chronic inflammatory demyelinating polyneuritis
G61.89	Other inflammatory polyneuropathies [anti-MAG neuropathy]
G72.81	Critical illness myopathy [necrotizing myopathy]
G73.1	Lambert-Eaton syndrome in neoplastic disease
G90.50 - G90.59	Complex regional pain syndrome I (CRPS I)
H05.10	Unspecified chronic inflammatory disorders of orbit [orbital pseudotumor]
H05.89	Other disorders of orbit [orbital apex sphenoid syndrome]
H15.001 - H15.099	Scleritis
H16.321 - H16.329	Diffuse interstitial keratitis [Cogan's syndrome]
H20.00 - H20.9	Iridocyclitis [uveitis]
H30.891 - H30.93	Other and unspecified chorioretinal inflammations
H35.00	Unspecified background retinopathy
H35.89	Other specified retinal disorders [autoimmune retinopathy]
H46.00 - H46.9	Optic neuritis
H49.40 - H49.43	Progressive external ophthalmoplegia [Tolosa-Hunt syndrome]
I67.7	Cerebral arteritis, not elsewhere classified [granulomatous angiitis of the central nervous system
I77.6	Arteritis, unspecified [primary angiitis of the central nervous system]
J42	Unspecified chronic bronchitis [bronchiolitis obliterans]
J60.8	Other hereditary and idiopathic neuropathies
J67.0 - J67.9	Hypersensitivity pneumonitis due to organic dust
J84.112	Idiopathic pulmonary fibrosis
J84.9	Interstitial pulmonary disease, unspecified [generic (idiopathic) interstitial lung disease]
J98.51 - J98.59	Mediastinitis
K52.831	Collagenous colitis [collagenous gastritis]
K75.4	Autoimmune hepatitis
K86.81 - K86.89	Other specified diseases of pancreas [autoimmune pancreatitis/atrophy of the pancreas]
K90.89	Other intestinal malabsorption [bile salt export pump deficiency after liver transplantation]
L40.50 - L40.59	Arthropathic psoriasis
L50.8	Other urticaria [chronic]
M07.60 - M07.69	Enteropathic arthropathies [arthritis associated with inflammatory bowel disease]
M08.00 - M08.99	Juvenile arthritis
M30.0	Polyarteritis nodosa
M30.3	Mucocutaneous lymph node syndrome [Kawasaki]
M30.8	Other conditions related to polyarteritis nodosa [Sneddon syndrome]
M31.0	Hypersensitivity angiitis [Goodpasture's syndrome]
M33.00 - M33.99	Dermatomyositis [juvenile]
M34.0 - M34.9	Systemic sclerosis [scleroderma]
M35.2	Behcet's disease
M45.0 - M45.9	Ankylosing spondylitis
M46.90 - M46.99	Unspecified inflammatory spondylopathy [axial spondyloarthritis]
M61.30 - M61.59	Calcification and ossification of muscles associated with burns [polymyositis ossificans]
N00.0 - N01.2 N01.4 - N07.9	Glomerular diseases
N13.8	Other obstructive and reflux uropathy [retroperitoneal fibrosis]
Z51.11 - Z51.12	Encounter for antineoplastic chemotherapy and immunotherapy
*Rituximab and hyaluronidase (Rituxan Hycela)*:
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401 - 96402	Chemotherapy administration, subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met :
J9311	Injection, rituximab 10 mg and hyaluronidase
ICD-10 codes covered if selection criteria are met:
C82.00 - C82.99	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma
C83.10 - C83.19	Mantle cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.50 - C83.59	Lymphoblastic (diffuse) lymphoma
C83.80 - C83.99	Other non-follicular lymphoma
C85.10 - C85.19	Unspecified B-cell lymphoma
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma
C88.0	Waldenstrom's macroglobulinemia
C88.4	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type
C91.40 - C91.42	Hairy cell leukemia
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2	Castleman disease

The above policy is based on the following references:

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Last Review 08/24/2021

Effective: 01/04/1999

Next Review: 06/23/2022
Review History
Definitions

Rituximab

Brand Selection for Medically Necessary Indications

Moderately to severely active rheumatoid arthritis (RA)

Policy

Treatment of Hematologic and Oncologic Conditions

Criteria for Initial Approval

Oncologic indications

Hematologic indications

Myasthenia gravis

Immune checkpoint inhibitor-related toxicities.

Continuation of Therapy

Oncologic indications

Immune checkpoint inhibitor-related toxicities

All other indications

Treatment of Rheumatoid Arthritis and Other Conditions

Criteria for Initial Approval

Rheumatoid arthritis (RA)

Granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis), microscopic polyangiitis (MPA), Churg-Strauss, or pauci-immune glomerulonephritis;

Sjögren’s syndrome

Relapsing remitting multiple sclerosis (MS);

Neuromyelitis optica (i.e., neuromyelitis optica spectrum disorder (NMOSD), Devic disease)

Autoimmune blistering disease

Cryoglobulinemia

Solid organ transplant treatment and prevention of antibody mediated rejection in solid organ transplant;

Opsoclonus-myoclonus-ataxia associated with neuroblastoma

Systemic lupus erythematosus (SLE) that is refractory to immunosuppressive therapy.

Continuation of Therapy

Rituximab and Hyaluronidase (Rituxan Hycela)

Criteria for Initial Approval

Continuation of Therapy

Dosage and Administration

Rituxan

Chronic Lymphocytic Leukemia (CLL)

Component of Zevalin (ibritumomab tiuxetan) Therapeutic Regimen for NHL

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

Non-Hodgkin’s Lymphoma (NHL)

Pemphigus Vulgaris (PV)

Rheumatoid Arthritis (RA)

Ruxience

Truxima

Riabni

Rituxan Hycela

Experimental and Investigational or Not Medically Necessary

Background

Rituximab (Rituxan), Rituximab-pvvr (Ruxience), Rituximab-abbs (Truxima), and Rituxmab-arrx (Riabni)

U.S. Food and Drug Administration (FDA)-Approved Indications

Compendial Uses for Rituxan, Ruxience, Truxima and Riabni

Rituximab and hyaluronidase human (Rituxan Hycela)

U.S. Food and Drug Administration (FDA)-Approved Indications

Compendial Uses

Rituximab-abbs (Truxima, a Biosimilar to Rituxan)

Rituximab-arrx (Riabni, a Biosimilar to Rituxan)

Rituximab-pvvr (Ruxience, a Biosimilar to Rituxan)

Hematologic and Oncologic Conditions

Rheumatoid Arthritis and Other Conditions

Acute Zonal Occult Outer Retinopathy (AZOOR)

Adrenal Gland Neoplasm

Amyopathic Dermatomyositis

Anti-Neutrophil Cytoplasmic Antibody-Associated (ANCA-associated) Vasculitides

Ankylosing Spondylitis and Axial Spondyloarthritis

Anterior Nodular Scleritis

Antibody Mediated Rejection

Anti-MAG Neuropathy

Anti-Synthetase Syndrome

Aplastic Anemia

Autoimmune Blistering Dermatoses

Autoimmune Epilepsy

Autoimmune Hepatitis

Autoimmune Limbic Encephalitis

Autoimmune Myopathy Associated with Anti-Signal Recognition Particle Antibodies

Autoimmune Retinopathy

Chronic Urticaria

Collagenous Gastritis

Crescentic IgA Nephropathy

CREST Syndrome

Dermatomyositis / Polymyositis

Factor VIII and Factor IX Inhibitors in People with Inherited Severe Hemophilia

Fibrosing Mediastinitis

Hypersensitivity Pneumonitis

Immune Thrombocytopenic Purpura