Infliximab [Medicare]

Number: 0341m

Commercial CPB  |  Medicare CPB

Medicare Part B Step Therapy Criteria

For Medicare Advantage plans that do not offer prescription drug coverage (MA)

Avosla and Inflectra, for the indications listed below:

• Crohn’s Disease (CD)
• Pediatric Crohn’s Disease

• Plaque Psoriasis (Ps)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Remicade or Renflexis
  2. Intolerable adverse event to Remicade or Renflexis
  3. Remicade or Renflexisis contraindicated for the member.
• Ankylosing Spondylitis (AS)
• Psoriatic Arthritis (PsA)

• Rheumatoid Arthritis (RA)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Remicade, Renflexis, or Simponi Aria
  2. Intolerable adverse event to Remicade, Renflexis, or Simponi Aria
  3. Remicade, Renflexis, or Simponi Aria is contraindicated for the member.

For Medicare Advantage plans that offer prescription drug coverage (MAPD)

Avsola, Inflectra, Remicade, and Renflexis, for the indications listed below:

• Crohn’s Disease (CD)

• Pediatric Crohn’s Disease

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Humira
  2. Intolerable adverse event to Humira
  3. Humira is contraindicated for the member.
• Ankylosing Spondylitis (AS)

• Juvenile idiopathic arthritis (JIA)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel or Humira
  2. Intolerable adverse event to Enbrel or Humira
  3. Enbrel or Humira is contraindicated for the member.

• Plaque Psoriasis (Ps)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, or Skyrizi
  2. Intolerable adverse event to Enbrel, Humira, or Skyrizi
  3. Enbrel, Humira, or Skyrizi is contraindicated for the member.

• Psoriatic Arthritis (PsA)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, or Xeljanz
  2. Intolerable adverse event to Enbrel, Humira, or Xeljanz
  3. Enbrel, Humira, or Xeljanz is contraindicated for the member.

• Rheumatoid Arthritis (RA)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, Rinvoq, or Xeljanz
  2. Intolerable adverse event to Enbrel, Humira, Rinvoq, or Xeljanz
  3. Enbrel, Humira, Rinvoq, or Xeljanz is contraindicated for the member.

For Medicare Advantage plans that do not offer prescription drug coverage (MA) and Medicare Advantage plans that offer prescription drug coverage (MAPD)

Avosla and Inflectra, for the indications listed below:

• Ulcerative Colitis (UC)

  Are not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Remicade or Renflexis
  2. Intolerable adverse event to Remicade or Renflexis
  3. Remicade or Renflexis is contraindicated for the member.

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of infliximab products (Avsola, Inflectra, Remicade, and Renflexis) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Avsola, Inflectra, Remicade, and Renflexis, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies.  For information on site of service for infliximab products (Avsola, Inflectra, Remicade, and Renflexis), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Medically Necessary Indications

   Aetna considers infliximab (Remicade), infliximab-abda (Renflexis), infliximab-axxq (Avsola), and inflixmab-dyyb (Inflectra) medically necessary for members with any of the following indications, where the member has had a documented negative tuberculosis (TB) test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnotes* within 6 months of initiating therapy for persons who are naive to biologic DMARDs or targeted synthetic DMARDs associated with an increased risk of TB, and repeated yearly for members with risk factorsFootnotes** for TB that are continuing therapy with biologics:

   1. Moderately to severely active Crohn’s disease (CD)

      1. For members who have previously received a biologic indicated for the treatment of moderately to severely active Crohn’s disease; or
      2. For the treatment of moderately to severely active CD when the member has had an inadequate response, intolerance or contraindication to at least one conventional therapy option (See Appendix A); or
      3. For the treatment of fistulizing CD.

   2. Moderately to severely active ulcerative colitis (UC)

      1. For members who have previously received a biologic or targeted synthetic DMARD (e.g., Xeljanz) indicated for moderately to severely active ulcerative colitis; or
      2. For the treatment of moderately to severely active UC when the member has had an inadequate response, intolerance or contraindication to at least one conventional therapy option (See Appendix B); or
      3. For members who have been hospitalized for acute severe UC (e.g., continuous bleeding, severe toxic symptoms, including fever and anorexia).

   3. Moderately to severely active rheumatoid arthritis (RA)

      1. For members who have previously received a biologic or targeted synthetic DMARD (e.g., Rinvoq, Xeljanz) indicated for moderately to severely active rheumatoid arthritis. The requested medication must be prescribed in combination with methotrexate or leflunomide unless the member has a clinical reason not to use methotrexate or leflunomide; or
      2. For treatment of moderately to severely active RA when all of the following criteria are met:
         
         
         1. Member is prescribed the requested medication in combination with methotrexate or leflunomide, or has a clinical reason not to use methotrexate or leflunomide; and
         2. Member meets any of the following criteria:
            
            
            1. Member has experienced an inadequate response to at least a 3-month trial of methotrexate despite adequate dosing (i.e., titrated to 20 mg/week); or
            2. Member has an intolerance or contraindication to methotrexate (see Appendix C).

   4. Active ankylosing spondylitis (AS) and active axial spondyloarthritis
      

      1. For members who have previously received a biologic indicated for active ankylosing spondylitis or active axial spondyloarthritis; or
      2. For treatment of active ankylosing spondylitis or active axial spondyloarthritis when any of the following criteria is met:
         
         
         1. Member has experienced an inadequate response to at least two non-steroidal anti-inflammatory drugs (NSAIDs); or
         2. Member has an intolerance or contraindication to two or more NSAIDs.

   5. Moderate to severe plaque psoriasis (PsO) or active psoriatic arthritis (PsA) 

      When member meets criteria in CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators or CPB 0658m - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators [Medicare]

   6. Behçet’s disease

      1. For members who have previously received a Otezla (apremilast) or a biologic indicated for the treatment of Behcet’s disease; or
      2. For the treatment of Behçet’s disease when the member has had an inadequate response to at least one nonbiologic medication for Behçet’s disease (e.g., apremilast, colchicine, systemic glucocorticoids, azathioprine).

   7. Granulomatosis with polyangiitis (Wegener’s granulomatosis)

      For treatment of granulomatosis with polyangiitis when either of the following criteria is met:

      1. Member has experienced an inadequate response to corticosteroids or immunosuppressant therapy (e.g, cyclophosphamide, azathioprine, methotrexate, or mycophenolate mofetil); or
      2. Member has an intolerance or contraindication to corticosteroids and immunosuppressive therapy.

   8. Hidradenitis suppurativa

      1. For members who have previously received a biologic indicated for the treatment of severe, refractory hidradenitis suppurativa; or
      2. For treatment of severe, refractory hidradenitis suppurativa when either of the following is met:
         
         
         1. Member has experienced an inadequate response to oral antibiotics for at least 90 days; or
         2. Member has an intolerance or contraindication to oral antibiotics.

   9. Juvenile Idiopathic arthritis (JIA)

      1. For members who have previously received a biologic or targeted synthetic DMARD indicated for juvenile idiopathic arthritis; or
      2. For the treatment of JIA when any of the following criteria is met:
         
         
         1. Member has an inadequate response to at least a 1-month trial of NSAIDs; or
         2. Member has an inadequate response to at least a 2-week trial of corticosteroids; or
         3. Member has an inadequate response to at least a 3-month trial of methotrexate or leflunomide.

   10. Pyoderma gangrenosum

       1. For members who have previously received a biologic indicated for pyoderma gangrenosum; or
       2. For treatment of pyoderma gangrenosum when either of the following is met:
          
          
          1. Member has experienced an inadequate response to corticosteroids or immunosuppressive therapy (e.g., cyclosporine or mycophenolate mofetil); or
          2. Member has an intolerance or contraindication to corticosteroids and immunosuppressive therapy (e.g. cyclosporine, mycophenolate mofetil).

   11. Sarcoidosis

       For treatment of sarcoidosis in members when any of the following criteria is met:

       1. Member has experienced an inadequate response to corticosteroids or immunosuppressants; or
       2. Member has an intolerance or contraindication to corticosteroids and immunosuppressive therapy.

   12. Takayasu’s arteritis

       For treatment of refractory Takayasu’s arteritis when any of the follow criteria is met:

       1. Member has experienced an inadequate response to corticosteroids or immunosuppressive therapy (e.g., methotrexate, azathioprine, or mycophenolate mofetil); or
       2. Member has an intolerance or contraindication to corticosteroids and immunosuppressive therapy (e.g., methotrexate, azathioprine, or mycophenolate mofetil). 

   13. Uveitis

       1. For members who have previously received a biologic indicated for uveitis; or
       2. For treatment of uveitis when any of the follow criteria is met:
          
          
          1. Member has experienced an inadequate response to corticosteroids or immunosuppressive therapy (e.g., methotrexate, azathioprine, or mycophenolate mofetil); or
          2. Member has an intolerance or contraindication to corticosteroids and immunosuppressive therapy (e.g., methotrexate, azathioprine, or mycophenolate mofetil).

   14. Reactive arthritis

       1. For members who have previously received a biologic indicated for reactive arthritis; or
       2. For treatment of reactive arthritis when any of the following criteria is met:
          
          
          1. Member has experienced an inadequate response to at least a 3-month trial of methotrexate despite adequate dosing (i.e., titrated to 20 mg/week); or
          2. Member has an intolerance or contraindication to methotrexate (see Appendix C).

   15. Immune Checkpoint Inhibitor Toxicity

       For the treatment of immune checkpoint inhibitor (e.g., CTLA-4, PD-L1 inhibitor) toxicity when either of the following is met:

       1. Member has had an inadequate response, intolerance, or contraindication to corticosteroids; or
       2. Member has cardiac toxicity.

   16. Acute graft verus host disease (GVHD)

       For treatment of acute graft versus host disease when either of the following criteria is met:

       1. Member has experienced an inadequate response to systemic corticosteroids; or
       2. Member has an intolerance or contraindication to corticosteroids.

2. Continuation of Therapy

   1. Immune Checkpoint Inhibitor Toxicity

      Aetna considers continuation of the requested medication medically necessary for members (including new members) with immune checkpoint inhibitor toxicity who meet all initial authorization criteria.

   2. All other indications

      Aetna considers continuation of the requested medication medically necessary for all other indications in members (including new members) who are using the requested medication for an indication outlined above and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition. 

3. Combination with Other Biologics

   Aetna considers the use of infliximab (Remicade), infliximab-abda (Renflexis), infliximab-axxq (Avsola), and infliximab-dyyb (Inflectra) with other biologics (e.g., Enbrel, Humira, Cimzia, Simponi, Orencia, or Kineret) or secukinumab (Cosentyx) for the same condition experimental and investigational because the effectiveness and safety of such combinations has not been established.

4. Infliximab Serum Levels and Antibodies

   Aetna considers measurements of serum levels of infliximab and antibodies to infliximab (human anti-chimeric antibodies (HACA)) (e.g., the Anser IFX test (Prometheus Lab) and InformTx therapeutic drug monitoring (TDM; Miraca Life Sciences)) experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.

5. Antihistone Antibodies

   Aetna considers measurements of anti-histone antibodies for monitoring infliximab therapy experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.

6. Experimental and Investigational Indications

   Aetna considers infliximab, infliximab-abda, infliximab-axxq, and infliximab-dyyb experimental and investigational for all other indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

   • Acne fulminans
   • Amyloid angiopathy
   • Asthma
   • Autoimmune cholangiopathy
   • Birdshot retinochoroidopathy
   • Bronchiolitis obliterans
   • Celiac disease
   • Central nervous system amyloidosis
   • Chemotherapy induced enterocolitis (not due to Yervoy or Opdivo)
   • Chronic immune-mediated myelitis
   • Chronic obstructive pulmonary disease
   • Cogan's syndrome
   • Corneal ulcer
   • Cranial nerve palsy
   • Cystoid macular degeneration
   • Disc herniation-induced sciatica
   • Discoid lupus erythematosus
   • Eczema
   • Eosinophilic fasciitis
   • Granuloma annulare
   • Granulomatous angiitis
   • Granulomatous mastitis
   • Hepatitis C genotype 1
   • IgG4-related disease
   • Iritis
   • Kawasaki disease
   • Localized scleroderma/morphea
   • Membranous glomerulopathy
   • Microscopic colitis
   • Multifocal osteomyelitis (e.g., (chronic recurrent multifocal osteomyelitis (CRMO))
   • Necrobiosis lipoidica diabeticorum
   • Nodular scleritis
   • Panniculitis
   • Polyarteritis nodosa
   • Polymyositis
   • Prevention of post-operative recurrence of Crohn's disease
   • Rejection following small bowel transplantation
   • Relapsing polychondritis
   • Renal cell carcinoma
   • Retinal vasculitis
   • Scleroderma
   • Sjogren's syndrome
   • Still's disease
   • Systemic lupus erythematosus
   • Tolosa-Hunt syndrome
   • Tubulo-interstitial nephritis with uveitis (TINU) syndrome

Dosing Recommendations

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information.

Infliximab products (Remicade, Avsola, Inflectra, and Renflexis) are available for injection using 100 mg of lyophilized infliximab, or its biosimilar, in a 20 mL single-dose vial for reconstitution and dilution, and administered as an intravenous infusion.

Table: Dosing for Infliximab, Infliximab-axxq, Infliximab-dyyb, and Infliximab-abda

Indication	Dose
Ankylosing spondylitis	Induction: 5 mg/kg IV at weeks 0, 2, and 6 Maintenance: 5 mg/kg IV every 6 weeks
Crohn's disease, moderate-to-severe or fistulizing (adults)	Induction: 5 mg/kg IV at weeks 0, 2, and 6 Maintenance: 5 mg/kg IV every 8 weeks For persons who respond and then lose their response, consideration may be given to treatment with 10 mg/kg IV every 8 weeks. Persons who do not respond by week 14 are unlikely to respond and consideration should be given to discontinue infliximab in these persons.
Crohn's disease, moderate-to-severe (pediatrics 6 years of age and older)	Induction: 5 mg/kg IV at weeks 0, 2, and 6 Maintenance: 5 mg/kg IV every 8 weeks
Plaque psoriasis, chronic (severe)	Induction: 5 mg/kg IV at weeks 0, 2, and 6 Maintenance: 5 mg/kg IV every 8 weeks
Psoriasis arthritis	Induction: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg IV every 8 weeks
Rheumatoid arthritis, moderate-to-severe	Induction: 3 mg/kg IV at weeks 0, 2 and 6 Maintenance: 3 mg/kg IV every 8 weeks Incomplete response: consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.
Ulcerative colitis (6 years of age and older)	Induction: 5 mg/kg IV at weeks 0, 2 and 6 Maintenance: 5 mg/kg IV every 8 weeks

Sources: Prescribing Information (Amgen, 2019a, Janssen, 2020; Merck, 2019; Pfizer, 2019)

Background

Infliximab products include Avsola (infliximab-axxq), Inflectra (infliximab-dyyb), Remicade (inflximab), and Renflexis (infliximab-abda) brands, which are considered tumor necrosis factor (TNF) blockers. 

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

• Moderately to severely active Crohn’s disease (CD) and fistulizing CD
• Moderately to severely active ulcerative colitis (UC)
• Moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate
• Active ankylosing spondylitis (AS)
• Active psoriatic arthritis (PsA)
• Chronic severe plaque psoriasis (PsO)

Compendial Uses

• Acute graft versus host disease
• Axial spondyloarthritis
• Behcet’s syndrome
• Granulomatosis with polyangiitis (Wegener’s granulomatosis)
• Hidradenitis suppurativa
• Immune checkpoint inhibitor toxicity
• Juvenile idiopathic arthritis
• Moderate to severe plaque psoriasis
• Pyoderma gangrenosum
• Reactive arthritis
• Sarcoidosis
• Takayasu’s arteritis
• Uveitis

Infliximab neutralizes the biological activity of tumor necrosis factor-alpha (TNF‐α) by binding to the soluble and transmembrane forms of TNF‐α therefore effectively inhibiting the binding of TNF‐α with its receptors. Infliximab does not neutralize TNF‐β (lymphotoxin α), a related cytokine that utilizes the same receptors as TNF‐α. TNF‐α is a cytokine that plays an important role in various inflammatory processes including: induction of pro‐inflammatory cytokines such as interleukins 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes.

Elevated concentrations of TNF-alpha have been found in the joints of rheumatoid arthritis (RA) patients and the stools of Crohn's disease patients, and correlate with elevated disease activity.  In Crohn's disease, treatment with infliximab reduced infiltration of inflammatory cells and TNF alpha production in inflamed areas of the intestine and reduced the proportion of mononuclear cells from the lamina propia able to express TNF alpha and interferon gamma.  In RA, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction, and tissue degradation.

The patient selection criteria outlined above were derived from the Food and Drug Administration (FDA)-approved prescribing information for Remicade, the studies that were presented to the FDA in support of the pre-market approval application, and studies in the peer-reviewed published medical literature.

The FDA-approved product labeling for Remicade includes a black box warning that patients treated with infliximab are at increased risk for infections, including progression to serious infections leading to hospitalization or death.  These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections.  The black box warning states that patients should be educated about the symptoms of infection, closely monitored for signs and symptoms of infection during and after treatment with infliximab, and should have access to appropriate medical care.  Patients who develop an infection should be evaluated for appropriate antimicrobial therapy and for serious infections infliximab should be discontinued.  The labeling states that tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving infliximab.  Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating infliximab and during therapy.  The labeling recommends that treatment of latent tuberculosis infection should be initiated prior to therapy with infliximab.  Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving infliximab. Some patients who tested negative for latent tuberculosis prior to receiving infliximab have developed active tuberculosis. Physicians should monitor patients receiving infliximab for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.

The black box warning states that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab. Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers including infliximab. Almost all had received azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of infliximab cases were reported in patients with Crohn’s disease or ulcerative colitis, most of whom were adolescent or young adult males (Janssen, 2020).

The labeling for Remicade states that infliximab has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options.  The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg.  The labeling states that there have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab.  There have also been post-marketing reports of new onset and worsening heart failure, including heart failure in patients without known pre-existing cardiovascular disease.  Some of these patients have been under 50 years of age.  The labeling recommends that, if a decision is made to administer infliximab to patients with heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear (Janssen, 2020).

In addition to risk of serious infections, malignancies and heart failure, other labeled warnings and precautions include the following:

• invasive fungal infections
• hepatitis B virus reactivation
• hepatotoxicity
• cytopenias
• hypersensitivity - serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. 
• cardiovascular and cerebrovascular reactions – cerebrovascular accidents, myocardial infarctions (some fatal), and arrhythmias have been reported during and within 24 hours of initiation of infliximab infusion.
• demyelinating disease – exacerbation or new onset may occur. 
• Lupus-like syndrome
• vaccinations and use of live vaccines/therapeutic infectious agents – prior to initiating infliximab bring pediatric and adult patients up to date with all vaccinations. Live vaccines or therapeutic infectious agents should not be given with infliximab. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab.

Most common adverse reactions (>10%) – infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain (Janssen, 2020).

The product labeling for Remicade recommends against use with other biologics. The prescribing information states: "The combination of Remicade with other biological therapeutics used to treat the same conditions as Remicade is not recommended."

Acne Fulminans

Iqbal and Kolodney (2005) stated that acne fulminans is a syndrome of sudden onset hemorrhagic and ulcerative acne involving the back, chest, and face combined with systemic symptoms.  It can be the dermatologic manifestation of the synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome.  Current therapy for acne fulminans consists of wound care, topical and systemic corticosteroids, isotretinoin, and non-steroidal anti-inflammatory drugs (NSAIDs).  Infliximab has shown efficacy in the treatment of psoriatic arthritis and ankylosing spondylitis both of which share clinical similarities to the SAPHO syndrome.  These investigators reported the case of a patient with the SAPHO syndrome and acne fulminans who was treated with infliximab; 10 months after initiating therapy with infliximab, the area of the patient's ulcerative lesions was reduced by 70 %.  The authors concluded that infliximab might be considered as a treatment option for patients with acne fulminans unresponsive to conventional therapies.

Furthermore, an UpToDate review on “Treatment of acne vulgaris” (Graber, 2019) states that “Oral glucocorticoids (typically, prednisone 0.5 to 1 mg/kg per day) and oral isotretinoin are the mainstays of treatment for acne fulminans.  There is a paucity of high-quality data to guide the approach to treatment”. 

Currently, there is insufficient evidence to support the use of infliximab for the treatment of acne fulminans.

Age-Related Macular Degeneration

An UpToDate review on “Age-related macular degeneration: Treatment and prevention” (Arroyo, 2013) states that “Several investigational clinical trials are underway to evaluate treatment options for dry AMD.  Potential new treatments include topical antioxidant eye drops, implantation of encapsulated human NTC cells, and fetal cell transplantation.  The first report of transplantation of cells derived from human embryonic stem cells (hESCs) into human beings involved subretinal transplantation of cells differentiated to retinal pigment epithelium in a patient with dry AMD.  At four months there was no evidence of rejection, tumorigenicity, or ectopic tissue; there was minimal visual improvement although the patient had advanced disease at baseline.  Ongoing trials for patients with neovascular AMD include evaluation of the angiogenesis inhibitor pazopanib given as topical eye drops, subconjunctival injection of an antiproliferative polyamine analog (CGC-11047), and various combination treatment protocols that combine photodynamic therapy with intravitreal anti-VEGF agents.  A topical kinase inhibitor with multiple growth factor targets, including VEGF, suppressed choroidal neovascularization in a mouse model.  Genetic defects in various loci in the complement factor H gene can be found in over 50 percent of cases of macular degeneration.  Gene-environment interactions compound the genetic risk for AMD and have been demonstrated for smokers and for antibodies to C pneumonia.  Rapid and affordable genetic screening is being developed commercially, with the intent to identify high risk patients who could modify some risk factors or benefit from targeted therapy.  Some genetic mutations associated with AMD are thought to result in increased complement activation and inflammation.  The effects of anti-inflammatory drugs or vaccines on the progression of AMD are under investigation.  Research trials include study of an intravitreal complement inhibitor (POT-4), vaccination with the immunomodulator copaxone, and treatment with anti-inflammatory agents (infliximab, sirolimus, and daclizumab).  Whenever possible, patients should be encouraged to enroll in clinical trials of treatments for AMD”.

Ankylosing Spondylitis and Spondyloarthropathies

Two published randomized controlled trials have reported on significant reductions in disease activity in patients with ankylosing spondylitis and other spondyloarthropathies who were treated with infliximab.  Spondyloarthropathy (literally arthritis of the spine) may be associated with ankylosing spondylitis, Reiter's syndrome, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease, or may be idiopathic (undifferentiated spondyloarthropathy).  Van den Bosch et al (2002) reported on a 12-week long clinical study involving forty patients with active spondyloarthropathy who were randomly assigned to receive an intravenous loading dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or placebo.  Both patient and physician global assessments of disease activity on a visual analog scale improved significantly in the infliximab group compared with the baseline value, with no improvement in the placebo group.  As early as week 2 and sustained up to week 12, there was a highly statistically significant difference between the values for these 2 endpoints in the infliximab versus the placebo group.  In most of the other assessments of disease activity (laboratory measures, assessments of specific peripheral and/or axial disease), significant improvements were observed in the infliximab group compared with the baseline value and compared with placebo.  There was 1 severe drug-related adverse event, in which a patient developed disseminated tuberculosis.

Braun et al (2002) reported the results of a 12-week randomized placebo-controlled clinical trial involving 35 patients with active ankylosing spondylitis treated with intravenous 5 mg/kg infliximab infusion (at weeks 0, 2 and 6) and 35 patients assigned to placebo.  Eighteen (53 %) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50 % compared with 3 (9 %) of 35 on placebo (difference 44 % (95 % confidence interval [CI]: 23 to 61, p < 0.0001).  Function and quality of life also improved significantly on infliximab but not on placebo (p < 0.0001 and p < 0.0001, respectively).  The investigators reported that treatment with infliximab was generally well-tolerated, but 3 patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.

These randomized controlled trials confirm the findings of an open label study of infliximab in 21 patients with active spondyloarthropathy who received a maintenance regimen of 5 mg/kg infliximab every 14 weeks, 19 of whom were followed for 1 year (Kruithof et al, 2002).  The investigators reported that, after each re-treatment a sustained significant decrease of all disease manifestations was observed.  Before re-treatment, symptoms recurred in 3/19 (16 %) at week 20, in 13/19 (68 %) at week 34, and in 15/19 (79 %) at week 48.  Twelve minor infectious episodes were observed in this cohort.

Based on the evidence of efficacy of infliximab in a variety of spondyloarthropathies where TNF plays a role, the U.S. Pharmacopeial Convention (2003) has concluded that reactive arthritis and inflammatory bowel disease arthritis are accepted off-label indications for infliximab.

Atopic Eczema

Schmitt et al (2007) noted that systemic immunosuppressive agents are recommended for patients with atopic eczema in whom disease activity can not be controlled adequately with topical treatments.  Guidelines do not give clear advice which agents to prefer.  These investigators systematically reviewed clinical trials on systemic treatment for severe atopic eczema to provide evidence-based treatment recommendations.  Standardized literature search, independent standardized assessment of eligibility and data abstraction was performed by 2 reviewers.  A total of 27 studies totaling 979 patients were included.  Eleven studies consistently showed effectiveness of cyclosporine.  Cyclosporine is recommended as first option for patients with atopic eczema refractory to conventional treatment.  Evidence from randomized controlled trials also exists for gamma interferon and azathioprine.  Although frequently used in clinical practice, systemic glucocorticosteroids have not been assessed adequately in studies.  Mycophenolate mofetile showed effectiveness in 2 small uncontrolled studies. Intravenous immunoglobulins and infliximab are not recommended based on published data.

Belloni et al (2008) stated that atopic eczema is a common inflammatory skin disease showing chronically relapsing eczema and high association with elevated serum IgE levels.  A subgroup of atopic eczema patients requires systemic immunomodulatory treatment for long time periods.  However, beyond cyclosporine A and azathioprine, only limited consent exists on systemic treatment options.  Timely published systemic treatment modalities include studies on efalizumab, infliximab, adalimumab, and etanercept, omalizumab, rituximab, specific immunotherapy, leflunomide, and leukotriene receptor antagonists with varying clinical results and with particular safety profiles.  The authors concluded that although there is not yet a treatment modality reaching clinical efficacy of cyclosporine A as gold standard of systemic therapy, limitation in its application duration as in its side effect profile as well as the search for alternatives has set a focus on the new alternatives of which especially B-cell-directed therapies might be promising candidates.

Autoimmune Cholangiopathy

Rojas-Feria et al (2013) noted that abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extra-intestinal manifestations for both Crohn's disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC.  Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90 %. Cholangiocarcinoma and colon cancer risks are increased in these patients.  Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 months after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 months after the end of therapy, and should be treated if the viral load increases.  On the other hand, immunosuppressive therapy did not seem to promote reactivation of hepatitis C, and hepatitis C anti-viral treatment did not influence IBD natural history either.  Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events (AEs) is low.  Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner.  Liver biopsy is not routinely recommended.  Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab.  Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the 1st month of treatment.  All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Furthermore, an UpToDate review on “Autoimmune hepatitis variants: Definitions and treatment” (Heneghan, 2018) does not mention infliximab as a therapeutic option.

Avsola

In December 2019, the U.S. Food and Drug Administration (FDA) approved the biosimilar, Avsola (infliximab-axxq), for all approved indications of the reference product, Remicade (infliximab). Thus, Avsola is FDA approved for the treatment of moderate-to-severe rheumatoid arthritis (RA), moderate-to-severe Crohn's Disease (CD) in the adult and pediatric population, moderate-to-severe ulcerative colitis (UC) in the adult and pediatric population, chronic severe plaque psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Avsola, an anti-tumor necrosis factor alpha (anti-TNF) monoclonal antibody, was found to be highly similar to Remicade with no clinically meaningful differences based on a totality of evidence which included comparative analytical, nonclinical and clinical data (Amgen, 2019b).

FDA approval was based on a randomized, double-blind comparative clinical study which evaluated the efficacy and safety of infliximab-axxq (ABP710; Avsola) compared to infliximab (Remicade) in 558 patients with moderate-to-severe RA. The patients were randomized (1:1) to receive either Avsola or Remicade at a dose of 3 mg/kg administered as an infusion on day 1, at weeks 2 and 6, and every 8 weeks thereafter. The primary endpoint was the response difference (RD) of 20% improvement in American College of Rheumatology core set measurements (ACR20) at week 22. Key secondary endpoints included DAS28-CRP change from baseline, RD of ACR20, ACR50 and ACR70 at weeks 2, 6, 14, 22, 30, 34, 38, 46 and 50. The study also incorporated the evaluation of a single transition in 119 subjects from Remicade to Avsola at week 22, which demonstrated similar safety and immunogenicity in patients who were previously on Remicade (Amgen 2019b, 2019c).

Avsola has the same pharmaceutical dosage form and strength as Remicade.

Behçet's disease

In a review on standard and novel treatments to Behçet's disease, Gul (2007) stated that multi-center, multi-disciplinary and long-term trials aiming to assess the effectiveness of interventions (including infliximab) in both the treatment of acute inflammatory attacks and the prevention of relapses are needed in order to provide more generalizable results that can lead to better management plans.  Kobayashi et al (2007) stated that 5-aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçet's disease.  Moreover, infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy.

In the 2018 update of the European League Against Rheumatism (EULAR) recommendations for the management of Behcet's syndrome (BS), Hatemi and colleagues (2018) noted that several new therapeutic modalities with different mechanisms of action have been studied in patients with BS. These researchers updated the recommendations in the light of these new data under the auspices of EULAR Standing Committee for Clinical Affairs. The recommendations on the medical management of muco-cutaneous, joint, eye, vascular, neurological and GI involvement of BS were modified; 5 overarching principles and a new recommendation about the surgical management of vascular involvement were added.  For BS with eye involvement, among the monoclonal anti-TNF antibodies, although there is more accumulated experience with IFX, ADA also appeared to be an effective alternative.  Switching between these agents appeared to be possible in patients with primary or secondary unresponsiveness or AEs.  Patients presenting with an initial or recurrent episode of acute sight-threatening uveitis should be treated with high-dose glucocorticoids, IFX or IFN-alpha. Intravitreal glucocorticoid injection is an option in patients with unilateral exacerbation as an adjunct to systemic treatment (Level of evidence: IIA; strength of recommendation: B).

Birdshot Retinochoroidopathy

In a retrospective case series, Artornsombudh et al (2013) reported the outcomes of infliximab treatment of birdshot retinochoroidopathy (BSRC) refractory to conventional immunomodulatory therapy.  A total of 22 BSRC patients (44 eyes) who received infliximab between July 2005 and June 2012 were identified by retrospective chart review.  All patients received 4 to 5 mg/kg infliximab at 4- to 8-week intervals.  Data regarding patient demographics, use of immunosuppressive drugs, biologic agents, and reason for conventional therapy discontinuation were gathered.  Disease activity markers, including signs of ocular inflammation, fluorescein angiography evidence of retinal vasculitis or papillitis, indocyanine green angiography evidence of active choroiditis, electroretinography parameters indicative of stable or worsening of retinal functions, and optical coherence tomography findings indicative of static or worsening macular edema were recorded.  Main outcome measures included abolition of all evidence of active inflammation, visual acuity (VA), presence of cystoid macular edema at 6 months and 1 year, and adverse responses to infliximab.  Mean duration of disease before starting infliximab was 58.6 months.  Before infliximab therapy, all patients received and failed conventional immunosuppressive therapy; 10 patients had received another biologic agent.  After initiating infliximab, control of inflammation was achieved in 81.8 % at 6 months and in 88.9 % at the 1-year follow-up.  Three patients had active inflammation during therapy.  The rate of cystoid macular edema decreased from 22.7 % at baseline to 13.9 % at 6 months and 6.7 % at 1 year after receiving the drug.  Initial VA of 20/40 or better was found in 34 eyes (84.1 %).  At 6 months and 1 year, 91.7 % and 94.4 % of eyes, respectively, had VA of 20/40 or better.  Six patients had adverse events; infliximab therapy was discontinued in these patients because of neuropathy, drug-induced lupus, allergic reaction, or fungal infection.  The authors concluded that these data suggested that infliximab is effective for controlling inflammation in otherwise treatment-refractory cases of BSRC.  The main drawbacks of this study were its retrospective design, small sample size, and the lack of a control group.  The authors stated that further prospective randomized controlled studies in larger populations are needed to ascertain the potential role of infliximab in the treatment of BSRC.

Cerebral Amyloid Angiopathy

An UpToDate review on "Cerebral amyloid angiopathy" (Greenberg, 2013) does not mention infliximab as a therapeutic option.

Chronic Cutaneous Sarcoidosis

Doherty and colleagues (2008) stated that although healthcare providers have arrived at a relatively comfortable zone of accepted clinical practice in the management of cutaneous sarcoidosis, virtually every treatment is based on minimal evidence-based data and relies almost exclusively on anecdotal information.  Although it would be convenient to blame this state of affairs on the lack of certainty about disease etiology, the unavoidable fact is that little has been executed, even in the realm of well-designed comparative trials.  Nonetheless, worldwide accepted standard therapies for sarcoidosis include the administration of corticosteroids, anti-malarials and methotrexate.  A step-wise approach to patient care is appropriate, and potent topical corticosteroids (e.g., clobetasol) or repeated intralesional injections of triamcinolone (3 to 10 mg/ml) may be all that is needed in mild skin-limited disease.  In patients requiring systemic therapy for recalcitrant or deforming skin lesions (or for widespread disease), corticosteroids (e.g., prednisone 40 to 80 mg/day, tapered accordingly) used alone or in combination with anti-malarials or methotrexate may be indicated.  Anti-malarials and methotrexate are considered 2nd-line interventions and may be used as monotherapy for steroid-resistant sarcoidosis or in patients unable to tolerate steroids.  Given the concern regarding ocular toxicity, the maximum dosages of chloroquine and hydroxychloroquine should not exceed 3.5 and 6.5 mg/kg/day, respectively.  Methotrexate is given in weekly doses of 10 to 30 mg, with the caveat that hematological, gastro-intestinal (GI), pulmonary and hepatic toxicities are possible.  Despite universal acceptance as standard care, the afore-mentioned treatments often result in an incomplete clinical response or unacceptable AEs.  In such situations, more innovative treatment options may be used.  Treatments that may well gain widespread future use include the TNF-alpha inhibitors infliximab and adalimumab.  Experience was limited, but early reports are promising.  Infliximab was administered via intravenous infusion at doses of 3 to 10 mg/kg at 0, 2 and 6 weeks and as indicated thereafter, whereas adalimumab was injected subcutaneously at doses of 40 mg either weekly or every 2 weeks.  Because adalimumab is not approved for the management of sarcoidosis, the optimum dose administration interval is uncertain.  However, it has been given in both weekly and every other week regimens.  Isotretinoin, 0.5 to 2 mg/kg/day, has been used successfully in a handful of reported cases.  However, the teratogenic potential of isotretinoin is often prohibitive considering that the primary demographic group likely to develop sarcoidosis is women of child-bearing potential.  Thalidomide at dosages of 50 to greater than 400 mg/day has limited, albeit promising, supporting data.  However, access is restricted in many countries because of a deserved pregnancy category X rating.  Melatonin (20 mg/day) and allopurinol (100 to 300 mg/day) are not well studied in cutaneous sarcoidosis, and the clinical experience with tetracycline derivatives has been mixed.  That said, there are compelling reports of therapeutic benefit with both doxycycline and minocycline.  Because neither of these agents is associated with the severe toxicity of cytotoxic drugs, they may serve as effective therapy in some patients.  Pentoxifylline (400 mg, 3 times daily) has been of use in a small number of reported cases of pulmonary sarcoidosis, but there are no reports on its use in patients with primarily cutaneous disease.  Both cyclosporine and chlorambucil have been largely abandoned given their associated toxicity and disappointingly unreliable efficacy.  Finally, laser therapy is a newer modality that may provide patients with a quick and non-invasive treatment option for cutaneous sarcoidosis.

Toussirot and Pertuiset (2010) noted that increased production of TNF-α by alveolar macrophages and involvement of TNF-α in granuloma formation suggested that this cytokine is involved in the pathophysiology of sarcoidosis.  The 3 available TNF-α blocking agents have been tested in sarcoidosis refractory to corticosteroids or immunosuppressive drugs.  Data were available from isolated case reports or limited series of patients treated in open-label trials with favorable issue with anti-TNF-α monoclonal antibodies; 2 randomized, placebo-controlled studies evaluated the efficacy of infliximab in pulmonary and extra-pulmonary sarcoidosis, showing that infliximab improved significantly extra-pulmonary disease.  There was no significant difference between infliximab and placebo in the treatment of pulmonary manifestations.  Etanercept showed no efficacy for treating ocular sarcoidosis in a controlled trial and for pulmonary disease in an open-label trial.  Paradoxical cases of proven sarcoidosis have been reported in patients receiving anti-TNF-α agents for chronic inflammatory rheumatic diseases.  A literature review identified 28 cases, including 16 with etanercept, 8 with infliximab and 4 with adalimumab.  Although these cases were mainly reported with etanercept, paradoxical sarcoidosis has been reported with the 3 available anti-TNF-α agents, suggesting a class effect.  Changes in the cytokine balance may be involved in these cases of induced sarcoidosis, which must be known by the clinician.

Drent et al (2014) stated that in severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the 3rd-line TNF-α inhibitors infliximab and adalimumab might be an alternative. However, appropriate studies to guide the clinician are lacking. These researchers established practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients. Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established. Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases. A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to investigate consensus in case of inadequate data to determine an objective answer. Of the 256 papers found, 101 were included. Randomized controlled trials (RCTs) about the use of TNF-α inhibitors in sarcoidosis were limited; 95 % (19 of 20) of the sarcoidologists contacted, completed the questionnaire (Europe 68 %, North America 32 %); 9 recommendations were formulated concerning general aspects of TNF-α inhibitor use. The authors concluded that based on earlier studies and consensus among world's leading sarcoidologists, practical recommendations for the use of TNF-α inhibitors in sarcoidosis were established. These recommendations, with emphasis on indications, dosage and discontinuation regimens, have been developed to support the clinician in the management of refractory sarcoidosis patients.

In a large, observational study, Heidelberger et al (2017) determined the safety and efficacy of anti-TNF in treating cutaneous sarcoidosis.  STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multi-center observational database that received data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments . Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016.  These researchers extracted data for patients with skin involvement at anti-TNF initiation. Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded.  The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop greater than or equal to 2 points from baseline but greater than 1 at last follow-up).  Among 140 patients in the STAT database, 46 had skin involvement.  The most frequent lesions were lupus pernio (n = 21 [46 %]) and nodules (n = 20 [43 %]).  The median cutaneous severity score was 5 and/or 6 at baseline; 21 patients were treated for skin involvement and 25 patients for visceral involvement.  Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93 %).  Most patients received infliximab (n = 40 [87 %]), with systemic steroids in 28 cases (61 %) and immunosuppressants in 32 cases (69.5 %).  The median (range) follow-up was 45 (3 to 103) months.  Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14 to 78) years, and 33 patients (72 %) were women.  The OCRR was 24 % after 3 months, 46 % after 6 months, and 79 % after 12 months.  Steroid sparing was significant.  Treatment was discontinued because of AEs in 11 patients (24 %), and 21 infectious events occurred in 14 patients (30 %).  Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48 %] versus n = 2 of 21 [9.5 %], respectively; p = 0.02).  The relapse rate was 44 % 18 months after discontinuation of treatment.  Relapses during treatment occurred in 35 % of cases, mostly during anti-TNF or concomitant treatment tapering.  The authors concluded that anti-TNF agents were effective but suspensive in cutaneous sarcoidosis.  The risk of infectious events must be considered.

Furthermore, an UpToDate review on “Management of cutaneous sarcoidosis” (Prystowsky and Sanchez, 2019) states that “For patients who fail to improve with 1st- and 2nd-line therapies for cutaneous sarcoidosis, we suggest a trial of anti-TNF therapy (Grade 2C).  Therapeutic options include infliximab, adalimumab, and thalidomide.  Additional study is necessary to confirm the efficacy of these therapies”.

Chronic Pulmonary Sarcoidosis

There is limited evidence of infliximab’s effectiveness in persons with chronic pulmonary sarcoidosis who remain symptomatic despite treatment with steroids or immunosuppressants.  Baughman et al (2005) reported on a randomized controlled clinical trial comparing 2 doses of infliximab (3 or 5 mg/kg) to placebo in 138 patients with chronic (greater than 1-year duration) sarcoidosis who remain symptomatic (American Thoracic Society dyspnea score greater than 1) despite treatment with 3 or more months of prednisone (10 mg or more) or immunomodulator therapy or both, with evidence of parenchymal disease (Stage II or II) on chest x-ray, and a forced vital capacity (FVC) of greater than 50 % to less than 75 % predicted.  The investigators reported significant (delta 2.5 %, p = 0.038) improvement in the percent of predicted FVC at week 24, the primary study endpoint, in the combined infliximab groups.  The results did not differ significantly between infliximab doses.  The investigators reported that subgroup analysis demonstrated greater benefit in patients with more extensive sarcoidosis disease burden, duration, activity, and severity. 

Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Deutschmann et al (2005) described the case of an 18-year old girl with chronic recurrent multifocal osteomyelitis (CRMO) over a period of 10 years.  She had suffered predominantly from very painful recurrent swelling of her cheeks.  Various therapeutic regimens including non-steroidal anti-inflammatory drugs (NSAIDs) and steroids had shown only a partial or temporary response.  Because tumor necrosis factor-alpha-blocking agents have been successfully applied in Crohn's-associated CRMO and the related SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, tumor necrosis factor-alpha-blocking therapy with infliximab was initiated.  Thereafter, apart from 1 mild episode, no additional recurrences were observed during 21 months of follow-up.  Infliximab was well-tolerated, and steroids were tapered off.  The authors concluded that their observation indicated that infliximab may be an effective therapeutic option in CRMO.

Crohn's Disease

Infliximab is indicated for the reduction in signs and symptoms of active Crohn's disease in patients who have had an inadequate response to conventional therapies (corticosteroids, sulfasalazine, mesalamine, olsalazine, or 6-mercaptopurine).  The safety and efficacy of infliximab for patients with active Crohn's disease was demonstrated in a randomized controlled clinical trial.  In clinical studies of infliximab for active Crohn's disease, all patients had experienced an inadequate response to prior conventional therapies, including corticosteroids, 5-aminosalicylates (5-ASA), and/or 6-mercaptupurine/ azathioprine (6-MP/AZA).  Initial therapy consists of a single infusion of infliximab (5 mg/kg).  In clinical studies, there was no evidence of a dose response; doses higher than 5 mg/kg did not result in a greater proportion of responders.  Re-treatment with infliximab may be necessary and is covered.  Although the optimal frequency of retreatment is uncertain, there is preliminary evidence to suggest that the optimal interval frequency of retreatments is 8-week intervals.

In a Cochrane review, Doherty et al (2009) examined the use of medical therapies for the prevention of post-operative recurrence of Crohn's disease.  MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify relevant studies.  References from selected papers and abstracts from Digestive Disease Week were also searched.  Randomized controlled trials that compared medical therapy to placebo or other medical agents for the prevention of recurrence of intestinal Crohn's disease were selected for inclusion.  Two authors reviewed all abstracts containing search terms, and those meeting inclusion criteria were selected for full data abstraction.  Dichotomous data were summarized using relative risk and 95 % CI.  A fixed-effects model was used, and sensitivity analysis performed.  A total of 23 studies were identified for inclusion.  Probiotics were not superior to placebo for any outcome measured.  The use of nitroimidazole antibiotics appeared to reduce the risk of clinical (RR 0.23; 95 % CI: 0.09 to 0.57, number needed to treat [NNT] = 4) and endoscopic (RR 0.44; 95 % CI: 0.26 to 0.74, NNT = 4) recurrence relative to placebo.  However, these agents were associated with higher risk of serious adverse events (RR 2.39, 95 % CI: 1.5 to 3.7).  Mesalamine therapy was associated with a significantly reduced risk of clinical recurrence (RR 0.76; 95 % CI: 0.62 to 0.94, NNT = 12), and severe endoscopic recurrence (RR 0.50; 95 % CI: 0.29 to 0.84, NNT = 8) when compared to placebo.  Azathioprine/6MP was also associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95 % CI: 0.38 to 0.92, NNT = 7), and severe endoscopic recurrence (RR 0.64; 95 % CI: 0.44 to 0.92, NNT = 4), when compared to placebo.  Neither agent had a higher risk than placebo of serious adverse events.  When compared to azathioprine/6MP, mesalamine was associated with a higher risk of any endoscopic recurrence (RR 1.45, 95 % CI: 1.03 to 2.06), but a lower risk of serious adverse events (RR 0.51; 95 % CI: 0.30 to 0.89).  There was no significant difference between mesalamine and azathioprine/6MP for any other outcome.  The authors concluded that there are insufficient randomized controlled trials of infliximab, budesonide, tenovil and interleukin-10 to draw conclusions.  Nitro-imidazole antibiotics, mesalamine and immunosuppressive therapy with azathioprine/6-MP or infliximab all appear to be superior to placebo for the prevention of post-operative recurrence of Crohn's disease.  The cost, toxicity and tolerability of these approaches require careful consideration to determine the optimal approach for post-operative prophylaxis.

Infliximab is an intravenous medication that is indicated for the reduction in the number of enterocutaneous fistulas in patients with fistulating Crohn's disease.  The safety and efficacy of infliximab in fistulizing Crohn's disease was demonstrated in a randomized, controlled study of patients with fistulizing Crohn's disease of at least 3 months duration. 

Dermatomyositis and Polymyositis

Hengstman et al (2008) examined the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis (DM) and polymyositis (PM) .  A multi-center, open-label, controlled trial was conducted.  Disease activity was assessed using patient's and physician's disease activity assessment, manual muscle testing (MMT), handheld dynamometry, and serum CK.  The primary objective was to assess the efficacy using MMT after a period of 26 weeks.  The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction.  The few patients who did reach the primary endpoint showed improvement in all aspects studied.  The authors concluded that infliximab combined with weekly methotrexate might be safe and well-tolerated in a small subgroup of patients with drug-naive recent-onset myositis.  At present, the authors do not advocate the use of this treatment because treatment response can not be predicted beforehand.

Dastmalchi et al (2008) investigated the effect of the TNF blocking agent infliximab in patients with treatment-resistant inflammatory myopathies.  A total of 13 patients with refractory PM, DM, or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks.  Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI.  Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analyzed in sera.  Nine patients completed the study.  Three patients discontinued due to adverse events and one due to a discovered malignancy.  Three of the completers improved by greater than or equal to 20 % in 3 or more variables of the disease activity core set, 4 were unchanged and 2 worsened greater than or equal to 30 %.  No patient improved in muscle strength by manual muscle test.  At baseline, 2 completers had signs of muscle inflammation by MRI, and 5 at follow-up.  T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment.  Type I IFN activity was increased after treatment.  The authors concluded that infliximab treatment was not effective in refractory inflammatory myopathies.  In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

Also, an UpToDate review on "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults" (Miller and Rudnicki, 2012) states that "[d]ata related to the efficacy of tumor necrosis factor inhibition in DM and PM are mixed.  Only small studies of etanercept and infliximab have been reported, and further studies will be required to further define their role".

Graft-Versus-Host-Disease

In a phase III clinical trial, Couriel et al (2009) examined if the addition of infliximab to steroids could improve results for patients with newly diagnosed grade II to IV acute graft-versus-host-disease (aGVHD).  A total of 63 patients were randomized either to 2 mg/kg/day methylprednisolone (MP) or infliximab + MP.  Average age was 47 years (range of 20 to 70 years); 64 % were male.  Fifty-three percent and 51 % of patients received a matched-sibling and/or bone marrow (BM) graft.  Sixty-seven percent had grade II, 33 % grade III to IV aGVHD; 62 % had skin, 53 % gastrointestinal (GI), and 7 % had liver involvement.  At days 7 and 28, the response rate for infliximab + MP versus MP was 52 % versus 78 %, p = 0.03 and 62 % versus 58 %, p = 0.7, respectively.  Cumulative incidences of GVHD-related mortality, non-relapse mortality (NRM), and overall survival (OS) were not significantly different between the 2 groups (GVHD-related mortality: 38 % versus 32 %, p = 0.6; NRM: 52 % versus 36 %, p = 0.3; OS: 17 % and 28 %, p = 0.4 for infliximab + MP versus MP, respectively).  Patients with newly diagnosed aGVHD derive no benefit from the addition of anti-TNF-alpha therapy with infliximab when compared to corticosteroids alone.

Pidala et al (2009) examined the effectiveness of infliximab as a salvage therapy for steroid-refractory aGVHD.  In a series of 52 patients, 71 % of whom had grade III to IV aGVHD, only 15 % achieved complete remission (CR) with the use of infliximab alone as salvage therapy.  Complete remission of aGVHD differed according to overall aGVHD grade at salvage (grade II, 5/15; grade III, 2/17; grade IV, 1/20; p = 0.03).  Median OS was only 1.7 months (95 % CI: 0.99 to 2.3 months).  Complete remission of aGVHD was significantly associated with OS, with a hazard ratio of 8.4 for death in those without CR (95 % CI: 3.6 to 19.6; p < 0.0001).  The authors concluded that this series demonstrated the limited activity of infliximab in patients with high-grade aGVHD.  They stated that further work is needed to identify effective therapy for aGVHD.

In a retrospective analysis, Motllo et al (2011) evaluated the activity and toxicity of infliximab in 9 patients with acute or chronic steroid-resistant GVHD.  Six patients had acute GVHD and 3 chronic GVHD.  The source of progenitors was peripheral blood in all patients except 1.  Six received matched-related stem cell transplant and 3 unrelated stem cell transplant.  Patients received between 2 and 7 doses of infliximab, and 5 achieved a partial response.  All patients presented infections: 4 developed pseudomonas aeruginosa septicemia and 5 probable or confirmed infection by aspergillus fumigatus.  The authors concluded that infliximab provides transient response in steroid-resistant GVHD.  However, it is associated with a high rate of infections.  The authors stated that earlier administration of infliximab should be explored to reduce the frequency of infections.

Rager et al (2011) noted that treatment options for steroid-refractory GVHD are unsatisfactory and prognosis is poor.  Inflammatory cytokines IL-2 and TNF-α are important mediators of GVHD and may be critical targets for therapy.  These researchers retrospectively reviewed their experience using combination anti-cytokine therapy of daclizumab and infliximab.  A total of 17 evaluable patients had a median age of 47 years (range of 35 to 63).  The conditioning regimen was myeloablative in 13 and non-myeloablative in 4 cases.  Graft-versus-host-disease occurred at a median of 49 days after transplant in 12 patients (range of 21 to 231 days) and at a median of 46 days (range of 25 to 119 days) after donor lymphocyte infusion in 5 patients.  All patients had persistent or progressive GVHD despite 1 to 2 mg/kg/day of corticosteroids for a median of 7 days (range of 2 to 26 days).  They received a combination of daclizumab and infliximab for acute GVHD Center for International Blood and Marrow Transplant Research (CIBMTR)severity index B (3), C (10) or D (4).  Of the 17 patients analyzed, 47 % responded to treatment, 24 % had complete resolution of symptoms and 24 % had partial responses.  Survival was limited and all the patients died a median of 6.7 months (range of 1.6 to 26) from transplant and 35 days from initiation of daclizumab/infliximab.  The findings of this retrospective analysis suggested that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in steroid-refractory GVHD, but outcomes remain poor.  New methods to prevent and treat GVHD are urgently needed.  The authors do no recommend combination of daclizumab and infliximab for advanced steroid-refractory GVHD.

Uhlving et al (2012) stated that bronchiolitis obliterans following allogeneic hematopoietic SCT 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, but the knowledge of etiology and pathogenesis is still limited.  The authors noted that there is only limited evidence of infliximab on bronchiolitis obliterans (case study and case-series studies).

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2020) provide a category 2A recommendation for use of infliximab in acute graft-versus-host disease (GVHD) as additional therapy in conjunction with systemic corticosteroids following no response (steroid-refractory disease) to first-line therapy options. Therapy for steroid-refractory acute GVHD is often used in conjunction with the original immunosuppressive agent.

The NCCN Clincial Practice Guidelines in Oncology for "Hematopoietic cell tranplantation (HCT): Pre-transplant recipient evaluation and management of graft-versus-host disease" (version 2.2020) states that infliximab is often used in conjuction with the original immunosuppressive agent for acute GVHD. "In a retrospective evaluation of 21 patients with steroid-refractory aGVHD who had received treatment with single-agent infliximab (10  mg/kg once weekly for at least 4 doses), the ORR was 67% with 62% of patients achieving CR". A "retrospective analysis involving 35 patients with steroid-refractory aGVHD reported an ORR of 40% for infliximab administered intravenously at 10 mg/kg weekly for a medial of 4 doses, with 83% of patients developing infectious complications. These data suggest that infliximab is active in the treatment of steroid-refractory aGVHD; however, the potential for excessive infections should be evaluated".

Herniated Disc and Sciatic Pain

A systematic evidence review in BMJ Clinical Evidence found that the effectiveness of infliximab in treatment of herniated disc is unknown (Jordan et al, 2008).  The assessment identified 1 randomized controlled clinical trial of 41 people with acute or subacute sciatic pain, caused by herniated discs confirmed by magnetic resonance imaging, comparing infliximab, given as a single intravenous infusion) versus control (saline infusion over 2 hours) (Korhonen et al, 2005).  The randomized controlled trial found no significant difference between infliximab and control in leg or back pain score improvements at 12 weeks or median reduction in back pain score at 12 weeks.  The trial also found no significant difference between groups in reduction of Oswestry Disability Index scores, median cumulative sick leave, or the proportion of people undergoing discectomy.

Hidradenitis Suppurativa

Haslund and associates (2009) noted that hidradenitis suppurativa (HS) is a common inflammatory skin disease.  Medical treatment is often disappointing and in severe disease surgery remains the therapy of choice.  Extensive surgery may be effective but also mutilating.  Patients experience a significant reduction in quality of life and the need for new treatment modalities are urgent.  In recent years, patients with HS have been treated off-label with TNF-alpha inhibitors with a varying degrees of effect.  These researchers performed a systematic review of papers retrieved from 2 databases (PubMed and Web of Science) using the following keywords: hidradenitis suppurativa, acne inversa, infliximab, etanercept, and adalimumab.  A total of 34 publications were retrieved, describing treatment of 105 patients.  Most cases reported treatment with infliximab (52/105).  A positive treatment outcome was reported in 90/105 cases, with only 7/105 non-responders and 8/105 patients experiencing side-effects.  The side-effects were comparable to those seen in other TNF-alpha inhibitor studies.  In the majority of cases, the treatment was effective when given as a suppressive therapy, but 15/105 cases were described with long-term remission (greater than or equal to 3 months) after the end of therapy.  In most publications follow-up was, however, insufficient to allow a systematic exploration of this.  The authors concluded that TNF-alpha inhibitors seem to be effective in the treatment of HS.  However, several questions remain to be answered through specific studies.  This review has also identified a need for more standardized reporting of the outcomes as well as randomized controlled trials in this disease.

Rambhatla et al (2012) conducted a systematic review of the effectiveness of various modalities to treat hidradenitis suppurativa (HS). The authors reported that treatments of HS shown to be effective were a clindamycin-rifampin combination regimen, a course of infliximab, monthly Nd:YAG laser sessions, and surgical excision and primary closure with a gentamicin sulfate-collagen sponge. The authors stated that most therapies used to treat HS were supported by limited or weak scientific evidence. The authors emphasized the need for large randomized controlled trials to evaluate treatment options for HS.

Randomized controlled clinical trials of tumor necrosis factor inhibitors for hydradenitis suppurativa have shown inconsistent results (Jemec, 2012). Grant, et al. (2011) reported positive results with infliximab therapy for patients with moderate to severe hidradenitis suppurativa in a randomized, double-blind, placebo-controlled crossover trial. Study subjects received infliximab or placebo during an eight-week double-blind treatment phase, followed by an open-label phase where subjects taking placebo were given the opportunity to cross over to infliximab, and an observational phase. Primary treatment efficacy was based on HS Severity Index. Secondary endpoints included Dermatology Life Quality Index, visual analog scale, and Physician Global Assessment scores. Inflammatory markers erythrocyte sedimentation rate and C-reactive protein were also assessed. The investigators found that more patients in the infliximab than in the placebo group showed a 50 percent or greater decrease from baseline HS Severity Index score. In addition, statistically and clinically significant improvement from baseline was observed at week 8 in Dermatology Life Quality Index score, visual analog scale score, erythrocyte sedimentation rate, and C-reactive protein compared with placebo. The investigators reported that patients in the placebo group treated with infliximab after week 8 (crossover) responded similarly to the original infliximab group. The investigators noted that many patients withdrew during the observational phase to continue anti-tumor necrosis factor-alfa therapy. No unexpected serious adverse events were observed. The investigators noted limitations of this study, including that patients were treated by a single physician at a single center, and some patients did not return after their last infusion, and the HS Severity Index requires validation. The investigators reported that infliximab was well tolerated, no unexpected safety issues were identified, and improvements in pain intensity, disease severity, and quality of life were demonstrated with concomitant reduction in clinical markers of inflammation.

However, another randomized, double-blind, placebo-controlled trial failed to show a significant benefit of the tumor necrosis factor inhibitor etanercept with the use of a physician's global assessment scale (Adams, et al., 2010). In a third randomized, controlled trial, the tumor necrosis factor inhibitor adalimumab resulted in significant improvement on the basis of a score that reflected the extent and severity of disease at 6 weeks, but this benefit was not maintained at 12 weeks (the primary outcome of the trial).

In a comparative study, Rappard et al (2012) compared the outcomes of the tumor necrosis factors infliximab and adalimumab HS, and found that infliximab was more effective than adalimumab. The authors performed a retrospective study to compare two cohorts of 10 adult patients suffering from severe, recalcitrant HS. Ten patients were treated with intravenous infliximab, and subsequently 10 other patients were treated in the same hospital with subcutaneous adalimumab. Both cohorts were followed up for one year using identical evaluation methods [Sartorius score, quality of life index, reduction of erythrocyte sedimentation rate and C-reactive protein, patient and doctor global assessment, and duration of efficacy]. The authors reported that 19 patients completed the study. In both groups, the severity of the HS diminished. The investigators found that infliximab performed better than adalimumab in all aspects. The average Sartorius score was reduced to 54 percent of baseline for the infliximab group and 66 percent of baseline for the adalimumab group. The authors concluded that subcutaneous adalimumab is less effective than intravenous infliximab.

Shuja et al (2010) noted that there are various treatment options for HS, but none is wholly satisfactory or effective.  There have been many reports on the efficacy of biologic drugs for the treatment of HS; this article was an in-depth review of the published evidence on this topic.  Because the current evidence is limited, randomized, double-blinded, placebo-controlled trials are needed to better elucidate the future of these drugs for the treatment of HS.

Idiopathic Membranous Nephropathy

UpToDate reviews on “Treatment of idiopathic membranous nephropathy” (Cattran, 2013) and “Alternative agents in the treatment of idiopathic membranous nephropathy” (Wetzels and Apppel, 2013) do not mention the use of infliximab as a therapeutic option.

IgG4-Related Disease

Karim et al (2017) stated that IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with unclear pathophysiology.  It may occur as a single organ disorder, but multi-organ presentation is common and can mimic several conditions.  The preferred therapy consists of steroids, but definite maintenance strategy remains unclear.  These researchers described a case of a 61-year old woman, initially diagnosed with idiopathic orbital inflammation refractory to multiple immunosuppressive agents.  The disease was complicated with epilepsy, vision loss, and trismus.  Treatment with various immunosuppressive agents was unsuccessful.  Eventually, the patient was effectively treated with infliximab.  This is the 2nd case of IgG4-RD treated with a TNF-blocker documented in literature and the 1st description to demonstrate its superiority over steroid sparing agents.  Although speculative, TNF-blockers might exert their effect in IgG4-RD by interfering with the possible overexpressed TNF-alpha due to fibrosis in this disease.  The authors concluded that treatment with infliximab appeared a good alternative for refractory IgG4-RD; however, further studies are needed to define the value of infliximab in IgG4-RD.

Immune Checkpoint Inhibitor-Induced Toxicities

Immunologic checkpoint inhibition agents such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (e.g., ipilimumab), programmed cell death receptor 1 (PD-1) (e.g. nivolumab , pembrolizumab), and anti-programmed cell death ligand 1 (PD-L1) agents (e.g. atezolizumab),  are indicated for treatment of various malignant diseases (e.g., melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, and microsatellite instability-high or mismatch repair deficient [dMMR] solid tumors). Treatment with these medications can be associated with immune-related adverse events (irAEs) that can become severe or fatal (Postow and Wolchok, 2018).

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have published guidelines and recommendations for the management of immunotherapy-related toxicities. The management approach to irAEs is based upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. The majority of data are derived from patients with advanced melanoma who were treated with ipilimumab, nivolumab, and pembrolizumab. In general, treatment of moderate or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid immunosuppression. Treatment is based upon the severity of the observed toxicity. (Postow and Wolchok, 2018).

• Moderate or severe colitis if no improvement after 48 hours of methylprednisolone.
• Severe pneumonitis if no improvement after 48 hours of methylprednisolone
• Severe or life-threatening renal failure/elevated serum creatinine if toxicity remains greater than G2 (creatinine remaining greater than 2 to 3 times above baseline) after 1 week of corticosteroids 
• Life-threatening myocarditis, pericarditis, arrhythmias, or impaired ventricular function
• Refractory/severe inflammatory arthritis not responding to corticosteroids or anti-inflammatory agents. 

Hillock and associates (2017) reviewed the outcomes of metastatic melanoma patients treated with infliximab for severe steroid-refractory colitis secondary to ipilimumab therapy.  These researchers retrospective reviewed evidence of patients administered infliximab for ipilimumab-induced colitis at South Australian public hospitals between October 2011 and April 2015.  Main outcome measures included resolution of colitis/diarrhea, duration of hospital stay, dosage regimen of infliximab used (single dose versus multiple dose) and surgical intervention if needed.  Between October 2011 and April 2015, a total of 106 patients were dispensed ipilimumab from South Australian public hospitals for the treatment of metastatic melanoma; 13 were administered infliximab for severe, steroid-refractory colitis secondary to ipilimumab; 62 % received a single-dose of infliximab only; 4 patients achieved resolution of colitis symptoms at 1 month post-infliximab; 33 % required surgical intervention despite treatment with infliximab; 1 patient declined surgery and subsequently died due to bowel perforation.  The average number of over-night bed days due to colitis was 27.  The authors concluded that the findings of this series of patients with severe ipilimumab-induced colitis suggested that despite treatment with infliximab a high proportion of patients did not achieve resolution of symptoms.  Review of these cases has highlighted the absence of evidence-based guidelines to treat severe, steroid refractory colitis secondary to ipilimumab.  They stated that further prospective studies may clarify the role of infliximab for the treatment of ipilimumab-induced colitis.

Wang et al. (2018) conducted a retrospective analysis to evaluate immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies. The authors state that immune checkpoint inhibitors (ICPIs) treatment can be complicated by diarrhea and colitis, in which systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. The study included 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. The authors used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups. The authors found that diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (p < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (p = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; p = 0.768). Diarrhea was an independent predictor of a favorable overall survival (p < 0.001), irrespective of treatment need (p = 0.003). Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (p = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (p = 0.089). The authors concluded that immunosuppressive treatment for diarrhea did not significantly affect overall survival; however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome. Future prospective studies are required to further elucidate the relationship between ICPI-induced GI tract adverse events and tumor response and patient survival. 

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2020) provide a category 2A recommendation for use of infliximab in immune checkpoint inhibitor-related toxicities. NCCN compendia states to consider adding infliximab for the management of immunotherapy-related moderate (G2) and strongly consider for severe (G3-4) diarrhea or colitis, severe (G3-4) pneumonitis if no improvement after 48 hours of methylprednisolone, severe (G3) or life-threatening (G4) acute renal failure/elevated serum creatinine if toxicity remains >G2 after 1 week of corticosteroids, G3 -4 uveitis that is refractory to high-dose systemic corticosteroids, severe (G3) or life-threatening (G4) myocarditis, pericarditis, arrhythmias, impaired ventricular function, or conduction abnormalities if no improvement within 24 hours of starting pulse-dose methylprednisolone, severe inflammatory arthritis as additional disease modifying anti-rheumatic therapy if symptoms do not improve within 2 weeks of starting high-dose corticosteroids, or moderate, severe, or life-threatening steroid-refractory myalgias or myositis.

Immune-mediated Enterocolitis

Ipilimumab (Yervoy) is a fully human IgG1 anti-CTLA-4 monoclonal antibody indicated for metastatic melanoma.These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are gastrointestinal. Case series support the use of infliximab for immune-mediated enterocolitis from ipilimumab (Cheng, et al., 2015; Merrill, et al., 2014; Slangen, et al., 2013; Pagès, et al., 2013; Lord, et al., 2010; Minor, et al., 2009; Johnston, et al., 2009; Phan, et al., 2008; Beck, et al., 2006). The prescribing information for Yervoy recommends antidiarrheals, steroids, interrupting treatment, and permanent discontinuation in severe cases (BMS, 2013). The Yervoy REMS program recommends alternative immunosuppressive therapy in cases of severe or life-threatening enterocolitis (defined as ≥ 7 stools/day over baseline, peritoneal signs consistent with bowel perforation, ileus or fever) that persists despite permanent discontinuation of Yervoy and administration of systemic corticosteroids (BMS, 2011). Sznol, et al. (2013) recommends administration of a single dose of infliximab 5 mg/kg in this situation unless infliximab is contraindicated or perforation or sepsis is present.

Inflammatory Bowel Disease

Yanai and Hanauer (2011) appraised the latest evolution in treatment strategies in IBD and suggested an evidence-based approach and risk stratification while coping with cases of non-responders or loss of response to biological therapies.  These researchers conducted a literature search of English publications listed in the electronic databases of Medline (source PubMed) and constructed an analytical review based on definitions of response and loss of response, considering potential responsible mechanisms, clinical assessment tools, and finally recommending a practical approach for its prevention and management.  Favorable clinical outcome appeared to be the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments.  When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class.  Efficacy is reduced with 2nd-line agents either within or across classes compared with naive patients.  In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision-making may be necessary to determine the choice of 2nd-line biological agents.  Optimal treatment strategies are still controversial.  The authors concluded that it is essential to recognize the spectrum of mechanisms affecting response and loss of response to form a logical and efficient management algorithm, and, perhaps, it is time to incorporate the measurement of trough levels and anti-drug antibodies in the strategy of such an assessment.  They stated that prospective controlled trials are direly needed to investigate the optimal tailored management in individual patients who lose response.  They noted that “Thus, at present, we must rely on clinical symptoms, signs, endoscopic responses, and generic biomarkers (CRP and fecal calprotectin) to assess individual patient responses and to correlate with dosing strategies”.

Wang et al (2012) stated that antibody-based drugs such as infliximab (IFX) are effective for the treatment of inflammatory bowel disease (IBD) and other immune-mediated disorders.  The development of antibodies against these drugs may result in unfavorable consequences, including the loss of drug efficacy, hypersensitivity reactions, and other adverse events.  Therefore, accurate monitoring of serum drug and anti-drug antibody levels should be an important part of therapy for patients being treated with an antibody-based drug.  Current methods for the assessment of anti-drug antibodies and drug levels, involving various bridging ELISA and radioimmunoassay techniques, are limited by their sensitivity, interference, and/or complexity.  To overcome these limitations, these researchers have developed a non-radiolabeled homogeneous mobility shift assay (HMSA) to measure the antibodies-to-infliximab (ATI) and IFX levels in serum samples.  Full method validation was performed on both the ATI- and IFX-HMSA, and the clinical sample test results were also compared with those obtained from a bridging ELISA method to evaluate the difference in performance between the 2 assays.  Validation of the ATI-HMSA revealed a lower limit of quantitation of 0.012 μg/ml in serum.  The linear range of quantitation was 0.029 to 0.54 μg/ml.  The intra- and inter-assay precision was less than 20 % of coefficient of variation (CV), and the accuracy (% error) of the assay was less than 20 %.  In serum samples, ATI as low as 0.036 μg/ml can be measured, even in the presence of 60 μg/ml of IFX in the serum.  Sera from 100 healthy subjects were tested to determine the cut-point of the assay.  ATI-positive samples that had been previously analyzed by using a bridging ELISA from 100 patients were also measured by the new method.  There was a high correlation between the 2 methods for ATI levels (p < 0.001).  Significantly, the new method identified 5 false-positive samples from the bridging ELISA method.  Validation of the mobility shift IFX assay also showed high assay sensitivity, precision and accuracy.  The authors concluded that the HMSA method may also be applied to other protein-based drugs to accurately detect serum drug and anti-drug antibody levels.  This article did not appear to address Prometheus Anser IFX test; and the authors stated that additional patient samples are needed to verify the clinical utility of ATI- and IFX-HMSA.

Ordas et al (2012) stated that “preliminary evidence suggests that multiple factors influence the PK of mAbs.  Understanding the determinants of the PK of mAbs has great potential s to improve and optimize the management of patients with IBD“.  This article was a review and the authors concluded that “Incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time”.

Inflectra

Inflectra (infliximab-dyyb) (Pfizer, Inc.) is a biosimilar to Remicade (infliximab) (Janssen Biotech, Inc), which was originally licensed in 1998. Inflectra was approved by the FDA in April 2016 for the treatment of the following indications, for which Remicade has the same approval. The indication and usage to include pediatric ulcerative colitis was later FDA-approved in June 2019.

• FDA-approved indications:
  
  
  • Moderately to severely active Crohn’s disease (CD)
  • Moderately to severely active ulcerative colitis (UC)
  • Moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate
  • Active ankylosing spondylitis (AS)
  • Active psoriatic arthritis (PsA)
  • Chronic severe plaque psoriasis (PsO)

Juvenile Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Evidence suggests that infliximab may be effective in juvenile rheumatoid arthritis.  A randomized, controlled clinical study found a non-significant trend in favor of infliximab in polyarticular juvenile idiopathic arthritis (Ruperto et al, 2007).  In this multi-center, randomized, placebo-controlled study, 122 children with persistent polyarticular juvenile idiopathic arthritis despite prior methotrexate therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44.  Patients received methotrexate plus infliximab 3 mg/kg through week 44, or methotrexate plus placebo for 14 weeks followed by methotrexate plus infliximab 6 mg/kg through week 44.  The investigators reported that a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8 % and 49.2 %, respectively), but the between-group difference in this primary efficacy end point was not statistically significant (p = 0.12).  The investigators reported that, by week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2 % of all patients.  By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6 % and 51.8 %, respectively, of patients.

An open-label extension of this study of juvenile idiopathic arthritis concluded that infliximab was safe and effective in the long-term, but had a high discontinuation rate (Ruperto et al, 2010).  Seventy-eight of the 122 subjects (64 %) entered this open-label extension study.  Of these, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (8 patients) or patient/physician/sponsor requirement (8 patients).  The authors reported that infliximab at a mean dose of 4.4 mg/kg per infusion was generally well-tolerated.  Infusion reactions occurred in 32 % (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58 %, 15/26).  At 4 years, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44 %, 40 %, 33 %, 24 %, and 13 %, respectively.

Kawasaki Disease

Han and Zhao (2018) stated that Kawasaki disease (KD) is a serious disease characterized by systemic lesions of the skin and mucous membranes, as well as lymphomas and vascular inflammation; KD threatens the health and lives of children, especially young ones.  These investigators compared the therapeutic effects of single intravenous immunoglobulin gamma (IVIG) versus a combination of IVIG and infliximab in young children with KD.  A total of 154 children with KD, younger than 5 years old, were enrolled in the study from January 2013 to January 2017.  Participants were randomly divided into an IVIG group and a combination of IVIG and infliximab treatment group.  After systematic treatments, the therapeutic indicators of the 2 groups were compared.  During the treatment process, body temperature and other important inflammatory indicators, including CRP, white blood cell count (WBC), and TNF-α, were monitored in the first 4 days.  There were fewer refractory KD patients in the combined treatment group than in the IVIG group (4 versus 14, p < 0.001); KD patients in the combined treatment group had better outcomes with shorter fever durations and hospital stays, as well as less coronary artery (CA) dilation.  However, there was no obvious differences in the incidence rate of CA aneurysms (CAA) between the 2 groups (p > 0.05).  Costs of administration were similar between groups (p > 0.05).  Body temperature, CRP, WBC, and TNF-α in the combined therapy group all showed an earlier drop than in the IVIG group, indicating a more effective anti-inflammation effect.  The authors concluded that the  introduction of IVIG combined with infliximab in the treatment of young children with KD had more advantages than single IVIG therapy and can be considered as a preferred treatment for KD.  However, these investigators stated that this study had certain limitations that need to be considered.  The therapeutic effect of IVIG and IVIG plus Infliximab treatments on atypical or incomplete KD patients has not been examined.  Other therapeutic regimens should also be considered and compared.  They stated that it is necessary to further examine if there is a significant difference in CAA frequency and long-term outcomes between these 2 strategies among a larger number of patients.

Eun (2019) stated that as TNF-alpha is a key inflammatory cytokine involved in KD.  Recently, infliximab has been introduced and used for IVIG-resistant KD.  This revealed early addition of infliximab treatment to be safe and well-tolerated and reduced fever duration, some markers of inflammation, left anterior descending coronary artery Z score.  Meanwhile, there have been opposite attention about treatment with infliximab.  The complications of infliximab administration include the reactivation of latent TB and an increased risk of bacterial sepsis, with concern about possible malignancy risk.  Luckily, it has been reported that infliximab exposure is not associated with an increased risk of malignancy in children patients with IBD.  In patients with refractory KD, infliximab is supposed to be administered only once, not repeatedly, which may not cause the worrisome complication, different with the CD or juvenile idiopathic arthritis (JIA)'s repetitive administration.  According to the investigation of infliximab in refractory KD patients, it overall appeared to cause rapid defervescence, resulting in a shorter length of hospital stay, and is relatively well-tolerated.  Retrospective studies have reported response rates (defined by a reduction in fever and C-reactive protein level) of 81.3 to 91.7 % when infliximab was used as a 2nd-line agent.  Thus, infliximab might be a noticeable promising treatment for IVIG-resistant KD to potential decrease coronary artery abnormalities, although, the most optimal choice of adjunctive therapy will be different for each KD patient.  The author concluded that further studies are needed to classify the subsets of KD patients according to immune status.

In a multi-center study, Kur and associates (2019) examined the status of infliximab use in IVIG-resistant KD patients and the incidence of CAAs according to treatment regimens.  Between March 2010 and February 2017, a total of 16 hospitals participated in this study; 102 (32.3 ± 19.9 months, 72 males) who received infliximab at any time after 1st IVIG treatment failure were enrolled.  Data were retrospectively collected using a questionnaire.  Subjects were divided into 2 groups according to the timing of infliximab administration.  Early treatment (group 1) had shorter fever duration (10.5 ± 4.4 days) until infliximab infusion than that in late treatment (group 2) (16.4 ± 4.5 days; p < 0.001).  These investigators examined the response rate to infliximab and the incidence of significant CAA (z-score of greater than 5).  Overall response rate to infliximab was 89/102 (87.3 %) and the incidence of significant CAA was lower in group 1 than in group 2 (1/42 [2.4 %] versus 17/60 [28.3 %], p < 0.001).  The authors concluded that the findings of this study suggested that the early administration of infliximab may reduce the incidence of significant CAA in patients with IVIG-resistant KD.  However, these researchers stated that further prospective randomized studies with larger sample sizes are needed.

Furthermore, an UpToDate review on “Refractory Kawasaki disease” (Sundel, 2019) states that “Anti-tumor necrosis factor (TNF) alpha agents such as infliximab and etanercept have been studied for the treatment of KD because elevated levels of TNF are a characteristic of KD.  TNF inhibition or blockade is a promising treatment for TNF-driven signs and symptoms in KD, based upon its relative safety, rapidity of action, and reported efficacy compared with plasmapheresis, cyclosporine, and cyclophosphamide … Therapeutic alternatives, which have demonstrated effectiveness for other forms of vasculitis, include inhibitors of tumor necrosis factor (TNF) alpha, other immunosuppressive agents, and plasmapheresis.  However, there are limited data concerning the risks and benefits of these agents for refractory KD and only a few, small trials with which to evaluate them.  The most commonly used of these agents is infliximab, a monoclonal antibody against TNF-alpha.  In multiple trials, it effectively lowers fever, laboratory markers of inflammation, and signs of mucocutaneous inflammation, but there is minimal evidence that it improves coronary artery outcomes.  Infliximab (5 mg/kg) is typically given to children who have evidence of active vasculitis despite receiving 2 courses of IVIG (total 4 mg/kg) and 1 to 3 doses of IV methylprednisolone”.

Localized Scleroderma/Morphea

Diab and colleagues (2010) reported the case of a 66-year old white woman with a history of hypertension and degenerative arthritis was seen in July 2003 by her primary care physician (PCP) for erythematous and sclerotic patches on her trunk.  A skin biopsy specimen taken by the PCP at that time was interpreted (by an outside pathology laboratory) to indicate granuloma annulare.  The patient began treatment with systemic corticosteroids and ceased taking her anti-hypertensive medication.  However, her cutaneous symptoms continued to progress, and she was referred to the authors’ clinic in January 2004.  TNF therapy was considered in light of the demonstration of TNF within the vascular endothelium of her biopsy specimen.  After her tuberculosis treatment was completed, these investigators initiated infliximab therapy at 5 mg/kg monthly.  The patient reported a halt in the progression of her skin lesions along with a decrease in skin tightness after the second infusion of infliximab.  The authors noted that their patient with GM demonstrated remarkable improvement after treatment with infliximab.  This agent may serve as an alternative therapeutic approach for patients with similar presentations.  However, it is important to note that the natural course of all sclerosing disorders is to “burn out” over time, and so randomized controlled studies are needed.  These studies are currently lacking, and all treatments that have appeared to show improvement in sclerosing disorders have failed to do so in the context of controlled studies.

Ferguson et al (2015) reported successful treatment of an adolescent Caucasian female with severe progressive localized scleroderma (mixed subtype, including generalized morphea and linear scleroderma of the trunk/limb) using infliximab and leflunomide.  The patient demonstrated improvement after the first 9 months of therapy based on her clinical examination, objective measures, and patient and parent global assessments.  The authors concluded that infliximab is a potential treatment option for pediatric localized scleroderma patients who have progression of disease or who are unable to tolerate the side effect profile of more standard systemic therapy.  They stated that larger longitudinal studies or case series are needed to confirm and further investigate infliximab's role in localized scleroderma.

Lupus Erythematosus

In a Cochrane review, Jessop et al (2009) assessed the effects of drugs for discoid lupus erythematosus. These investigators updated their searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2009), MEDLINE, EMBASE, LILACS, and online ongoing trials registers.  The reference lists of relevant reviews were searched.  Index Medicus (1956 to 1966) was handsearched and we approached authors for information about unpublished trials.  They included all randomized trials of drugs to treat people with discoid lupus erythematosus.  Drugs included in the search were azathioprine, chloroquine, clofazimine, corticosteroids, (oral and topical), dapsone, gold, interferon alpha-2a, methotrexate, phenytoin, retinoids, sulphasalazine, thalidomide, topical calcineurin blockers (pimecrolimus and tacrolimus), and biological agents (etanercept, efalizumab, infliximab, and rituximab).  Two reviewers independently examined each retrieved study for eligibility.  Two trials involving 136 participants were included.  No new trials were included in this update.  In a cross-over study of 12 weeks duration, fluocinonide 0.0 5 % cream (a potent topical corticosteroid), appeared to be better than hydrocortisone 1 % cream (a mild corticosteroid) when the first arm of the trial involving 78 subjects was analyzed at 6 weeks.  Clearing or excellent improvement was seen in 27 % of individuals using fluocinonide and in 10 % of those using hydrocortisone, giving a 17 % absolute benefit in favor of fluocinonide (95 % CI: 0.0 to 0.34, NNT = 6).  In the second trial, acitretin (50 mg/day) was compared with hydroxychloroquine (400 mg/day) in 58 people in a parallel trial of 8 weeks duration.  There was marked improvement or clearing in 46 % of people using acitretin and in 50 % of those on hydroxychloroquine, but there was no significant difference between the 2 interventions.  The adverse effects were more frequent and more severe in the acitretin group.  In this trial clearing of erythema was measured and found to be better in the hydroxychloroquine group (RR 0.61, 95 % CI: 0.36 to 1.06).  The authors concluded that fluocinonide cream may be more effective than hydrocortisone in treating people with discoid lupus erythematosus.  Hydroxychloroquine and acitretin appear to be of equal efficacy, although adverse effects are more frequent and more severe with acitretin.  There is not enough reliable evidence about other drugs used to treat discoid lupus erythematosus.

Lateef and Petri (2010) stated that the pathogenesis of systemic lupus erythematosus (SLE) involves aberrations in multiple components of the immune system including B cells, T cells, cytokines and growth factors.  Therapeutic agents targeting these mediators selectively have been tested for the treatment of SLE.  This review summarized the recent advances in these biological therapies.  The 2 large phase II/III randomized placebo-controlled trials of B-cell depletion, using rituximab, in SLE, reported unexpected negative results.  On the contrary, 2 large phase III trials of belimumab, the monoclonal antibody against B-lymphocyte stimulator (BLyS), showed significant clinical benefit.  Response rates were 57.6 and 43.2 % for 10 mg/kg belimumab, compared with 43.6 and 33.8 % for placebo in BLISS-52 and BLISS-76, respectively.  Studies of a co-stimulation blocker (abatacept), TNF inhibitor (infliximab), and interleukin-6 inhibitor (tocilizumab) were either negative (abatacept) or were associated with high rates of adverse events.  Studies of T cell and interferon inhibition remain in the early development phase.  The authors concluded that despite the enthusiasm in the field of biologic therapies, the majority of these new modalities have fallen short of expectations for various reasons.  Only belimumab has recently met its primary outcome in 2 phase III trials.

Measurement of Serum Levels of Infliximab and Human Anti-Chimeric Antibodies (HACA)

There is insufficient scientific evidence regarding the clinical value of measurements of serum levels of infliximab and/or HACA for patients receiving infliximab therapy.

The protocol in the study by Maini et al (1999) pre-specified that pharmacokinetic data would be analyzed in the first 200 subjects.  However, the number of subjects with human anti-chimeric antibodies (HACA) formation was not stated.  Because of the murine component of the antibody, patients receiving infliximab can develop HACA that are associated with an increased rate of infusion reactions.  Pharmacokinetic measurements were actually performed in 197 patients and results were consistent with the previously defined half-life of 8 to 12 days.  It should be noted that HACA formation could not be measured in patients receiving infliximab since the drug interferes with the assay.  However, 27 patients who discontinued treatment before 30 weeks were tested for HACA formation, and 3 patients (11 %) tested positive for HACA (2 with a titer of 1/10 and 1 with a titer of 1/40).  The rate of HACA formation in patients with Crohn's disease (CD) treated with infliximab is reported to be 13 %, but this rate appears to be less if a patient is on concurrent immunosuppressive therapy (Hanauer, 1999; Sanborn and Hanauer, 2002).  It is unclear whether serum infliximab levels may decline more rapidly in the presence of HACA resulting in reduced effectiveness of infliximab therapy. 

St Clair et al (2002) examined the relationship between serum concentrations of infliximab and clinical improvement from RA following infliximab treatment.  Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multi-center, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the safety and effectiveness of infliximab therapy.  Serum levels of infliximab were measured by enzyme-linked immunosorbent assay.  Dose-response trends were analyzed using generalized logistic regression techniques.  Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.  At week 54, 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (p < 0.001).  Increased magnitude of ACR response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR-20 criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (p < 0.001), as was less progression of radiographical joint damage (p = 0.004), providing support for a dose-response relationship.  Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.  The authors concluded that these results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

In the study by St. Clair et al (2002), the relatively low proportion of ACR-50 responders in patients receiving 3mg/kg every 8 weeks may be due to inadequate exposure to infliximab during the course of therapy.  The trough serum levels of infliximab at 54 weeks varied more than 100-fold in this group suggesting marked differences among patients in exposure to infliximab.  The basis for this individual variability is unclear, but HACA and/or metabolic differences may offer some explanations.  However, it is unlikely that HACA are the sole reason for the rapid clearance of serum infliximab in this group of patients.  After completion of the study, HACA were detected in 25 patients (8.5 %) with analyzable samples.  These antibodies were distributed across all infliximab-treated groups.  The appropriate serum samples were available for measuring HACA in 19 of 21 patients from the group that received 3mg/kg every 8 weeks; and this group of patients had undetectable trough levels of infliximab.  Of these 19 subjects, only 6 were HACA-positive, and 2 had inconclusive results.  Therefore, metabolic factors probably are responsible for the rapid clearance of infliximab in some patients.

The relationship between clinical improvement and trough serum levels of infliximab bears clinical implications.  Although there was a trend towards a slightly higher proportion of serious side effects in the group receiving 3mg/kg every 4 weeks compared with the group receiving 3mg/kg every 8 weeks (16 % versus 11 %), this incidence was no higher than that observed in the placebo-controlled group (21 %).  Presently, there is a lack of evidence to identify which patients might benefit from a dose increase based on any clinical, laboratory, or radiographical factors.  Additionally, the relationship between trough serum levels of infliximab and clinical improvement is imprecise.  At 54 weeks, 6 (21 %) of the 28 patients in the study attained ACR-50 or better despite trough serum infliximab levels of less than 0.1 ug/ml.  Thus, trough serum levels of infliximab are not, by themselves reliable predictors of treatment response.  St Clair et al (2002) stated that they would not advocate the routine measurement of serum infliximab levels for this reasons.  It should also be noted that poor or lack of response to infliximab therapy may be the result of a particular disease characteristics (e.g., joint inflammation not primarily driven by TNF-alpha) or other host factors that preclude an adequate response to treatment.

The clinical significance of HACA formation, if any, has yet to be established.  HACA is associated with an increased frequency of infusion reactions, although overall, the presence of HACA is poorly predictive of infusion reactions (Smith et al, 2005).  Guidelines from the Canadian Consensus Group on the Use of Infliximab in Crohn’s Disease (Panaccione, 2001) noted that most infusion reactions are easily dealt with by stopping the infusion and restarting at a decreased rate.  Furthermore, formation of antibodies to infliximab can be prevented by coadministration of infliximab with methotrexate or other immunosuppressants (Panaccione, 2004).  It should be noted that HACA-positive patients who received repeated treatment with infliximab have demonstrated sustained clinical benefit and have tolerated such treatment well even though they may be more likely to experience an infusion reaction to the administration of infliximab.

Measurement of anti-histone antibodies has been employed for monitoring of infliximab therapy.  However its clinical value has yet to be established.  Allanore et al (2004) examined autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab.  These investigators included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide.  They tested the sera of the patients for anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30.  Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after 3 infusions.  At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 % versus 42 %, p = 0.009).  At week 30, the frequency of patients with ANA had increased from 29 % to 69 % (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0 % to 3 % for IgG (NS) and from 0 % to 32 % for IgM (p < 0.001); the frequency of anti-histone IgG detection had increased from 22 % to 32 % (p = 0.04) and that of IgM detection, from 18 % to 79 % (p < 0.001).  No lupus-like syndrome was observed.  RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001).  No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy.  The authors concluded that Infliximab therapy lead to the selective and delayed induction of autoantibodies.  This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.

Elkayam and colleagues (2005) noted that therapy with TNFa blocking agents has been associated with increased rate of ANA and rare cases of lupus like syndromes.  The objective of this study was to prospectively analyze a wide array of autoantibodies in RA patients before and 14 weeks after starting infliximab.  In this study, 26 consecutive active RA patients participated.  All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and every 8 weeks, along with weekly low dose methotrexate.  Patients were evaluated at week 0 and 14.  Clinical assessment included the number of tender and swollen joints, duration of morning stiffness, adverse events (AEs) (including SLE-like) and erythrocyte sedimentation rate (ESR).  Sera were collected before the 1st infusion of infliximab at week 0 and 14.  The autoantibodies studied were: fluorescent ANA, anti dsDNA, IgG and IgM anti-cardiolipin (ACA), anti-histone- H1 and C (H1, H2A, H2B, H3, H4), anti-SSA, -SSB, -ENA, -scleroderma 70, -thyroid peroxidase (TPO) and -neutrophilic cytoplasmic (ANCA) antibodies.  Of 26 patients, 17 were women.  A significant decrease in duration of morning stiffness, number of tender and swollen joints and ESR were observed between week 0 and 14.  During follow-up (mean of 20.5 +/- 7.3 months), 9 patients stopped infliximab due to inefficacy or AE (most of them after the 4th infusion).  Two patients developed lupus-like phenomena.  ANA was found positive at baseline in 7 out of 26 patients.  In 5 of them, an increase in the titer of ANA was observed at week 14.  ANA negative turned positive for 8 patients.  A significant increase of anti-cardiolipin (ACA)-IgM levels was observed in 8 patients and of ACA-IgG in 6, in parallel with ANA seroconversion.  The mean level of anti dsDNA) -IgG significantly increased from 66 +/-3 3 to 93 +/- 68 IU/ml, in 4 patients to pathological levels.  Four patients demonstrated an increase in anti-histone H1.  Levels of ANCA, anti-ENA, -SSA, -SSB, -RNP, -scleroderma70 and -thyroid peroxidase (TPO) were negative in all patients and remained unchanged during the study.  Cessation of treatment with infliximab was found to be associated with the appearance of ANA.  The authors concluded that an increased titer or a new appearance of ANA was observed in 12 out of 26 patients.  The main autoantibodies found were anti dsDNA, ACA-IgM and -IgG and anti-histone.  The authors noted that in their cohort, the appearance of some autoantibodies seemed to predict late cessation of treatment.

Afif et al (2010) evaluated the clinical utility of measuring human anti-chimeric antibodies (HACA) and infliximab concentrations. The investigators reviewed the medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured to determine whether the result affected clinical management. The investigators reported that 155 patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49 percent), partial response after initiation of infliximab (22 percent), and possible autoimmune / delayed hypersensitivity reaction (10 percent). HACAs were identified in 35 patients (23 percent) and therapeutic infliximab concentrations in 51 patients (33 percent). The investigators found, of 177 tests assessed, the results impacted treatment decisions in 73 percent. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92 percent of patients, whereas dose escalation had a response of 17 percent. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86 percent of patients, whereas changing to another anti-TNF agent had a response of 33 percent. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76 percent of the time and had no evidence of active inflammation by endoscopic / radiographic assessment 62 percent of the time. The investigators concluded that these results indicate that measurement of HACA and infliximab concentration impacts management and is clinically useful. The investigators stated that increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent. An accompanying editorial by D'Haens (2010) noted limitations of the study by Afif, et al., which were acknowledged in the discussion of the paper. The editorialist stated that the retrospective nature of the study by Afif, et al., without standard measurements of disease activity and the random selection of patients included in the analysis (based on the investigators’ individual practice) warrant cautious interpretation of the results.

Pariente et al (2012) reported that trough levels and antibodies to infliximab did not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. The investigators sought to assess the clinical value of measuring infliximab trough levels and antibodies to infliximab concentrations in IBD patients who lost response to infliximab therapy. The investigators retrospectively studied records of IBD patients who lost response to infliximab therapy. The investigators first assessed clinical responses of different therapeutic strategies that were applied when patients lost response to infliximab and then we looked at the correlation between clinical response and infliximab trough levels and infliximab antibody concentrations. The investigators reported that 76 IBD patients were included.; 31 patients (41%) continued infliximab therapy without any modification, 39 patients (51%) had an intensification of infliximab therapy, five patients (7%) had switched to adalimumab therapy, and one patient (1%) underwent surgery. Clinical response was observed in 27 patients (69%) with an intensification of infliximab therapy. The investigators found no significant difference in mean infliximab trough level at inclusion in patients who responded to intensification of infliximab therapy (3.3 + 4.1 mcg/mL) as compared with patients who did not respond (2.3 + 2.2 mcg/mL, p = 0.85). In all, 16/76 patients (22.4%) presented detectable infliximab antibodies in the serum. Ten antibody-positive patients had an intensification of infliximab therapy and six (60%) demonstrated a clinical response. After intensification of infliximab therapy the infliximab antibody concentration decreased in five patients. The investigators concluded that, in patients with IBD who lose response to infliximab, clinical improvement may occur upon intensification of infliximab therapy, irrespective of infliximab serum concentration or presence of infliximab antibodies.

Yanai et al (2015) stated that there is controversy about whether levels of anti-TNF and anti-drug antibodies are accurate determinants of loss of response to therapy.  These researchers analyzed the association between trough levels of anti-TNF agents or anti-drug antibodies and outcomes of interventions for patients with loss of response to infliximab or adalimumab.   They performed a retrospective study of pediatric and adult patients with IBD and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013.  The authors concluded that the findings of this retrospective analysis suggested that trough levels of drug or anti-drug antibodies may guide therapeutic decisions for more than 2/3 of IBD patients with either clinically suspected or definite inflammatory loss of response to therapy.  These findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Overview of the medical management of mild to moderate Crohn disease in adults” (Farrell and Peppercorn, 2017) does not mention infliximab level and antibody monitoring.

The development of antibodies is a possible concern with TNF-alpha inhibitors and is associated with allergic reactions or loss of drug efficacy. Adalimumab and infliximab antibody testing is currently available. Anti-adalimumab antibody detects the formation of human antihuman antibodies (HAHA) for individuals using adalimumab (Humira) therapy. Anti-infliximab antibody tests detects the formation of human anti-chimeric antibodies (HACA) for patients using infliximab (Remicade). Each of these drugs has been proposed to assist in therapeutic decisions (eg, Anti-Adalimumab Antibody Test, Prometheus Anser ADA, Anser IFX).

Similarly, tests for serum drug concentration levels of infliximab (Remicade) and adalimumab (Humira) have been proposed to determine dosing and guide infusion intervals (eg, Adalimumab Concentration, Prometheus Anser ADA).

The Anser IFX (Prometheus, Inc., San Diego, CA) is a test that simultaneously measure and monitor serum infliximab and antibodies to infliximab concentrations to clarify factors that may be contributing to a patient's loss of response and help guide treatment decisions.  However, there is a lack of evidence regarding the clinical value of this test.

Lee and colleagues (2012) stated that IFX is a chimeric monoclonal antibody directed against TNF-alpha.  When used in IBD, primary non-response is found in at least 10 % of patients, with secondary loss of response occurring in a further 10 to 15 % per year.  It has been suggested that this may in part be a result of the development of anti-IFX antibodies (ATIs).  These researchers determined in patients receiving IFX the prevalence of ATIs, the effect of immunosuppressants on the prevalence of ATI, the effect of ATIs on the prevalence of infusion reactions and the effect of ATIs on the rates of remission.  MEDLINE and EMBASE databases were searched from 1948 and 1980, respectively, to October 2011.  A total of 18 studies involving 3,326 patients were included.  The prevalence of ATIs was 45.8 % when episodic infusions of IFX were given and 12.4 % when maintenance IFX was given.  The rates of infusion reactions were significantly higher in patients with ATIs (relative risk: 2.07; 95 % CI: 1.61 to 2.67).  Immunosuppressants resulted in a 50 % reduction in the risk of developing ATIs (p < 0.00001).  However, the presence or absence of ATIs did not affect the rates of clinical remission.  The prevalence of ATIs depends on the regimen of IFX administration and the use of immunosuppressants.  Patients who tested positive for ATIs were at an increased risk of infusion reactions, but had similar rates of remission compared with patients who tested negative for ATIs.  The authors noted that further analysis is needed to determine whether loss of response is dependent on the titer of ATIs.

Steenholdt (2013) examined the clinical utility of measuring IFX and anti-IFX Ab by novel radioimmunoassay (RIA) techniques.  Specifically, the aim was to investigate if these measurements could aid in evaluating and optimizing safety and effectiveness of IFX therapy in patients with Crohn's disease.  An experimental study for comparison of analytical properties of assays for measuring IFX and anti-IFX Ab was applied.  In addition, 3 observational, retrospective, single-center cohort studies of all patients with Crohn's disease treated with IFX were carried out.  Serum levels of IFX and anti-IFX Ab measured by RIA strongly associated with clinical response types to IFX maintenance therapy.  Cut-off values providing optimal discrimination of patients with loss of response or maintained remission were established.  An algorithm for evaluating and optimizing therapy in individual patients with loss of treatment response based on IFX and anti-IFX Ab levels was proposed.  Acute severe infusion reactions appeared not to be true IgE-mediated anaphylactic reactions, but rather associated with development of anti-IFX IgG Ab.  Risk was increased during episodic therapy, but absence of anti-IFX Ab prior to a re-initiation series did not exclude reactions and assessments hereof could not be used for risk stratification.  Several factors may potentially interfere with associations of IFX and anti-IFX Ab with clinical outcome including use of different analytical techniques, different cut-off values for reporting of positive test results, differences in timing of measurements, and transiency of anti-IFX Ab.  The author concluded that monitoring serum levels of IFX and anti-IFX Ab by novel RIA techniques appears promising for evaluating and optimizing the safety and effectiveness of IFX therapy in Crohn's disease.  Moreover, the author noted that previous conflicting reports on the importance of tests are potentially biased by use of different types of assays, different cut-off values for binary classification of test results, and inconsistent timing of measurements; prospective validation of proposed treatment algorithms in larger cohorts is needed.

Hernandez et al (2014) determined the sensitivity and specificity of an available commercial ELISA assay; considering cut-off of DAS28 for IFX levels and HACA in RA patients.  These researchers assessed 60 serum samples from patients diagnosed with RA treated with IFX (1st line of biological treatment) taken prior to infusion.  Patients were classified as responders, based on low disease activity (DAS28 less than 3.2; greater than 6 months) or non-responders, based on DAS28greater than 3.2 with more than 1 swollen joint and/or elevated CRP/ESR.  Infliximab levels and anti-IFX HACA were measured using a commercial ELISA kit (Progenika^™) following manufacturer's recommendations.  The sample size was previously calculated to ensure a sensitivity of 0.8 and specificity of 0.6, with a CI of 95 %, related to the clinical activity index DAS28.  Statistical analysis to establish the appropriate values for the cut-off was performed using median (percentiles 25 to 75), U test Mann-Whitney and ROC curves (Receiver operating characteristic).  Median IFX levels in non-responder RA patients (n = 24) was lower compared with responder patients (n = 36).  These investigators identified the optimal cut-off with ROC analysis for DAS28 less than 5.1 and IFX levels less than 0.046 ug/ml, with a sensitivity and specificity of 100 % and 79 %, respectively.  Receiver operating characteristic analysis could not be calculated because of the low percentages of positivity for anti-IFX HACA in the selected patient group (n = 8/60, 13.33 %).  The authors concluded that the cut-off values for IFX levels, rather than anti-IFX HACA determination, may be useful in evaluating clinical response measured by DAS28 in RA.  However, they stated that there is a priority in standardizing laboratory techniques (variability inter-/intra-assay and inter-/intra-laboratory) to validate this information and its possible clinical application.

Also, an UpToDate review on “Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases” (Stone, 2014) states that “The development of HACA has potentially important clinical effects.  However, the full clinical impact of HACA is not clear.  Solid data have linked HACA to the development of infusion reactions, but it is less clear that HACA is responsible for the blunting of clinical responses to infliximab that occur with regular administration over time.  In addition, testing for HACA is not widely available, and there is no consensus about the optimal use of such assays.  More than half of patients with RA receiving infliximab require increases in their regular dose over time or shortening of the interval at which the medication is administered.  Although this “dose creep” may be related to the formation of HACA, there is no evidence to confirm this theory.  An alternative theory is that the need to increase infliximab doses over time simply reflects underdosing at the start of therapy.  Thus, some patients with RA or Crohn’s disease may benefit from infliximab given at doses higher than the recommended 3 mg/kg or more frequently than every eight weeks.  The usual approach to lessening clinical efficacy of infliximab is either to increase the dose or to increase the frequency with which the medication is administered”.

In a retrospective, interventional, non-comparative cohort study, Kruh and colleagues (2014) examined the safety and effectiveness of IFX for the treatment of refractory non-infectious uveitis.  A total of 88 patients from a single-center private practice were included in this study.  Patients with chronic, recalcitrant uveitis treated with IFX were identified through an electronic medical record database.  All charts were reviewed for sex, diagnosis, location of inflammation, presence of vasculitis, prior immunomodulatory treatments, duration of IFX treatment, dose received, secondary side effects, and other medications continued while receiving treatment with IFX.  The primary outcome measures were the rate of remission, time to remission, relapse rate, failure rate, and patient tolerance.  Additional analysis aimed to identity risk factors that would predict a higher success rate of IFX to treat various types of non-infectious uveitis.  Of the 72 patients (81.8 %) who achieved clinical remission while being treated with IFX, 42 (58.3 %) required additional immunomodulatory medications.  At 7, 18.1, and 44.7 weeks, 25 %, 50 %, and 75 % of patients, respectively, achieved clinical remission off all corticosteroids.  Moreover, 32 patients (36.4 %) experienced at least 1 side effect while on IFX therapy, and 17 patients (19.3 %) discontinued treatment secondary to 1 or more intolerable side effects.  The most common adverse effects were skin rash (9.1 %) and fatigue (8 %).  Factors associated with a higher chance to achieve clinical remission were non-idiopathic uveitis (p < 0.001), intermediate or panuveitis (p < 0.001), absence of vasculitis (p < 0.001), and a starting dose greater than or equal to 5 mg/kg (p < 0.011).  The authors concluded that IFX induces a high rate of complete clinical remission in recalcitrant uveitis and is well-tolerated by most patients.  Moreover, they stated that "Although our study is limited by the follow-up period and the retrospective design without a control group, we have shown that our infliximab protocol is highly effective in inducing clinical remission in refractory uveitis, with a relatively low rate of treatment-ending adverse events.  Few patients achieved durable remission off infliximab during our follow-up period, but extended maintenance therapy may well be a necessary component in the treatment of recalcitrant uveitis.  Continued follow-up of our cohort will be required to fully determine the long-term effects of infliximab, and our results will need to be confirmed by a larger multicenter study".

Cooper and associates (2014) noted that serum TNF-alpha levels correlate negatively with hepatitis C virus (HCV) anti-viral response.  In a phase IIIB, randomized, prospective, open-label pilot trial conducted at 8 Canadian sites, these researchers tested the hypothesis that a single IFX induction dose would positively influence on-treatment virological response and sustained virological response (SVR).  Treatment-naive HCV genotype 1-infected patients 18 to 65 years of age with high serum TNF-alpha values (greater than 300 pg⁄ml) were randomly assigned to receive a single pre-treatment induction IFX infusion (5 mg⁄kg) 7 days before anti-viral therapy (arm A) or no pre-treatment (arm B).  All patients received pegylated interferon alpha 2b (1.5 μg⁄kg⁄week) plus weight-based ribavirin (800 mg⁄day to 1,400 mg⁄day) for up to 48 weeks.  A total of 85 patients (arm A [n = 41], arm B [n = 44]; 70 % male) received pegylated interferon alpha 2b.  The mean age (48.1 years), race (81 % white) and METAVIR fibrosis stage (F0-2 = 79 %, F3-4 = 21 %) were similar between groups.  Infliximab was well-tolerated without attributable severe adverse events; 56.5 % completed the study (arm A [n = 21], arm B [n = 27]).  Most discontinuations were due to virological failure at weeks 12 (n = 20 [23.5 %]) and 24 (n = 7 [8.2 %]) and did not differ according to group.  Numerically lower proportions of IFX recipients achieved rapid virological response (19.5 % versus 36.4 %), complete early virological response (43.9 % versus 59.1 %) and SVR (34.1 % versus 52.3 %).  However, between-group differences did not reach statistical significance.  No differences in adverse event profile or laboratory measures were noted.  The authors concluded that a single IFX dose before pegylated-interferon alpha 2b and ribavirin therapy did not result in greater viral decline during the first 12 weeks of HCV therapy or improved SVR.

Nanda et al (2013) performed a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients' ATI status.  MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies.  Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria.  Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates.  Sensitivity analysis was performed for all outcomes.  Funnel plot was performed to assess for publication bias.  A total of 13 studies met the inclusion criteria, and reported results in 1,378 patients with IBD.  All included studies had a high risk of bias in at least 1 quality domain.  The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95 % confidence interval (CI): 2.0 to 4.9, p < 0.0001), when compared with patients without ATIs.  This effect estimate was predominantly based on data from patients (n = 494) with Crohn's disease (RR: 3.2, 95 % CI: 1.9 to 5.5, p < 0.0001).  Data only from patients with ulcerative colitis (n = 86) exhibited a non-significant RR of loss of response of 2.2 (95 % CI: 0.5 to 9.0, p = 0.3) in those with ATIs.  Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported.  Three studies (n = 243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was -0.8 (95 % CI: -1.2 to -0.4, p < 0.0001).  A funnel plot suggested the presence of publication bias.  The authors concluded that the presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD.  Moreover, they stated that published studies on this topic lack uniform reporting of outcomes; high risk of bias was present in all the included studies.

Microscopic Colitis

Primary Systemic Vasculitis

In a retrospective descriptive case series, Eleftheriou and colleagues (2009) reported the safety and effectiveness of biologic therapies in a multi-center series of 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 of biologic therapy in systemic vasculitis of the young is needed.

Psoriatic Arthritis and Psoriasis

Based on limited evidence, the U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab.  A controlled clinical study (Chaudhari et al, 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis.  In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of 2 doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo.  Nineteen of 22 patients assigned to infliximab achieved good or better physician's overall assessments, compared with 2 of 11 patients assigned to placebo.  In initial studies, remissions seemed to be durable, with many patients improving for 6 months or longer.

Pyoderma Gangrenosum

A clinical trial has demonstrated that infliximab is superior to placebo in the treatment of pyoderma gangrenosum.  Pyoderma gangrenosum is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease.  Pyoderma gangrenosum is treated by managing the underlying cause.  Topical and oral steroids are used.  If resistant, oral dapsone or minocycline, and occasionally cyclosporine is used.  Brooklyn et al (2006) reported on the results of a randomized controlled trial of infliximab.  Patients 18 years of age and older with pyoderma gangrenosum were randomized to receive infliximab at 5 mg per kilogram (n = 13) or placebo (n = 17).  Patients were assessed 2 weeks later and, during the open label portion of the study, non-responders were offered open labeled infliximab, and were re-assessed 4 weeks later.  At week 2, significantly more patients in the infliximab group had improved (46 % (6/13) compared with the placebo group (6 % (1/17) (p = 0.025).  Overall, 29 patients received infliximab with 69 % (20/29) demonstrating a clinical beneficial response.  Remission rate at week 6 was 21 % (6/29).  There was no response in 31 % (9/29) of patients.  The authors concluded that infliximab is superior to placebo in the treatment of pyoderma gangrenosum. 

Relapsing Polychondritis

Also, an UpToDate review on "Treatment of relapsing polychondritis" (Michet, 2013) states that "[t]he major second-line drugs in RPC include cyclophosphamide, azathioprine, cyclosporine, pulse methylprednisolone, methotrexate, and other newer therapies.  Response to antiinflammatory/immunomodulatory compounds with potential efficacy, such as leflunomide, soluble tumor necrosis factor alpha receptor (etanercept) or anti-tumor necrosis factor antibody (infliximab, adalimumab), and anti-interleukin 1 receptor (anakinra), have been largely limited to individual case reports .... Successful treatments with infliximab (5 mg/kg by intravenous infusion at two, four, then eight-week intervals) and etanercept (50 mg weekly) have been reported.  Potential efficacy has been shown in refractory RPC associated laryngo-tracheal disease, necrotizing vasculitis, episcleritis/scleritis, aortic valve disease, synovitis, and auricular and nasal cartilage inflammation.  These promising uncontrolled results warrant further investigation to assess the role of anti-TNF alpha therapies".

Renal Cell Carcinoma

Harrison and colleagues (2007) stated that tumor necrosis factor-alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC).  These researchers performed 2 sequential phase-II clinical trials of infliximab in patients with immunotherapy-resistant or refractory RCC.  Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks.  Treatment continued until disease progression (PD).  Response was assessed according to Response Evaluation Criteria in Solid Tumors.  Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment.  TNF-alpha and its receptors were detected in malignant cells in RCC biopsies.  In study 1, 3 patients (16 %) achieved partial response (PR) and 3 patients (16 %) achieved stable disease (SD).  Median duration of response (PR + SD) was 7.7 months (range of 5.0 to 40.5+ months).  In study 2, 11 patients (61 %) achieved SD.  Median duration of response was 6.2 months (range of 3.5 to 24+ months); 1 patient developed grade-3 hypersensitivity and another died as a result of pulmonary infection/sepsis.  Enzyme-linked immunosorbent assay (ELISA) analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD.  There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (less than 12 months).  The authors concluded that this was the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC.  Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.

Larkin et al (2010) noted that there is clinical evidence to suggest that TNF-α may be a therapeutic target in RCC.  Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC.  The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action.  These researchers conducted a phase I/II clinical trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC.  Eligible patients were systemic treatment-naive or had received previous cytokine therapy only.  Sorafenib and infliximab were administered according to standard schedules.  The study had 2 phases: in phase-I, the safety and toxicity of the combination of full-dose sorafenib and 2 dose levels of infliximab were evaluated in 3 and 3 patients, respectively, and in phase-II, further safety, toxicity and efficacy data were collected in an expanded patient population.  Acceptable safety was reported for the 1st 3 patients (infliximab 5 mg kg⁻¹) in phase-I.  Sorafenib 400 mg twice-daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (3 in phase-I and 10 in phase-II).  Adverse events included grade-3 hand-foot syndrome (31 %), rash (25 %), fatigue (19 %) and infection (19 %).  Although manageable, toxicity resulted in 75 % of the patients requiring at least 1 dose reduction and 81 % requiring at least 1 dose delay of sorafenib; 4 patients were progression-free at 6 months (PFS₆ 31 %); median PFS and overall survival(OS) were 6 and 14 months, respectively.  The authors concluded that sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed.  There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC.  These investigators stated that the combination of sorafenib and infliximab did not warrant further evaluation in patients with advanced RCC.  Moreover, they noted that the putative anti-tumor activity of infliximab that has been previously demonstrated in advanced RCC warrants further investigation and combination with alternative agents or in subgroups of patients should be considered.

An UpToDate review on “Overview of the treatment of renal cell carcinoma” (Atkins, 2019) does not mention infliximab as a therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Kidney cancer” (Version 3.2019) does not mention infliximab as a therapeutic option.

Renflexis

In 2017, the U.S. Food and Drug Administration (FDA) approved infliximab-abda (Renflexis), a biosimilar referencing infliximab (Remicade), across all eligible indications. Infliximab-abda has labeled indications for reducing signs and symptoms in patients with adult and pediatric Crohn’s disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, and for the treatment of adult plaque psoriasis. The indication and usage to include pediatric ulcerative colitis was later FDA-approved in June 2019. Renflexis is manufactured by Samsung Bioepis of Incheon, Korea. Renflexis is marketed and distributed in the United States by Merck.

Retinal Vasculitis

Cheema et al (2011) reported their experience in treating 2 patients of idiopathic retinal vasculitis, aneurysm, and neuroretinitis (IRVAN) syndrome with infliximab who showed a very favorable response to treatment.  Two patients with clinical diagnosis of IRVAN syndrome were included in the study.  The visual acuity (VA) was affected due to ocular inflammation and presence of macular edema due to exudation around the optic nerve.  The patients did not respond to initial treatment with oral steroids, and VA continued to deteriorate due to macular exudation.  Infliximab therapy resulted in prompt resolution of the inflammatory reaction and retinal exudation, with improvement in VA, that was subsequently maintained with maintenance therapy.  The intravenous infliximab infusions were scheduled at 0, 4, 8, and 12 weeks initially, and every 2 months thereafter.  Retinal neovascularization in each patient was managed by pan retinal photocoagulation.  The authors concluded that infliximab therapy may be useful in reducing inflammation and leakage from the optic nerve in patients with IRVAN syndrome.  This may help preserve or improve VA. 

The American Academy of Ophthalmology (AAO) EyeWiki’s review on “Retinal vasculitis” (Agarwal, 2014) stated that “Unlike systemic vasculitis that can be managed with colchicines and non-steroidal anti-inflammatory agents, retinal vasculitis due to causes such as Adamantiades-Behcet’s disease (ABD) requires a more aggressive approach.  Available immunosuppressive agents include cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil or biologic agents such as infliximab or etanercept.  Cyclosporine has been used as a drug of choice in previous studies.  In eyes with vasculitis associated with birdshot chorioretinopathy, sarcoidosis and Harada’s disease, azathioprine has been used for treatment.  Alkylating agents such as chlorambucil and cyclophosphamide have also been used in combination with corticosteroids.  Biologic agents have been increasingly used to achieve remission in eyes with retinal vasculitis.  These include infliximab, tacrolimus and adalimumab, apart from other agents targeting molecules such as tumor necrosis factor and interleukins”.

Furthermore, an UpToDate review on “Retinal vasculitis associated with primary ocular disorders” (Tolentino and Dana, 2019) states that “Treatment of idiopathic retinal vasculitis is usually reserved for those who develop poor vision.  Systemic glucocorticoids, azathioprine, methotrexate, cyclosporine, and plasma exchange have all been used with variable efficacy, but none has been evaluated in a randomized fashion.  One retrospective study of 29 patients with vision-threatening disease found that the administration of prednisone (initial dose 1 mg/kg per day) was associated with visual improvement in 60 % of patients.  Laser therapy is reserved for complications of retinal vasculitis, such as rubeosis iridis, recurrent vitreous hemorrhage, or retinal neovascularization.  Other local procedures are warranted in selected patients.  Vitrectomy has been indicated in dense vitreous inflammation, vitreous hemorrhage, retinal detachment, or epiretinal membrane formation.  In some patients, filtering procedures (to increase drainage of aqueous) must be performed to treat the secondary glaucoma that may accompany retinal vasculitis and ocular inflammation.  Secondary glaucoma can occur because of inflammation and/or new blood vessel growth on the angle (drainage portion of the eye).  In patients in whom macular edema develops, bevacizumab has been shown to reduce the edema and to improve vision.  For idiopathic retinal vasculitis aneurysm neuroretinitis (IRVAN), a single systemic dose of infliximab and ranibizumab appears to be helpful in improving vision and in suppressing complications related to this rare form of retinal vasculitis”.

Rheumatoid Arthritis

Consistent with FDA-approved product labeling, infliximab, in combination with methotrexate, is considered medically necessary for the reduction of signs and symptoms of RA in patients who have had an inadequate response to methotrexate monotherapy.  The safety and efficacy of infliximab for RA was demonstrated in a 30-week-long, multi-center, randomized, controlled clinical study involving RA patients who had failed to adequately respond to 6 or more months of methotrexate monotherapy.  When used for treatment of RA, infliximab is administered intravenously in 3 mg/kg doses at 0, 2 and 6 weeks and then every 8 weeks thereafter.  Infliximab may be administered as frequently as every 4 weeks in patients with an inadequate response to less frequent dosing.  However, in clinical trials, higher doses and/or more frequent administrations did not result in higher response rates.

In a double-blind, placebo-controlled, phase III clinical trial, Maini and colleagues (1999) examined if infliximab would provide additional clinical benefit to patients who had active RA despite receiving methotrexate.  A total of 428 patients who had active RA and had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomized to placebo (n = 88) or one of four regimens of infliximab at weeks 0, 2, and 6.  Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for greater than or equal to 6 months, range 10 to 35 mg/wk).  Patients were assessed every 4 weeks for 30 weeks.  At 30 weeks, the American College of Rheumatology (ACR)-20 response criteria, representing a 20 % improvement from baseline, were achieved in 53, 50, 58, and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20 % of patients receiving placebo plus methotrexate (p < 0.001 for each of the four infliximab regimens versus placebo).  A 50 % improvement was achieved in 29, 27, 26, and 31 % of infliximab plus methotrexate in the same treatment groups, compared with 5 % of patients on placebo plus methotrexate (p < 0.001).  Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.  The authors concluded that during 30 weeks, treatment with infliximab plus methotrexate was more effective than methotrexate alone in patients with active RA not previously responding to methotrexate.

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). 

Sarcoidosis

Sodhi and colleagues (2009) stated that CNS involvement is a severe manifestation of sarcoidosis that often requires aggressive immunosuppressive therapy.  The most effective approach for refractory disease is unknown.  These investigators reviewed the cases of 4 subjects who demonstrated active progression of neurosarcoidosis while under treatment with cyclophosphamide, and who were subsequently treated with infliximab.  All 4 subjects demonstrated rapid and substantial reversal of their clinical course.  Radiological findings were concordant with the clinical responses.  There were no notable toxicities.  Infliximab may be more effective than cyclophosphamide for refractory CNS sarcoidosis.  The authors noted that a larger, prospective study is warranted.

Drent and colleagues (2014) noted that in severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the 3rd-line TNF-α inhibitors IFX and ADA might be an alternative.  However, appropriate studies to guide the clinician are lacking.  These investigators established practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients.  Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established.  Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases.  A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to examine consensus in case of inadequate data to determine an objective answer.  Of the 256 papers found, 101 were included; RCTs on the use of TNF-α inhibitors in sarcoidosis were limited; 95 % (19 of 20) of the sarcoidologists contacted, completed the questionnaire (Europe 68 %, North America 32 %).  A total of 9 recommendations were formulated concerning general aspects of TNF-α inhibitor use; specific sarcoidosis related items, including indications, starting and maintenance dosage, interval of treatment, treatment duration, and discontinuation regimen of IFX and ADA, were addressed.  The authors concluded that based on earlier studies and consensus amongst world's leading sarcoidologists, practical recommendations for the use of TNF-α inhibitors in sarcoidosis were established.  These recommendations, with emphasis on indications, dosage and discontinuation regimens, had been developed to support the clinician in the management of refractory sarcoidosis patients.

Schimmelpennink and co-workers (2018) stated that IFX is effective 3rd-line therapy in severe sarcoidosis.  The originator product IFX, Remicade, is expensive, limiting universal access.  Recently, a less expensive biosimilar of IFX, Inflectra, has become available, but the efficacy and tolerability has not been studied in sarcoidosis.  In this retrospective, cohort study, a total of 29 patients treated with the IFX biosimilar Inflectra, were analyzed.  Patients received Inflectra intravenously monthly at a dose of 5 mg/kg.  These  researchers measured trough levels before every infusion.  Before and after 6 months of induction therapy pulmonary function and disease activity were evaluated using standardized uptake value (SUV) of the 18F-fluorodeoxyglucose by positron emission tomography (18F-FDG PET), soluble interleukin-2 receptor (sIL-2R), angiotensin converting enzyme (ACE) and health-related quality of life (HRQOL).  In patients with pulmonary sarcoidosis as main treatment indication (n = 15) the predicted FVC improved with 8.1 % (p < 0.05).  Furthermore, in the whole group HRQoL improved significantly (p < 0.001), whereas SUVmax and sIL-2R significantly reduced (p < 0.001 and p = 0.001, respectively).  Hospitalization due to infections occurred in 4 patients.  None of the patients discontinued Inflectra due to side-effects.  Furthermore, all patients had detectable trough levels indicating development of neutralizing antibodies.  The authors concluded that IFX biosimilar Inflectra appeared effective in the treatment of refractory sarcoidosis with a comparable safety profile to the reference product Remicade.  These investigators stated that Inflectra can be considered as an alternative and less expensive option for patients with refractory sarcoidosis.

Adler and associates (2019) stated that although anti-TNFs have been recommended as 3rd-line therapy for sarcoidosis, an up-to-date systematic synthesis of their safety and  efficacy is lacking.  These investigators reviewed the literature to characterize the safety and efficacy of anti-TNFs in sarcoidosis.  All countries and treatment settings were included.  The authors searched Medline, Embase, CINAHL, Web of Science, ClinicalTrials.gov, Cochrane Library, and Google Scholar from inception to November 27, 2017.  Studies of 5 or more cases of sarcoidosis treated with anti-TNFs were included.  Descriptive statistics were performed.  A total of 65 studies (including 5 RCTs) were identified, comprising 1,525 patients.  For pulmonary sarcoidosis, 1 RCT found IFX significantly improved vital capacity versus placebo; a 2nd detected no difference.  In non-randomized studies, IFX improved pulmonary function in 79 % of patients.  For cutaneous sarcoidosis, compared to placebo, ADA showed greater Physician Global Assessment (PGA) response and significantly reduced target lesion area, and IFX significantly decreased Sarcoidosis Area and Severity Index (SASI) induration and erythema scores.  In non-randomized studies of cutaneous, ocular, neurologic, and multi-system sarcoidosis, IFX improved 89 %, 69 %, 77 %, and 71 % of cases, respectively; ADA improved 77 % of ocular sarcoidosis cases; IFX displayed a steroid-sparing effect; 50 % of patients relapsed after discontinuation of IFX, ADA, ETA, or certolizumab pegol.  In RCTs, compared to placebo, anti-TNFs had comparable overall and serious AEs and slightly more serious infections.  The authors concluded that available evidence suggested the safety and efficacy of IFX in pulmonary, cutaneous, ocular, neurologic, and multi-system sarcoidosis, and ADA in cutaneous and ocular sarcoidosis.

Scleritis

An UpToDate review on “Treatment of scleritis” (Stone and Dana, 2014) states that “Case reports and small, uncontrolled case series suggest that the tumor necrosis factor (TNF) alpha inhibitor infliximab may be partially effective in the treatment of scleritis that is resistant to treatment with other agents.  Doses in the range of 3 to 5 mg/kg administered every four to eight weeks have been employed for this purpose.  Additional investigation of infliximab for this indication is required”.

Sjogren's Syndrome

Dry eye affects many individuals worldwide.  Significant proportion of patients with dry eye has underlying Sjogren's syndrome (SS), a progressive autoimmune condition.  Akpek et al (2011) reported treatment options for patients with dry eye secondary to SS.  A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases.  Eligible references were restricted to English-language articles published after 1975.  These sources were augmented by hand searches of reference lists from accessed articles.  Study selection, data extraction, and grading of evidence were completed independently by 4 or more review authors.  The searches identified 3,559 references as of August 10, 2010.  After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review.  In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations.  The review noted that prospective trials using infliximab and etanercept failed to demonstrate any objective improvement in the sicca component of SS syndrome.

Still's Syndrome

Kraetsch and colleagues (2001) examined the efficacy of infliximab in the treatment of patients with severe and active adult onset Still's syndrome (AOSD) despite conventional immunosuppressive therapy.  A total of 6 patients with the diagnosis of AOSD according to the Yamagushi criteria of 1992 were treated with infliximab.  All patients had severe disease with high clinical and serological activity.  Patients were treated initially with high dose steroids or more intensive immunosuppressive therapy.  Two patients had a history of multiple disease modifying antirheumatic drug (DMARD) treatments.  One patient had a history of 3 years of AOSD with fever, chills, pleural and pericardial effusions, and hepatosplenomegaly.  Despite these treatments, the patient developed increasing serological signs of inflammation and arthritis of both hips and peripheral joints.  Another patient had a history of 5 years of AOSD with oligoarthritis, myalgias, and recurrent fever despite multiple DMARD treatment, including cyclophosphamide pulse therapy.  These patients with AOSD presented with massive polyarthralgias, polyarthritis, splenomegaly or hepatomegaly, the typical rash, sore throat, weight loss, serositis, continuing fever, leucocytosis, and raised C reactive protein (CRP), ESR, and ferritin levels.  Four patients with early onset of the disease, fulfilling the diagnostic criteria for AOSD and a clinical and serological high disease activity, were included in this pilot study without any further DMARD treatment apart from the initial steroid treatment.  Reduction of established treatment, mainly with steroids, caused a relapse of the disease in all these patients.  Patients then received 3 to 5 mg/kg infliximab on weeks 0, 2, and 6, continuing with intervals of 6 to 8 weeks depending on the patient's individual disease activity.  In all patients, fever, arthralgias, myalgias, hepatosplenomegaly, and the rash resolved after the first courses of treatment with infliximab.  All serological variables (CRP, ESR, hyperferritinaemia) returned to normal.  After 3 courses of infliximab infusions, splenomegaly could not be detected in any of these patients.  After 3 courses of treatment with infliximab, splenomegaly could not be detected in any of the  patients.  Up to now, these patients have received infliximab infusion treatment for between 5 and 28 months.  Throughout this period, all patients have continued to benefit from this treatment, with improvement in their clinical symptoms, joint counts, and serological disease activity.  One of the patients had a moderate infusion reaction during the second treatment.  The infusion was discontinued for 1 hour and then was resumed with no further problems.  The authors concluded that the disease improved remarkably in all 6 patients with AOSD after treatment with infliximab, also in the early stage of AOSD.  These preliminary data suggested the potential therapeutic benefit of anti-TNF-alpha treatment in AOSD.

In a prospective, non-comparative case-series study, Kokkinos et al (2004) examined the effects of infliximab on refractory AOSD.  A total of 4 patients with severe and highly active AOSD, refractory to high doses of corticosteroids (which had been combined with methotrexate in 3 of them) and methotrexate were treated with infliximab (initial dose 3 to 5 mg/kg, continuing at intervals depending on the patient's individual disease activity).  Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all.  Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well-tolerated, and complete disease remission was sustained during a 5 to18 months follow-up period.  The authors noted that although further studies are needed to confirm long-term efficacy and safety in larger numbers of patients, they suggested that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.

Takayasu Arteritis

In a retrospective study, Molloy and co-workers (2008) assessed the efficacy of anti-TNF therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies.  Patients (n = 25) were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months; range of 2 to 84) and 9 with ETA (median 28 months; range of 4 to 82); 5 patients initially treated with ETA subsequently switched to IFX.  Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60 %) and successfully tapered below 10 mg/day in an additional 7 patients (28 %).  Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50 %) could taper or discontinue the additional agent.  Major relapses occurred in 4 patients that initially achieved stable remission.  Four patients suffered adverse events, including 1 with opportunistic infections and 1 with breast cancer.  The authors concluded that in this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy.  These findings strengthen the rationale for the conducting of a randomized controlled trial of anti-TNF therapy in TAK.

Filocamo et al (2008) noted that 4 children with TAK were treated with TNF antagonists because of disease relapse during conventional therapy or as a first-line agent.  Two patients went into remission; in the other 2, the response was partial.  The authors concluded that anti-TNF agents can have a role in the treatment of TAK; however, further controlled studies are needed.

Tubulointerstitial Nephritis and Uveitis Syndrome

An UpToDate review on "Tubulointerstitial nephritis and uveitis (TINU syndrome)" (Lee and Ashfaq, 2013) does not mention the use of infliximab as a therapeutic option.

Ulcerative Colitis

Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy.  Studies have shown that infliximab, improves clinical, endoscopic, and histologic outcomes in patients with severely active ulcerative colitis refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy.  This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade.  Two phase III randomized, placebo-controlled clinical trials have demonstrated efficacy of infliximab in inducing and maintaining clinical response and remission of refractory moderate to severe ulcerative colitis (Rutgeerts et al, 2005; Sandborn et al, 2005).  In these clinical trials, subjects with moderate-to-severe ulcerative colitis that was refractory to at least one standard therapy were randomly assigned to infliximab in doses of 5 mg per kg or 10 mg per kg, or to placebo.  In 1 clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 62 % of subjects in the 10-mg group and 69 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 37 % of subjects in the placebo group (p < 0.001 for both).  At that time, 32 % of subjects in the 10 mg group and 39 % of subjects in the 5 mg group were in clinical remission, versus 15 % of subjects in the placebo group (p = 0.002 and p < 0.001, respectively).  By 30 weeks, 51 % of the 10-mg group and 52 % of the 5-mg group achieved clinical response versus 30 % of placebo-treated subjects (p = 0.002 and p < 0.001).  At that time, 37 % of the 10-mg group and 34 % of the 5-mg group were in clinical remission, versus 16 % of the placebo group (p < 0.001 and p = 0.001).

In a 2nd clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 69 % of subjects in the 10-mg group and 65 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 29 % of subjects in the placebo group (p < 0.001 for both).  At that time, 28 % of subject in the 10-mg group and 34 % of subjects in the 5-mg group were in clinical remission, versus 6 % of subjects in the placebo group (p < 0.001 for both).  By 30 weeks, 60 % of subjects in the 10-mg group and 47 % of subjects in the 5-mg group had a clinical response, compared to  26 % of subjects receiving placebo (p < 0.001 for both).  At that time, 36 % of subjects in the 10-mg group and 26 % of subjects in the 5-mg group were in clinical remission, compared to 11 % in the placebo group (p < 0.001 and p = 0.003).

On September 23, 2011, the FDA approved infliximab to treat moderately to severely active ulcerative colitis in children older than 6 years who have had inadequate response to conventional therapy.

Additional studies are needed to evaluate the optimal timing and duration of infliximab therapy, the utility of adjuvant medical treatments during infliximab therapy, and the long-term safety and comparative efficacy of the various treatments for ulcerative colitis to better define the role of infliximab in the treatment of this condition.  Other TNF antagonists for ulcerative colitis in various phases of investigation include the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide.

Adedokun and colleagues (2014) analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to evaluate relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.  These researchers compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only).  Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses.  They also evaluated factors that affected the relationship between exposure and response.  Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria.  There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (p < 0.01).  Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles.  Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/ml infliximab at week 8 of induction therapy and 3.7 μg/ml at steady-state during maintenance therapy produced optimal outcomes in patients.  The authors concluded that serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response.  They stated that a prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies.

Uveitis

Infliximab is under investigation as a treatment for uveitis.  Current evidence is limited to case reports and uncontrolled case series.  In the largest series of infliximab for uveitis published to date, Suhler and colleagues (2005) reported that at 10 weeks’ follow-up, 18 of 23 patients were considered successfully treated.  Those successfully treated for 1 year fell to 7 of 14 eligible patients, with 5 not completing the 1 year of treatment because of significant adverse effects.  An editorial by Robert Nussenblatt of the National Eye Institute (Nussenblatt, 2005) that accompanied this report noted, however, that only 4 of 23 patients demonstrated an improvement in their visual acuity of 2 lines or better.  "Perhaps the most striking part of the report is the litany of adverse effects associated with the administration of this medication" (Nussenblatt, 2005).

Commenting on the available literature on infliximab for uveitis, Nussenblatt (2005) stated: "More than 60 publications have appeared in the literature to date describing the effects of infliximab in the treatment of uveitis.  This large number reflects a serious problem that needs to be addressed in this field.  While small, often single, case reports are important in generating hypotheses, these studies seem to produce not hypotheses but merely more of the same case reports.  Further, the reports use criteria that are not standardized, so comparing one study to another is difficult to do. This is the case for the present study as well."

Well-designed clinical studies are necessary for assessing the effectiveness and safety of infliximab in uveitis.  It should also be noted that another TNF inhibitor, etanercept, showed apparently positive results in the treatment of uveitis in case reports and uncontrolled case series, but subsequently published controlled clinical trials demonstrated no significant benefit (Foster et al, 2003; Smith et al, 2005).

Kahn et al (2006) reported their experience in using infliximab for the treatment of childhood uveitis.  A total of 17 children (3 males, 14 females) with chronic uveitis were administered high-dose infliximab (10 to 20 mg/kg/dose).  Main outcome measure was the ability to eliminate all signs of intra-ocular inflammation.  All 17 patients showed a dramatic, rapid response, with no observed inflammation in 13 patients after the second infusion, and 4 patients requiring 3 to 7 infusions to achieve disease quiescence.  Additional immunosuppressives and topical glucocorticoids were tapered when patients achieved no intra-ocular inflammation.  The authors noted that in this series, high-dose infliximab was a rapidly effective, well-tolerated therapeutic agent for the treatment of chronic, medically refractory, non-infectious uveitis.  Moreover, they stated that larger, randomized, controlled studies will provide a better understanding of the dose, interval, and duration of treatment needed and will provide data on long-term safety.

A phase II clinical trial by Suhler and associates (2009) reported the 2-year follow-up data of patients with refractory uveitis treated with intravenous infliximab as part of a prospective clinical trial.  Their 1-year data, published in 2005 (Suhler, 2005) reported reasonable initial success, but an unexpectedly high incidence of adverse events.  Of their 23 patients, 7 developed serious adverse events, including 3 thromboses, 1 malignancy, 1 new onset of congestive heart failure, and 2 cases of drug-induced lupus.  Of patients who received at least 3 injections of infliximab, 75 % also developed elevated antinuclear antibody titers, although the significance of this is unknown.  The protocol initially permitted 1 year of therapy, but was extended to 2 years midway through the study.  Longer-term follow-up data were also collected for patients who continued with infliximab therapy after study completion.  Of the 31 patients who received infliximab in this study, approximately 75 % had an initial favorable response, and the drug was effective in select patients for 2 to 4 years.  Of 23 patients who demonstrated initial success at 10 weeks, 15 completed 1 year in the study and 8 completed 2 years of therapy, 7 in the study and 1 outside the study protocol prior to its extension to 2 years.  Three patients developed a drug-related lupus-like illness.  Two developed fatal solid malignancies, which were considered by the authors to have an unclear relation to the drug.  There were no further cases of congestive heart failure or venous thrombosis.  Unfortunately, 2 of the 7 patients who completed 2 years of the study were ultimately lost to follow-up, and another 2 patients who completed the 1-year protocol were also lost to follow-up.  It may be, in fact, that the risk of long-term adverse effects is even higher than reported in this article.  The study by Suhler is difficult to interpret because of the small size, lack of comparison group, and substantial loss to followup.

In an accompanying editorial of the afore-mentioned article, Goldstein (2009) noted that Suhler et al (2009) are to be congratulated for adding to the literature on the use of TNF inhibitors in uveitis.  The editorialist stated that, while the trial is small and is neither randomized nor controlled, the data are collected in a prospective fashion, with at least 2 years of follow-up.  Although infliximab was not universally successful at controlling inflammation in this series, it was effective in selected patients, with 60 % of patients retained in the study per year.  This series also demonstrated that while infliximab is well-tolerated in terms of immediate treatment-limiting adverse effects, significant late toxicity may occur.  Furthermore, Goldstein noted that the rate of adverse events reported by Suhler et al (2009) is much higher than reported in retrospective uveitis series.  Because this is a prospective trial, its results may be more clinically relevant than those from retrospective series and may offer the clinician a more accurate estimate of the risks associated with the use of infliximab in patients with uveitis.  Clinical trials of infliximab for uveitis are currently ongoing.

Mirshahi et al (2012) stated that TNF-α plays an important role both in inflammation and apoptosis.  In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders.  Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis.  Tumor necrosis factor-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in non-infectious uveitis.  Preliminary studies suggested a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration.  Unfortunately, much of the current data raises considerable safety concerns for intra-vitreal use of TNF-α inhibitors, in particular, intra-ocular inflammatory responses have been reported after intra-vitreal injection of infliximab.  Results of dose-finding studies and humanized antibody or antibody fragments (e.g., adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

Cordero-Coma et al (2013) established evidence-based recommendations regarding the use TNF-α agents for managing uveitis patients.  Medline was searched via OVID (1950 - October Week 3, 2011) using a Cochrane highly sensitive search (phases 1 and 2).  Additional literature searches were also conducted including the following databases: the Cochrane, LILACS and the TRIP Database.  A total of 54 studies met all of the inclusion criteria and were included in this review.  A different level of recommendation and evidence is assigned to each anti-TNF-α agent.  The overall rate of reported side effects with anti-TNF-α agents for the treatment of uveitis that required discontinuation of therapy was 2.2 % (26/1,147 patients).  The authors concluded that based on the evidence gathered, infliximab and adalimumab seem to be effective in the management of immune-mediated uveitis.  Moreover, they stated that further randomized studies evaluating the efficacy of these agents are warranted.  It is the most common cause of inflammatory eye disease, with an estimated prevalence of 115 cases per 100,000 persons.  Endogenous or associated with a systemic disease, non-infectious uveitis accounts for approximately 75 % of total cases comprising of a heterogeneous group of inflammatory conditions responsible for about 10 % of legal blindness in developed nations.  Endogenous uveitides are thought to have an autoimmune component mediated by T lymphocytes specific to intraocular antigens that have failed to successfully pass basic processes designed to maintain self-tolerance.

A systematic evidence review of tumor necrosis factor inhibitors in childhood chronic uveitis found that most of the studies were case series; the only randomized controlled trial (RCT) (of Enbrel) found no significant benefit (Simonini et al, 2013). Most of the evidence relates to uveitis association with a rheumatologic condition that would qualify persons for anti-TNF treatment; among the 229 children included in this systematic evidence review, only about 60 had idiopathic uveitis not associated with another rheumatologic condition.  Simonini et al (2013) summarized the evidence regarding the effectiveness of anti-TNFα treatments in childhood autoimmune chronic uveitis (ACU), refractory to previous DMARDs.  A systematic search between January 2000 and October 2012 was conducted using Embase, Ovid Medline, Evidence Based Medicine Reviews-ACP Journal Club, Cochrane libraries, and EBM Reviews.  Studies investigating the efficacy of anti-TNFα therapy, in children (less than or equal to 16 yrs), as the first biologic treatment for ACU, refractory to topical and/or systemic steroid therapy and at least 1 DMARD, were eligible for inclusion.  The primary outcome measure was the improvement of intraocular inflammation, as defined by the SUN working group criteria.  The authors determined a combined estimate of the proportion of children responding to anti-TNFα: etanercept (ETA), infliximab (INF), or ADA.  The authors initially identified 989 articles, of which 148 were potentially eligible; 22 retrospective chart reviews, and 1 RCT, were deemed eligible, thus including 229 children (ADA n  =31; ETA n = 54 and INF n = 144).  On pooled analysis of observational studies, the proportion of responding children was 87 % (95 % CI: 75 to 98 %) for ADA, 72 % (64 to 79 %) for INF, and 33 % (95 % CI: 19 to 47 %) for ETA.  There was no difference in the proportion of responders between ADA and INF (χ(2) = 3.06, p = 0.08), although both showed superior efficacy compared to ETA (ADA versus ETA χ(2) = 20.9, p < 0.001; INF vs ETA χ(2) = 20.9, p < 0.001).  The authors concluded that, although randomized controlled trials are needed, the available evidence suggests that INF and ADA provide proven similar benefits in the treatment of childhood ACU, and they are both superior to ETA.

A review by Sanchez-Cano (2013) found that evidence for tumor necrosis factor inhibitors in noninfectious uveitis is primarily case reports and case series. The authors observed that TNF α plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. The authors said that, theoretically, some other autoimmune disorders may benefit from these agents. The authors reviewed off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. The authors concluded that, due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series.

An UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2013) states that “The role of tumor necrosis factor-alpha (TNF) inhibitors such as infliximab, adalimumab, or etanercept in the management of patients with uveitis is uncertain.  Further data from controlled trials are needed to clarify the indications and risks of TNF inhibition in the treatment of ocular inflammatory disease”.

A consensus panel organized by the American Uveitis Society (Levy-Clarke, et al., 2014) provided recommendations for the use of TNF-α biologic agents in patients with ocular inflammatory disorders. The authors performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) group criteria. The panel found that numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the panel made the following recommendations. Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.

Furthermore, an UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2019) states that “Non-infectious uveitis -- The approach to therapy is generally not affected by the etiology of the uveitis, but there are important exceptions.  As examples, Behcet syndrome is especially responsive to infliximab … The response of uveitis associated with Behcet syndrome to infliximab has been encouraging in observational studies.  For example, in an open-label observational study of 43 patients, 33 patients responded to conventional therapy (oral glucocorticoids, cyclosporine, azathioprine, or methotrexate).  Ten patients who failed to respond were subsequently treated with infliximab (5 mg/kg) every 2 weeks for a total of 6 doses.  Patients treated with infliximab had fewer relapses and longer remissions than patients who were treated conventionally.  Infliximab has been approved in Japan to treat Behcet syndrome, which is a relatively common cause of uveitis in that country.  Several reports suggest that infliximab may be more effective than etanercept for the treatment of uveitis.  Etanercept, adalimumab, certolizumab, or infliximab appear to reduce the risk of developing eye inflammation in patients with ankylosing spondylitis, a disease frequently associated with acute anterior uveitis”.

Appendix 

Appendix A: Examples of Conventional Therapy Options for CD

1. Mild to moderate disease – induction of remission:

   1. Oral budesonide
   2. Alternatives: metronidazole, ciprofloxacin, rifaximin 

2. Mild to moderate disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternatives: oral budesonide, methotrexate intramuscular (IM) or subcutaneous (SC), sulfasalazine 

3. Moderate to severe disease – induction of remission:

   1. Prednisone, methylprednisolone intravenously (IV)
   2. Alternatives: methotrexate IM or SC 

4. Moderate to severe disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: methotrexate IM or SC

5. Perianal and fistulizing disease – induction of remission

   Metronidazole ± ciprofloxacin, tacrolimus 

6. Perianal and fistulizing disease – maintenance of remission

   1. Azathioprine, mercaptopurine
   2. Alternative: methotrexate IM or SC

Appendix B: Examples of Conventional Therapy Options for UC

1. Mild to moderate disease – induction of remission:

   1. Oral mesalamine (e.g., Asacol, Asacol HD, Lialda, Pentasa), balsalazide, olsalazine
   2. Rectal mesalamine (e.g., Canasa, Rowasa)
   3. Rectal hydrocortisone (e.g., Colocort, Cortifoam)
   4. Alternatives: prednisone, azathioprine, mercaptopurine, sulfasalazine 

2. Moderate disease – maintenance of remission:

   1. Oral mesalamine, balsalazide, olsalazine, rectal mesalamine
   2. Alternatives: azathioprine, mercaptopurine, sulfasalazine 

3. Severe disease – induction of remission:

   1. Prednisone, hydrocortisone IV, methylprednisolone IV
   2. Alternatives: cyclosporine IV, tacrolimus, sulfasalazine 

4. Severe disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: sulfasalazine 

5. Pouchitis: Metronidazole, ciprofloxacin

   Alternative: rectal mesalamine

Appendix C: Examples of Contraindications to Methotrexate  

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

Appendix D: Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Cyclosporine or Acitretin

1. Clinical diagnosis of alcohol use disorder, alcoholic liver disease, or other chronic liver disease
2. Breastfeeding
3. Drug interaction
4. Cannot be used due to risk of treatment-related toxicity
5. Pregnancy or currently planning pregnancy
6. Significant comorbidity prohibits use of systemic agents (examples include liver or kidney disease, blood dyscrasias, uncontrolled hypertension)

Appendix E: RA Classification and Disease Activity

RA Classification

Rheumatoid arthritis (RA) classification criteria include a scoring system for the following four domains: joint distribution (0-5), serology (0-3), symptom duration (0-1), and acute phase reactants (0-1). A score of 6 or more (out of possible 10) equals definite RA; however, a person might fulfill the criteria prospectively over time (cumulatively), or retrospectively if data on all four domains have been adequately recorded in the past. The criteria are meant to be used for persons with clinical synovitis in at least one joint. The classification are not diagnostic criteria, but they can inform the diagnosis. For more information see, American College of Rheumatology (ACR) - Endorsed Criteria.

Source: 2010 ACR/EULAR 

Disease Activity

Disease activity is categorized as low, moderate, or high as per validated scales. Moderate and high disease activity categories have been combined (Singh et al., 2016). Structured assessments of disease activity which include multiple composite measures have been developed for RA. Eleven measures have been identified by the American College of Rheumatology (ACR) as having utility in clinical practice to accurately reflect disease activity. The choice of measure is based upon clinician preference; some measures require both patient and clinician input, while others are based only upon patient-reported data (England et al., 2019; Moreland and Cannella, 2020).

To assist clinicians in the care of persons with RA, the ACR recommend eleven measures that fulfilled minimum standard for RA disease activity. These measures include: Clinical Disease Activity Disease Index (CDAI), Disease Activity Score (DAS), Disease Activity Score 28 Joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), Multi-Biomarker Disease Activity Score (MBDA score, VECTRA DA), Rheumatoid Arthritis Disease Activity Index (RADAI), Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), and Simplified Disease Activity Index (SDAI). For more information see 2019 Updated ACR Recommended RA Disease Activity Measures.

Source: 2019 Update of the American College of Rheumatology Recommended RA Disease Activity Measures

Appendix F: Hurley Staging System for Hidradenitis Suppurativa

Table: Hurley Staging System for Hidradenitis Suppurativa

Stage	Characteristics
I	Solitary or multiple isolated abscess formation without scarring or sinus tracts. (A few minor sites with rare inflammation; may be mistaken for acne.)
II	Recurrent abscesses, single or multiple widely separated lesions, with sinus tract formation. (Frequent inflammation restrict movement and may require minor surgery such as incision and drainage.)
III	Diffuse or broad involvement across a regional area with multiple interconnected sinus tracts and abscesses. (Inflammation of sites to the size of golf balls, or sometimes baseballs; scarring develops, including subcutaneous tracts of infection – see fistula. Obviously, patients at this stage may be unable to function.)

Source: Wieczorek and Walecka (2018)

Appendix G: Brands of Targeted Immune Modulators and FDA-approved Indications

Table: Brands of Targeted Immune Modulators and FDA-approved Indications

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
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 Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis 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 Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behçet’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	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis 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 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 "+":
CPT codes not covered for indications listed in the CPB:
80230	Infliximab
83516	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen, qualitative or semiquantitative; multiple step method [measurement of anti-histone antibodies for monitoring infliximab therapy]
83520	Immunoassay, analyte, quantitative, not otherwise specified [human anti-climeric antibody (HACA), infliximab-specific ELISA] or [serum infliximab level] [InformTx therapeutic drug monitoring]
86235	Extractable nuclear antigen, antibody to, any method (e.g., nRNP, SS-A, SS-B, Sm, RNP, Sc170, J01), each antibody [measurement of anti-histone antibodies for monitoring infliximab therapy]
Other CPT codes related to the CPB:
71045 - 71048	Radiologic examination, chest
86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
86481	Tuberculosis test, cell mediated immunity antigen response measurement; enumeration of gamma interferon - producing T cells in cell suspension
86580	Skin test; tuberculosis, intradermal
96360 - 96361	Intravenous infusion, hydration
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96374	intravenous push, single or initial substance/drug
96375	each additional sequential intravenous push of a new substance/drug
96379	unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection of infusion
96401 - 96450	Chemotherapy administration
96910 - 96913	Photochemotherapy
99601 - 99602	Home infusion/specialty drug administration
HCPCS codes covered if selection criteria are met:
J1745	Injection, infliximab, 10 mg
Q5103	Injection, infliximab-dyyb, biosimilar, (inflectra), 10 mg
Q5104	Injection, infliximab-abda, biosimilar, (renflexis), 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
Q5121	Injection, infliximab-axxq, biosimilar, (AVSOLA), 10 mg
S9359	Home infusion therapy, anti-tumor necrosis factor intravenous therapy; (e.g., Infliximab); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
Other HCPCS codes related to the CPB (examples of other drug therapies):
G0069	Professional services for the administration of subcutaneous immunotherapy for each infusion drug administration calendar day in the individual's home, each 15 minutes
J0129	Injection, abatacept, 10 mg
J0135	Injection, adalimumab, 20 mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1438	Injection, etanercept, 25 mg
J1600	Injection, gold sodium thiomalate, up to 50 mg
J1628	Injection, guselkumab, 1 mg
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg [Solu-Medrol]
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg [Solu-Medrol]
J3245	Injection, tildrakizumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7502	Cyclosporine, oral, 100 mg
J7509	Methylprednisolone, oral, per 4 mg
J7510	Prednisolone, oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Cyclosporine, parenteral, 250 mg
J8530	Cyclophosphamide, oral, 25 mg
J8540	Dexamethasone, oral, 0. 25 mg
J8610	Methotrexate, oral, 2.5 mg
J9070	Cyclophosphamide, 100 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
S0108	Mercaptopurine, oral, 50 mg
S9338	Home infusion therapy, immunotherapy, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
C43.0 - C43.9, D03.0 - D03.9	Malignant melanoma of skin [severe or life-threatening enterocolitis that persists despite permanent discontinuation of ipilimumab (Yervoy) and administration of systemic corticosteroids]
D86.0 - D86.9	Sarcoidosis
D89.810	Acute graft-versus-host disease
D89.812	Acute on chronic graft-versus-host disease
H20.041 - H20.049	Secondary noninfectious iridocyclitis
I30.0 - I30.9	Acute pericarditis [cardiac toxicities]
I40.0 - I40.9	Acute myocarditis [cardiac toxicities]
J18.8	Other pneumonia, unspecified organism [immune checkpoint inhibitor-induced toxicities pneumonitis]
K50.00 - K50.919	Crohn's disease
K51.00 - K51.919	Ulcerative colitis
K60.3 - K60.5	Anal fistula
K63.2	Fistula of intestine, excluding rectum and anus
L40.0 - L40.4, L40.8 - L40.9	Other psoriasis [see CPB 658 Psoriasis: Biological Therapies]
L40.50 - L40.59	Arthropoathic psoriasis [see CPB 658 Psoriasis: Biological Therapies]
L73.2	Hidradenitis suppurativa [severe; refractory to systemic antibiotics] [(Hurley Stage II or III) refractory to at least 90 days of oral antibiotics for hidradenitis suppurativa, unless contraindicated]
L88	Pyoderma gangrenosum
M00.00 - M01.x9	Arthropathy associated with infections
M02.30 - M02.39	Reiter's disease
M05.00 - M06.9 M14.60 - M14.89	Arthropathy associated with other disorders classified elsewhere and rheumatoid arthritis and other inflammatory polyarthropathies
M08.00 - M08.99	Juvenile arthritis
M08.1, M45.0 - M45.9	Ankylosing spondylitis [moderate to severe and failed two or more NSAIDS]
M13.80 - M13.89	Other specified arthritis [allergic]
M31.30 - M31.31	Wegener's granulomatosis
M31.4	Aortic arch syndrome [Takayasu]
M35.2	Behcet's syndrome
M46.50 - M46.99, M49.80 - M49.89	Other and unspecified inflammatory spondylopathies
N17.0 - N17.9	Acute kidney failure
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B17.10 - B17.11	Acute hepatitis C with or without hepatic coma
B18.2	Chronic viral hepatitis C
B19.20 - B19.21	Unspecified viral hepatitis C with or without hepatic coma
B58.01	Toxoplasma chorioretinitis
C64.1 - C65.9	Malignant neoplasm of kidney and of renal pelvis [renal cell carcinoma]
D80.3	Selective deficiency of immunoglobulin G [IgG] subclasses
D89.811	Chronic graft-versus-host disease
D89.813	Graft versus-host disease, unspecified
E08.620	Diabetes mellitus due to underlying condition with diabetic dermatitis [necrobiosis lipoidica diabeticorum]
E09.620	Drug or chemical induced diabetes mellitus with diabetic dermatitis [necrobiosis lipoidica diabeticorum]
E10.620	Type 1 diabetes mellitus with diabetic dermatitis [necrobiosis lipoidica diabeticorum]
E11.620	Type 2 diabetes mellitus with diabetic dermatitis [necrobiosis lipoidica diabeticorum]
E13.620	Other specified diabetes mellitus with diabetic dermatitis [necrobiosis lipoidica diabeticorum]
E50.3	Vitamin A deficiency with corneal ulceration and xerosis
E85.81 - E85.89	Other amyloidosis [central nervous system amyloidosis]
H15.111 - H15.119	Episcleritis periodica fugax
H16.001 - H16.079	Corneal ulcer
H16.321 - H16.329	Diffuse interstitial keratitis [Cogan's syndrome]
H20.00 - H20.039, H20.051 - H20. 059	Iridocyclitis
H20.10- H20.13	Chronic iridocyclitis
H20.20 - H20.23	Lens-induced iridocyclitis
H20.811 - H20.819	Fuchs' heterochromic cyclitis
H20.9	Unspecified iridocyclitis [uveitis]
H30.131 - H30.139	Disseminated chorioretinal inflammation, generalized
H30.90 - H30.93	Unspecified chorioretinal inflammation [birdshot retinochoroidopathy]
H35.061 - H35.069	Retinal vasculitis
H35.351 - H35.359	Cystoid macular degeneration
H44.131 - H44.139	Sympathetic uveitis
J42	Unspecified chronic bronchitis [bronchiolitis obliterans]
J44.9	Chronic obstructive pulmonary disease, unspecified
J45.20 - J45.998	Asthma
K52.0 - K52.9	Other and unspecified noninfective gastroenteritis and colitis
K65.4	Sclerosing mesenteritis [mesenteric panniculitis]
K83.0	Cholangitis [autoimmune cholangiopathy]
K90.0	Celiac disease
L70.1	Acne conglobate [fulminans]
L92.0	Granuloma annulare
L92.1	Necrobiosis lipoidica, not elsewhere classified
L93.0	Discoid lupus erythematosus
L94.0	Localized scleroderma [morphea]
M30.3	Mucocutaneous lymph node syndrome [Kawasaki]
M33.20 - M33.29	Polymyositis
M34.0 - M34.9	Systemic sclerosis [scleroderma]
M35.00 - M35.09	Sicca syndrome (Sjögren)
M35.4	Diffuse (eosinophilic) fasciitis
M51.26 - M51.27	Other intervertebral disc displacement lumbar or lumbosacral region [disc-herniation-induced sciatica]
M54.00 - M54.09	Panniculitis affecting regions of neck and back
M79.3	Panniculitis, unspecified
M86.00 - M86.9	Osteomyelitis [multi-focal]
M94.1	Relapsing polychondritis
N02.1 - N02.7	Recurrent and persitent hematuria [membranous glomerulopathy]
N04.1 - N04.7	Nephrotic syndrome [membranous glomerulopathy]
N05.0 - N05.9	Unspecified nephritic syndrome [membranous glomerulopathy]
N61.0 - N61.1	Inflammatory disorders of breast [granulomatous mastitis]
T86.850	Intestine transplant rejection

The above policy is based on the following references: