Tocilizumab (Actemra)

Number: 0799

Commercial CPB  |  Medicare CPB

Least Cost Medically Necessary Brands

For Aetna commercial plans, Actemra (tocilizumab) brand is more costly to Aetna than other brands of targeted immune modulators (“least cost brands of targeted immune modulators”) for certain indications. There is a lack of reliable evidence that Actemra is superior to the least cost brands of targeted immune modulators for the medically necessary indications listed below. Therefore, Aetna considers Actemra to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost brands of targeted immune modulators per criteria below:

• Moderately to severely active rheumatoid arthritis (RA)
  

  • Actemra subcutaneous (SQ) formulation only: for the treatment of RA, member has a contraindication, intolerance or ineffective response to all of the following least cost brands (one-month trial each): Enbrel, Humira, Kevzara, Orencia, Rinvoq, and Xeljanz/Xeljanz XR
  • Actemra intravenous (IV) formulation only: for the treatment of RA, member has a contraindication, intolerance or ineffective response to all of the following least cost brands (one-month trial each): Enbrel, Humira, Kevzara, Orencia, Remicade, Rinvoq, Simponi Aria, and Xeljanz/Xeljanz XR.
    
    

• Moderately to severely active articular juvenile idiopathic arthritis

  • Actemra SQ and IV formulations: for the treatment of articular JIA, member has a contraindication, intolerance or ineffective response to all of the following least cost brands (one-month trial): Enbrel and Humira.

Policy

Note: REQUIRES PRECERTIFICATION

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

Note: Site of Care Utilization Management Policy applies to tocilizumab (Actemra). For information on site of service for Actemra infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Aetna considers tocilizumab (Actemra) medically necessary for the following indications where the member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnote 1* within 6 months of initiating therapy for persons who are naïve to biologic DMARDs or targeted synthetic DMARDs associated with an increased risk of TB, and repeated yearly for members with risk factors for TBFootnote 2 for risk factors for TB** that are continuing therapy with biologics:
   

   1. 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; or
      2. For treatment of moderately to severely active RA 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).

   2. Active articular juvenile idiopathic arthritis

      1. For members who have previously received a biologic or targeted synthetic DMARD indicated for active articular juvenile idiopathic arthritis; or
      2. For the treatment of active articular juvenile idiopathic arthritis when any of the following criteria are met:
         
         
         1. The member has had an inadequate response to methotrexate or another non-biologic DMARD administered at an adequate dose and duration; or
         2. The member has risk factors (see Appendix) and the member also meets one of the following:
            
            
            1. High-risk joints are involved (e.g., cervical spine, wrist, or hip); or
            2. High disease activity; or
            3. Are judged to be at high risk for disabling joint disease.

   3. Active systemic juvenile idiopathic arthritis (sJIA)

      1. For members who have previously received a biologic indicated for active systemic juvenile idiopathic arthritis; or
      2. For the treatment of active sJIA 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.

   4. Giant cell arteritis

      For the treatment of giant cell arteritis when the member’s diagnosis was confirmed by the following:
      
      
      1. Temporal artery biopsy or cross-sectional imaging; or
      2. Acute-phase reactant elevation (i.e., high erythrocyte sedimentation rate [ESR] and/or high serum C-reactive protein [CRP]).

   5. Cytokine release syndrome

      1. For the treatment of chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS); or
      2. For the treatment of cytokine release syndrome in members with refractory CRS related to blinatumomab therapy.

   6. Unicentric Castleman’s disease

      For treatment of unicentric Castleman’s disease when all of the following are met:
      
      
      1. The member is HIV-negative; and
      2. The member is human herpesvirus-8-negative; and
      3. The requested drug will be used as monotherapy; and
      4. The requested drug is being used as second-line therapy for relapsed/refractory disease.

   7. Multicentric Castleman’s disease

      For treatment of multicentric Castleman’s disease when both of the following are met:
      
      
      1. The requested drug will be used as monotherapy; and
      2. The requested drug is being used as second-line therapy for relapsed/refractory or progressive disease.

   8. Immunotherapy-related inflammatory arthritis

      For treatment of severe/refractory immunotherapy-related inflammatory arthritis that is not responding to corticosteroids and anti-inflammatory agents.

   9. Acute graft versus host disease

      For the 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. Aetna considers continuation of tocilizumab (Actemra) medically necessary for the following indications:

1. Cytokine release syndrome and immunotherapy-related inflammatory arthritis for all members (including new members) who meet all initial authorization criteria; or
2. For all other diagnoses outlined in section I in which all members (including new members) achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.

3. Aetna considers use of toclizumab in combination with biological DMARDs such as adalimumab (Humira), etanercept (Enbrel), ixekizumab (Taltz), rituximab (Rituxan), infliximab (Remicade), certolizumab (Cimzia), golimumab (Simponi), abatacept (Orencia), or anakinra (Kineret), or apremilast (Otezla) experimental and investigational because the safety and effectiveness of these combinations has not been established.

4. Aetna considers tocilizumab experimental and investigational for the prevention of coronary heart disease, and the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

   1. Adult-onset Still disease
   2. Ankylosing spondylitis
   3. Cardiac transplant rejection
   4. Crohn's disease
   5. Hemophagocytic lymphohistiocytosis
   6. Neuromyelitis optica
   7. Polymyalgia rheumatica
   8. Psoriatic arthritis
   9. Relapsing polychondritis
   10. Retinal vasculitis
   11. Sjogren's syndrome myelopathy
   12. Systemic lupus erythematosus
   13. Systemic sclerosis
   14. Systemic sclerosis-associated myopathy/polyarthritis
   15. Systemic vasculitis
   16. Takayasu arteritis
   17. TAFRO syndrome
   18. Thyroid eye disease
   19. Tumor nerosis factor receptor associated periodic syndrome (TRAPS)
   20. Uveitis.

See also

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.

Actemra (tocilizumab) is available as:

• Intravenous (IV) infusion: single‐use vials (20 mg/mL) as 80 mg/4 mL, 200 mg/10 mL and 400 mg/20 mL strengths.
• Subcutaneous (SC) injection: 162 mg/0.9 mL single‐dose pre‐filled syringe or single-dose prefilled autoinjector (ACTPen) for self‐administration.

Rheumatoid Arthritis

• IV dosing: given as a 60-minutes single IV infusion, the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Doses exceeding 800 mg per infusion are not recommended in RA.
• SC dosing:
  
  
  • Persons less than 100 kg body weight, administer 162 mg SC every other week, followed by an increase to every week based on clinical response
  • Persons at or above 100 kg body weight, administer 162 mg SC every week.
    
    
• Doses exceeding 800 mg per infusion are not recommended in persons with RA.

Giant Cell Arteritis

• The recommended dose for adults is 162 mg given once every week as a SC injection in combination with a tapering course of glucocorticoids.
• A dose of 162 mg given once every other week as a SC injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations.

Polyarticular Juvenile Idiopathic Arthritis

• IV dosing: given as a 60-minute single IV infusion, the recommended dose is once every 4 weeks based on body weight measurement. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate
  
  
  • Persons less than 30 kg weight, IV dose is 10 mg per kg
  • Persons at or above 30 kg weight, IV dose is 8 mg per kg.
    
    
• SC dosing: is based on body weight measurement
  
  
  • Persons less than 30 kg weight, SC dose is 162 mg once every 3 weeks
  • Persons at or above 30 kg weight, SC dose is 162 mg every 2 weeks.

Systemic Juvenile Idiopathic Arthritis

• IV dosing: the recommended dose is given once every 2 weeks as a 60-minute single IV infusion based on body weight measurement
  
  
  • Persons less than 30 kg weight, IV dose is 12 mg per kg
  • Persons at or above 30 kg weight, IV dose is 8 mg per kg.
    
    
• SC dosing: is based on body weight measurement
  
  
  • Persons less than 30 kg weight, SC dose is 162 mg once every 2 weeks
  • Persons at or above 30 kg weight, SC dose is 162 mg every week.

Cytokine Release Syndrome (CRS)

• IV dosing: the recommended dose, alone or in combination with corticosteroids, is given as a 60-minute IV infusion based on body weight measurement

  • Persons less than 30 kg weight, IV dose is 12 mg per kg
  • Persons at or above 30 kg weight, IV dose is 8 mg per kg.
    
    
• If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses may be administered. The interval between consecutive doses should be at least 8 hours.
• Doses exceeding 800 mg per infusion are not recommended in persons with CRS.
• Subcutaneous administration is not approved for CRS.

Source: Genentech, 2020

Background

Rheumatoid Arthritis

A better understanding of the inflammatory pathway in RA has led to the development of a number of targeted biological therapies.  Over-activity of the cytokine, interleukin-6 (IL-6), plays an important role in both the exudative as well as the proliferative phase of rheumatoid inflammation, joint destruction and osteoporosis.  Thus, inhibition of IL-6 activity is a rational approach in the treatment of patients with RA.  Tocilizumab, a humanized monoclonal antibody, blocks inflammatory responses by inhibiting both the soluble as well as the membrane-bound IL-6 receptor.

The effectiveness of tocilizumab in rheumatoid arthritis has been demonstrated in multicenter, randomized clinical studies. In a double-blind, randomized, placebo-controlled, parallel group phase III study, Smolen et al (2008) evaluated the therapeutic effects of tocilizumab in patients with RA.  A total of 623 patients with moderate-to-severe active RA were randomly assigned to receive tocilizumab 8 mg/kg (n = 205), tocilizumab 4 mg/kg (n = 214), or placebo (n = 204) intravenously every 4 weeks, with MTX at stable pre-study doses (10 to 25 mg/week).  Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts.  The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of RA according to ACR20 response at week 24.  The intention-to-treat analysis population consisted of 622 patients: 1 patient in the 4 mg/kg group did not receive study treatment and was thus excluded.  At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59 %] patients in the 8 mg/kg group, 102 [48 %] in the 4 mg/kg group, 54 [26 %] in the placebo group; odds ratio 4·0 [95 % confidence interval (CI): 2.6 to 6.1], p < 0.0001 for 8 mg/kg versus placebo; and 2.6 [1.7 to 3.9], p < 0.0001 for 4 mg/kg versus placebo).  More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69 %] in the 8 mg/kg group; 151 [71 %] in the 4 mg/kg group; 129 [63 %] in the placebo group).  The most common serious adverse events (SAE) were serious infections or infestations, reported by 6 patients in the 8 mg/kg group, 3 in the 4 mg/kg group, and 2 in the placebo group.  The authors concluded that tocilizumab could be an effective therapeutic approach in patients with moderate-to-severe active RA.

In a phase III clinical study, Emery and co-workers (2008) examined the safety and effectiveness of tocilizumab in patients with RA refractory to TNF antagonist therapy.  A total of 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable MTX for 24 weeks.  ACR20 responses, secondary safety and effectiveness endpoints were assessed.  ACR20 was achieved at 24 weeks by 50.0 %, 30.4 % and 10.1 % of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p < 0.001 both tocilizumab groups versus control).  At week 4, more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001).  Patients responded regardless of most recently failed anti-TNF or the number of failed treatments.  Disease activity score 28 (DAS28) remission (i.e., DAS28 less than 2.6) rates at week 24 were clearly dose-related, being achieved by 30.1 %, 7.6 % and 1.6 % of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control).  Most AEs were mild or moderate with overall incidences of 84.0 %, 87.1 % and 80.6 %, respectively.  The most common AEs with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache.  The incidence of SAE was higher in controls (11.3 %) than in the 8 mg/kg (6.3 %) and 4 mg/kg (7.4 %) groups.  The authors concluded that tocilizumab in combination with MTX is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.

Genovese et al (2008) examined the safety and effectiveness of tocilizumab combined with conventional DMARDs in patients with active RA.  A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multi-center TOWARD (Tocilizumab in Combination with Traditional DMARD Therapy) study.  Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.  At week 24, the proportion of patients achieving a response according to ACR20 was significantly greater in the tocilizumab plus DMARD group than in the control group (61 % versus 25 %; p < 0.0001).  Secondary end points including ACR50/70, DAS28, DAS28 remission responses (DAS28 less than 2.6), European League Against Rheumatism (EULAR) responses, and systemic markers such as the C-reactive protein (CRP) and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone.  Seventy-three percent of patients in the tocilizumab group had greater than or equal to 1 AE, compared with 61 % of patients in the control group.  Adverse events leading to withdrawal from the study were infrequent (4 % of patients in the tocilizumab group and 2 % of those in the control group); SAE occurred in 6.7 % and 4.3 % of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7 % and 1.9 %, respectively.  Elevations in the alanine aminotransferase level, from normal at baseline to greater than 3-fold the upper limit of normal, occurred in 4 % of patients in the tocilizumab group and 1 % of those in the control group, and elevated total cholesterol levels were observed in 23 % and 6 % of patients, respectively.  Sixteen patients started lipid-lowering therapy during the study.  Grade 3 neutropenia occurred in 3.7 % of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.  The authors concluded that tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

In an open-label, long-term extension trial following an initial 3-month randomized phase II trial, Nishimoto and colleagues (2009a) assessed the safety and effectiveness of 5-year, long-term tocilizumab monotherapy for patients with RA.  A total of 143 out of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks.  Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted.  All patients were evaluated with ACR improvement criteria, DAS28, and EULAR response, as well as for safety issues.  A total of 94 (66 %) of the 143 patients had completed 5 years as of March 2007; 32 patients (22 %) withdrew from the study due to AEs and 1 patient (0.7 %) due to unsatisfactory response.  Fourteen patients withdrew because of the patient's request or other reasons.  The SAE rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years.  Of the 88 patients receiving corticosteroids at baseline, 78 (88.6 %) were able to decrease their corticosteroid dose, and 28 (31.8 %) discontinued corticosteroids.  At 5 years, 79/94 (84.0 %), 65/94 (69.1 %) and 41/94 (43.6 %) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively.  Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3 %) of the patients.  The authors concluded that in this 5-year extension study, tocilizumab demonstrated sustained long-term effectiveness and a generally good safety profile.

In a multi-center, double-blind, randomized, controlled study, Nishimoto et al (2009b) examined the safety and effectiveness of tocilizumab monotherapy in active RA patients with an inadequate response to low dose MTX.  A total of 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks.  The clinical responses were measured using the ACR criteria and the DAS in 28 joints.  Serum vascular endothelial growth factor (VEGF) levels were also monitored.  At week 24, 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response.  The tocilizumab group showed superior ACR response criteria over control at all time points.  Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment.  The overall incidences of AEs were 72 and 92 % (SAE: 4.7 and 6.6 %; serious infections: 1.6 and 3.3 %) in the control and the tocilizumab groups, respectively.  All SAE improved by adequate treatment.  The authors concluded that tocilizumab monotherapy was well-tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.

Oldfield et al (2009) stated that intravenous tocilizumab 8 mg/kg (and no less than 4.8 mg), in combination with MTX, is approved in the European Union for the treatment of moderate-to-severe active RA in adult patients with inadequate response to, or who are intolerant of, prior DMARD or TNF antagonist therapy.  It may also be administered as monotherapy in patients intolerant of MTX or in whom MTX therapy is inappropriate.  Tocilizumab is also approved in Japan for the treatment of polyarticular-course juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease.  Intravenous tocilizumab was effective and generally well-tolerated when administered either as monotherapy or in combination with conventional DMARDs in several well-designed clinical studies in adult patients with moderate-to-severe RA.  Tocilizumab-based therapy was consistently more effective than placebo, MTX or other DMARDs in reducing disease activity, and some trials also showed significant benefits with tocilizumab in terms of reducing structural joint damage and improving health-related quality of life.  In particular, tocilizumab-based therapy was effective in patients with long-standing disease in whom anti-TNF therapy had previously failed.  The authors noted that more data are needed to determine the comparative safety and effectiveness of tocilizumab versus other biological agents and to establish their relative cost effectiveness.  However, the present data suggest that tocilizumab is an important emerging treatment option in adult patients with moderate-to-severe RA.

On January 8, 2010, the Food and Drug Administration (FDA) approved tocilizumab (Actemra) for the treatment of adults with moderate-to-severe RA who have not adequately responded to or cannot tolerate other approved drug classes for RA.  Actemra can be used alone or with methotrexate and DMARDs and after the use and failure of at least one TNF antagonist.  Actemra recommended use is limited to patients who have failed other approved therapies because of serious safety concerns that were noted in clinical studies.  These safety concerns include elevated liver enzymes, elevated low-density lipoprotein (LDL), hypertension, and gastrointestinal perforations.  The FDA is requiring the manufacturer to perform a post-marketing clinical trial to further assess the long-term safety of Actemra.  Specifically, the FDA wants to evaluate the impact of elevated LDL cholesterol and blood pressure observed in some patients in shorter-term trials on the cardiovascular health of patients treated with Actemra.  Furthermore, a Risk Evaluation and Mitigation Strategy (REMS) will require the drug sponsor to implement a communication plan for physicians informing them how to appropriately monitor their patients for liver and/or gastrointestinal side effects. The REMS will include a medication guide to ensure that patients are informed of the benefits and risks of Actemra.

On October 12, 2012, the FDA expanded the approved indication for tocilizumab (Actemra) for the treatment of adults with moderately to severely active RA who have had an inadequate response to 1 or more DMARDs. Actemra can be used both alone as a single-agent therapy and in combination with MTX or other DMARDs.

The SAE reported in Actemra global clinical studies included serious infections and hyper-sensitivity (allergic) reactions including a few cases of anaphylaxis.  The most common side effects were upper respiratory tract infection, nasopharyngitis, headache, hypertension.  Increases in liver function tests (alanine transaminase and aspartate transferase, also known as serum glutamic-oxaloacetic transaminase) were seen in some patients.  These increases were generally mild and reversible, with no hepatic injuries or any observed impact on liver function.

Actemra use should be avoided in combination with biological DMARDs such as Humira, Enbrel, Rituxan, Remicade, Cimzia, Simponi, Orencia, or Kineret because of the possibility of increased immunosuppression and increased risk of infection.

Actemra (tocilizumab) carries a boxed warning for serious infections including tuberculosis (TB), bacterial, invasive fungal, viral and other opportunistic infections. If a serious infection develops, the warning suggests interrupting Actemra (tocilizumab) until the infection is controlled. The warning further suggests testing for latent TB before starting Actemra (tocilizumab), and monitoring all patients for active TB during treatment, even if initial TB test was negative.

The following warnings and precautions should be considered prior to prescribing Actemra (tocilizumab):

• Serious Infections – do not administer Actemra during an active infection, including localized infections. If a serious infection develops, interrupt Actemra until the infection is controlled
• Gastrointestinal (GI) perforation – use with caution in patients who may be at increased risk
• Laboratory monitoring is recommended due to potential consequences of treatment‐related changes in neutrophils, platelets, lipids, and liver function tests. It is recommended that Actemra not be initiated in patients with an absolute neutrophil count (ANC) below 2000/mm³, platelet count below 100,000/mm³, or who have ALT or AST above 1.5 times the upper limit of normal (ULN)
• Anaphylaxis or serious hypersensitivity reactions have occurred
• Live vaccines should not be given with Actemra
• Monitor for potential drug interactions.

Actemra doses exceeding 800 mg per infusion are not recommended.

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 or without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with or 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).

Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA), commonly referred to as juvenile RA, is the most common chronic rheumatic disease in children with onset before age 16.  Typical symptoms include stiffness when awakening, limping, and joint swelling.  Any joint can be affected, and inflammation may limit the mobility of the affected joints.  About half of JIA cases involve fewer than 5 joints (pauciarticular forms) and often include uveitis.  Polyarticular forms of JIA affect 5 or more joints, usually in a symmetrical fashion.  It can be rheumatoid factor positive or negative.  Overall, JIA affects more girls than boys, however late onset pauciarticular JIA is more common in boys.  While it was once believed that most children eventually outgrow JIA, it is now known that between 25 and 70 % of children with JIA will still have active disease into adulthood. 

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

Herlin (2008) stated that in recent years the treatment of JIA has undergone marked changes.  There is substantial evidence that inhibitors of TNF-alpha (e.g., etanercept, infliximab and adalimumab) show significant effectiveness when standard therapy fails, and long-term tolerability is fairly good.  Patients with systemic JIA do not respond well to treatment with TNF inhibitors, but they may benefit from treatment with IL-1 and IL-6 receptor antagonists.  Moreover, the author noted that "our knowledge is still limited regarding which patients respond to a specific biological therapy".

Ilowite (2008) summarized the recent data on biologic therapies in the treatment of JIA.  New data from large prospective randomized trials have demonstrated efficacy of anti-TNF agents and a co-stimulator signal inhibitor.  The results of a pivotal trial of infliximab in polyarticular JIA suggested efficacy, but the primary outcome was not significantly different from placebo.  Important information regarding dosing in children was obtained, however.  A pivotal trial of adalimumab did prove efficacy which resulted in FDA approval.  The monoclonal antibodies to TNF appear to be more effective in treating chronic uveitis associated with JIA than etanercept.  Anti-IL-1 and anti-IL-6 therapy, particularly for systemic disease patients, looks very promising, as well.  The co-stimulation modifier abatacept was shown to be effective and relatively well-tolerated in the short-term, also resulting in FDA approval.  Continued experience with these agents and appropriate systems-based methods such as formal registries, to complement existing FDA procedures for monitoring safety, will improve the ability to identify short-term and long-term toxicities of these new agents.  The author concluded that as experience is gained, and longer-term safety is shown, it is likely that biologics will be introduced as therapy earlier in the course of patients who inadequately respond to conventional DMARDs.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by inflammatory arthritis with intermittent fever, rash, anemia, hepatosplenomegaly, pleuritis, and pericarditis.  The peak age of onset of sJIA is between 18 months and 2 years, although persistence of the disease into adulthood occurs.  It has a poorer long-term prognosis than other subtypes of juvenile arthritis, accounting for almost 2/3 of all deaths in children with arthritis, and an overall mortality rate between 2 and 4 %.  There are currently no FDA approved therapies of sJIA.  Current treatment consists of high-dose corticosteroids. Interleukin-6 is thought to contribute to the major features of sJIA including chronic synovial inflammation, articular cartilage damage, fever, anemia, growth impairment, and osteoporosis.

A phase 3 study found that the IL-6 inhibitor tocilizumab was significantly more effective than placebo in the short-term (12-week) treatment of patients with sJIA (de Bendetti et al, 2010).  Children and adolescents (aged 2 to 17 years) with active sJIA, with disease duration of 6 or more months, and inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, were randomized (2:1) to receive tocilizumab every 2 weeks (at a dose of 8 mg/kg for patients 30 kg or more body weight, and a dose of 12 mg/kg for patients less than 30 kg) or placebo.  Stable doses of NSAIDs and methotrexate were continued.  Tapering of corticosteroids was allowed starting at week 6.  Patients who met rescue criteria received standard of care and were offered open-label tocilizumab and considered non-responders.  The primary end point was the proportion of patients with JIA ACR30 response plus absence of fever at week 12 for tocilizumab patient versus control (intention-to-treat analysis).  These investigators enrolled 112 patients (75 subjects treated with tocilizumab and 30 control subjects) with a mean age of 9.6 years.  The authors reported that baseline characteristics were similar across groups.  By week 12, 1 control patient and 2 tocilizumab patients withdrew from the study, and more control subjects than tocilizumab subjects required rescue therapy (54 % versus 1 %).  These investigators found that significantly more tocilizumab patients than control patients achieved JIA ACR30 response plus absence of fever at week 12 (85 % versus 24 %, p < 0.0001).  In addition, 70 % of patients on tocilizuma achieved a JIA ACR70 and 37 % achieved a JIA ACR90, compared to 8 % and 5 % of control patients, respectively.  Nearly 2/3 of patients in the study were free of rash after 3 months.  No control patients and 3 tocilizumab patients experienced significant adverse events (angioedema and urticaria in 1 patient, varicella, and bacterial arthritis), all of which resolved without sequelae, according to investigators.

Doggrell (2008) stated that some patients with RA and systemic-onset JIA are resistant to inhibitors of IL-1 and TNF.  Increased levels of IL-6 are associated with both these conditions.  Tocilizumab has recently been used in phase III trials in RA and systemic-onset JIA.  The author carried out a study to assess findings of phase III clinical trials with tocilizumab.  In the study of the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders, the primary efficacy end-point was the proportion of subjects with a 20 % improvement in their RA signs and symptoms according to the ACR criteria and, at 24 weeks, this value was 26 % with placebo and was increased to 48 and 59 % with tocilizumab at 4 and 8 mg respectively.  In the trial of tocilizumab in systemic-onset JIA, the primary end-point in the open-label lead-in was the proportion of subjects achieving an ACR Pedi 30 response and 91 % of subjects had achieved this at 6 weeks.  This response was maintained by the majority of subjects being treated with tocilizumab during a 12-week double-blind trial and 48 weeks of open trial follow-up.  Small numbers of subjects developed infections in both studies.  The author concluded that if long-term safety can be established, tocilizumab will probably become part of the treatment for RA and may become a major breakthrough for the treatment of systemic-onset JIA.

Yokota and associates (2008) examined the safety and effectiveness of tocilizumab in children with JIA.  A total of 56 children (aged 2 to 19 years) with disease refractory to conventional treatment were given 3 doses of tocilizumab 8 mg/kg every 2 weeks during a 6-week open-label lead-in phase.  Patients achieving an American College of Rheumatology Pediatric (ACR Pedi) 30 response and a CRP concentration of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks or until withdrawal for rescue medication in a double-blind phase.  The primary endpoint of the double-blind phase was an ACR Pedi 30 response and CRP concentration of less than 15 mg/L.  Patients responding to tocilizumab and needing further treatment were enrolled in an open-label extension phase for at least 48 weeks.  At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91 %), 48 (86 %), and 38 (68 %) patients, respectively.  A total of 43 patients continued to the double-blind phase and were included in the efficacy analysis.  Four (17 %) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L compared with 16 (80 %) of 20 in the tocilizumab group (p < 0.0001).  By week 48 of the open-label extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98 %), 45 (94 %), and 43 (90 %) of 48 patients, respectively.  Serious side effects were anaphylactic reaction, gastrointestinal hemorrhage, bronchitis, and gastroenteritis.  The authors concluded that tocilizumab is effective in children with systemic-onset JIA.  It might therefore be a suitable treatment in the control of this disorder, which has so far been difficult to manage.

On April 15, 2011, the FDA approved tocilizumab, given alone or in combination with methotrexate, for the treatment of active sJIA in children aged 2 years or older.

Tocilizumab has been approved by the FDA for the treatment of polyarticular juvenile idiopathic arthritis in persons 2 years of age and older (Genentech, 2013). FDA approval of Actemra was based on the CHERISH study, a three-part study including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis, who had an inadequate response to methotrexate or inability to tolerate methotrexate. Part I consisted of a 16-week active tocilizumab treatment lead-in period (n = 188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints).  

At the conclusion of the open-label Part I, 91% of patients taking background methotrexate in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study (Genentech, 2013). The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background methotrexate in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape.

The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16 (Genentech, 2013). JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. The most common serious adverse events were serious infections.

On May 14, 2018, the FDA approved the subcutaneous formulation of tocilizumab for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) in patients two years of age and older. The approval is based on data from the JIGSAW-117 study, a 52-week, open-label, multicenter, phase 1b pharmacokinetic (PK)/pharmacodynamic (PD) bridging study designed to determine the appropriate dosing regimen of Actemra SC across a range of body weights (BWs) in children with PJIA. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with tocilizumab-IV and tocilizumab-naïve patients with active disease, were treated with subcutaneous tocilizumab based on body weight. Patients weighing at or above 30 kg (n=25) were treated with 162 mg of tocilizumab-SC every 2 weeks and patients weighing less than 30 kg (n=27) received 162 mg of tocilizumab-SC every 3 weeks for 52 weeks. Of these 52 patients, 37 (71%) were naive to tocilizumab and 15 (29%) had been receiving tocilizumab-IV and switched to tocilizumab-SC at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in polyarticular JIA patients and subcutaneous tocilizumab in patients with RA. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), and neutropenia. During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in tocilizumab-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in tocilizumab-SC treated PJIA patients compared to what was seen in adult RA or GCA patients.

Tocilizumab is being studied in the treatment of other diseases/disorders including autoimmune diseases.  Venkiteshwaran (2009) stated that tocilizumab has also been studied for potential use in the treatment of other IL-6 related disorders including Crohn disease.

On September 13, 2018, the FDA approved the subcutaneous formulation of tocilizumab (Actemra) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) alone or in combination with methotrexate in persons at least two years of age. The intravenous formulation was previoulsy approved for this indication. The subcutaneous formulation allows for flexibility so that a prefilled syringe can be injected at home. Approval was based on data from the JIGSAW-118 study, which was a 52-week, open-label, multicenter, pharmacokinetic/pharmacodynamic study included 51 patients aged 1-17 years with SJIA. Patients were either naïve to Actemra SC (N=26) or were receiving Actemra IV and switched to the SC formulation at baseline (N=25). The efficacy of Actemra SC was based on PK exposure and extrapolation of the established efficacy of Actemra IV in SJIA. According to the prescribing information, when transitioning from Actemra IV therapy to SC administration, the first SC dose should be administered when the next scheduled IV dose is due. For SJIA patients, Actemra SC may be self-injected by the patient or patient's caregiver if both the clinician and the parent/legal guardian determines it is appropriate (Ernst, 2018).

Giant Cell Arteritis

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels (FDA, 2017). This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries. For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

Unizony et al (2013a) noted that “Encouraging preliminary results have been obtained with the IL-6 receptor (IL-6R) antagonist tocilizumab for the treatment of large-vessel vasculitides, including both giant cell arteritis and Takayasu arteritis …. At this time, better delineation of the immunopathogenic mechanisms of this spectrum of diseases and prospective randomized clinical trials are required to move the field forward and decrease the cumulative glucocorticoid toxicity seen in these disorders”. 

Unizony et al (2013b) described the design of the tocilizumab in giant cell arteritis trial.  These researchers stated that the GiACTA trial is a multi-center, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA).  Approximately 100 centers will enroll 250 patients with active disease.  The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension.  Patients will be randomized into 1 of 4 groups.  Group A (TCZ 162mg weekly plus a 6-month prednisone-taper); group B (TCZ 162mg every other week plus a 6-month prednisone-taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper).  These investigators hypothesized that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy end-point of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids.  The authors stated that GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA.  

An UpToDate review on “Treatment of giant cell (temporal) arteritis” (Hunder, 2015) states that “Tocilizumab -- Several case series and case reports have reported that tocilizumab (TCZ) may be effective in patients with GCA in whom it has been difficult to taper glucocorticoids to an acceptable level or in whom disease has been refractory or relapsing, even despite therapy with additional agents.  The use of TCZ in GCA is also supported by the evidence that IL-6 may be important in disease pathogenesis …. Data from randomized trials and long-term follow-up would be helpful to more fully assess the degree of benefit that TCZ may provide”. 

Walsh (2015) stated that “Tocilizumab (Actemra) may offer a treatment option for refractory giant cell arteritis (GCA), providing symptomatic relief and reductions in markers of inflammation, a small multicenter study suggested …. The efficacy and safety of IL-6 blockade in patients with GCA should be assessed in prospective controlled clinical trials with long-term follow-up.  Gonzalez-Gay and colleagues concluded.  One such double-blind placebo-controlled study is known as GiACTA, which will enroll 250 patients from 100 centers”.  

Osman et al (2014) stated that giant cell arteritis (GCA) and Takayasu's arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment.  In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness.  These researchers systematically reviewed the safety and effectiveness of biological agents in patients with LVV.  They searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions.  Two reviewers independently selected studies, extracted data, and assessed methodological quality.  The protocol was registered in PROSPERO.  These investigators included 25 studies (3 RCTs and 22 case series with greater than or equal to 2 cases); 95 GCA and 98 TAA patients received biological agents.  The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA.  GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, -16.55 mg/day (95 % CI: -26.24 to -6.86)).  In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32 % of the time.  Remission was variably defined, and the studies were clinically heterogeneous which precluded further analysis.  The authors concluded that this systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV.  Evidence from RCTs suggested that anti-TNF agents are not effective for remission or reduction of CS use.  Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series.  They stated that future analytical studies are needed to confirm these findings. 

In a retrospective multi-center open-label study, Loricera and colleagues (2014) evaluated the effectiveness of TCZ in GCA patients with refractory disease and/or with unacceptable side effects due to corticosteroids.  A total of 22 GCA patients were treated with TCZ at standard dose of 8 mg/kg/month.  The main outcomes were achievement of disease remission and reduction of corticosteroid dose.  The mean age ± standard deviation of patients was 69 ± 8 years.  The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2).  Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs.  Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy.  Also, after a median follow-up of 9 (interquartile range of 6 to 19) months, the C-reactive protein level had fallen from 1.9 (1.2 to 5.4) to 0.2 (0.1 to 0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20 to 81) to 12 (2 to 20)mm/1st hour (p = 0.001).  The median dose of prednisone was also tapered from 18.75 (10 to 45) to 5 (2.5 to 10) mg/day (p < 0.0001).  However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection.  Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis.  The authors concluded that TTCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids.  However, the risk of infection should be kept in mind when using this drug in patients with GCA. 

Oliveira et al (2014) noted that patients with GCA often respond to corticosteroid (CS) therapy; however, the majority of patients relapse when CS therapy is tapered or withdrawn.  These researchers assessed the effectiveness of TCZ in patients with relapsing GCA.  A total of 4 patients with relapsing GCA received TCZ monthly (4 mg/kg or 8 mg/kg).  Disease activity and drug tolerability were evaluated clinically and via laboratory test results at the beginning of the study and every 3 months until the publication of this study.  All 4 patients were still receiving TCZ monthly at the time of manuscript submission.  All 4 patients treated with TCZ achieved clinical and laboratory response.  No adverse events were detected.  The authors concluded that in this small case series, TCZ was effectives and well-tolerated in patients with relapsing GCA.  Moreover, they stated that proper randomized controlled trials are required to achieve confident conclusions regarding the safety and efficacy of TCZ in GCA.

On May 22, 2017, the FDA approved tocilizumab subcutaneous injection for the treatment of GCA (Genentech, 2017; FDA, 2017). The approval is based on the positive outcome of the Phase III GiACTA study, a Phase III, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of tocilizumab as a treatment for GCA. The multicenter study was conducted in 251 patients across 76 sites in 14 countries. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone. The results showed that tocilizumab, initially combined with a six-month steroid regimen, more effectively sustained remission through 52 weeks (56 percent in the tocilizumab weekly group and 53.1 percent in the tocilizumab bi-weekly group) compared to placebo combined with a 26-week steroid taper (14 percent) and placebo combined with a 52-week steroid taper (17.6 percent). The cumulative prednisone dose was lower in treated patients with tocilizumab relative to placebo. The overall safety profile observed in the tocilizumab treatment groups was generally consistent with the known safety profile of tocilizumab (FDA, 2017).

Cytokine Release Syndrome (CRS)

Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment that involves T cells that are genetically reengineered in a lab to produce the chimeric antigen receptor on their surface. This allows the T cells to recognize an antigen on targeted tumor cells. This immunotherapy is aimed at treating certain types of cancer, and continues to be studied in clinical trials (Han et al 2017; LLS, 2017).

A serious side effect associated with CAR-T therapy is cytokine release syndrome (CRS), which is caused by an overactive immune response. CRS is the result of T-cell activation, which produces large amounts of cytokines that subsequently develops into an overactive immune system. Most people with CRS experience mild or moderate flu-like symptoms; however, some patients experience more severe symptoms that may lead to potentially life-threatening complications such as cardiac dysfunction, acute respiratory distress syndrome or multi-organ failure (Genentech, 2017).

On August 30, 2017, in addition to the approval of the CAR-T cell therapy drug, tisagenlecleucel (Kymriah), the U.S. Food and Drug Administration (FDA) announced the approval of a label expansion for Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. This is the first FDA-approved treatment to manage severe cytokine release syndrome associated with CAR T cell therapy.

FDA approval was based on a “retrospective analysis of pooled outcome data from clinical trials of CAR-T cell therapies for blood cancers, which assessed the efficacy of Actemra in the treatment of CRS. The study population included 45 pediatric and adult patients treated with Actemra, with or without additional high-dose corticosteroids, for severe or life-threatening CRS. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response, defined as resolution of CRS within 14 days of the first dose of Actemra, no more than two doses of Actemra were needed, and no drugs other than Actemra and corticosteroids were used for treatment. No adverse reactions related to Actemra were reported. A second study confirmed resolution of CRS within 14 days using an independent cohort that included 15 patients with CAR T cell-induced CRS” (Genentech, 2017).

Idiopathic Multicentric Castleman Disease

Tabata et al (2019) noted that idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA).  A 43-year old man who presented with multiple swollen lymph nodes was diagnosed with iMCD.  He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study.  The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies; thus, tocilizumab was switched to rituximab, and his anemia was improved.  The authors concluded that complication with AIHA should be carefully considered when iMCD patients present with severe anemia.

Multicentric Castleman disease

Multicentric Castleman disease (MCD) is an atypical lympho-proliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms.  Dysregulated over-production of IL-6 is responsible for the clinical abnormalities.  In a multi-center prospective study, Nishimoto et al (2005) evaluated the safety and effectiveness of a humanized anti-human IL-6 receptor monoclonal antibody (MRA) in patients with MCD.  These researchers reported results of the first 60 weeks of the study enrolling 28 patients.  The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered bi-weekly.  Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks.  Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters.  Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly.  In addition, fatigue diminished.  Chronic inflammatory symptoms were successfully managed over 60 weeks.  In 8 (28.6 %) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation.  Eleven (73.3 %) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose.  Most adverse events were mild to moderate in severity.  The authors concluded that MRA was well-tolerated and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.  These preliminary findings need to be validated by well-designed studies.

An UpToDate review on “Multicentric Castleman's disease” (Aster et al, 2014) states that “Monoclonal antibodies targeted against IL-6 (siltuximab) or the IL-6 receptor (tocilizumab, also called atlizumab or MRA) have demonstrated clinical efficacy in HIV/HHV-8 negative MCD, resulting in symptom resolution.  Tocilizumab has been approved for use in Japan since 2005, but not in Europe or the United States.  Siltuximab is approved in the United States for the treatment of patients with MCD who are HIV/HHV-8 negative, and it is under review by regulatory agencies in Europe.  Data about combining other modalities with anti-IL-6-directed treatment are limited”.

Acute Graft Versus Host Disease

Gergis and van Besien (2019) noted that acute graft-versus-host disease (aGVHD) was first described by Barnes et al in 1962, who reported a “secondary disease” in mice after irradiation and infusion of allogeneic spleen cells.  The disease manifested as fatal diarrhea and skin abnormalities.  They postulated that aGVHD resulted from introducing immunologically competent cells into an immunocompetent host.  Treatments were developed to address this problem, and most centers use calcineurin inhibitors (tacrolimus or cyclosporine) combined with mycophenolate mofetil or methotrexate to prevents aGVHD.  This classic GVHD prophylaxis is associated with an incidence of acute GVHD of approximately 60 %.  Other methods of GVHD prevention, including T-cell depletion and more recently post-transplant cyclophosphamide, have been tested, but all have their own limitations.  The most effective methods tend to be more immunosuppressive and are not clearly superior in regard to long-term survival.  Acute GVHD then remains a major problem in hematopoietic stem cell allogeneic transplantation (HCT).  Its initial treatment consists of high-dose glucocorticoid (1 to 2 mg/kg daily).  However, only 1/3 of patients are cured, leaving the majority of patients requiring more therapy.  Patients with glucocorticoid-refractory acute GVHD (SR aGVHD) have a very high mortality and to-date, there is no effective treatment.

Other Indications

Adult-Onset Still disease

Puechal and colleagues (2011) reported the first series of patients with AOSD treated with tocilizumab.  All AOSD patients treated with tocilizumab in France between July 2006 and July 2009 after failure to all available therapies were included in this cohort study.  The main outcome measures were the EULAR improvement criteria and resolution of systemic symptoms at the 3- and 6-month follow-up periods.  A total of 14 patients with refractory AOSD were included.  At the start of tocilizumab treatment, despite a mean prednisone dosage of 23.3 mg/day, based on a 28-joint count, mean tender joints were 10.5, mean swollen joints were 7.9, and the mean DAS in 28 joints was 5.61.  Recurrent systemic involvement, including fever and rash, was present in 7 patients.  Tocilizumab was administered at 5 to 8 mg/kg every 2 or 4 weeks (8 mg/kg/month, n = 9).  Eleven patients successfully completed the 6-month study; 1 withdrew due to necrotizing angiodermatitis, another due to chest pain at each tocilizumab infusion, and a third due to systemic flare.  A good EULAR response was observed in 64 % of patients (9 of 14) at 3 months and EULAR remission was observed in 57 % (8 of 14) at 6 months.  Systemic symptoms were resolved in 86 % of patients (6 of 7).  Moreover, corticosteroid dose was reduced by 56 %.  No other severe adverse effects occurred.  The authors concluded that tocilizumab is a promising new treatment for AOSD.  The limitations of this study were its observational nature and the lack of a control group.  Well-designed studies (i.e., multi-center randomized controlled trials) are needed to ascertain the potential of tocilizumab for the treatment of adult Still's disease.

de Boysson et al (2013) reviewed the safety and effectiveness of tocilizumab in the treatment of patients with AOSD.  These investigators reported on 2 patients with AOSD who were successfully treated with tocilizumab.  All published information on the use of tocilizumab in this disease was also retrieved through a systematic review of the English-language literature.  Including the authors’ cases, a total of 35 patients were given tocilizumab for AOSD (8 mg/kg/month in 22 patients).  The main clinical manifestations were arthritis in all 35 patients and systemic symptoms such as fever or skin rash in 28 (80 %).  Thirty-three (94 %) patients had unsuccessfully tried other immunosuppressive agents such as MTX, TNF-α blockers, or anakinra.  Most of the patients achieved a response with tocilizumab, such as a prompt articular improvement in 30/35 (86 %) patients and a disappearance of systemic symptoms in 27/28 (96 %).  Twenty-eight (80 %) patients tapered their steroid intakes, including 7 (20 %) who were able to discontinue them.  Four (11 %) patients relapsed, and 2 were successfully retreated with tocilizumab.  Regarding safety, tocilizumab is a well-tolerated treatment, but severe side effects such as macrophage activation syndrome or cytomegalovirus reactivation are possible and require ongoing vigilance.  The authors concluded that these findings suggested that tocilizumab should probably be proposed in refractory AOSD, as it allows for remission to be induced and the dose of steroid intakes to be reduced.  It is a well-tolerated treatment that can be administered according to the therapeutic sequence of RA.  Moreover, they stated that further prospective studies are needed to assess the better use of this treatment (dosage and duration) and its place among other conventional treatments.

Elkayam et al (2014) described the Israeli experience of treating AOSD with TCZ.  Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), CRP, and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of follow-up.  A total of 9 males and 6 females, aged 33 ± 12 years, mean disease duration 9 years (range of 1 to 25) were identified.  They had used a mean of 3.6 disease-modifying drugs, including 10 patients with TNF blockers.  Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients).  All patients completed at least 6 months of treatment.  The mean follow-up period was 15.7 ± 9 months.  At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain.  Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dL, respectively.  After 6 months of treatment and at the end of follow-up, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly.  Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of follow-up.  The authors concluded that TCZ 8 mg/kg was extremely effective in treating adult patients with refractory Still's disease.  Both TCZ and IL-1 blockade should be considered in the treatment algorithm of AOSD.  Moreover, they stated that RCTs are needed to validate these findings.

Ankylosing Spondylitis

Kiltz et al (2012) noted that axial spondyloarthritis (SpA) -- including ankylosing spondylitis (AS) -- is a frequent chronic inflammatory disease that affects mainly the axial skeleton.  There is evidence that NSAIDs and TNF-α blockers are effectives, but not all patients achieve remission or a major clinical response.  A variety of new drug classes have been investigated during the last years for the treatment of patients with AS in whom TNF blockers have failed or are contraindicated.  Data for abatacept, anakinra, apremilast, bisphosphonates, rituximab, secukinumab, sulfasalazine, thalidomide and tocilizumab (TCZ) were found.  All studies had problems with design and methodology.  The authors concluded that although some trends for effectiveness were seen, there is at present insufficient evidence to support a recommendation for any of these compounds.  So far, none of these new drugs has been shown to reach response rates compared to TNF-blockers.

Sieper and associates (2014) noted that clinical trials BUILDER-1 and BUILDER-2 were aimed to evaluate the safety and effectiveness of TCZ in patients with AS.  BUILDER-1 was a 2-part, phase II/III parallel-group trial in patients with AS naive to anti-TNF (aTNF) treatment.  Patients in part 1 received TCZ 8 mg/kg or placebo for 12 weeks.  In part 2 (beginning after part 1 enrolment ended), newly enrolled patients received TCZ 4 or 8 mg/kg or placebo for 24 weeks.  The same treatment arms were used in BUILDER-2, a phase III study in aTNF-inadequate responders.  The primary end-point for both studies was the proportion of patients achieving 20 % improvement in the Assessments in Axial SpondyloArthritis international Society (ASAS).  Secondary and exploratory end-points included ASAS40 response rates, Bath Ankylosing Spondylitis Disease Activity Index improvement, changes in joint counts, enthesitis score and CRP.  A total of 102 patients were randomized in BUILDER-1 part 1; 99 (48 TCZ, 51 placebo) completed 12 weeks.  Week 12 ASAS20 response rates were 37.3 % and 27.5 % in the TCZ and placebo arms, respectively (p = 0.2823).  Secondary and exploratory end-points did not differ between treatment arms.  Levels of CRP declined with TCZ treatment, suggesting adequate IL-6 receptor blockade.  As a result, BUILDER-1 part 2 and BUILDER-2 were terminated.  The authors stated that TCZ safety results were consistent with previous observations in RA, except for a cluster of anaphylactic and hypersensitivity events at Bulgarian study sites.  No apparent explanation for this clustering could be found.  They concluded that BUILDER-1 failed to demonstrate TCZ efficacy in treating aTNF-naive patients with AS.

Cardiac Transplant Rejection

Choi et al (2017) noted that extending the functional integrity of renal allografts is the primary goal of transplant medicine.  The advent of donor-specific antibodies (DSAs) post-transplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States.  This reduces the quality and length of life for patients and increases cost.  There are no approved treatments for cAMR; available evidence suggests the proinflammatory cytokine IL-6 may play an important role in DSA generation and cAMR.  These researchers identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with intravenous immunoglobulin (IVIG) plus rituximab with or without plasma exchange.  Patients were offered rescue therapy with tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes.  Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80 % and 91 % at 6 years, respectively.  Significant reductions in DSAs and stabilization of renal function were observed at 2 years.  No significant AEs or SAE were observed.  The authors concluded that tocilizumab provided good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments.  These researchers stated that inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.  These researchers stated that the findings of this case-series study were not definitive; and rigorous evaluation in a controlled clinical trials setting is needed.

Jordan et al (2017) stated that the success of kidney transplants is limited by the lack of robust improvements in long-term survival.  It is now recognized that allo-immune responses are responsible for the majority of allograft failures.  Development of novel therapies to decrease allo-sensitization is critical.  The lack of new drug development in kidney transplantation necessitated re-purposing drugs initially developed in oncology and autoimmunity.  Among these is tocilizumab that holds promise for modulating multiple immune pathways responsible for allograft injury and loss.  Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity.  Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation.  Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG.  Tocilizumab is the 1st-in-class drug developed to treat diseases mediated by IL-6.  Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy.  This suggested that anti-IL-6/IL-6R blockade could be effective in modifying T- and B-cell responses to allografts.  Initial data from the authors’ group suggested anti-IL-6R therapy is of value in desensitization and prevention and treatment of antibody-mediated rejection (AMR).  In addition, human trials have shown benefits in treatment of graft-versus-host disease (GVHD) in matched or mis-matched stem cell transplants.

Montgomery et al (2018) stated despite the success of desensitization protocols, AMR remains a significant contributor to renal allograft failure in patients with DSA.  Plasmapheresis and high-IVIG have proved to be effective treatments to prevent and treat AMR, but irreversible injury in the form of transplant glomerulopathy can commonly manifest months to years later.  There is an unmet need to improve the outcomes for patients at risk for AMR.  Updated Banff criteria now take into account the increasing understanding of the complex and heterogeneous nature of AMR phenotypes, including the timing of rejection, subclinical and chronic AMR, C4d-negative AMR, and antibody-mediated vascular rejection.  Treatment for AMR is not standardized, and there is little in the way of evidence-based treatment guidelines.  Refining more precisely the mechanisms of injury responsible for different AMR phenotypes and establishing relevant surrogate end-points to facilitate more informative studies will likely allow for more accurate determination of prognosis and effective intervention using new therapeutic approaches.  In addition to plasma exchange and IVIG, a number of other add-on therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-IL-6 blockers, and immunoglobulin G-degrading enzyme of Streptococcus pyogenes (called IdeS).

Coronary Heart Disease

Hingorani and Casas (2012) stated that a high circulating concentration of Il-6 is associated with increased risk of coronary heart disease (CHD).  Blockade of the IL-6 receptor (IL6R) with tocilizumab licensed for treatment of RA reduces systemic and articular inflammation.  However, whether IL6R blockade also reduces risk of CHD is unknown.  Applying the Mendelian randomization principle, these researchers used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely safety and effectiveness of IL6R inhibition for primary prevention of CHD.  These investigators compared genetic findings with the effects of tocilizumab reported in randomized trials in patients with RA.  In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log IL-6 concentration (increase per allele 9.45 %, 95 % CI: 8.34 to 10.57) as well as reduced CRP (decrease per allele 8.35 %, 95 % CI: 7.31 to 9.38) and fibrinogen concentrations (decrease per allele 0·85 %, 95 % CI: 0.60 to 1.10).  This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4 to 8 mg/kg every 4 weeks) in patients with RA studied in randomized trials.  In 25,458 CHD cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of CHD events (per allele odds ratio 0.95, 95 % CI: 0.93 to 0.97, p = 1.53 × 10(-5)).  The authors concluded that on the basis of genetic evidence in human beings, IL6R signaling seems to have a causal role in development of CHD.  Blockade of IL6R could provide a novel therapeutic approach to prevention of CHD that warrants testing in suitably powered randomized trials.  Genetic studies in populations could be used more widely to help to validate and prioritize novel drug targets or to re-purpose existing agents and targets for new therapeutic uses.

Coronavirus Disease 2019 (COVID-19) / COVID-19-Induced Cytokine Release Syndrome

Antwi-Amoabeng and colleagues (2020) stated that current evidence suggests an important role of the IL-6 pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cytokine release storm in severely ill coronavirus disease 2019 (COVID-19) patients.  Inhibition of the IL-6 pathway with tocilizumab has been employed successfully in some of these patients, however, the data were mostly consistent of case reports and series.  These researchers carried out a systematic search of PubMed, Embase, and Medline from April 22, 2020 and again on April 27, 2020 using the following search terms alone or in combination: "COVID-19", "coronavirus", "SARS-CoV-2", "COVID", "anti-interleukin-6 receptor antibodies", "anti-IL-6", "tocilizumab", "sarilumab", and "siltuximab".  They included studies that reported individual patient data; and extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes.  The primary end-point was in-hospital mortality; secondary end-points included in-hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers.  A total of 352 records were identified through a systematic search, of which 10 studies met the inclusion criteria.  A single study currently under review was also added; 11 observational studies encompassing 29 patients were included in the present review.  There were more men (n = 24 [82.8 %]), and hypertension was the most common co-morbidity (n = 16 [48.3 %]).  Over an average of 5.4 hospital days, the primary end-point occurred in 6 (20.7 %) patients.  Among surviving patients, approximately 10 % had worsened disease and 17 % recovered.  The most common complication was acute respiratory distress syndrome (n = 8 [27.6 %]).  The IL-6 level was significantly higher after the initiation of tocilizumab with median (inter-quartile range [IQR]) of 376.6 (148 to 900.6) pg/ml compared to the baseline of 71.1 (31.9 to 122.8) pg/ml (p = 0.002).  Mean (standard deviation [SD]) levels of CRP were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (p < 0.0001).  Baseline demographics were not significantly different among survivors and non-survivors by Fisher's exact test.  The authors concluded that in COVID-19 patients treated with tocilizumab, IL-6 levels are significantly elevated, which are supportive of cytokine storm.  Following initiation of tocilizumab, there was elevation in the IL-6 levels and CRP levels dramatically decreased, suggesting an improvement in this hyper-inflammatory state.  These researchers stated that ongoing RCTs will allow for further evaluation of this promising therapy.

Radbel and associates (2020) noted that COVID-19 emerged in late December 2019 in Wuhan, China.  Since then, COVID-19 has become a pandemic affecting more than 1.5 million people worldwide.  Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH).  Anti-cytokine therapy such as tocilizumab is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking.  These investigators reported 2 cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab.  Both patients progressed to sHLH despite treatment with tocilizumab, and 1 developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS.  These researchers stated that there are currently no data from rigorously conducted clinical trials evaluating the use of tocilizumab in COVID-19.  Although off-label use based on hypothetical benefit may drive the use of this and other drugs during the COVID-19 pandemic, there must be recognition that the true clinical benefits of untested medications are unknown.  However, several clinical trials are actively recruiting subjects to determine the safety and efficacy of tocilizumab in the treatment of severe COVID-19 pneumonia in adult patients.  These clinical trials will further elucidate the effects of tocilizumab on COVID-19-induced organ failure and mortality and correlate these outcomes with inflammatory marker trends.  The authors concluded that this report highlighted that off-label drugs are best used in the context of a randomized clinical trial, where the timing of tocilizumab administration in the disease course and indications based on clinical parameters and biomarkers can be determined.

Hemophagocytic Lymphohistiocytosis

Tanaka et al (2016) stated IL-6 contributes to host defense against infections and tissue injuries.  However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as “cytokine storm”, since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function.  Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with CRS complicated by T-cell engaged therapy.  In this review, the authors proposed the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

An UpToDate review on “Treatment and prognosis of hemophagocytic lymphohistiocytosis” (McClain, 2019) does not mention tocilizumab as a therapeutic option.

Neuromyelitis Optica

In a pilot study, Araki et al (2014) evaluated the safety and effectiveness of TCZ in patients with neuromyelitis optica (NMO).  A total of 7 patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment.  They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year.  These researchers evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue.  Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells; 6 females and 1 male with NMO were enrolled.  After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005).  The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly.  The ameliorating effects on intractable pain exceeded expectations.  The authors concluded that IL-6 receptor blockade is a promising therapeutic option for NMO.

Nivolumab-Mediated Side Effects (e.g., Joint Pain)

Liu et al (2016) stated that nivolumab has shown notable success as a cancer treatment.  These investigators reported that nivolumab was susceptible to aggregation during manufacturing, particularly in routine purification steps.  The experimental results showed that exposure to low pH caused aggregation of nivolumab, and the Fc was primarily responsible for an acid-induced unfolding phenomenon.  To compare the intrinsic propensity of acid-induced aggregation for other IgGs subclasses, tocilizumab (IgG1), panitumumab (IgG2) and atezolizumab (aglyco-IgG1) were also investigated.  The accurate pH threshold of acid-induced aggregation for individual IgG Fc subclasses was identified and ranked as: IgG1 < aglyco-IgG1 < IgG2 < IgG4.  This result was cross-validated by thermo-stability and conformation analysis.  These researchers also assessed the effect of several protein stabilizers on nivolumab, and found mannitol ameliorated the acid-induced aggregation of the molecule.  The authors concluded that these findings provided valuable insight into down-stream manufacturing process development, especially for immune check-point modulating molecules with a human IgG4 backbone.  This study did not provide any data on the use of tocilizumab for nivolumab-induced side effects.

Rotz (2017) noted that CRS is a phenomenon of immune hyper-activation described in the setting of cellular and bi-specific T-cell engaging immunotherapy.  Check-point blockade using anti-programmed cell death 1 (anti-PD-1) inhibitors is an approach to anti-tumor immune system stimulation.  These researchers described the case of a 29-year old woman with alveolar soft part sarcoma who developed severe CRS after treatment with anti-PD-1 therapy.  CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of tocilizumab and corticosteroids.  This was a single-case study; its findings need to be validated by well-designed studies.

Stroud et al (2019) noted that immune check-point inhibitors are poised to revolutionize the management of a growing number of malignancies.  Unfortunately, the management of steroid-refractory immune mediated AEs is based on a paucity of randomized data and limited to single-center experiences.  The authors' initial experience with tocilizumab showed clinical improvement in a wide variety of immune-related AEs (irAEs).  As a result, these investigators adopted the use of tocilizumab for the management of steroid refractory immune-related AEs (irAEs).  In this study, the character and clinical course of irAEs were abstracted from the medical record and analyzed.  The dose of tocilizumab was 4 mg/kg given IV over 1 hour; CRP was drawn at 1st nivolumab infusion and at q 2 weeks (and with irAEs) thereafter.  Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within 7 days.  Of the initial 87 patients who were treated with nivolumab, 34 required tocilizumab (39.1 %).  All patients were on corticosteroids.  The majority (88.2 %) were lung cancer patients.  The index grade 3/4 irAE was pneumonitis in 35.3 %, serum sickness/SIRS in 35.3 %, cerebritis in 14.7 % and 1 case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy.  Median time between 1st nivolumab and initiation of tocilizumab was 76 days (range of 1 to 429).  There was a statistically significant increase in CRP from a median of 23 mg/L (range of 0.1 to 238.5) at baseline to 109.3 mg/L (21.5 to 350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25 to 149) after tocilizumab (p < 0.00001).  Clinical improvement was noted in 27/34 patients (79.4 %).  Some patients (52.9 %) required a single dose, while 38.2 % required 2, 8.8 % required 3 and 1 patient required 4 doses; 27 doses were given in the inpatient setting (49.1 %).  Median time to discharge was 4 days (range of 1 to 27); 74 % of patients were discharged home.  For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18-month study period.  The authors concluded that tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune check-point blockade.  However, they stated that randomized trials are needed to better elucidate the relative safety and efficacy of these agents.  This was a small, single-center study; well-designed studies are needed to validate these preliminary findings.

Polymyalgia Rheumatica

Macchioni and colleagues (2013) stated that glucocorticoids (GCs) are the mainstay of treatment of polymyalgia rheumatica (PMR).  However, GCs-related adverse events occur frequently, particularly in patients with relapsing disease.  Several studies have demonstrated that IL-6 is a key player in the pathogenesis of PMR.  These investigators reported 2 patients with PMR treated with TCZ and reviewed the published evidence on the safety and effectiveness of TCZ in patients with PMR.  These researchers treated 2 GCs-naive patients with newly diagnosed pure PMR with monthly TCZ infusions (8 mg/kg body weight) for 6 months.  Disease activity and drug tolerability were assessed clinically, by laboratory tests, and bilateral shoulder ultrasonography before starting the treatment and subsequently every month during TCZ therapy.  They performed a systematic literature search (PubMed until July 2012) using the terms "tocilizumab", "anti-IL-6-receptor", "polymyalgia rheumatica", "giant cell arteritis", and "large-vessel vasculitis" to identify published reports of patients with PMR treated with TCZ.  One of the 2 patients responded well to TCZ, while the other patient required GCs therapy after the 2nd TCZ infusion because of lack of appreciable clinical response.  Both patients tolerated TCZ well.  The review of the literature revealed 4 reports with a total of 9 patients who received TCZ for PMR.  In 7 of these 9 patients, PMR was associated with giant cell arteritis.  Including the 2 patients in this study, 5 patients received TCZ alone and 6 TCZ plus GCs.  A good response to TCZ treatment was observed in all patients reported in the literature without any major adverse events.  The authors concluded that TCZ both as monotherapy and in association with GCs appears to be mostly effective and safe to treat patients with PMR.  Moreover, they stated that larger controlled studies are needed to confirm these favorable data.

Al Rashidi et al (2013) noted that despite their disadvantages, GCs remain a mainstay of therapy for PMR.  Second-line anti-rheumatic and immune-modulatory drugs are not infrequently required because of disease relapses during GCs tapering and GCs adverse effects.  Therapy with MTX or with an anti-TNF drug showed modest efficacy in this situation. Tocilizumab is an anti-IL-6 receptor antibody that is being recently studied in the treatment of PMR patients who are intolerant or refractory to GCs, especially after failure of a second-line agent.  These researchers reported a case of PMR in which GCs were stopped because of adverse effects despite good response.  The condition responded to neither MTX nor etanercept.  Treatment with TCZ has led to significant improvement of the patient's clinical and biochemical PMR activity parameters, and the patient was kept in a solid remission for 1 year without any TCZ-related adverse effects.  The authors concluded that tocilizumab is a promising drug in the management of PMR.  Moreover, they stated that further studies are needed to clearly define the indications and duration of TCZ therapy in the management of PMR.

Relapsing Polychondritis

Kemta et al (2012) evaluated the safety and effectiveness of biologics in patients with active relapsing polychondritis (RP).  A systematic review of the literature using PubMed was performed through December 2010.  MeSH terms and keywords were used relating to RP and biologics.  All papers reporting the safety and/or effectiveness of biologics in RP were selected.  Reference lists of included papers were also searched.  All publications related to case-series or isolated case-reports.  No RCT has been performed; a total of 30 papers that included 62 patients were published.  These patients were treated with TNF-alpha blockers (n = 43), rituximab (n = 11), anakinra (n = 5), tocilizumab (n = 2), and abatacept (n = 1).  The end point of treatment differed from 1 publication to the other and therefore made the comparison of effectiveness among the various biologics difficult.  Biologics were effective in 27 patients, partially effective in 5 patients, and ineffective in 29 patients.  Safety appeared to be good.  However, 4 deaths were recorded (2 sepsis, 1 post-operatively after aortic aneurysm surgery, and 1 after accidental dislocation of the tracheostomy device).  The authors concluded that the experience with biologics in RP is very limited and their effectiveness and indications need to be better defined.  They stated that RCTs, although difficult to perform because of the rarity of RP, are needed to determine the place of biologics in the treatment strategy of this orphan disease.

Retinal Vasculitis

Agarwal et al (2016) described the clinical course of a patient with non-infectious idiopathic unilateral panuveitis and retinal vasculitis treated with subcutaneous repository adrenocorticotropic hormone (ACTH) gel.  A 33-year old man presented with blurry vision and floaters in the left eye (OS).  The best-corrected visual acuity (BCVA) was 20/20 in the right eye (OD) and 20/50 in OS at the time of initial presentation.  Slit-lamp examination revealed mild anterior segment inflammation in OS.  There were 1 + vitreous haze and 2 + cells noted in OS.  Clinical examination and ancillary imaging assessment including fluorescein angiography (FA) revealed retinal vasculitis and optic nerve head inflammation.  After infectious etiologies were ruled out, the patient was started on oral corticosteroids and enrolled in a clinical trial employing intravenous tocilizumab (TCZ) therapy; 6 months after completion of the tocilizumab trial, the patient demonstrated recurrence of disease.  Twice-weekly subcutaneous ACTH gel was initiated and the patient demonstrated improvement of retinal vascular inflammation.  The authors concluded that repository subcutaneous ACTH gel formulation may be a safe and viable therapeutic option for patients with non-infectious uveitis and retinal vasculitis.  Clinical trials using this formulation in a larger patient cohort with longer monitoring are indicated to evaluate its tolerability and bioactivity.

In a multi-center, retrospective study, Atienza-Mateo et al (2018) evaluated the efficacy of TCZ in refractory uveitis of Bechet’s disease (BD).  Patients were refractory to conventional and biologic immunosuppressive drugs.  The main outcome measures were intra-ocular inflammation, macular thickness, VA and corticosteroid-sparing effects.  These researchers studied 11 patients (7 men) (20 affected eyes); median age was 35 years.  Uveitis was bilateral in 9 patients.  The patterns of ocular involvement were panuveitis (n = 8, with retinal vasculitis in 4), anterior uveitis (n = 2) and posterior uveitis (n = 1).  Cystoid macular edema was present in 7 patients.  The clinical course was recurrent (n = 7) or chronic (n = 4).  Before TCZ, patients had received systemic corticosteroids, conventional immunosuppressants and the following biologic agents: adalimumab (n = 8), infliximab (n = 4), canakimumab (n = 1), golimumab (n = 3), etanercept (n = 1).  TCZ was used as monotherapy or combined with conventional immunosuppressants at 8 mg/kg/i.v./4 weeks (n = 10) or 162 mg/s.c./week (n = 1).  At TCZ onset the following extra-ocular manifestations were present: oral and/or genital ulcers (n = 7), arthritis (n = 4), folliculitis/pseudofolliculitis (n = 4), erythema nodosum (n = 2), livedo reticularis (n = 1) and neurological involvement (n = 2).  TCZ yielded rapid and maintained improvement in all ocular parameters of the patients, with complete remission in 8 of them.  However, this was not the case for the extra-ocular manifestations, since TCZ was only effective in 3 of them.  After a mean (S.D.) follow-up of 9.5 (8.05) months, TCZ was withdrawn in 2 cases, due to a severe infusion reaction and arthritis impairment, respectively.  The authors concluded that TCZ could be a therapeutic option in patients with BD and refractory uveitis.

Furthermore, an UpToDate review on “Retinal vasculitis associated with primary ocular disorders” (Tolentino and Dana, 2019) does not mention tocilizumab as a therapeutic option.

Sjogren's Syndrome Myelopathy

Ishikawa et al (2019) noted that 5 to 34 % of Sjogren's syndrome (SS) cases are complicated by neuropathy in the form of myelitis.  Although SS myelopathy (SSM) is often treated with glucocorticoid (GC) and immunosuppressants such as cyclophosphamide (CY), a therapeutic strategy for SSM has not been established.  In this case, a 65-year old woman was admitted with weakness and thermal hypoalgesia in the lower limbs.  Four months before this admission, she showed weakness in her lower limbs and thermal hypoalgesia of bilateral upper and lower limbs.  Magnetic resonance imaging (MRI) revealed that the cause of her neurological symptoms was cervical myelitis.  She was diagnosed with SS because she tested positive for the ophthalmic test (Schirmer's test and fluorescent test) and for the anti-SS-A antibodies.  Thus, myelitis was thought to be a complication of SS.  The patient was treated with GC and CY.  Both neurological symptoms and MRI findings temporarily improved, and the GC dose was gradually decreased.  One month before this admission, her neurological symptoms and MRI findings were exacerbated.  Upon relapse of SSM, serum amyloid A protein (SAA) level was markedly elevated.  Based on MRI findings, the diagnosis was SSM relapse.  Treatment by subcutaneous TCZ 162-mg every 2 weeks was introduced.  After introducing TCZ, her neurological symptoms and MRI findings gradually improved; SAA levels remained low.  At 8 months after the introduction of TCZ, the GC dose has been decreased and so far, the myelitis has not relapsed.  The authors concluded that this case reported was the 1st report suggesting the effectiveness of TCZ for refractory SSM.  These researchers stated that subcutaneous TCZ might be an effective therapeutic option for treating refractory SSM when SAA levels are elevated.

Systemic Lupus Erythematosus

In an open-label, phase I, dosage-escalation study Illei et al (2010) evaluated the safety of tocilizumab and collected preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).  A total of 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients.  Patients were then monitored for an additional 8 weeks.  The infusions were well-tolerated.  Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38 % in the 4 mg/kg dosage group and 56 % in the 8 mg/kg dosage group.  Neutrophil counts returned to normal after cessation of treatment.  One patient was withdrawn from the study because of neutropenia.  Infections occurred in 11 patients; none was associated with neutropenia.  Disease activity showed significant improvement, with a decrease of greater than or equal to 4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients.  Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them.  Levels of anti-double-stranded DNA antibodies decreased by a median of 47 % in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8 % decrease in their IgG levels.  These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells.  The authors concluded that although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.

Systemic Sclerosis

In an observational study, Elhai and co-workers (2013) evaluated the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-associated polyarthritis or SSc-associated myopathy.  A total of 20 patients with SSc with refractory polyarthritis and 7 with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept.  All patients with SSc-myopathy received abatacept.  Clinical and biological assessments were made at the start of treatment and at the last infusion.  After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response.  Treatment was stopped in 2 patients because of inefficacy.  After 11 months' treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria.  Abatacept did not improve muscle outcome measures in SSc-myopathy.  No significant change was seen for skin or lung fibrosis in the different groups.  Both treatments were well-tolerated.  The authors concluded that tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc.  No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria.  They stated that larger studies with longer follow-up are needed to further determine the safety and effectiveness of these drugs in SSc.

In an open-label, extension phase-II RCT (the fascinate Trial), Khanna et al (2018) examined the safety and efficacy of tocilizumab in patients with systemic sclerosis (SSc).  Patients with SSc were treated for 48 weeks with weekly 162-mg subcutaneous tocilizumab.  Exploratory end-points included modified Rodnan Skin Score (mRSS) and percent predicted forced vital capacity (%pFVC) through week 96.  Overall, 24/44 (55 %) placebo-tocilizumab and 27/43 (63 %) continuous-tocilizumab patients completed week 96.  Observed mean (SD (95 % CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96.  Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42 % (95 % CI: 22 % to 63 %)) placebo-tocilizumab and 12/26 (46 % (95 % CI: 27 % to 67 %)) continuous-tocilizumab patients in the open-label period; no patients had greater than 10 % absolute decline in %pFVC.  Serious infection rates/100 patient-years (95 % CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.  The authors concluded that together with the findings from the first 48 weeks of double-blind treatment, results from the open-label period of the faSScinate Trial suggested that treatment with tocilizumab was associated with benefits for skin fibrosis, lung fibrosis and physical function in patients with SSc; but increased risk for serious infections.  These researchers stated that tocilizumab may be a promising targeted therapy for patients with progressive SSc who have few therapeutic options.  They stated that further studies are needed to examine the safety and efficacy of tocilizumab in the treatment of patients with SSc and to examine if tocilizumab produces significant improvement in skin sclerosis and stabilization of lung function.

The authors stated that this study had several drawbacks.  First, all patients received open-label tocilizumab after week 48; thus, the data collected during the open-label period were uncontrolled.  There was a high discontinuation rate.  During the open-label period, 7 of the 31 (23 %) patients originally assigned to placebo who entered the open-label period and 3 of the 30 (10 %) patients originally assigned to tocilizumab who entered the open-label period withdrew from the study.  The discontinuation rate from 48 to 96 weeks (16 %) was lower than it was in the first 48 weeks of the study (28 %).  Overall, 63 % of patients originally assigned to receive tocilizumab and 55 % of patients originally assigned to receive placebo completed the full 96 weeks of treatment.  It was likely that patients who completed week 48 and entered the open-label period were less ill or responded better to treatment and perhaps had already experienced more improvement.  This selection bias was a common problem associated with open-label, long-term extension studies.  Withdrawal of patients who experienced AEs led to the selection of healthier patients, which should be considered when interpreting the longer-term rates of AEs and SAEs.  Second, patients with elevated acute-phase reactants were enrolled in this study; thus, further studies may be needed to examine the safety and efficacy of tocilizumab in other patient subsets.  Third, given the limited numbers of patients with serious infections, analysis of the data to identify potential risk factors, in particular for any interaction of risk factors with tocilizumab, would be under-powered and was not performed.  A phase-III clinical trial with a larger sample size is under way.  Last, another drawback was that the study was not designed or powered for formal statistical comparison of the 2 treatment arms during the open-label period, and formal testing of these exploratory data was not pre-specified.  For the same reason, a comparison of placebo patients who completed the open-label phase with those in the tocilizumab treatment arm at week 48 was not appropriate.  Thus, although trends could be observed, comparative analyses could not be interpreted in a meaningful way, and formal statistical testing was not feasible.

Wakabayashi et al (2019) reported the findings of 2 RA patients with SSc who were administered tocilizumab, along with a review of the literature.  Two RA patients with SSc with inadequate responses to DMARDs were given tocilizumab 162-mg every 2 weeks for 18 months.  RA disease activity was evaluated by DAS28 score with erythrocyte sedimentation rate (DAS28-ESR) and the clinical disease activity index (CDAI).  The skin condition of SSc was evaluated by pinching the skin according to the mRSS.  Softening of the skin and improvements of arthritis and the patient global assessment were observed during tocilizumab treatment, with reduction of not only RA disease activity, but also of the mRSS.  The authors concluded that tocilizumab may be effective in patients with RA and SSc overlap syndrome for which conventional treatment is inadequate.  Moreover, these researchers stated that further research is needed because this report included only 2 patients.

Systemic Vasculitis

Silva-Fernandez et al (2014) analyzed the current evidence on the therapeutic use of biological agents for systemic vasculitis (SV).  Medline, Embase, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to the end of April 2013.  Systematic reviews and meta-analysis, clinical trials, cohort studies, and case series with more than 3 patients were included.  Independent article review and study quality assessment was done by 2 investigators with consensus resolution of discrepancies.  Of 3,447 citations, abstracts, and hand-searched studies screened, 90 were included.  Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients.  Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV.  A number of studies used different anti-TNFα agents with contrasting results.  A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found.  The authors concluded that current evidence on the use of biological therapies for SV is mainly based on uncontrolled, observational data.  Rituximab is not inferior to cyclophosphamide for remission induction in AAV and might be superior in relapsing disease.  Infliximab and adalimumab are effective as steroid-sparing agents.  Etanercept is not effective to maintain remission in patients with granulomatosis with polyangiitis, and serious adverse events have been reported.  For LVV, both infliximab and etanercept had a role as steroid-sparing agents, and tocilizumab might be effective also for remission induction in LVV.

TAFRO Syndrome

Sakai et al (2018) stated that thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is considered as a unique clinicopathologic variant of multi-centric Castleman's disease and was recently reported in Japan.  This entity represents a severe inflammatory state leading to organ failures such as severe liver dysfunction as observed in this case, and can be treated by immunosuppressive agents, steroids, and cyclosporine shown in several case reports.  The authors concluded that a systematic review and this case suggested the potential utility of tocilizumab as a treatment for TAFRO syndrome.

Takayasu Arteritis

Nishimoto et al (2008) noted that Takayasu arteritis (TA) is a chronic inflammatory disease that involves the aorta and its major branches.  Since over-production of IL-6 appears to play a pathogenic role in TA, these researchers reported the use of tocilizumab in the treatment a 20-year-old woman with refractory active TA complicated by ulcerative colitis (UC).  Treatment with tocilizumab improved the clinical manifestations of TA and the abnormal laboratory findings in this patient and ameliorated the activity of UC.  These results indicated that IL-6 receptor inhibition with tocilizumab might be a future treatment option for TA.

Keser et al (2014) stated that since there is no completed, placebo-controlled, RCT, the level of evidence for management of TA is low, generally reflecting the results of open studies, case series and expert opinion.  The most commonly used agents include corticosteroids and conventional immunosuppressive agents such as azathioprine, leflunomide, MTX, and mycophenolate mofetil.  In patients who remain resistant and/or intolerant to these agents, biologic drugs including TNF inhibitors, rituximab and tocilizumab seem to be promising.  Anti-platelet treatment may also lower the frequency of ischemic events in TA.  In the presence of short-segment, critical arterial stenosis, balloon angioplasty or stent graft replacement may be useful.  On the other hand, long-segment stenosis with extensive peri-arterial fibrosis or occlusion requires surgical bypass of the affected segment, which is clearly associated with superior results compared with endovascular intervention.  As a general rule, both endovascular intervention and surgical procedures should be avoided during the active phase of the disease.  Earlier diagnosis, better assessment of disease activity and future clinical trials will obviously improve the management of TA.

Abisror et al (2013) analyzed the efficacy and tolerance of tocilizumab in patients with TA.  These researchers retrospectively studied patients with TA (ACR and/or Ishikawa's criteria): 5 French multi-center cases and 39 from the literature.  Clinical, biological, radiological disease activity and treatment were analyzed before tocilizumab, during the follow-up and at the last available visit.  A total of 44 patients (median age of 26 years [3 to 65]) were included in the present study: 5 patients from the 3 French university hospitals and 39 cases from the literature review.  Median follow-up after initiation of tocilizumab was 15months [8 to 33].  Clinical and biological activities significantly decreased within 3 months, similarly to steroid amount (from 15 mg/day [5 to 75] at baseline to 10 mg/day [2 to 30] at 6 months; p < 0.05) and steroid-dependence rate.  Even radiological activity did not significantly decrease at 6 months, significant decrease of arterial FDG uptake was noted at 6 months.  Median duration of tocilizumab treatment was 9 months [3 to 180].  At the last visit, tocilizumab was continued in 17/32 patients (53 %), and was discontinued in the 15 remaining cases because of the remission (n = 5), relapse (n = 3), persistent radiological activity (n = 3), cutaneous rash (n = 2), severe infection (n = 1) and lacking of care welfare system (n = 1).  No death related to tocilizumab treatment was noted.  The authors concluded that this study showed the efficacy of tocilizumab in terms of clinical, biological and radiological response, as well as steroid-sparing agent.  Moreover, they stated that only well-designed studies could definitely address the efficacy of tocilizumab in TA.

Singh and colleagues (2020) noted that TCZ has been tried as an option for patients with Takayasu arteritis (TAK).  In a systematic review, these investigators analyzed the evidence from RCTs examining the safety and efficacy of TCZ in patients with TAK.  Medline, Embase, the Cochrane Library, and clinical trial registries were searched from inception to July 2018.  These researchers included RCs evaluating the safety and efficacy of TCZ versus placebo/other comparators for the treatment of patients with TAK.  The risk of bias (RoB) was assessed using Cochrane RoB tool.  A total of 2,799 articles were screened as per abstract and title; 42 selected full-texts articles were assessed for the potential inclusion.  One trial, reported in 2 publications, comparing subcutaneous TCZ (162 mg/week) versus matching placebo in 36 patients with TAK was included.  The relapse-free rate at 24 weeks was 50.6 % and 22.9 % in TCZ and placebo arm, respectively.  The hazard ratio (HR) for time to 1st relapse was statistically significant in the per-protocol population (HR 0.34 [95.41 % CI: 0.11 to 1.00]; p = 0.0345), while non-significant in the intention-to-treat population (HR 0.41 [95.41 % CI: 0.15 to 1.10]; p = 0.0596).  The SAE were higher in the placebo arm.  The authors concluded that this systematic review found the existing evidence from RCTs on the safety and efficacy profile of TCZ in TAK to be promising but limited.  They stated that additional evidence is needed to draw a stronger conclusion.

Thyroid Eye Disease

In a Cochrane review, Hamed Azzam et al (2018) examined the efficacy and harms of tocilizumab for the treatment of individuals with thyroid eye disease (TED).  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); Medline Ovid; Embase Ovid; LILACS BIREME; OpenGrey; the ISRCTN registry; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the EU Clinical Trials Register.  The date of the search was July 31, 2018.  They searched for trials of tocilizumab administered by intravenous infusion using any dosage regimen, compared with placebo or intravenous glucocorticoid therapy for people with TED.  These researchers planned to use standard methods recommended by Cochrane.  The primary outcome was change in TED score (as defined by investigators).  Secondary outcomes included measurement of the following parameters: change in proptosis, change in extra-ocular motility, change in palpebral aperture measurements, number of relapses, development of optic neuropathy and change in quality of life (QOL) score.  They planned to measure these outcomes at 3 months (range of 2 to 6 months) and 12 months (range of 6 to 18 months) post-treatment.  Adverse outcomes included any adverse effects identified in the trials at any time-point.  No studies met the inclusion criteria of this review.  These investigators found 1 randomized, placebo-controlled, double-masked study (NCT01297699).  This study plans to evaluate the efficacy and harms of tocilizumab administration in people with moderate-to-severe or sight-threatening graves' ophthalmopathy (GO), that had not responded adequately to treatment with intravenous corticosteroid pulses.  It was completed in December 2015 and will be assessed for inclusion in the review when data become available.  The authors concluded that there is currently no evidence from RCTs evaluating the efficacy and harms of tocilizumab for the treatment of people with TED

TRAPS

Tumor necrosis factor receptor associated periodic syndrome (TRAPS), also known as familial Hibernian fever, is a periodic fever syndrome associated with mutations in a receptor for TNF that is inheritable in an autosomal dominant manner.  Individuals with TRAPS exhibit episodic symptoms such as abdominal pain, rash, recurrent high fever, as well as joint/muscle aches and puffy eyes.  Since IL-6 levels are elevated in TRAPS, it has been hypothesized that tocilizumab might be effective in treating this disorder.

Vaitla and colleagues (2011) described treatment outcomes in the first case of a patient with TRAPS treated with tocilizumab.  The patient, a 52-year-old man with lifelong TRAPS in whom treatment with etanercept and anakinra had failed, was administered tocilizumab for 6 months, and the therapeutic response was assessed by measurement of monocyte CD16 expression and cytokine levels.  Following treatment, the evolving acute attack was aborted, and further attacks of TRAPS were prevented.  The patient did not require corticosteroids and showed significant clinical improvement in scores for pain, stiffness, and well-being.  Moreover, the acute-phase response diminished significantly with treatment.  Monocyte CD16 expression was reduced and the numbers of circulating CD14+CD16+ and CD14++CD16- monocytes were transiently decreased.  However, cytokine levels were not reduced.  The authors concluded that this case supported the notion of a prominent role for IL-6 in mediating the inflammatory attacks in TRAPS, but blockade of IL-6 did not affect the underlying pathogenesis.  They stated that these preliminary findings require confirmation.

Uveitis

In a review on “The future of uveitis treatment”, Lin and colleagues (2014) provided examples of some promising targets for immunomodulation in systemic and ocular diseases, which are currently in pre-clinical and early clinical (phase I/II) testing.  These investigators noted that several case reports showed efficacy of tocilizumab in uveitis.

Furthermore, an UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2014) does not mention tocilizumab as a therapeutic option.

FDA-Approved Indications (Genentech, 2020)

• Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).
• Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.
• Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.
• Adult patients with giant cell arteritis (GCA).
• Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS).

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN, 2020) provides the following recommendations for tocilizumab (Actemra):

• Acute Lymphoblastic Leukemia

  Consider as supportive care for patients who develop refractory cytokine release syndrome (CRS) related to blinatumomab therapy (Category 2A)

• B-cell lymphomas

  Castleman's Disease:

  • Subsequent therapy as a single agent for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease (Category 2A)
  • Second-line therapy as a single agent for relapsed or refractory unicentric CD for patients who are human immunodeficiency virus-negative and human herpesvirus-8-negative (Category 2A).
    
    

• Management of Immunotherpay-Related Toxicities

  • Immune Checkpoint Inhibitor-Related Toxicities:

    Consider as additional disease modifying antirheumatic therapy for management of severe immunotherapy-related inflammatory arthritis if symptoms do not improve within 2 weeks of starting high-dose corticosteroids (Category 2A)

  • CAR T-Cell-Related Toxicities:
    
    
    • Consider for management of prolonged (>3 days) G1 cytokine release syndrome (CRS)Footnote 3*** in patients with significant symptoms and/or comorbidities (Category 2A)
    • Used for management of (Category 2A)
      
      
      • G2-4 cytokine release syndrome (CRS)Footnote 3***
      • G1-4 neurotoxicity as additional single-dose therapyFootnote 4 **** if concurrent CRS
        
        

      Footnote 3*** Assess need for subsequent dosing after each dose (no more than 3 doses in 24 hours up to a maximum of 4 doses)

      Footnote 4**** Repeat dosing as needed (no more than 3 doses in 24 hours up to a maximum of 4 doses) if not responsive to IV fluids or increasing supplemental oxygen

Appendix

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 or axial spondyloarthritis 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	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
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
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
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 "+":
Other CPT codes related to the CPB:
0537T - 0540T	Chimeric antigen receptor T-cell (CAR-T) therapy
37609	Ligation or biopsy, temporal artery
71045 - 71048	Radiologic examination, chest
85651	Sedimentation rate, erythrocyte; non-automated
86140	C-Reactive Protein
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	Intravenous infusion, hydration; initial, 31 minutes to 1 hour
96361	each additional hour (List separately in addition to code for primary procedure)
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (List separately in addition to code for primary procedure)
96367	additional sequential infusion, up to 1 hour (List separately in addition to code for primary procedure)
96368	concurrent infusion (List separately in addition to code for primary procedure)
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J3262	Injection, Tocilizumab (Actemra), 1 mg
Other HCPCS codes related to the CPB:
Rinvoq and Xeljanz - no specific code
J0135	Injection, adalimumab, 20 mg
J1130	Injection, diclofenac sodium, 0.5 mg
J1438	Injection, etanercept, 25 mg
J1745	Injection, infliximab, 10 mg
J9039	Injection, blinatumomab, 1 microgram
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
Q2042	Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
ICD-10 codes covered if selection criteria are met for age 0-1:
D47.Z2	Castleman's disease [not covered for Idiopathic multicentric Castleman disease] [not covered for TAFRO syndrome]
D89.810	Acute graft-versus-host disease
M05.00 - M06.9	Rheumatoid arthritis
ICD-10 codes covered if selection criteria are met for age 2-17:
D47.Z2	Castleman's disease [not covered for Idiopathic multicentric Castleman disease] [not covered for TAFRO syndrome]
D89.810	Acute graft-versus-host disease
M05.00 - M06.9	Rheumatoid arthritis
M08.00 - M08.979	Juvenile arthritis [polyarticular juvenile idiopathic arthritis]
ICD-10 codes covered if selection criteria are met for adults age 18 and older:
D47.Z2	Castleman disease [not covered for Idiopathic multicentric Castleman disease] [not covered for TAFRO syndrome]
D89.810	Acute graft-versus-host disease
M05.00 - M06.9	Rheumatoid arthritis
M08.00 - M08.979	Juvenile arthritis [Polyarticular juvenile idiopathic arthritis]
M31.5 - M31.6	Giant cell arteritis
ICD-10 codes not covered for indications listed in the CPB:
B10.89	Other human herpesvirus infection [with Castleman's disease]
B20	Human immunodeficiency virus [HIV] disease [with Castleman's disease]
D76.1	Hemophagocytic lymphohistiocytosis
E05.00 - E05.01	Thyrotoxicosis with diffuse goiter [thyroid eye disease]
G36.0	Neuromyelitis optica
H20.00 - H20.9	Iridocyclitis
H35.061 - H35.069	Retinal vasculitis
I77.0 - I77.9	Other disorders of arteries and arterioles [systemic vasculitis]
K50.00 - K50.919	Crohn's disease [regional enteritis]
L40.50 - L40.59	Arthropathic psoriasis
M06.1	Adult-onset Still's disease
M08.1, M45.0 - M45.9	Ankylosing spondylitis
M08.40 - M08.48	Pauciarticular juvenile rheumatoid polyarthritis
M14.60 - M14.89	Arthropathies in other diseases classifiable elsewhere [sclerosis associated myopathy/polyarthritis]
M30.0 - M30.8	Polyarteritis nodosa and related conditions
M31.4	Aortic arch syndrome [Takayasu]
M32.0 - M32.9	Systemic lupus erythematosus (SLE)
M34.0 - M34.9	Systemic sclerosis [scleroderma]
M35.00 - M35.09	Sicca syndrome [Sjogren]
M35.3	Polymyalgia rheumatica
M94.1	Relapsing polychondritis
T86.21	Heart transplant rejection

The above policy is based on the following references: