Medical Policy


Subject:Tocilizumab (Actemra®)
Policy #:  DRUG.00043Current Effective Date:  08/12/2013
Status:RevisedLast Review Date:  08/08/2013

Description/Scope

Tocilizumab (Actemra, Genentech, Inc., Roche USA, South San Francisco, CA) is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody that works by binding and inhibiting both soluble and membrane bound IL-6, produced in inflamed joints of individuals with rheumatoid arthritis (RA), polyarticular juvenile arthritis (PJIA) and systemic juvenile idiopathic arthritis (SJIA). This document addresses the use of tocilizumab for the treatment of adults with moderately to severely active RA and children two years of age and older with active PJIA or active SJIA.

Note: Please see the following documents for information on additional drugs which may be used in the treatment of moderately to severely active RA, active PJIA, or active SJIA:

Position Statement

Medically Necessary:

Tocilizumab is considered medically necessary for the treatment of an individual with moderately to severely active RA when all of the following criteria are met:

Tocilizumab is considered medically necessary for the treatment of an individual with active PJIA when the following criteria are met:

Tocilizumab is considered medically necessary for the treatment of an individual with active SJIA when the following criteria are met:

Not Medically Necessary:

Tocilizumab is considered not medically necessary for an individual with any of the following:

  1. Use of tocilizumab in combination with other biologic DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies or selective co-stimulation modulators; or
  2. At initiation of therapy, absolute neutrophil count (ANC) less than 2000/mm3, platelet count less than 100,000/mm3, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal (ULN); or
  3. Tuberculosis, invasive fungal infection, or other  active serious infections or a history of recurrent infections; or
  4. Individual has not had a tuberculin skin test (TST) or Centers for Disease Control (CDC)-recommended equivalent to evaluate for latent tuberculosis.

Investigational and Not Medically Necessary:

Tocilizumab is considered investigational and not medically necessary when the medically necessary criteria are not met and for all other indications, including but not limited to the treatment of:

Rationale

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody. It works by binding and inhibiting both soluble and membrane bound IL-6, which is produced in inflamed joints. The IL-6 receptor is also involved in T-cell activation, induction of immunoglobulin, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation.

Tocilizumab for Rheumatoid Arthritis (RA)

Tocilizumab (Actemra) was first approved on January 8, 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of moderately to severely active RA in individuals who have had an inadequate response to one or more TNF antagonists. Tocilizumab may be used as monotherapy or concomitantly with MTX or other non-biologic DMARDs. The efficacy and safety of tocilizumab was assessed in five randomized, double-blind, multicenter studies in adults with moderately to severely active RA diagnosed according to American College of Rheumatology (ACR) criteria (Emery, 2008; Genovese, 2008; Maini, 2006; Nishimoto, 2007, 2009a, and 2009b; Smolen, 2008). In three of the trials (Emery, 2008 [RADIATE]; Genovese, 2008 [TOWARD]; Smolen, 2008 [OPTION]), significant improvements over treatment with conventional DMARDs were shown in individuals with RA who experienced DMARD-failures, MTX-failures, or TNF-failures as measured by the percent of subjects achieving a 20%, 50%, or 70% improvement in ACR measures (joint stiffness, pain, swelling, lab measures, and/or disability).

Since the initial approval, the FDA granted approval of additional wording to the drug's label, stating it can be used for the inhibition and slowing of structural joint damage, improvement of physical function, and achievement of major clinical response in adults with RA. This approval was based on data from the phase III LITHE trial (Kremer, 2011), which demonstrated that individuals receiving tocilizumab in combination with MTX demonstrated significantly less joint damage and significant improvement in physical function after one year, compared to individuals who received MTX and placebo. A subsequent study by Smolen and colleagues (2012) randomly sampled data from the LITHE trial and evaluated whether tocilizumab interferes with joint destruction beyond its effects on disease activity. After baseline and one-year values of clinical and serological variables were correlated with changes to one year (as measured by various tests that scored erosion and joint space narrowing with low and high disease activity compared for placebo and tocilizumab), the authors concluded that tocilizumab plus MTX retards joint damage progression independently of its impact on disease activity.

Subsequently, the product information (PI) label for tocilizumab was updated on October 12, 2012 with the FDA approving removal of the requirement of an inadequate response to a TNF antagonist before prescribing tocilizumab for use in adult RA. This approval was based on the results of the AMBITION trial (Jones, 2010) and the 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter phase IIIb rapid onset and systemic efficacy (ROSE) clinical trial (Yazici, 2012), the latter evaluating the efficacy and safety of tocilizumab in adults with moderate to severely active RA who have had an inadequate clinical response to DMARD therapy. Participants in the ROSE trial were randomly assigned 2:1 to tocilizumab (n=412) or placebo (n=207) every four weeks while continuing doses of stable DMARDs in both groups throughout the study; however, dose reductions were allowed as clinically warranted for safety reasons. The primary efficacy endpoint, percentage of participants achieving ACR-50% (ACR50) response at week 24, was significantly higher in the tocilizumab group than in the placebo (30.1% versus 11.2%; p<0.0001). Percentages of ACR20 and ACR50 responders were significantly higher in the tocilizumab versus the placebo group as early as week 4 and continued to week 24; significantly more participants in the tocilizumab versus the placebo group also achieved ACR70 responses beginning at week 8 (p<0.01). Significant improvements associated with tocilizumab versus placebo were seen in routine assessment of participant index data responses, European League Against Rheumatism (EULAR) good response, disease activity score (DAS) DAS28 and percentages of participants achieving low disease activity and clinical remission (based on DAS28). Rapid improvements in clinical outcomes were also demonstrated in a substudy as early as week 1 as shown by DAS28 scores, participant measures and C-reactive protein. Safety findings were consistent with the known tocilizumab safety profile, with rates of serious infections (per 100 patient-years) were 7.87 (95% confidence interval [CI] 4.30 to 13.2) and 1.2 (96% CI 0.03 to 6.66) in the tocilizumab and placebo groups, respectively. No opportunistic infections, including tuberculosis, were reported during the study, and no cases of gastrointestinal perforation. Seven neoplasms were reported, four in the tocilizumab group and three in the placebo group. There was no clinical evidence of liver injury or clinical hepatitis following treatment with tocilizumab. Mean lipid levels increased in participants treated with tocilizumab compared with placebo, but the clinical relevance of these lipid elevations is unclear in the RA population at this time.

Dougados and colleagues (2013) compared the efficacy of adding tocilizumab to MTX to that of switching to tocilizumab monotherapy in adults with active RA despite MTX monotherapy. In this 24-month double-blind, placebo controlled parallel-group clinical trial (ACT-RAY), participants were randomly assigned either to continue MTX with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28 erythrocyte sedimentation rate (ESR) (DAS28-ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage. Of the 556 participants, 512 (92%) completed 24 weeks with DAS28-ESR remission rates reported as 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); differences in the ACR20/50/70/90 rates between groups was not significant. A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO participants, respectively. The investigators stated that no clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination of TCZ+MTX was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in select individuals with RA.

In a network meta-analysis and Cochrane review, Singh and colleagues (2011) compared the potential adverse effects of the biologic therapies, including tocilizumab, in individuals with any disease condition except human immunodeficiency disease (HIV). The rate of serious adverse events, lymphoma and congestive heart failure were not statistically significantly different between the biologics and control treatment. Due to the different mechanisms of action for the biologics, several adverse events such as neutropenia and lipid abnormalities associated with tocilizumab are drug specific. In indirect comparisons, no statistically significant differences were noted between biologics in total adverse events or withdrawals due to adverse events. The authors stated that some biologics had a statistically higher association with certain adverse outcomes compared with control, but there was no consistency across the outcomes so caution was needed in interpreting these results.

An Agency for Healthcare Research and Quality (AHRQ) (Donahue, 2012) updated review examined the comparative effectiveness of corticosteroids, oral DMARDs, and biologic DMARDs, including tocilizumab, in the treatment of individuals with RA. Limited head-to-head comparative evidence does not support one therapy over another for adults with RA. Network meta-analyses from placebo-controlled trials of biologics suggest some differences, including higher odds of reaching ACR50 response, but the strength of evidence was low. Mixed treatment comparisons found no significant differences in disease activity with tocilizumab, abatacept, adalimumab, golimumab, infliximab, and rituximab (strength of evidence is low). Evidence was insufficient to assess comparative risk of serious adverse events among biologic DMARDs. Combinations of biologic DMARDs have higher rates of serious adverse events than biologic DMARD monotherapy.

In April 2012, the ACR updated their 2008 recommendations for the use of DMARDs and biologic agents in the treatment of RA, following the same methodology used to develop the 2008 recommendations. The 2012 revision updates the following areas:

  1. Indications for DMARDs and biologic agents (including new agents not covered in 2008);
  2. Switching between DMARD and biologic therapies;
  3. Use of biologic agents in high-risk individuals (those with hepatitis, congestive heart failure [CHF], and malignancy);
  4. Screening for TB in individuals starting or currently receiving biologic agents; and
  5. Vaccination in individuals starting or currently receiving DMARDs or biologic agents (Singh, 2012).

For each final recommendation, the strength of evidence was assigned using a three-level method from the American College of Cardiology. A key assumption for clinical scenarios state the recommendations focus on "common patients, not exceptional cases" and vary with each person with RA. Indications for starting, resuming, adding, or switching DMARDs or biologic agents address use in early RA (disease duration less than six months), and for initiating and switching between DMARDs and biologic agents in established RA (disease duration greater than or equal to six months or meeting the 1987 ACR RA classification criteria). The 2012 guideline algorithm recommends initiating treatment using non-biologic DMARD combination-therapy (including two or more DMARDs/double and triple therapy) for the majority of individuals with early RA with moderately or highly active disease and poor prognostic features (Level of Evidence: A-B, except for MTX and leflunomide: C), or, moving to a biologic agent with or without MTX (Level of Evidence: B) if each option fails to control the disease. When switching from DMARDs to biologics, physicians should use either an anti-TNF biologic or a non-TNF biologic if an individual has moderate or high disease activity after three months of MTX treatment or DMARD combination therapy (Level of Evidence: A-C).

The 2012 updated recommendations for use of biologic agents in high-risk individuals otherwise qualifying for RA management strategy with a history of hepatitis, malignancy, or congestive heart failure are as follows (Level of Evidence: C [i.e., data were derived from consensus opinion of experts, case studies, or standards of care]):

The 2012 ACR panel recommendation for TB screening and use of vaccines considers the current CDC recommendations along with an increased awareness of the risk of preventable infections in individuals with RA who are starting or currently receiving DMARDs or biologic agents:

In 2010, a joint working group from the ACR and the EULAR (Aletaha, 2010) developed a new approach to classifying RA. The focus of the workgroup was to identify, among individuals newly presented with undifferentiated inflammatory synovitis, the factors that best discriminated between individuals who were not at high risk for persistent and/or erosive disease. The new ACR/EULAR criteria set, classified as "definite RA," is "based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of six or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1)." From this new classification criteria for RA, the ACR/EULAR hopes that early identification of those individuals with a short duration of symptoms may benefit from "early institution of DMARD therapy or entry into clinical trials of promising new agents that may halt the development of disease that currently fulfills the 1987 ACR criteria."

Tocilizumab for Polyarticular Juvenile Idiopathic Arthritis (PJIA)

Tocilizumab was approved by the FDA on April 29, 2013 for the treatment of active PJIA in children two years of age and older. Tocilizumab may be used as monotherapy or concomitantly with MTX. The FDA approval is based on data from the phase III (CHERISH) study reported on the current PI (Actemra PI, 2013) that demonstrated clinically meaningful improvement in the signs and symptoms of PJIA with tocilizumab therapy. To date, the study results have not been published in the peer-reviewed medical literature.

Participants in the three-part study were 2 to 17 years of age with active PJIA of at least six months duration who had an inadequate clinical response or were intolerant to MTX. Treatment with a stable dose of MTX was permitted (but not required) and concurrent use of DMARDs (other than MTX) or other biologics (TNF antagonists or T-cell costimulation modulator) were not permitted in the study. At baseline, approximately half of the participants were taking oral corticosteroids and almost 80% were taking MTX.

Part I of the study consisted of a lead-in period of tocilizumab every four weeks for 16 weeks (n=188). At the conclusion of the open-label Part I, 91% of participants taking tocilizumab plus MTX and 83% taking tocilizumab as monotherapy achieved an ACR 30 response at week 16 compared to baseline. In Part II, the 24-week randomized double-blind placebo-controlled withdrawal phase of the trial, tocilizumab-treated participants experienced significantly fewer disease flares compared to placebo-treated participants, 26% (21 of  82) compared to 48% (39 of 81) of participants, respectively. The safety data collected to date is reported as consistent with that observed in previous studies of tocilizumab-treated individuals with SJIA (De Benedetti, 2012) and RA. Infections were the most common adverse events over 40 weeks, with the rate of serious infections numerically higher  in participants weighing at or above 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to participants weighing at or above 30 kg treated with 8 mg/kg tocilizumab (4.0 per patient years). Laboratory abnormalities known to occur with tocilizumab were also observed in this study, including decreases in white blood cell counts and platelet counts, and elevation in ALT and AST liver enzyme levels.

Tocilizumab for Systemic Juvenile Idiopathic Arthritis (SJIA)

Tocilizumab was approved on April 15, 2011 by the FDA for the treatment of active SJIA in children ages two years and older. Tocilizumab may be used as monotherapy or concomitantly with MTX.

The efficacy of tocilizumab for the treatment of active SJIA was assessed in a 12-week randomized, double-blind, placebo-controlled, parallel group, industry-funded two-arm (TENDER) study of 112 children, ages two to 17 years old, who had an inadequate clinical response to NSAIDs or corticosteroids due to toxicity or lack of efficacy (Di Benedetti, 2012). At baseline, approximately half of the participants were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking MTX. Participants treated with or without MTX were randomized (tocilizumab to placebo = 2:1) to one of two treatment groups: 75 participants received tocilizumab infusions every two weeks (8 or 12 mg per kg based on body weight) and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for participants who achieved a JIA ACR70 response. After 12 weeks or at the time of escape due to disease worsening, participants were treated with tocilizumab in the open-label extension phase at weight appropriate dosing.

The primary endpoint was the proportion of participants with at least 30% improvement in JIA ACR core set (JIA ACR30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding seven days). JIA ACR responses are defined as the percentage improvement (30%, 50%, and 70%) in three of any six core outcome variables compared to baseline, with worsening in no more than one of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per participant global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (Childhood Health Assessment Questionnaire-CHAQ). The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Of participants with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to five out of 24 (21%) of placebo-treated participants, and 14 out of 22 (64%) became free of rash compared to two out of 18 (11%) of placebo-treated participants. Responses were consistent in the open label extension (data available through 44 weeks).

Corticosteroid dose reduction was achieved in some participants that received oral corticosteroids at baseline. Eight out of 31 (26%) placebo and 48 out of 70 (69%) participants on tocilizumab achieved a JIA ACR70 response at week six or week eight. Seventeen (24%) tocilizumab participants compared to one (3%) placebo participant were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab participants off oral corticosteroids. Of these 44 participants, 50% were off corticosteroids 18 weeks or more. Health-related outcomes were reported as physical function and disability, assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of participants in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of greater than or equal to 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group (Actemra PI, 2013 ; Yokota, 2008).

The most common adverse events (at least 5%) seen in tocilizumab-treated participants in the 12 week controlled phase of the trial were upper respiratory tract infection, headache, nasopharyngitis and diarrhea. The rate of serious infections in the tocilizumab group was "11.5 per 100 patient years." In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was "11.4 per 100 patient years." The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. The FDA noted in the follow-up period to the trial, there were three cases of macrophage activation syndrome (MAS), a potentially fatal complication of childhood systemic inflammatory disorders. Therefore, tocilizumab carries a black boxed warning alerting users to the risk of serious infections (Actemra PI, 2013).

In 2011, the ACR issued recommendations for the treatment of JIA which included initiation and safety monitoring of therapeutic agents for the treatment of systemic features. These recommendations, however, were issued before the FDA approval of tocilizumab for the treatment of active SJIA. The ACR states the appropriateness of initiating recently available therapeutic agents, such as interleukin-6 inhibitors (tocilizumab) for "the treatment of systemic arthritis may need to be the focus of a timely update to these recommendations" (Beukelman, 2011).

Off-FDA Label and other Proposed Indications for Tocilizumab

At this time, the FDA has not approved the use of tocilizumab for the treatment of moderately to severely active RA in individuals with no previous treatment failure. There continues to be insufficient evidence in the published peer-reviewed medical literature to support the use of tocilizumab as first line therapy for this indication.

Ongoing clinical trials and several cohort studies and case series published in the peer-reviewed literature have evaluated the use of tocilizumab in the treatment of adult onset Still's disease (AOSD) (Puéchal,2011; Suematsu, 2011), ankylosing spondylitis (AS) (Shima, 2011; Sieper, 2013), Castleman's disease (Nishimoto, 2000; Nishimoto, 2005), Crohn's disease (CD) (Ito, 2004), graft versus host disease (GVHD) (Drobyska, 2011), large vessel vasculitis (LVV) (giant cell and Takayasu's arteritis) (Beyer, 2011; Salvarani, 2012; Seitz, 2011), polymyositis (Narazaki, 2011), relapsing polychondritis, systemic lupus erythematosus (SLE) (Illei, 2010), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Vaitla, 2011). At this time the FDA has not approved the use of tocilizumab for the treatment of these conditions. Further evidence in the form of randomized, double-blind, controlled studies with long-term follow-up is required to evaluate the safety and efficacy of tocilizumab for these indications.

Background/Overview

RA is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. The disease affects approximately 2.1 million Americans usually striking people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. RA is three times more common in women than in men.

Clinical studies support the safety and efficacy of tocilizumab for the treatment of moderately to severely active RA when used as described on the FDA-approved PI label. The most common adverse events reported in clinical trials were respiratory tract infections, nasopharyngitis, headache, hypertension, and increased liver enzymes.

The FDA has required the sponsor to conduct a post-marketing clinical trial to further evaluate the long-term safety of tocilizumab for the treatment of moderately to severely active RA. Specifically, the FDA wants to evaluate the impact of elevated LDL cholesterol and blood pressure seen in some individuals in shorter-term trials on the cardiovascular health of individuals treated with the drug. In addition, 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 individuals for liver and/or gastrointestinal side effects. The REMS will include a Medication Guide to ensure that individuals are informed of the benefits and risks of tocilizumab.

Juvenile idiopathic arthritis (JIA) is the most common form of arthritis in children, affecting roughly 100 in 100,000 children, of which PJIA accounts for about 30%. PJIA is characterized by inflammation in five or more joints within the first six months of onset of the disease. Small joints in the body such as hands and feet are most commonly affected. Girls are more frequently affected by PJIA than boys, and in teenagers, it often resembles RA.

SJIA (formerly known as Still's disease), is a rare, potentially life-threatening disorder in children that causes severe inflammation throughout the body. The etiology is largely unknown, and the genetic component is complex, making a clear distinction between the various subtypes difficult. The prevalence of JIA is an estimated one to two per 1,000 children; SJIA affects about 10 percent of all children with JIA. SJIA is distinguished from other forms of JIA by the prominence of systemic and inflammatory features, including spiking fevers, rash, swelling and inflammation of lymph nodes, liver, and spleen, and high white blood cell and platelet counts. Arthritis may persist even after the fevers and other symptoms have disappeared. Up to 30% of children will still have active disease after 10 years, and morbidity within this group is high. Secondary medical complications include amyloidosis, growth failure, osteoporosis, deformities, and loss of function; non-medical complications may include serious developmental and social consequences.

The following are important limitations of use of tocilizumab from thePI Label (Actemra PI, 2013):

The following are warnings and precautions from the PI Label (Actemra PI, 2013):

Definitions

Adult onset Still's disease (AOSD): A rare inflammatory condition first described in children that may lead to persistent chronic arthritis and other complications including swollen lymph glands or enlargement of the spleen and liver, a marked increase in the white blood cell count, inflammation of the lungs (pleuritis) or around the heart (pericarditis), and severe anemia. 

Ankylosing spondylitis (AS): A disease that causes inflammation of the joints between the spinal bones and the joints between the spine and pelvis.

Anti-CD20 monoclonal antibody: A class of biologic DMARDs that targets a specific protein, known as CD20 found on the surface of normal and malignant B-lymphocytes. A drug in this class includes rituximab (Rituxan, Genentech, Inc. South San Francisco, CA), a genetically engineered monoclonal antibody.

Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing IL-1ß, Il-12 and/or IL-23, or by directly suppressing lymphocytes. Drugs in this class include the interleukin-1 receptor antagonists (IL-1Ra), interleukin-1 beta (IL-1ß) antagonists, interleukin-6 (IL-6) receptor antagonists, interleukin (IL)-12 and IL-23 antagonists, selective co-stimulation modulators, and the tumor necrosis factor (TNF) antagonists.

Castleman's disease: A rare, non-cancerous disorder that affects the lymph nodes and other immune-cell structures throughout the body; also known as multicentric Castleman's disease (MCD), giant lymph node hyperplasia and angiofollicular lymph node hyperplasia.

Crohn's disease (CD): An idiopathic, inflammatory bowel disease (IBD) characterized by discontinuous, transmural inflammation located anywhere in the gastrointestinal tract from the mouth to the anus. 

Disease activity score 28 (DAS28): A measure of disease activity used to monitor the treatment of RA. The score uses a formula that includes the number of tender joints and swollen joints (28 joints maximum).

Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).

Interleukin-1 receptor antagonist (IL-1Ra): A class of biologic DMARDs that inhibits inflammation and pain by blocking pro-inflammatory interleukin-1 cytokine which plays a role in cell destruction. A drug in this class includes anakinra (Kineret®, Amgen, Thousand Oaks, CA), a recombinant form of human IL-1Ra.

Interleukin-1 beta (IL-1ß) antagonist: A class of biologic DMARDs that work by binding human IL-1ß and neutralize its activity by blocking its interaction with IL-1 receptors. A drug in this class includes canakinumab (Ilaris®, Novartis Pharma Stein AG, East Hanover, NJ).

Interleukin-6 (IL-6) receptor antagonist: A class of biologic DMARDs shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation; produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as RA. A drug in this class includes tocilizumab (Actemra).

Nonbiologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown. Drugs in this class include azathioprine, hydroxychloroquine, leflunomide, MTX, minocycline, organic gold compounds, penicillamine, and sulfasalazine.

Polyarticular juvenile idiopathic arthritis (PJIA): A form of JIA characterized by inflammation in five or more joints, most commonly affecting the same joints on both sides of the body (symmetrical arthritis), such as the hands and feet, although weight-bearing joints such as the knees, hips, and ankles may also be affected.

Selective co-stimulation modulator: A class of biologic DMARDs that inhibits T cell (T lymphocyte) activation; activated T lymphocytes are implicated in the development of RA and are found in the synovium of individuals with RA. A drug in this class includes abatacept (Orencia, Bristol-Myers Squibb Company, Princeton, NJ).

Systemic juvenile idiopathic arthritis (SJIA): A condition, formerly known as Still's disease or systemic onset juvenile rheumatoid arthritis (SJRA), in children that generally occurs prior to the age of 16, favors one or more large joints, and can interfere with normal bone growth.

Systemic lupus erythematosus (SLE): A chronic inflammatory autoimmune disease of the heart, joints, kidneys, lungs, nervous system, and skin that occurs when the body's tissues are attacked by its own immune system.

Tumor necrosis factor (TNF) antagonist: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response. Drugs in this class with an FDA-approved indication for the treatment of adults with moderately to severely active RA include adalimumab (Humira®, Abbott Laboratories, North Chicago, IL), certolizumab pegol (Cimzia®, UCB, Inc., Smyrna, GA), etanercept (Enbrel®, Immunex Corporation, Thousand Oaks, CA), golimumab (Simponi® and Simponi Aria®, Janssen  Biotech Inc., Horsham, PA), and infliximab (Remicade®, Janssen  Biotech Inc., Horsham, PA).

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

HCPCS  
J3262Injection, tocilizumab, 1 mg [Actemra] 
   
ICD-9 Diagnosis 
714.0-714.1Rheumatoid arthritis, Felty's syndrome 
714.2Other rheumatoid arthritis with visceral or systemic involvement [excluding adult-onset Still's disease] 
714.30-714.31Polyarticular juvenile rheumatoid arthritis 
714.4-714.9Chronic postrheumatic arthropathy, other and unspecified inflammatory polyarthropathies 
   
ICD-10 DiagnosisICD-10-CM draft codes; effective 10/01/2014: 
M05.00-M05.9Rheumatoid arthritis with rheumatoid factor 
M06.00-M06.09Rheumatoid arthritis without rheumatoid factor 
M06.4Inflammatory polyarthropathy 
M06.80-M06.89Other specified rheumatoid arthritis 
M06.9Rheumatoid arthritis, unspecified 
M08.20-M08.29 Juvenile rheumatoid arthritis with systemic onset 
M08.3Juvenile rheumatoid polyarthritis (seronegative) 

When services are Not Medically Necessary:
When the code describes tocilizumab for the situations indicated in the Position Statement as not medically necessary. 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses including, but not limited to, those listed below; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

ICD-9 Diagnosis 
 All other diagnoses including, but not limited to, the following: 
446.5Giant cell arteritis 
446.7Takayasu's disease 
555.0-555.9Regional enteritis (Crohn's disease) 
710.0Systemic lupus erythematosus 
720.0Ankylosing spondylitis 
785.6Enlargement of lymph nodes [Castleman's disease] 
   
ICD-10 DiagnosisICD-10-CM draft codes; effective 10/01/2014: 
 All other diagnoses including, but not limited to, the following: 
K50.00-K50.919Crohn's disease 
M06.1Adult-onset Still's disease 
M08.1Juvenile ankylosing spondylitis 
M31.4-M31.6Aortic arch syndrome (Takayasu), giant cell arteritis with polymyalgia rheumatic, other giant cell arteritis 
M32.0-M32.9Systemic lupus erythematosus 
M45.0-M45.9Ankylosing spondylitis 
R59.0-R59.9Enlarged lymph nodes 
   
References

Peer Reviewed Publications:

  1. An MM, Zou Z, Shen H, et al. The addition of tocilizumab to DMARD therapy for rheumatoid arthritis: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2010; 66(1):49-59.
  2. Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis. 2011; 70(10):1874-1875.
  3. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012; 367(25):2385-2395.
  4. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant. 2011; 17(12):1862-1868.
  5. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013; 72(1):43-50.
  6. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008; 67(11):1516-1523.
  7. Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum. 2010; 62(1):33-43.
  8. Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004; 50(5):1412–1419.
  9. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008; 58(10):2968-2980.
  10. Herlin T. Tocilizumab: the evidence for its place in the treatment of juvenile idiopathic arthritis. Core Evid. 2010; 4:181-189.
  11. Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010; 62(2):542-552.
  12. Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology. 2004; 126(4):989-996; discussion 947.
  13. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69(1):88-96.
  14. Kremer JL, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011; 63(3):609-621.
  15. Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006; 54(9):2817-2829.
  16. Narazaki M, Hagihara K, Shima Y, et al. Therapeutic  effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxford). 2011; 50(7):1344-1346.
  17. Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007; 66(9):1162-1167.
  18. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized  anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005; 106(8):2627-2632.
  19. Nishimoto N, Miyasaka N, Yamamoto K, et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis. 2009a; 68(10):1580-1584.
  20. Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009b; 19(1):12-19.
  21. Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood. 2000; 95(1):56-61.
  22. Puéchal X, DeBandt M, Berthelot JM, et al. Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken). 2011; 63(1):155-159.
  23. Salvarani C, Magnani L, Catanoso M, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford). 2012; 51(1):151-156.
  24. Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly. 2011; 141:w13156. doi: 10.4414/smw.2011.13156.
  25. Shima Y, Tomita T, Ishii T, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod Rheumatol. 2011; 21(4):436-439.
  26. Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2013 Jun 13. [Epub ahead of print].
  27. Smolen JS, Avila JC, Aletaha D. Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction. Ann Rheum Dis. 2012; 71(5):687-693.
  28. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008; 371(9617):987-997.
  29. Suematsu R, Ohta A, Matsuura E, et al. Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan. Mod Rheumatol. 2012; 22(5):712-719.
  30. Vaitla PM, Radford PM, Tighe PJ, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011; 63(4):1151-1155.
  31. Weinblatt M, Combe B, Covucci A, et al. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study. Arthritis Rheum 2006; 54:2807-2816.
  32. Woo P, Wilkinson N, Prieur AM, et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther. 2005; 7(6):R1281-1288.
  33. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012; 71(2):198-205.
  34. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008; 371(9617):998-1006.
  35. Yokota S, Kishimoto T. Tocilizumab: molecular intervention therapy in children with systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol. 2010; 6(5):735-743.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Actemra [Product Information], Genentech, Inc., Roche USA, South San Francisco, CA; April 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125276s064lbl.pdf. Accessed on June 10, 2013.
  2. Aletaha D, Neoga T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College  of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62(9):2569-2581.
  3. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2013®. Bethesda, MD: American Society of Health-System Pharmacists®; 2013.
  4. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011; 63(4):465-482.
  5. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on June 10, 2013.
  6. Donahue KE, Jonas DE, Hansen RA, et al. Drug therapy for rheumatoid arthritis in adults: an update. Comparative Effectiveness Review No. 55. Agency for Healthcare Research and Quality. AHRQ Publication No. 12-EHC025-EF. June 1, 2012. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1044&pageaction=displayproduct. Accessed on June 10, 2013.
  7. Kemper AR, Coeytaux R, Sanders GD, et al. Disease-modifying antirheumatic drugs (DMARDs) in children with juvenile idiopathic arthritis. Executive Summary. Comparative Effectiveness Review No. 28. AHRQ Publication No. 11-EHC039-EF. Rockville, MD: Agency for Healthcare Research and Quality. August 2011. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/108/705/JIA_ES.pdf. Accessed on June 13, 2013.
  8. Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2011; 38(1):10-20.
  9. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012; 64(5):625-639.
  10. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011; (2):CD008794.
  11. Tocilizumab. In: DrugPoints System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated May 8, 2013. Available at: http://www.micromedexsolutions.com. Accessed on June 10, 2013.
Web Sites for Additional Information
  1. U.S. National Library of Medicine. MedlinePlus. Juvenile rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html. Accessed on June 10, 2013.
  2. U.S. National Library of Medicine. MedlinePlus. Rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/rheumatoidarthritis.html. Accessed on June 10, 2013.
Index

QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
T-SPOT.TB Test (T-Spot)

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. 

Document History

Status

Date

Action

Revised08/08/2013Medical Policy & Technology Assessment Committee (MPTAC) review. Added medically necessary criteria for FDA approval of tocilizumab for active PJIA and removed PJIA from the investigational and not medically necessary statement. Revised medically necessary criteria for SJIA, removing "may be used alone or in combination with MTX" criterion. Updated Description, Rationale, Background, Definitions, Coding, References, and Web Sites for Additional Information sections.
Revised02/14/2013MPTAC review. Revised medically necessary criterion for use of tocilizumab in adult RA. Clarification to investigational and not medically necessary statement. Updated Rationale, Background, Definitions, References, Web Sites for Additional Information, and Index sections.
Revised05/10/2012MPTAC review. Revised not medically necessary criterion for specific laboratory testing prior to initiation of tocilizumab. Clarified not medically necessary criteria for evaluating for serious infections and tuberculosis. Added non-FDA approved conditions to the investigational and not medically necessary statement. Updated the Rationale, Definitions, Coding, and References.
Revised05/19/2011MPTAC review. Medically necessary statement added for active systemic juvenile idiopathic arthritis (SJIA). Medically necessary and not medically necessary statements reformatted. Investigational and not medically necessary statement updated with additional conditions. Updated Description, Rationale, Background, Definitions, Coding, References, Web Sites for Additional Information, and Index sections.
 01/01/2011Updated Coding section with 01/01/2011 HCPCS changes; removed C9264 deleted 12/31/2010.
 07/01/2010Updated Coding section with 07/01/2010 HCPCS changes.
New05/13/2010MPTAC review. Initial document development.