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) 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 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:

• DRUG.00002 Tumor Necrosis Factor Antagonists
• DRUG.00040 Abatacept (Orencia^®)
• DRUG.00041 Rituximab (Rituxan^®)

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:

• Individual is 18 years of age or older; and
• Has had an inadequate response to one or more tumor necrosis factor (TNF) antagonist drugs; and
• May be used alone or in combination with methotrexate (MTX) or with other non-biologic disease modifying anti-rheumatic drugs (DMARDs).

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

• Individual is two years of age or older, and
• Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs); and
• May be used alone or in combination with MTX.

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. Absolute neutrophil count (ANC) less than 2000/mm^3_, platelet count less than 100,000/mm^3_, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal (ULN); or
3. Tuberculosis 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 rule out latent tuberculosis.

Investigational and Not Medically Necessary:

Tocilizumab is considered investigational and not medically necessary for all other indications, including but not limited to the treatment of adult onset Still's disease (AOSD), ankylosing spondylitis (AS), Castleman's disease, Crohn's disease (CD), polyarticular juvenile idiopathic arthritis (JIA), and systemic lupus erythematosus (SLE).

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. According to the American College of Rheumatology (ACR) 2008 Recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis, combinations of biologic agents are not recommended in the treatment of RA, "based in part on data suggesting a higher rate of adverse events with combinations and/or lack of additive efficacy"(Genovese, 2004; Weinblatt, 2006). According to the Product Information (Actemra^®_, 2011), tocilizumab "has not been studied and its use should be avoided in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection."

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 ACR criteria (Emery, 2008; Genovese, 2008; Maini, 2006; Nishimoto, 2007 and 2009; Smolen, 2008). In three of the trials (Emery, 2008 [RADIATE]; Genovese, 2008 [TOWARD]; Smolen, 2008 [OPTION]), significant improvements over treatment with conventional DMARDs was shown in individuals with RA who were DMARD-failures, MTX-failures, or TNF-failures as measured by the percent of subjects achieving a 20%, 50%, or 70% improvement in ACR measures (e.g., joint stiffness, pain, swelling, lab measures, and/or disability).

Since the initial approval of tocilizumab for moderately to severely active RA, the FDA has 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 latest 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.

In 2010, a joint working group from the ACR and the European League Against Rheumatism (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 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, two-arm 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. 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 (e.g., 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^® Product Information, 2011; 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 (FDA, 2011).

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 (e.g., 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

In the randomized, double-blind, double-dummy, parallel Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy (AMBITION) trial, adults (n=570) who were successfully treated with MTX or biological agents for active RA received tocilizumab as monotherapy, resulting in significantly more subjects achieving an ACR criteria improvement of 20% (ACR20 response) at week 24, compared with MTX monotherapy (Jones, 2010). Subjects were randomized to either tocilizumab 8 mg/kg every four weeks, or MTX, starting at 7.5 mg/week and titrated to 20 mg/week within eight weeks, or placebo for eight weeks followed by tocilizumab 8 mg/kg. Subjects were excluded from the study if they experienced previous treatment failure with a TNF antagonist, had discontinued MTX due to treatment failure or adverse events, or had received MTX six months prior to randomization. The intention-to-treat analysis demonstrated that tocilizumab was more effective than MTX treatment with a higher ACR20 response (69.9 versus 52.5%; p<0.001), and disease activity severity in 28 joints (DAS28) less than 2.6 rate (33.6 versus 12.1%) at week 24. Tocilizumab-treated subjects also achieved significantly improved results on secondary endpoints of ACR 50% response, and ACR 70% response compared with MTX. There were significant improvements in tocilizumab-treated subjects compared with MTX in the reduction in the mean number of swollen joints and tender joints. However, when comparing tocilizumab with MTX-treated subjects, increases in ALT elevations of more than three times the ULN to five times the upper limit of normal (ULN) occurred in 2.5% and 1% of subjects and increases of five times the ULN or greater occurred in 1.1% versus 0.7%, respectively. In addition, increases in total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol were observed in more subjects in the tocilizumab group than in the MTX group. Long-term follow-up is needed during chronic treatment to determine the safety profile for lipid elevations and the implications of any cardiovascular risk that may occur as a result of these elevations. 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.

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), ankylosing spondylitis (AS), Castleman's disease, Crohn's disease (CD), polyarticular juvenile idiopathic arthritis (JIA), and systemic lupus erythematosus (SLE) (Illei, 2010). 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.

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 product information. 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.

Systemic juvenile idiopathic arthritis (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 theProduct Information Label (2011):

• Tocilizumab has not been studied in combination with biologic DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators.
• Upon initiation or discontinuation of tocilizumab in individuals being treated with CYP450 substrates, therapeutic monitoring of effect (e.g. warfarin) or drug concentrations (e.g. cyclosporine or theophylline) should be performed and the individual dose of the product be adjusted as needed.
• Tocilizumab should be administered with caution when administered with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable (e.g. oral contraceptives, statins).

The following are warnings and precautions from the Product Information Label (2011):

• Black Boxed Warning: Risk of Serious Infections
  • Serious infections leading to hospitalization or death including tuberculosis (TB), mycobacterial, invasive fungal, viral, protozoal, and other opportunistic infections have occurred in individuals receiving tocilizumab. Most individuals who developed these infections were taking concomitant immunosuppressants such as MTX or corticosteroids.
  • If a serious infection develops, interrupt tocilizumab until the infection is controlled;
  • Screen for latent TB infection prior to initiating therapy. Individuals testing positive should be treated prior to initiating tocilizumab;
  • Monitor all individuals for active TB during treatment, even if initial latent TB test is negative.
• Tocilizumab should not be initiated in individuals with an absolute neutrophil count below 2000/mm^3_, platelet count below 100,000^3_,or who have ALT or AST above 1.5 times the upper limit of normal:
  • For individuals with RA: Neutrophils, platelets, ALT and AST should be monitored every 4 to 8 weeks;
  • For children with SJIA: Neutrophils, platelets, ALT and AST should be monitored at the time of the second infusion and thereafter every 2 to 4 weeks.
• Treatment with tocilizumab was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol. For individuals with RA and SJIA:
  • Lipid parameters should be performed approximately 4 to 8 weeks following initiation of tocilizumab therapy, then at approximately 24 week intervals;
  • Manage individuals according to clinical guidelines (e.g., National Cholesterol Educational Program) for the management of hyperlipidemia.
• Use with caution in individuals who may be at increased risk for gastrointestinal perforation.
• Anaphylaxis or serious hypersensitivity reactions have occurred with infusion of tocilizumab.
• Closely monitor individuals for signs and symptoms indicative of demyelinating disorders such as multiple sclerosis; the impact of treatment with tocilizumab on these disorders is unknown.
• Treatment is not recommended in individuals with active hepatitis disease or hepatic impairment.
• Live vaccines should not be given concurrently with tocilizumab. Individuals should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with tocilizumab.
• There are no adequate and well-controlled studies in pregnant women. Tocilizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Safety and effectiveness of tocilizumab in children with conditions other than SJIA have not been established. Children under the age of two have not been studied.

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-12 and IL-23, or by directly suppressing lymphocytes. Drugs in this class include the interleukin-1 receptor antagonists (IL-1Ra), 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 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 modifying anti-rheumatic drugs (DMARDs): A variety of drugs (i.e., methotrexate, sulfasalazine, hydroxychloroquine) that work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including RA.

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-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, methotrexate (MTX), minocycline, organic gold compounds, penicillamine, and sulfasalazine.

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 include adalimumab (Humira^®_, , Abbott Laboratories, North Chicago, IL), certolizumab pegol (Cimzia^®_, UCB, Inc., Smyrna, GA), etanercept (Enbrel^®_, Immunex Corporation, Thousand Oaks, CA), golimumab (Simponi^®_, Centocor Ortho Biotech Inc., Horsham, PA), and infliximab (Remicade^®_, Centocor Ortho Biotech Inc., Horsham, PA).

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  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: 

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 not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

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. 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.
3. 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.
4. 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.
5. 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.
6. Herlin T. Tocilizumab: the evidence for its place in the treatment of juvenile idiopathic arthritis. Core Evid. 2010; 4:181-189.
7. 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.
8. 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.
9. Kremer JL, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at 1 year: The LITHE study. Arthritis Rheum. 2011; 63(3):609-621.
10. 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.
11. 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.
12. 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. 2009; 68(10):1580-1584.
13. 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. 2009; 19(1):12-19.
14. Puéchal X, DeBandt M, Berthelot JM, et al. Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken). 2011; 63(1):155-159. 
15. 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.
16. 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.
17. 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.
18. 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.
19. 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 15, 2011. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed on April 18, 2011.
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. 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.
4. American College of Rheumatology (ACR). Recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59(6):762-784.
5. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®_. Bethesda, MD: American Society of Health-System Pharmacists^®_; 2011.
6. 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 April 18, 2011.
7. Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2011; 38(1):10-20.
8. Tocilizumab. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified March 7, 2011. Available at: http://www.thomsonhc.com. Accessed on April 19, 2011.
9. U.S. Food and Drug Administration (FDA). FDA approves Actemra to treat rare form of juvenile arthritis. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251572.htm. Posted April 15, 2011. Accessed on April 19, 2011.

1. U.S. National Library of Medicine. MedlinePlus. Juvenile rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html. Accessed on April 19, 2011.
2. U.S. National Library of Medicine. MedlinePlus. Rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/rheumatoidarthritis.html. Accessed on April 19, 2011.

Actemra^®
Disease Modifying Anti-Rheumatic Drug
Interleukin-6 Receptor Antagonist
Methotrexate
QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
Rheumatoid Arthritis
Systemic Juvenile Idiopathic Arthritis
T-SPOT.TB test (T-Spot)
Tocilizumab
Tumor Necrosis Factor Antagonist

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.