Description:
Rheumatoid arthritis is a chronic condition in which the person’s own immune system causes inflammation of the joints and the tissue around the joints. The body is equipped with a defense mechanism called the immune system that protects you from disease and infection. When a person has an autoimmune condition, the immune system creates antibodies that attack its own tissues by mistake. Rheumatoid arthritis usually starts between the age of 25 and 55 and the cause is unknown. Symptoms of rheumatoid arthritis (RA) are described as painful inflammation of the synovial tissue lining the joints. These patients have elevated levels of tumor necrosis factor alpha (TNF-a) in their joints. Chronic joint inflammation leads to tissue breakdown, cell damage to the bone, edema, warmth, redness, joint stiffness and pain. These patients are also fatigued, weak, have a low-grade fever and loss of appetite.

Systemic Juvenile Idiopathic Arthritis (sJIA) is a rare, potentially life-threatening disorder in children that causes severe inflammation throughout the body. sJIA is distinguished from other forms of juvenile idiopathic arthritis (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.

Tocilizumab (Actemra^®) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1. subclass with a typical H2L2 polypeptide structure. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 has been 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. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. Tocilizumab is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. 

Policy
Coverage of Tocilizumab (Actemra) is provided when the FDA-approved indications below are met and there has been a trial and failure of preferred therapy. 

Actemra IV is considered MEDICALLY NECESSARY when one of the following criteria is met along with specific diagnosis criteria:

• Physician attests that the patient or caregiver is not competent or is physically unable to administer the Actemra product FDA labeled for self-administration. 
• Patient has experienced severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, or hypotension) to Actemra within the past 6 months and requires administration and direct monitoring by a healthcare professional.

Tocilizumab (Actemra) is considered MEDICALLY NECESSARY for the treatment of individuals with moderate-to-severe active rheumatoid arthritis who meet the following criteria:

1. 18 years of age and older
2. Inadequate response, intolerance, or contraindication to a 3-month trial of at least ONE conventional disease-modifying antirheumatic drugs (DMARDs)
3. Patient MUST have tried TWO self-injectable TNF antagonists or oral Janus Kinase Inhibitor, unless the patient has a valid medical exception (e.g., inadequate treatment response, intolerance, contraindication)
4. Patient has NEGATIVE pretreatment screening for latent tuberculosis (TB) infection with either a TB skin test or an interferon gamma release assay

Continued treatment with Tocilizumab (Actemra) is considered MEDICALLY NECESSARY for individuals with moderate-to-severe active rheumatoid arthritis who meet the following criteria:

1. Patient has achieved or maintained positive clinical response to treatment as evidenced by the following:

• • Low disease activity as measured by one of the following standardized disease activity measurement tools/scales:
    1. CDAI less than or equal to 10.0
    2. DAS28 < 3.2
    3. PAS or PASII less than or equal to 3.70
    4. RAPID-3 less than or equal to 2.0
    5. SDAI less than or equal to 11.0
  • Improvement in signs and symptoms of rheumatoid arthritis  

Tocilizumab is considered MEDICALLY NECESSARY for active systemic onset juvenile idiopathic arthritis who meet the follow criteria: 

1. 2 years of age or older with a disease duration of 6 or more months
2. Inadequate treatment response to at least a 2-week trial of corticosteroids and non-steroidal anti-inflammatory drugs
3. Inadequate treatment response to at least a 3-month trial of methotrexate or leflunomide  

Toclizumab is considered MEDICALLY NECESSARY for the treatment of moderate to severely active polyarticular juvenile idiopathic arthritis (juvenile rheumatoid arthritis) who meet the following criteria:  

1. 2 years of age or older
2. Patient has an intolerance or has experienced an inadequate treatment response to a 6-week trial of a biologic DMARD or targeted synthetic DMARD
3. Patient MUST have tried and failed TWO of the self-injectable TNF antagonists or oral Janus Kinase Inhibitor after at least 3 months of treatment, unless the patient has a valid medical exception (e.g., intolerance, contraindication)  

Continued treatment with Tocilizumab (Actemra) is considered MEDICALLY NECESSARY for individuals with moderate to severely active polyarticular juvenile idiopathic arthritis (juvenile rheumatoid arthritis) and systemic onset juvenile idiopathic arthritis who meet the following criteria:  

Patient has achieved or maintained positive clinical response to treatment as evidenced by one of the following: 

• Reduction in the total active (swollen and tender) joint count from baseline

• Improvement in clinical features or symptoms (e.g., pain, fever, inflammation, rash, lymphadenopathy, serositis) from baseline

Tocilizumab is considered MEDICALLY NECESSARY as subsequent therapy for the treatment of an individual with relapsed/refractory or progressive multicentric Castleman  (MCD) disease or unicentric Castleman's disease when all of the following criteria are met:  

• Used as a single agent
• Human immunodeficiency virus (HIV)-negative
• Human herpes-8 (HHV-8)-negative
• No concurrent clinically significant infection (for example, Hepatitis B or C)
• No concurrent lymphoma

Tocilizumab is considered MEDICALLY NECESSARY in adult patients with Giant Cell Arteritis in patients who are 18 years of age and older and had an inadequate treatment response to at least a 3-month trial corticosteroids.  

Tocilizumab is considered MEDICALLY NECESSARY in adult and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.   

Tocilizumab is considered MEDICALLY NECESSARY for treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) as documented by the following: 

• Exclusion of other known causes of interstitial lung disease (ILD) 
• One of the following: 
  • In patients not subjected to surgical lung biopsy, the presence of idiopathic interstitial pneumonia (e.g., fibrotic nonspecific interstitial pneumonia [NSIP], usual interstitial pneumonia [UIP] and centrilobular fibrosis) pattern on high-resolution computed tomography (HRCT) revealing SSc-ILD or probable SSc-ILD 
  • In patients subjected to a lung biopsy, both HRCT and surgical lung biopsy pattern revealing SSc-ILD or probable SSc-ILD

Tocilizumab is investigational/unproven and therefore considered NOT MEDICALLY NECESSARY 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: 

• Adult-onset Still disease
• Crohn's disease
• Psoriatic arthritis
• Relapsing polychondritis
• Systemic lupus erythematosus
• Takayasu arteritis
• Tumor nerosis factor receptor associated periodic syndrome (TRAPS).  

Tocilizumab (Actemra^®) is considered NOT MEDICALLY NECESSARY when used for 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.  

Tocilizumab (Actemra^®) is considered NOT MEDICALLY NECESSARY  for patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiation of Tocilizumab (Actemra^®) in patients:  

• With chronic or recurrent infection.
• Who have been exposed to tuberculosis.
• With a history of serious or opportunistic infection.
• Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to these infections.
• With recently active GI problems such as diverticulitis possibly placing them at risk of perforation.

Tocilizumab (Actemra^®) is considered NOT MEDICALLY NECESSARY when used in combination with biological DMARDs such as TNF antagonists, anakinra (Kineret^®), rituximab (Rituxan^®), and abatacept (Orencia^®).

Policy Guidelines
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Tocilizumab for rheumatoid arthritis. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. 

Tocilizumab may be used alone or in combination with methotrexate or other DMARDs.
The safety and effectiveness of Tocilizumab in pregnant or nursing women has not been established. 

According to the Food and Drug Administration(FDA) approved labeling for Tocilizumab, the dose should not exceed 800 mg every 28 days. 

According to the Food and Drug Administration (FDA) approved labeling for Tocilizumab, in children 2 years of age and older with active Systemic Juvenile Idiopathic Arthritis (sJIA), the dosing interval is every 2 weeks. 

According to the Food and Drug Administration (FDA) approved labeling for Tocilizumab, in children 2 years of age and older with active Polyarticular Juvenile Idiopathic Arthritis (pJIA), the dosing interval is every 4 weeks. 

The approved labeling does not describe circumstances in which dosages above this maximum would be considered safe and effective.

Rationale:
American College of Rheumatology (ACR): Juvenile Idiopathic Arthritis (JIA)
The ACR provides recommendations for the use of DMARDs and other therapeutic agents as treatment for JIA. JIA treatment recommendations are separated by disease classification (involvement of four or fewer joints, polyarticular, sacroiliac and systemic with or without arthritic feature). Although methotrexate and other DMARDs are considered appropriate treatments, combination DMARD therapy was not considered due to the concern of increased infection in adult populations. The ACR-published guidelines for the treatment of JIA (2011) note that at the time of the guidelines literature search, tocilizumab was not widely commercially available for JIA treatment. Therefore, tocilizumab was not considered in the development of the JIA recommendations. The guidelines also acknowledge that since options for the treatment of sJIA appear to be increasing, the appropriateness of initiating recently available therapeutic agents for treatment of sJIA may need to be the focus of a timely update to these recommendations.

ACR: Rheumatoid Arthritis (RA)
The ACR updated its 2008 recommendations for the use of DMARDs and biologic agents in the treatment of RA in April 2012. The updated recommendations follow the same methodology used to develop the 2008 recommendations. While the recommendations are extensive and include new areas and new agents not covered in 2008, they are not comprehensive and should be used as a guide for clinicians treating RA patients.

It is important that RA patients be seen regularly to assess disease activity, evaluate disease severity and determine whether alternative therapies are warranted. Because there was no evidence to support a specific recommendation on the frequency of provider visits, a specific and potentially arbitrary time frame is not recommended. However, based on these recommendations, commonly used but not exclusive tools to assess the RA disease activity include: Disease Activity Score (DAS) in 28 joints, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Rheumatoid Arthritis Disease Activity Index, Patient Activity Scale (PAS) and Routine Assessment Patient Index Data. In addition, the use of the combinations of commonly used, but not exclusive prognostic factors, to evaluate the patients with RA is recommended for determining prognosis. These factors include functional limitations (e.g., Health Assessment Questionnaire (HAQ) score), evidence of radiographic erosions, elevated erythrocyte sedimentation rate, elevated C-reactive protein level and elevated levels of rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies (e.g., seropositivity) and the presence of disease outside the joints (e.g., rheumatoid nodules, RA vascuiltis). Presence of one or more of these factors is indicative of poor prognosis. Due to the absence of a single "gold standard" measure, multiple measures or pooled indices are used to determine a diagnosis, estimate prognosis and to assess and monitor disease activity and response to treatment. Other commonly used measures in the clinical settings include: Visual Analog scale (VAS), Likert scales of global response to pain by the patient/doctor and Global Arthritis Score (GAS).

The ACR plans to periodically update RA treatment recommendations depending upon the availability of new therapies, new evidence on the benefits and harms of existing treatments and changes in policies to reflect the rapidly evolving care of RA patients. The 2012 revision updates the 2008 recommendations in the following areas:

• Indications for DMARDs and biologic agents
• Switching between DMARD and biologic therapies
• Use of biologic agents in high-risk patients (those with hepatitis, congestive heart failure [CHF] and malignancy)
• Screening for TB in patients starting or currently receiving biologic agents
• Vaccination in patients starting or currently receiving DMARDs or biologic agents

ACR treatment recommendations are based on whether RA is early (duration < six months) or established (> six-month duration or meeting 1987 ACR RA classification criteria), the degree of disease activity level (low, moderate or high) and the presence of poor prognostic factors. Though recommendations vary with each patient, the 2012 guidelines generally recommend physicians start treatment with a DMARD, proceed to therapy combining two or more DMARDs and then to a biologic when and if each option fails to control the disease. Biologics are grouped as either non-TNF (Abatacept, Riruximab, Tocilizumab) or anti-TNF (Adalimumab, Etanercept, Infliximab, Certolizumab pegol, Golimumab). When switching from DMARDs to biologics, for example, physicians should use either an anti-TNF biologic or a non-TNF biologic if a patient has moderate or high disease activity after three months of methotrexate treatment or DMARD combination therapy.

Due to increasing awareness of the risk of preventable infections in RA patients, the recommendations place a priority on screening and vaccination. RA is an autoimmune disease in which the immune system attacks the body’s own tissues. Treatments suppress the immune system and make those treated vulnerable to infections.

For that reason, the 2012 guidelines recommend that prior to initiation of therapy, all patients taking biologics for RA be screened for latent tuberculosis infection (LTBI) — statistics show that 5 to 10 percent of these patients will go on to develop active TB later. Preferred screening tests for active or latent tuberculosis include the tuberculin skin test (TST) or interferon-y-release assays (IGRAs) as the initial test, regardless of risk factors. For individuals who received a prior BCG (bacille Calmette-Guerin) vaccination, the preferred test is IGRA, due to high false-positive rates. Annual testing is recommended for individuals on biologic agents who live, travel or work in situations considered high risk for TB exposure.

The 2012 guidelines recommend that all killed (pneumococcal, influenza intramuscular and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer) and live attenuated (herpes zoster) vaccinations should be undertaken before starting a DMARD or a biologic agent. If not previously done, vaccination with indicated pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed) and HPV vaccine (recombinant) should be undertaken in RA patients already taking a DMARD or a biologic agent. Vaccination with herpes zoster vaccine in RA patients already taking a DMARD is recommended but is not recommended in patients taking a biologic agent. All vaccines should be given based on age and risk, and physicians should refer to vaccine instructions and CDC recommendations for details about dosing and timing issues related to vaccinations.

The 2012 guidelines literature search included eight DMARDs and nine biologic agents most commonly used for the treatment of RA. DMARDs included azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. Similar to 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on their infrequent use and lack of new data. The biologic agents included abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab. Anakinra was not included in the recommendations due to infrequent use and lack of new data.

Adverse Reactions
The most common side effects occurring in patients treated with tocilizumab or tocilizumab in combination with other DMARDs include an increase in alanine aminotransferase concentrations, hypertension, nasopharyngitis, headache and upper respiratory tract infection. The most common serious adverse event associated with tocilizumab is serious infection as noted in the Black Box Warning. The overall rate of serious infection in clinical trials was 4.7 events per 100 patient-years. Other less common serious side effects include gastrointestinal perforation, demyelinating disorders and malignancy. Do not administer tocilizumab in combination with biologic DMARDs such as TNF antagonists or rituximab. Tocilizumab may result in increased metabolism of CYP450 substrates. Do not administer live vaccines to patients receiving tocilizumab.

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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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