Biologic DMARDs for Rheumatoid Arthritis

Las Vegas—Soon after patients are diagnosed with rheumatoid arthritis (RA), they experience symptoms, and, within 2 years, they have a moderate loss of function that can contribute to health problems, lost work time, and other issues.

To reduce the likelihood of major problems in the these patients, it is important to treat them early and in an aggressive manner, according to Gary M. Owens, MD, president, Gary Owens Associates, who spoke at a session at the NAMCP meeting.

Dr. Owens discussed biologic disease-modifying antirheumatic drugs (DMARDs), however, he recommended that health plans should cover all mechanism of action categories for RA drugs. He added that plans should consider limiting the number of switches between drugs in the same categories and also design a disease management approach to measure outcomes and track costs.

RA, a chronic systemic inflammatory disorder of unknown etiology, affects bones, cartilage, and ligaments, and commonly leads to deformities. Patients with RA can experience fatigue, anemia, and fever.

Approximately 1% to 2% of adults in the United States have RA, with most cases occurring from age 30 to 60 years. The disease is 3 times more common in women than men and first-degree relatives of people with RA have double the risk of being diagnosed with the disease compared with those whose relatives do not have RA.

Dr. Owens said 40% to 85% of patients with RA are unable to work within 8 to 10 years of disease onset, while life expectancy is decreased by 5 to 15 years. Compared with the general population, those with RA are twice as likely to have myocardial infarction or cerebrovascular accident and 3 times more likely to have lymphoma.

According to the American College of Rheumatology (ACR), patients are diagnosed with RA if they meet 4 of the following 7 criteria: (1) morning stiffness in a joint for at least 1 hour for at least 6 weeks; (2) arthritis in ≥3 joint areas for at least 6 weeks; (3) arthritis of the hand; (4) symmetric arthritis; (5) rheumatoid nodules; (6) rheumatoid factor; and (7) radiographic changes.

Dr. Owens said functional decline begins early in patients with RA. A moderate loss of function occurs within 2 years of diagnosis, a severe loss of function occurs within 5 to 7 years, and very severe loss of function occurs within 10 years. The definitions of loss of function are based on scores from Stanford University’s Health Assessment Questionnaire functional disability index.

When treating patients, the goals are remission or lowering of disease activity, according to Dr. Owens. He defined remission as the complete absence of clinical signs and symptoms of synovitis, elimination of silent synovial inflammation, and normalization of acute phase reactants.

DMARDs were commonly used to initially treat RA, but physicians now utilize early, aggressive treatment with biologics and combination therapies.

The 2012 ACR criteria feature 8 biologic agents: abatacept, rituximab, adalimumab, etanercept, infliximab, toclizumab, certolizumab pegol, and golimumab. In 2008, there were only 5 biologics; in the past 4 years, toclizumab, certolizumab pegol, and golimumab have been approved by the FDA.

For early RA patients, the 2012 ACR criteria suggest first assessing disease activity. If it is low, patients should take a DMARD. Patients with moderate disease activity should take ≥1 DMARD therapy. If patients have high disease activity, they are advised to take DMARD monotherapy, DMARD combination therapy, a combination of hydroxychloroquine and methotrexate, or an anti-tumor necrosis factor (TNF) with or without methotrexate.

Dr. Owens provided an overview of the treatment options available to treat RA. He said nonpharmacologic options such as rest, pain relieving therapy, physical therapy, occupational therapy, and patient education are useful.

Small molecule DMARDs include minocycline, which Dr. Owens said may work best in early treatment and provides a modest effect; sulfasalazine and hydroxychlorique, which also have a moderate effect, but have a low cost; and intramuscular gold, which decreases disease progression and has a slow onset, but requires close monitoring.

Immunosuppressant drugs include methotrexate, which Dr. Owens considers the most effective DMARD with a good benefit-to-risk ratio; azathioprine, which Dr. Owens considers reasonably effective and has a slow onset; cyclophosphamide, which is effective for vasculitis, but not as effective for arthritis; and cyclosporine, which is superior to placebo, but has led to renal toxicity.

FDA-approved biologic DMARDs are in the following categories: anti-TNF antagonists (adalimumab, etanercept, infliximab, golimumab, and certolizumab), interleukin antagonists (anakinra and actemra), suppress T-cell activation (abatacept), and anti B-cell monoclonal antibody (rituximab).

Dr. Owens added that several drugs are in the late-stage pipeline to treat RA. Phase 3 trials have been conducted or are underway for sirukumab (a human anti-interleukin-1 beta monoclonal antibody), secukinumab (a human anti-interleukin-1 beta monoclonal antibody), ofatumumab (a human anti-CD20 monoclonal antibody), tofacitinib (a janus kinase inhibitor), and fostamatinib (a spleen tyrosine kinase inhibitor).

None of the current therapies cure the disease, but approximately 50% of patients who take any of the FDA-approved biologics meet the ACR’s criteria of 20% to 50% improvement, according to Dr. Owens. He added that an issue with biologics is that most have fixed doses within a narrow range. In addition, some of the contraindications associated with biologics are active hepatitis B infection, multiple sclerosis, optic neuritis, active serious infections, chronic or recurrent infections, current neoplasia, history of tuberculosis or positive purified protein derivative, and congestive heart failure.

The wholesale acquisition costs for the 8 biologic DMARDs are similar, ranging from $20,500 per year for abatacept to $21,500 for rituximab, according to Dr. Owens.

Dr. Owens also discussed results of a study that examined an overview of The Cochrane Library reviews. An analysis of 27 randomized controlled trials found that any biologic DMARD was more effective than placebo, with all but anakinra being 2 to 3 times more effective. For the most part, the DMARDs were similar in effectiveness, although the authors found that etanercept, rituximab, and adalimumab were superior to anakinra.

Another analysis of 29 randomized controlled trials found that compared with a placebo group, patients who took adalimumab, anakinra, and infliximab were at a higher risk for withdrawing from the studies because of adverse events. The risk was similar between the group and patients who took abatacept, etanercept, and rituximab. In addition, compared with the etanercept group, patients who took adalimumab, anakinra, and infliximab had more withdrawals because of adverse events.