PharmacotherapyReview articleUse of Biologics in Rheumatoid Arthritis: Current and Emerging Paradigms of Care
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects 1.3 million people in the United States.1 Patients experience persistent joint inflammation that manifests as joint pain, stiffness, and swelling, resulting in progressive destruction of cartilage and bone in multiple joints.2 If inadequately treated, RA can lead to permanent joint damage and deformity. Systemic symptoms including fatigue, anemia, and low-grade fever are common; other extra-articular manifestations and complications (eg, pericarditis, myocarditis, vasculitis, and pulmonary fibrosis) are sometimes present and generally are associated with more severe clinical disease.3 Overall, the disease is associated with substantial disability, reduced quality of life, and loss of work capacity. Within 2 years of disease onset, ∼20% of patients are work disabled, and almost 50% are unable to work after 10 years.4 It is important to note that patients with severe RA have a higher risk of premature mortality than age-matched counterparts without RA, and they have enjoyed none of the increase in life expectancy experienced by the general population over the last 4 decades.5 In fact, life expectancy is reduced on average by 5 to 10 years.6 Thus, RA places a significant burden on patients and health care systems.
Although there is currently no cure for RA, the availability of new biologic treatments that directly target components of the RA inflammatory cascade has transformed management of this disease over the past 10 years. Pharmacists and other health care professionals play a vital role in caring for patients with RA. As the availability of new treatments for RA increases, it is important for health care professionals to maintain awareness of the cost of treatment and of treatment-switching patterns. The aim of this review is to provide pharmacists and individuals who are responsible for decision making within managed care environments with a comprehensive review of biologic therapies currently used for the treatment of RA.
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Methods
A narrative search of MEDLINE was conducted (up to October 2010) and abstracts and citations were manually reviewed for relevance. We gave preference to English language systematic reviews, practice guidelines, meta-analyses, large-scale cost-effectiveness analyses, and large-scale Phase III, double-blind, randomized controlled trials (RCTs) of biologic treatments in patients with RA.
Conventional Treatments
Traditional pharmacologic approaches have relied on combinations of NSAIDs (eg, aspirin, ibuprofen), analgesics, glucocorticoids (eg, prednisone, methylprednisone), and disease-modifying anti-rheumatic drugs (DMARDs).7, 8 NSAIDs and glucocorticoids act rapidly to suppress inflammation, thereby reducing pain and swelling. They may be useful as a “bridging therapy,” to control symptoms in the first few weeks after diagnosis while slower-acting DMARDs take effect. Because long-term glucocorticoids
Costs of Biologics in Rheumatoid Arthritis
The treatment of RA places a substantial financial burden on health care systems and individual patients. Indeed, a major problem associated with the use of biologics is cost, $1200 to $1400 per month ($14,400–$16,800 per year).25, 77 Estimates show that the introduction of biologics has increased, 3-fold, the total annual direct costs of treating RA patients.78 However, the overall costs of biologics should take into account the benefits of reducing RA impact. To date, few cost-benefit
Current Guidelines for Biologic Use in Rheumatoid Arthritis
In 2008, the ACR developed recommendations for biological use in RA patients (Table VI).14 The ACR Task Force Panel recommendations assumed a background of optimal and appropriate use of nonmedical therapies, such as physical and occupational therapies. The recommendations focused primarily on TNF antagonists, abatacept and rituximab; anakinra was not recommended for patients starting or resuming treatment with DMARDs. Patients with RA who do not meet the criteria in Table VI should be treated
Focus on Remission: Early Aggressive Treatment and Optimal Switching Patterns
Treatment of RA should be aimed at achieving the lowest possible disease activity and, ideally, disease remission. Although clinicians have typically reserved biologics for patients with severe disease who have failed other therapies, there is now a shift toward biologic use in selected patients with early RA and high disease activity.14 Clinical and radiographic data consistently show that early, aggressive treatment can improve the potential for superior clinical responses and remission
Assessment of Rheumatoid Arthritis Disease Activity
In terms of assessing clinical response to therapy, there is no universally accepted tool for monitoring RA disease activity in daily practice.104, 105 While ACR criteria are used extensively to evaluate responses in RCTs, these criteria are difficult to apply to routine care settings and have not been widely adopted. The DAS and its popular derivative DAS28 (which includes a 28-joint count) are widely used in clinical trials. DAS provides an absolute score for current disease activity (as
Unmet Needs: Newly Approved and Investigational Treatments
Besides the biologics described above, there are other agents that are newly approved or in late-stage clinical development for the treatment of RA. As outlined in Table II, tocilizumab⁎ is a new, once-monthly, intravenous IL-6–receptor antagonist that is approved in the United States for patients with moderate or severe RA who have had an inadequate response to at least 1 anti-TNF agent. Further information about this agent is not provided, because a focused review
Discussion
The introduction of biologics in 1998 has transformed the treatment of RA, and many patients have clinical responses to these agents. Patients typically experience improvements within a few weeks, and many do so after the first or second dose. According to recent ACR recommendations, RA patients who may be candidates for biologics (eg, infliximab, etanercept, adalimumab) include those with high disease activity and those who have previously failed to respond adequately to conventional DMARD
Conclusions
Overall, the use of biologics in the treatment of RA has led to markedly improved outcomes for patients. Evidence suggests that although biologics are costly, they remain cost-effective because of the major clinical benefits that patients may experience.
Acknowledgments
Dr. Curtis has received support from the National Institutes of Health (AR 053351) and the Arthritis Foundation. This work was supported in part by Roche and developed independently of Roche. Editorial support was provided by Sara Duggan, PhD, and Maribeth Bogush, PhD.
Dr. Curtis has received research grants and/or consulting fees from Roche/Genentech, Novartis, CORRONA, Amgen, Pfizer, Centocor, and UCB. Dr. Singh has received speaker honoraria from Abbott; research and travel grants from Takeda
References (114)
- et al.
Extra-articular manifestations and complications of rheumatoid arthritis
Best Pract Res Clin Rheumatol
(2007) - et al.
Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events
Am J Med
(1994) - et al.
Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trialFIN-RACo trial group
Lancet
(1999) - et al.
New therapies for treatment of rheumatoid arthritis
Lancet
(2007) - et al.
Tumor necrosis factor antagonist mechanisms of action: a comprehensive review
Pharmacol Ther
(2008) - et al.
From the bench to the bedside: ways to improve rituximab efficacy
Blood
(2004) - et al.
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial
Lancet
(1999) - et al.
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Lancet
(2004) - et al.
Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial
Lancet
(2008) - et al.
Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial
Lancet
(2009)