Elsevier

Clinical Therapeutics

Volume 33, Issue 6, June 2011, Pages 679-707
Clinical Therapeutics

Pharmacotherapy
Review article
Use of Biologics in Rheumatoid Arthritis: Current and Emerging Paradigms of Care

https://doi.org/10.1016/j.clinthera.2011.05.044Get rights and content

Abstract

Background

Improved understanding of rheumatoid arthritis (RA) pathogenesis has led to the development of new biologic treatments that target specific elements of RA inflammatory response.

Objective

Our aim was to provide a comprehensive review of biologic therapies currently used for the treatment of RA.

Methods

A search of MEDLINE (up to October 2010) was conducted. Preference for article inclusion was given to English language meta-analyses and large, Phase III, randomized controlled trials (RCTs) of biologic treatments in patients with RA.

Results

In large RCTs, significantly more patients treated with tumor necrosis factor–α (TNF-α) antagonists (as monotherapy, or as an adjunct to methotrexate) versus controls (35%–67% vs 9%–33% of patients; P ≤ 0.01) achieved an American College of Rheumatology 20 response as a primary study end point. However, safety concerns—especially the potential for serious infections and malignancy—remain for TNF-α blockade. For example, 1 meta-analysis (>5000 patients) reported a 2-fold increase (95% CI, 1.3–3.1) in the risk of serious infections and a 3.3-fold increase (95% CI, 1.2–9.1) in the risk of malignancy. Abatacept and rituximab (given in combination with methotrexate) may be useful clinical alternatives for RA patients with an inadequate response to TNF-α antagonists. These agents do not appear to increase the risk of serious infections (OR, 1.35–1.45; 95% CI, 0.56–3.73), although rituximab may rarely cause progressive multifocal leukoencephalopathy (0.4 cases per 100,000 hospitalizations).

Conclusions

Over the last decade, targeted biologic agents have transformed RA treatment. Although relatively expensive in the short term, the direct costs of these biologics may be offset by slowed disease progression and significant improvements in RA symptoms, physical function, and quality of life.

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.

Section snippets

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)

  • E. Zintzaras et al.

    Infliximab and methotrexate in the treatment of rheumatoid arthritis: a systematic review and meta-analysis of dosage regimens

    Clin Ther

    (2008)
  • C.G. Helmick et al.

    Estimates of the prevalence of arthritis and other rheumatic conditions in the United StatesPart I

    Arthritis Rheum

    (2008)
  • E.D. Harris

    Rheumatoid arthritisPathophysiology and implications for therapy

    N Engl J Med

    (1990)
  • T. Sokka et al.

    Work disability in rheumatoid arthritis 10 years after the diagnosis

    J Rheumatol

    (1999)
  • A. Gonzalez et al.

    The widening mortality gap between rheumatoid arthritis patients and the general population

    Arthritis Rheum

    (2007)
  • T.K. Kvien

    Epidemiology and burden of illness of rheumatoid arthritis

    PharmacoEconomics

    (2004)
  • A. Gaffo et al.

    Treatment of rheumatoid arthritis

    Am J Health Syst Pharmacy

    (2006)
  • J.R. Curtis et al.

    Drug-specific and time-dependent risks of bacterial infection among patients with rheumatoid arthritis who were exposed to tumor necrosis factor alpha antagonists

    Arthritis Rheum

    (2007)
  • L. Sizova

    Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs

    Br J Clin Pharmacol

    (2008)
  • D. Aletaha et al.

    The rheumatoid arthritis patient in the clinic: comparing more than 1300 consecutive DMARD courses

    Rheumatology (Oxford)

    (2002)
  • C.J. Edwards et al.

    The changing use of disease-modifying anti-rheumatic drugs in individuals with rheumatoid arthritis from the United Kingdom General Practice Research Database

    Rheumatology (Oxford)

    (2005)
  • D. Aletaha et al.

    Practical progress in realisation of early diagnosis and treatment of patients with suspected rheumatoid arthritis: results from two matched questionnaires within three years

    Ann Rheum Dis

    (2002)
  • K.G. Saag et al.

    American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis

    Arthritis Rheum (Arthritis Care Res)

    (2008)
  • V.P. Nell et al.

    Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis

    Rheumatology (Oxford)

    (2004)
  • B.N. Cronstein

    Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis

    Pharmacol Rev

    (2005)
  • R.B. Landewe et al.

    COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention

    Arthritis Rheum

    (2002)
  • J.M. Cash et al.

    Second-line drug therapy for rheumatoid arthritis

    N Engl J Med

    (1994)
  • M. Nagashima et al.

    Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1,358 Japanese patients with rheumatoid arthritis

    Clin Exp Rheumatol

    (2006)
  • Enbrel (etanercept)

    (2007)
  • Remicade (infliximab)

    (2009)
  • Humira (adalimumab)

    (2008)
  • Kineret (anakinra)

    (2001)
  • Abatacept (Orencia) for rheumatoid arthritis

    Med Lett Drugs Ther

    (2006)
  • Rituxan (rituximab)

    (2009)
  • Cimzia (certolizumab pegol)

    (2009)
  • Simponi (golimumab)

    (2009)
  • Y. Yazici et al.

    Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy

    Bull NYU Hosp Joint Dis

    (2008)
  • I.B. McInnes et al.

    Cytokines in the pathogenesis of rheumatoid arthritis

    Nat Rev Immunol

    (2007)
  • R. Fleischmann et al.

    Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis

    Expt Opin Biol Ther

    (2004)
  • D.J. Todd et al.

    Abatacept in the treatment of rheumatoid arthritis

    Int J Clin Pract

    (2007)
  • V. Strand et al.

    Improved health-related quality of life with effective disease-modifying antirheumatic drugs: evidence from randomized controlled trials

    Am J Manag Care

    (2007)
  • S.B. Cohen et al.

    Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

    Arthritis Rheum

    (2006)
  • M.C. Genovese et al.

    Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition

    N Engl J Med

    (2005)
  • L.W. Moreland et al.

    Etanercept therapy in rheumatoid arthritisA randomized, controlled trial

    Ann Intern Med

    (1999)
  • M.E. Weinblatt et al.

    Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

    Arthritis Rheum

    (2003)
  • W.J. Shergy et al.

    Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis

    J Rheumatol

    (2002)
  • D.T. Felson et al.

    The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trialsThe Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials

    Arthritis Rheum

    (1993)
  • E.C. Keystone et al.

    Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

    Arthritis Rheum

    (2004)
  • L.B. Van de Putte et al.

    Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

    Ann Rheum Dis

    (2004)
  • G.J. Wolbink et al.

    Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis

    Arthritis Rheum

    (2006)
  • Cited by (228)

    • Rationally engineered novel AAV capsids for intra-articular gene delivery

      2024, Molecular Therapy Methods and Clinical Development
    • Cannabidiol (CBD) and potential in medicinal use in rheumatoid arthritis

      2023, Medicinal Usage of Cannabis and Cannabinoids
    • Rheumatic diseases: From bench to bedside

      2023, Translational Autoimmunity: Volume 6: Advances in Autoimmune Rheumatic Diseases
    View all citing articles on Scopus
    View full text