NEW AND EMERGING THERAPIES FOR RHEUMATOID ARTHRITIS

VOLUME 30 • NUMBER 2 • MAY 2004 v

CONTENTS

Preface xiJoel M. Kremer

Safety Overview of New Disease-Modifying Antirheumatic Drugs 237John J. Cush

Beginning in 1998, a surge of new agents has expanded treatmentoptions for rheumatoid arthritis (RA) patients. Although the disease-modifying potential of these agents is encouraging, their use must beweighed against an evolving array of new safety concerns. Becauseof the popularity of these agents with patients and rheumatologistsalike, clinicians must be prepared to discuss the potential risks asso-ciated with novel disease-modifying antirheumatic drugs and bio-logic therapies as they begin to appear with greater frequency inpractice. This article discusses the safety issues arising from clinicaltrial and postmarketing experience with several new and commonlyused agents, with specific emphasis on adalimumab, etanercept,infliximab, anakinra, and leflunomide.

Consideration of the Risk and Treatment of Tuberculosis in Patients Who Have Rheumatoid Arthritis and Receive Biologic Treatments 257Jeffry Bieber and Arthur Kavanaugh

Evidence supports the association of tuberculosis (TB) with tumornecrosis factor inhibitor therapy in patients who have rheumatoidarthritis. There seem to be differential risks of TB with the cur-rently available inhibitors. Screening for latent TB infection withpurified protein derivative is indicated for patients who are beingconsidered for treatment; it seems to be effective in reducing theoccurrence of TB in treated patients.

Associations Between Rheumatoid Arthritis and Malignancy 271Eliza F. Chakravarty and Mark C. Genovese

There are many complex associations between rheumatoid arthri-tis (RA) and malignancy. Patients with rheumatic diseases on thewhole appear to be at increased risk for the development of certain malignancies. The data from several studies are persuasivethat the presence of RA conveys an increased risk for the devel-opment of lymphoproliferative disorders and may convey adecreased risk for the development of malignancies of the diges-tive tract. Understanding the complex interrelationships betweenRA and malignancy will lead to more accurate diagnosis of under-lying pathology, more effective treatment of symptoms andunderlying disease, and appropriate surveillance for the develop-ment of later complications.

Overview of Radiologic Efficacy of New Treatments 285D.M.F.M. van der Heijde

Randomized, double-blind trials on new treatments, includinganakinra, etanercept, infliximab, and leflunomide, show convincingreduction in radiographic progression. The relative efficacy of thesenew treatments is unknown. Head-to-head comparisons have notbeen performed and comparing treatment arms across trials hasseveral pitfalls. These possible pitfalls are discussed.

Leflunomide 295Grant W. Cannon and Joel M. Kremer

Leflunomide is a low-molecular weight, synthetic, oral agentspecifically developed for immunosuppression. Because of activityin animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomidereduces the clinical symptoms and signs of RA, improves health-related quality of life, and retards structural damage. Leflunomidehas been evaluated in RA patients as monotherapy and in combi-nation with methotrexate. Close monitoring for adverse eventswith particular attention for monitoring liver enzymes for hepatictoxicity is important during treatment with leflunomide.

Treatment of Rheumatoid Arthritis with Etanercept 311Mark C. Genovese and Joel M. Kremer

Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed signifi-cantly when the drug was used for a 24-month period and was sta-tistically significantly better than MTX. In addition to its use in RA,

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etanercept is approved by the U.S. Food and Drug Administrationfor other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.

Infliximab Treatment of Rheumatoid Arthritis 329Sir Ravinder Maini

Infliximab was the first anti-TNF agent used to treat rheumatoidarthritis to provide proof of concept of the role of TNF-α in this condition. It has become widely used since, principally as an effectivetreatment in combination with methotrexate, but also as monother-apy for the treatment of Crohn’s disease, ankylosing spondylitis,and psoriatic arthritis. The benefits of infliximab in controllingsigns and symptoms, improving quality of life, preventing struc-tural joint damage, and possible healing of bone provide an impor-tant option for the treatment of rheumatoid arthritis.

Adalimumab Therapy in Rheumatoid Arthritis 349Edward Keystone and Boulos Haraoui

Adalimumab is a recombinant human immunoglobulin G1 mono-clonal antibody that is specific for human tumor necrosis factor.Based on the data presented in this article, adalimumab adminis-tered alone or in patients partially responsive to methotrexateexhibits a rapid onset of action, provides a substantial reduction insigns and symptoms, and results in an improvement in physicalfunction and health-related quality of life. Adalimumab has beendemonstrated to inhibit progression of structural joint damage in patients who have long-standing rheumatoid arthritis. Takentogether, the data support adalimumab as a new therapeutic optionfor patients with moderate to severe rheumatoid arthritis.

The Use of Anakinra, an Interleukin-1 Receptor Antagonist, in the Treatment of Rheumatoid Arthritis 365Stanley B. Cohen

Interleukin-1 (IL-1) is a primary cytokine that is involved in thepathogenesis of rheumatoid arthritis; it contributes to inflamma-tion and joint destruction. Anakinra (Kineret) is an IL-1 receptorantagonist that blocks the biologic activity of IL-1. It was approvedby the U.S. Food and Drug Administration (FDA) for the treatmentof rheumatoid arthritis in 2001. Anakinra is safe and effective in thetreatment of rheumatoid arthritis, both as monotherapy and incombination with other disease-modifying antirheumatic drugs.This article reviews the preclinical, clinical, and postmarketing dataon the safety and efficacy of anakinra in the treatment of rheuma-toid arthritis and focuses on the pivotal clinical trials that led toFDA approval.

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Cytotoxic T-Lymphocyte Antigen 4–Immunogolbulin in Rheumatoid Arthritis 381Joel M. Kremer

It is apparent that the potential to significantly affect the immuneresponse exists through artificial modulation of a system of mole-cules on the surface of T cells that has been designed to specificallyprovide on–off switches to support or abrogate the activation of Tcells. This approach holds considerable promise because it avoidstoxicities associated with cell lysis, while theoretically specificallyaffecting only those T cells, which are being continuously stimulatedto become activated. Although there is presently a paucity of studiesin humans on the clinical effects of cytotoxic T-lymphocyte antigen4–immunoglobulin in patients who have rheumatoid arthritis, theexisting studies indicate a clear therapeutic value with this approach.

B Lymphocyte Depletion Therapy with Rituximab in Rheumatoid Arthritis 393J.C.W. Edwards, M.J. Leandro, and G. Cambridge

B lymphocyte depletion therapy in rheumatoid arthritis can providemajor clinical benefits. Widespread use in the future will depend oncontinued evidence of safety, particularly in the context of long-term use. Rituximab is a highly effective agent, but it may be bestused in combination with other agents. Substantial improvementfollowing a single course of therapy has been found to last up to 42months, and it is reasonable to hope that further development ofstrategies targeting B cells will extend this toward the original aimof truly long-term remission.

Clinical Experience with Inhibition of Interleukin-6 405Ernest Choy

Rheumatoid arthritis (RA) is a systemic disease that is associatedwith increased mortality and morbidity. Prognosis depends on disease severity and response to treatment. Those patients whosediseases are refractory to treatment with disease-modifying anti-rheumatic drugs (DMARDs) and have persistent inflammationhave reduced survival similar to patients with triple-vessel coro-nary artery disease and Hodgkin’s lymphoma. Although DMARDsreduce inflammation and improve symptoms, they do not improvelong-term prognosis. Chronic synovial inflammation results indamage to the articular cartilage and adjacent bone. Consequently,after 10 years of disease most patients develop significant disabilitydue to joint damage. Interleukin-6 (IL-6) is a key mediator of inflam-mation in RA. Inhibition of IL-6 reduces synovitis and improvessymptoms. Therapies targeting IL-6 are promising new treatmentsfor RA.

Interleukin-18 and the Treatment of Rheumatoid Arthritis 417Charles A. Dinarello

Interleukin (IL)-18 is a new member of the IL-1 family of proin-flammatory cytokines. Based on preclinical studies in animals, IL-18likely plays a role in rheumatoid arthritis, and strategies to block IL-18 activity are underway in clinical trials. In one of these trials, a naturally occurring IL-18 binding protein (IL-18BP) binds IL-18with a high affinity and reduces disease severity in models ofinflammatory diseases. IL-18BP is not the soluble receptor for IL-18but rather a distinct molecule, which appears to be distantly relatedto the IL-1 receptor type II, both structurally and functionally, andhence represents part of the IL-1 family of receptors.

Index 435

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