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Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis
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     This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations.

    Rheumatoid arthritis developed in a 25-year-old woman, who was found to have a positive rheumatoid factor (150 IU per milliliter); she had no periarticular radiologic erosions or extraarticular disease. Oral methotrexate was started and incrementally increased to 20 mg weekly. Subsequently, sulfasalazine (Salazotyrin, Pharmacia; Azulfidine, Pfizer) was added and gradually increased to 2 g daily. Despite six months of combination therapy, she had 10 swollen and tender joints and an elevated erythrocyte sedimentation rate (54 mm per hour). Twelve months after onset, we were asked to evaluate her for possible tumor necrosis factor (TNF) inhibitor therapy.

    The Clinical Problem

    Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis. RA occurs worldwide, and 75 percent of those affected are women. Its prevalence among adults is approximately 1 percent but varies across racial and ethnic groups, reflecting the prevalence of predisposing genes such as the HLA-DR4 allele.

    Joint destruction, characterized by progressive bone erosion, is the dominant cause of disability in RA. A minority of patients have extraarticular features such as rheumatoid nodules and lung disease. RA is associated with increased risks of coronary artery disease, infection, and lymphoma as well as reduced life expectancy.1

    Patients with RA and society at large incur substantial direct and indirect costs for medical and social care and for loss of employment. One systematic review of the costs of RA that predated the introduction of "biologic" therapies showed very high costs — $98 million to $122 million per million population — that were similar in developed nations.2

    Pathophysiology and Effect of Therapy

    The cause of RA is unknown, but a current model3 is shown in Figure 1. It is likely that, in genetically predisposed persons, an infective agent or another stimulus binds to toll-like receptors on peripheral dendritic cells and macrophages. This triggers a rapid response by the innate immune system involving cytokines and other inflammatory mediators, complement, natural killer cells, and neutrophils.

    Figure 1. Pathophysiological Role of Cytokines and Other Mediators and Their Inhibitors in RA.

    In the current model of the pathogenesis of RA, an infective agent or other stimulus binds to receptors on dendritic cells, activating the innate immune system. Dendritic cells migrate into lymph nodes, presenting antigen to T cells, which are activated by the dual signal of antigen presentation and costimulation through CD28. Activated T cells proliferate and migrate into the joint. In the synovial tissue, T cells produce interferon- and other proinflammatory cytokines that stimulate macrophages and fibroblasts as well as chondrocytes, osteoclasts, and B cells. Activated macrophages and fibroblasts release a variety of cytokines, including TNF-. TNF- is a central component in the cascade of cytokines, stimulating the production of additional inflammatory mediators and the further recruitment of immune and inflammatory cells into the joint. Infliximab and adalimumab are monoclonal anti–TNF- antibodies that bind to TNF- with high affinity and prevent it from binding to its receptors. Etanercept is a fusion protein consisting of two p75 TNF receptors that are linked to the Fc portion of human IgG1. It also binds to TNF- and prevents it from interacting with its receptors on cell surfaces.

    Dendritic cells then migrate to lymph nodes, where they activate the adaptive immune system by presenting antigen to T cells. T-cell activation requires two signals: signal 1 is generated by antigen (major-histocompatibility-complex–bound peptide on the antigen-presenting cell stimulates the T-cell receptor), whereas signal 2 is generated by CD28 costimulation (CD80 or CD86 on the antigen-presenting cell interacts with CD28 on the T cell). These activated T cells proliferate and migrate into the joint, where they stimulate a multimolecular immune–inflammatory cascade.

    T cells produce interferon- and other proinflammatory cytokines, which stimulate macrophages, fibroblasts, chondrocytes, and osteoclasts. Activated macrophages and fibroblasts release tumor necrosis factor (TNF-), interleukin-1, interleukin-6, interleukin-15, interleukin-18, and other proinflammatory cytokines that stimulate the production of additional inflammatory mediators (chemokines, prostaglandins), proteases, and growth factors and activate neutrophils, B cells, and endothelial cells. This endothelial transformation perpetuates the immune response by enhancing cell recruitment to the joint. Finally, joint damage, associated with the development of locally invasive pannus tissue, occurs through the actions of proteases, growth factors, and activated osteoclasts.

    TNF-, a central component in the cascade of cytokines induced in RA, exerts its effects through binding to two receptors, the type 1 TNF receptor (p55) and the type 2 TNF receptor (p75), which are found on immune, inflammatory, and endothelial cells. The rationale for choosing TNF- as a target is that it is found in high concentration in the rheumatoid joint, that in vitro experiments have shown that it induces other (inflammatory) cytokines in the synovial cytokine network, and that in experimental models arthritis is suppressed by TNF inhibitors.

    TNF inhibitors were first licensed for clinical use in 1998; three have been approved for the treatment of RA (Figure 1). Infliximab (Remicade, Centocor) is a chimeric (human–murine) IgG1 anti–TNF- antibody that is administered intravenously. It binds with high affinity to soluble and membrane-bound TNF- and inhibits its effect by blocking TNF-–receptor interactions. Unlike the other agents, infliximab is also cytotoxic for TNF-expressing cells. Etanercept (Enbrel, Amgen and Wyeth) is a recombinant soluble p75 TNF receptor:Fc fusion protein given subcutaneously. It is a dimer of covalently bound receptors of the higher-affinity type 2 TNF receptor (p75) linked to the Fc portion of human IgG1. Etanercept binds to TNF-, preventing it from interacting with its receptor; unlike the other two agents, it also targets TNF- (lymphotoxin). Adalimumab (Humira, Abbott) is a recombinant humanized monoclonal anti–TNF- antibody that is administered subcutaneously. It binds to human TNF- with high affinity and, as a consequence, stops the cytokine from binding to its receptors.

    Clinical Evidence

    TNF inhibitors have been evaluated in a series of randomized, controlled trials enrolling nearly 6000 patients with RA.4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 In most of the trials, these agents were studied in comparison with, or in addition to, methotrexate. In five such trials, patients with early RA who had not been treated with methotrexate were studied, whereas in six others, patients with established RA who had not had a response to methotrexate were studied.

    The clinical response to treatment of RA is often assessed by determining how frequently patients achieve substantial clinical improvement with therapy. One standard measure of improvement is the proportion of patients who have 70 percent or greater improvement according to seven clinical and laboratory measures of disease activity according to the American College of Rheumatology (ACR). Such patients are designated as having ACR-70 responses. ACR-70 responses were found in 19 to 21 percent of patients receiving methotrexate monotherapy in trials in early RA but in 33 to 40 percent of those receiving TNF inhibitors combined with methotrexate. In established RA, ACR-70 responses occurred in fewer than 5 percent of patients receiving methotrexate monotherapy but in 10 to 27 percent of those receiving TNF inhibitors combined with methotrexate.

    TNF inhibitors substantially reduce the erosive damage assessed on radiography19 and with magnetic resonance imaging.20 They also decrease the disability self-assessed with the use of instruments such as the Health Assessment Questionnaire21 and improve the quality of life assessed with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey.22 Patients describe highly positive overall effects.23

    In early and established RA, TNF inhibitors in combination with methotrexate, the most widely used disease-modifying antirheumatic drug (DMARD), are more effective than monotherapy with either methotrexate or a TNF inhibitor. A crucial question is whether TNF inhibitors combined with methotrexate are better than combinations of established DMARDs. Since there has been only a single head-to-head study,17 which showed only a modest benefit, the question is largely unanswered.

    Clinical Use

    Treatment of RA is typically initiated with nonsteroidal antiinflammatory drugs and simple analgesics to relieve pain and stiffness. DMARDs, which improve symptoms and reduce erosive damage, are initiated as early as possible. Standard conventional DMARDs include methotrexate, sulfasalazine, leflunomide (Arava, Aventis), hydroxychloroquine (Plaquenil, Sterling Winthrop), and cyclosporine (Sandimmune, Novartis); methotrexate is the most widely used. There is increasing emphasis, especially in severe disease, on using combinations of two or more conventional DMARDs.24 Steroids (intraarticular, intramuscular, or oral) are often used to manage disease flares.

    TNF inhibitors are usually given to patients with active RA in whom there has not been a satisfactory response to one or more conventional DMARDs such as methotrexate. Views differ on what constitutes active RA.25 One definition is six or more tender and three or more swollen joints together with either an erythrocyte sedimentation rate greater than 30 mm per hour or at least 45 minutes of morning stiffness. Another definition is a disease activity score of more than 5.1 (range of scores, 0 to 10, with higher scores indicating more active disease), although some experts have expressed concern about the inherent variability of these scores.26 Many rheumatologists rely on clinical opinion alone.

    The concept of treatment failure with DMARDs is also inadequately defined. Many rheumatologists use clinical opinion alone, whereas others rely on predetermined definitions. In the United Kingdom, such failure is defined as "failure to respond to or tolerate adequate therapeutic trials of at least two standard DMARDs," with an adequate therapeutic trial involving at least six months of therapy unless limited by significant toxic effects.27 This strict definition is not universally accepted.

    Prior to the initiation of TNF inhibitor therapy, patients should be screened for latent tuberculosis, and antituberculosis prophylaxis should be considered for patients at risk.28 Patients should also be evaluated for evidence of other preexisting infections, which may constitute contraindications to treatment. TNF inhibitors should probably be avoided in the presence of certain chronic infections such as with hepatitis B; however, etanercept has been used safely in small series of patients with hepatitis B and hepatitis C infections. Practitioners should exercise extreme caution when considering whether to prescribe a TNF inhibitor for a patient with a coexisting infection and seek expert advice. Live vaccination is contraindicated in patients receiving TNF inhibitors as well as in those taking some other DMARDs such as methotrexate; where an alternative nonlive vaccine is not available, consideration should be given to vaccination before starting TNF inhibitor therapy.

    Other precautions that should be taken before commencing TNF inhibitors include ruling out significant concomitant illness (including those noted in the section on Adverse Effects). Although initial complete blood counts and biochemical profiles are not mandatory, they are generally used to rule out serious coexisting diseases and because patients taking DMARDs such as methotrexate require blood monitoring.

    There are no clinical trials comparing one TNF inhibitor with another. The choice of agent therefore depends on other factors, including patients' convenience, access to treatment, and patients' preferences. Infliximab requires infusion intravenously every four to eight weeks performed by a health care professional. The usual dose is 3 mg per kilogram of body weight; some patients require higher doses. Infliximab is given with methotrexate to prevent the formation of human antichimeric antibody (HACA), since HACA increases the likelihood of infusion reactions and accelerates infliximab clearance. Etanercept and adalimumab are self-administered by subcutaneous injection. Etanercept is given at a dose of 25 mg twice weekly or 50 mg weekly, and adalimumab is given at a dose of 40 mg every two weeks. Although concomitant methotrexate therapy is not essential with the use of these agents, combination therapy is more effective and is now recommended for adalimumab, unless there are contraindications.

    As noted, TNF inhibitors have been studied primarily in comparison with, or in addition to, methotrexate. There are no trial data on the use of TNF inhibitors with other conventional DMARDs, but observational studies suggest that this is practical and effective when methotrexate cannot be used. The combination of TNF inhibitors with new biologic agents such as anakinra (Antril, Synergen) (an interleukin-1–receptor antagonist) and abatacept (Orencia, Bristol-Myers Squibb) (a T-cell–costimulation inhibitor) is not recommended, since studies have shown an increased risk of serious infections.

    DMARDs such as methotrexate require routine safety monitoring to detect blood and liver toxicity, and monitoring should continue when these agents are prescribed along with TNF inhibitors. Although there are no specific monitoring requirements for the use of TNF inhibitors, patients should regularly undergo assessment for clinical evidence of serious side effects such as infection and should be warned to contact a physician immediately in the event of fever or other symptoms of infection.

    TNF inhibitors are expensive, with annual costs ranging from $10,000 to $25,000 or more per patient, depending on the circumstances and the country. Data supplied by the manufacturers suggest that TNF inhibition is cost-effective according to a commonly applied threshold of $50,000 per quality-adjusted life-year gained.29,30 However, reports commissioned by regulators and reports based on independent data both suggest that they are substantially less cost-effective.31,32 The relative expense of TNF inhibitors makes their universal use impractical. Conversely, cost-effectiveness studies cannot examine the moral case for ensuring that they remain a potential treatment option.

    Treatment with TNF inhibitors should be stopped if there is evidence of drug-related toxic effects or no evidence of efficacy within three to six months. The definition of clinical efficacy is also contentious. One European view suggests that a fall in the score for disease activity of more than 1.2 indicates efficacy. If treatment with one TNF inhibitor is stopped because of inefficacy or an adverse event, there is some evidence that an alternative TNF inhibitor can be effective. Temporary withdrawal of treatment is also required with severe intercurrent infection and in the event of pregnancy. Many experts recommend temporarily stopping TNF inhibitors at the time of surgery because of concern about infections, although the evidence for doing so is incomplete.

    Adverse Effects

    Common minor adverse events include injection-site reactions with etanercept and adalimumab and infusion reactions with infliximab.33 Rare serious adverse events include optic neuritis, exacerbations of previously quiescent multiple sclerosis, aplastic anemia, and interstitial lung disease; lupus-like syndromes and hepatotoxicity may also occur.

    Serious infections are a particular concern,34,35,36 especially respiratory and skin infections. TNF inhibitors should be stopped in the presence of serious infections. Susceptibility to intracellular pathogens may be increased, and primary tuberculosis and reactivation of prior tuberculosis are specific problems.37,38 As noted, patients should be screened for tuberculosis before the initiation of therapy.

    The overall risk of cancer is controversial. The only systematic review, which focused on randomized, controlled trials involving infliximab and adalimumab but not etanercept, reported a dose-related increased risk of cancer.36 In contrast, national registries have not yet found an increase in solid cancers after treatment with TNF inhibitors.39,40 An increase in lymphomas has been reported with all TNF inhibitors.36,41,42,43 However, because there is a preexisting association of lymphomas with severe RA and systemic inflammation,44 the exact contribution of therapy with TNF inhibitors is difficult to dissect. Given these uncertainties, it seems sensible to use extreme caution when considering the use of TNF inhibitors in many patients with a history of malignant disease, or even to avoid them altogether, and to warn patients that the risk of cancer with this form of therapy remains unknown. Table 1 summarizes the risks of serious infection and cancer.

    Table 1. Serious Adverse Events Associated with TNF Inhibitors.

    Since infliximab increases mortality when used to treat severe heart failure in patients without arthritis,45 TNF inhibitors should be used cautiously, if at all, when mild heart failure is present and are best avoided when heart failure is severe. However, there is no evidence that TNF inhibitors increase the risk of new-onset cardiac failure in patients with RA.46,47

    Patients are usually advised not to conceive while taking TNF inhibitors and to avoid these treatments during pregnancy or lactation. To date no actual adverse events have been described in those pregnancies that have occurred in patients taking TNF inhibitors.48

    Areas of Uncertainty

    Like other randomized, controlled trials in RA, trials of TNF inhibitors have enrolled patients with active RA. The generalizability of the results to patients with milder disease in routine practice remains contentious.24,49 Equally important is concern regarding adverse events. In the United Kingdom, Sweden, and other European countries, long-term national registries have not identified unexpected major toxic effects during the first five years of observation, but caution remains essential. Reducing TNF inhibitors when patients have a sustained good response appears to be rational, but its feasibility has not been examined in established RA and there is only minimal evidence in its favor in early RA.20

    The relative advantage of TNF inhibition compared with optimal combinations of conventional DMARDs has also not been adequately evaluated. Systematic reviews suggest small benefits of TNF inhibition.24 Only one randomized, controlled trial of early RA compared combination treatment including TNF inhibition with combination DMARDs.17 The study reported sustained low disease activity in 81 percent of patients treated with a TNF inhibitor plus methotrexate, as compared with 73 percent of patients who received optimal combination treatment with the use of methotrexate, sulfasalazine, and prednisolone, suggesting only limited benefit from TNF inhibition. In contrast, 39 percent of the patients treated with methotrexate monotherapy had sustained low disease activity.

    TNF inhibitors are not the immunologic "magic bullet" that cures RA; consequently, their use needs constant reassessment, especially as comparative data with combination DMARDs and new biologic agents become available. There is growing evidence that new biologic agents such as abatacept, rituximab (Rituxan, Genentech and Biogen Idec), and tocilizumab (Actemra, Roche) are effective and can be used in patients who do not have a response to TNF inhibition.

    Finally, these exciting advances in drug treatment should not obscure the contributions of nondrug treatment methods to the overall management of RA. These methods include education, exercise, psychological approaches, and joint-replacement surgery.

    Guidelines

    Many international groups,50 specialist societies,27,51 and regulatory bodies52 have produced guidelines for the use of TNF inhibitors in patients with RA. Most of these guidelines recommend that TNF inhibitors should be used in patients with active RA who have not had a response to conventional DMARDs, particularly methotrexate. Definitions of active RA and an inadequate response to DMARDs differ. A rigid approach, exemplified by British guidelines,52 requires that patients have no satisfactory response to two DMARDs before receiving TNF inhibitors. Other countries, including the United States, have adopted more flexible approaches.

    Recommendations

    Four evidence-based approaches have been considered. Since none of them were a definite best option, the advantages and disadvantages were explored with the patient described in the vignette. First, she could change from oral methotrexate to subcutaneous methotrexate, which is slightly more effective. Second, a new DMARD, such as leflunomide, could be used. Third, she could change to an evidence-based combination such as methotrexate–sulfasalazine–hydroxychloroquine or methotrexate–cyclosporine; aggressive combinations with high-dose prednisolone were not considered, because they have been studied only as initial treatment for early arthritis. Finally, the patient fulfilled U.K. guidelines for starting a TNF inhibitor, which was her preferred option. She started etanercept because she preferred frequent self-administration. She continued to take methotrexate at a dose of 20 mg weekly; sulfasalazine was stopped.

    Patient-related factors, such as convenience, acceptability to the patient, and risks (including risks to future pregnancy), and issues related to a patient's health care system, such as cost-effectiveness and access to treatment, all influence the decision of whether to start a TNF inhibitor and the choice of agent. We recommend that, since there is no clear best choice on medical grounds, priority should be given to the patient's preference from among the options available locally. Patients should be given sufficient information to allow them to make genuinely informed choices.

    Dr. Scott reports having received consulting fees from Novartis and Sumitomo Chemical and lecture fees from Wyeth, Sanofi-Aventis, Merck, and Novartis. His department has received funding for clinical trials from Pfizer, Q-Med, AstraZeneca, Sumitomo Chemical, and Roche and unrestricted clinical research grants from Amgen, Schering-Plough, and Sanofi-Aventis. His department also receives grants from the Arthritis Research Campaign (ARC), the Medical Research Council, the Nuffield Foundation, and the Myositis Support Group. Dr. Kingsley reports having received grants from the ARC and the Nuffield Foundation. No other potential conflict of interest relevant to this article was reported.

    Source Information

    From the Department of Rheumatology, Kings College London School of Medicine, Weston Education Centre, Kings College (D.L.S., G.H.K.); the Department of Rheumatology, Kings College Hospital (D.L.S.); and the Department of Rheumatology, University Hospital Lewisham (G.H.K.) — all in London.

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