Changing Management of Rheumatoid Arthritis in Clinical Practice: New Data, New Options
Author: E. William St. Clair, MD Writer: John A. Smith, PhD, FACSM Table of Contents Introduction Cytokines and the Inflammatory Response
Rationale for Anti-TNF Therapies
Clinical Trials of TNF-alpha Antagonist Therapies
Anti-TNF Therapy in the Clinic
The diagnosis of RA is based on clinical manifestations and the results of selected laboratory tests. Approximately 75% of patients will test positive for rheumatoid factor (an autoantibody reactive with the Fc portion of immunoglobulin G [IgG]), but this finding may not be present during the first year of disease. Furthermore, rheumatoid factor is not specific for rheumatoid arthritis and is found in 5% of healthy individuals. The erythrocyte sedimentation rate is increased in most patients with RA, and C-reactive protein, another acute phase reactant, is typically elevated in patients with active disease. X-rays of the hands and feet, or possibly other joints, may be useful in some cases, demonstrating periarticular bony demineralization, joint space narrowing, and bony erosions.
There is no cure for RA. Since the cause of the disease is unknown, current therapies are directed toward suppression of the inflammatory response. Like most chronic arthritides, the goal of treatment is to preserve joint function and limit disease progression. The medication list of a patient with active RA may include a nonsteroidal anti-inflammatory drug (NSAID), a low dose of prednisone (eg, 5-10 mg/d), and one or more disease-modifying antirheumatic drugs (DMARDs). Physicians may choose from a variety of effective DMARDs, such as hydroxychloroquine, sulfasalazine, leflunomide, methotrexate (MTX), and cyclosporine. Recent studies indicate that patients with active RA develop significant joint damage during the first few years of disease. This knowledge has led to a more aggressive treatment approach using combinations of DMARDs.
However, combination DMARD therapy does not completely abrogate disease activity and may result in serious drug-related complications. Moreover, most patients still develop joint erosions despite aggressive treatment.
The most commonly prescribed DMARD is MTX. It is prescribed commonly as a single DMARD and increasingly in combination with other DMARDs. Low-dose MTX therapy, administered weekly, inhibits DNA and RNA synthesis, accounting for its antiproliferative effects, and stimulates the release of adenosine, a mediator with anti-inflammatory activity. In a survey of 645 members of the American College of Rheumatology (ACR), MTX was rated the most effective DMARD after 1 and 4 years of treatment; 90% of respondents rated it as excellent after 1 year and 65% after 4 years. Adverse effects of MTX include nausea, diarrhea, fatigue, mouth ulcers, and hematologic suppression. Rarely, patients may develop a pneumonia-like reaction or cirrhosis.
Methotrexate is usually initiated at a dose of 7.5 to 10 mg per week. The dose is increased as tolerated during the next several months, up to 20 to 25 mg per week. However, lower MTX doses should be prescribed to the elderly and those patients with mild renal dysfunction; MTX should not be given to patients with a serum creatinine level higher than 2.5 mg/dL. The ACR has established guidelines for monitoring patients receiving MTX, recommending that blood cell counts and liver enzymes be assessed at 4- to 8-week intervals.
The relatively recent discovery and characterization of cytokines -- and our understanding of their part in the inflammatory cascade -- has prompted research on the role of cytokines in the pathogenesis of RA. A widely accepted model for the pathogenesis of RA includes a step in which an unknown arthrogenic antigen is presented to CD4+ T cells. Activated CD4+ T cells are presumed to incite macrophages to produce proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1). These cytokines play a major part in stimulating the inflammatory response.
Overactivity of TNF has been associated with synoviocyte proliferation, neo-angiogenesis, the recruitment of inflammatory cells, and the production of degradative enzymes. These findings have stimulated the development of anticytokine therapies. Further investigation has shown that the signs and symptoms of RA can be abrogated when certain proinflammatory cytokines, such as TNF and IL-1, are neutralized by monoclonal antibodies, naturally occurring cytokine antagonists, or cytokine receptor blockers.
For example, initial phase 1 and 2 studies have shown that TNF-alpha antagonists afford beneficial treatment effects in patients with RA, and these results have been confirmed in larger clinical trials.[12-15] In fact, the TNF-alpha monoclonal antibody infliximab (Remicade, Centocor, Malvern, Pa), has just been approved for use in combination with MTX for the treatment of RA. Etanercept (Enbrel, Wyeth Ayerst, Philadelphia, Pa) is similarly approved, both as monotherapy and in combination with MTX. Both drugs appear to have similar efficacy in reducing joint tenderness and swelling, but they have not been directly compared in a clinical trial.
The pharmacology and clinical use of these new agents in the treatment of RA were discussed at a symposium held during the recent annual meeting of the ACR.
Cytokines and the Inflammatory Response
Many features of RA can be explained by excess synthesis of TNF-alpha. TNF-alpha either directly or indirectly stimulates macrophages to produce other proinflammatory mediators, such as IL-1, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and nitric oxide. TNF-alpha also induces secretion of chemokines (molecules that attract immune cells to an inflammatory tissue site) and upregulates the expression of adhesion molecules on the surface of endothelial cells, bringing more lymphocytes and other inflammatory cells to the affected joint. In addition, TNF-alpha promotes the secretion of matrix metalloproteinases (degradative enzymes) by synovial fibroblasts and the activation of osteoclasts, causing damage to articular cartilage and bone. The acute phase response, as reflected by a high erythrocyte sedimentation rate and serum C-reactive protein level, occurs in patients with active RA as a consequence of abundant TNF-alpha production.
Rationale for Anti-TNF Therapies
Clinical trials of anti-TNF therapies have demonstrated clinical efficacy in the treatment of RA. These clinical benefits include a reduction in acute phase reactants and rheumatoid factor titers as well as normalization of hemoglobin and platelet counts. These improvements in clinical laboratory parameters result directly or indirectly from neutralization of excessive TNF-alpha.
Clinical Trials of TNF-alpha Antagonist Therapies
Infliximab is a chimeric TNF-alpha monoclonal antibody approved for the treatment of Crohn disease and more recently, RA. The molecule consists of the Fc region of human IgG and the Fab, or antigen-binding sequences, of a mouse anti-TNF-alpha antibody. The antibody neutralizes unbound TNF-alpha. Studies in vitro suggest that infliximab may also act by dislodging TNF-alpha already bound to cells as well as inducing cytolysis of TNF-alpha expressing cells. In clinical studies, infliximab has been shown to reduce synovial tissue levels of TNF, IL-1, IL-6, and IL-8, decrease factors that stimulate angiogenesis, and diminish synovial leukocyte infiltration.
These biological effects explain, at least in part, the encouraging results seen in clinical trials. In one study, multiple infusions of infliximab at doses of 3 and 10 mg/kg (either alone or in combination with MTX) ameliorated the signs and symptoms of RA, and infliximab was well-tolerated. For example, when infliximab at a dose of 10 mg/kg was added to 7.5 mg per week of MTX, the numbers of tender and swollen joints decreased by 70%.
Although TNF-alpha is the focus here, promising results have also been obtained with antagonists of IL-1 and IL-6. In contrast, investigations of anti-T cell strategies have largely been disappointing. Further trials with other anti-inflammatory cytokines and anti-adhesion molecules are awaited.
ATTRACT enrolled 428 patients from 34 centers in the United States, Canada, and Europe. Patients were eligible for this trial if they had active disease (6 or more tender and swollen joints) despite MTX doses of more than 12.5 mg per week. They were randomly allocated into 5 treatment groups: MTX alone; MTX plus 3 mg/kg of infliximab every 4 or 8 weeks; or MTX plus 10 mg/kg of infliximab every 4 or 8 weeks (Figure 1). At baseline, most patients were also receiving NSAIDs (74%) and corticosteroids (61%). DMARDs other than MTX were not allowed and, if necessary, withdrawn before beginning study treatment. The 5 treatment groups were comparable with respect to age (median, 54 years), gender distribution (78% were women), disease duration (8-9 years), functional class, number of swollen and tender joints, and levels of C-reactive protein (Figure 2a, 2b, 2c).
Table 3. Summary Results of the ATTRACT Trial a.. All infliximab treatment regimens in combination with MTX effectively reduced the signs and symptoms of RA for 54 weeks.
b.. The group treated with 3 mg/kg of infliximab every 8 weeks had a significantly lower proportion of ACR 50 responders than the other infliximab treatment groups, suggesting some patients may require greater than the 3 mg/kg dose to obtain maximal clinical benefit.
c.. All infliximab regimens significantly delayed the progression of joint damage compared with MTX alone, with most infliximab-treated patients showing no radiographic progression during 54 weeks.
d.. Treatment with infliximab plus MTX was well tolerated and did not cause a higher rate of serious infections than MTX alone.
Infliximab was well tolerated and produced no serious adverse effects (Figure 4). The frequency of adverse effects was similar across all treatment groups, including serious bacterial infections. Infusion reactions were infrequently observed; they were generally mild and clinically manageable. Typically, itching, rash, or hives are treated with an oral dose of 25 to 50 mg of diphenhydramine and 650 mg of acetaminophen, and in moderately severe cases, by slowing the infusion rate and subsequent clinical monitoring. If the patient develops respiratory difficulties, then the infusion should be stopped and the patient treated with 50 mg of intravenous diphenhydramine and supplemental oxygen. The infusion should also be stopped in the event of a severe anaphylactic reaction, and the patient treated with epinephrine.
Anti-TNF Therapy in the Clinic
Postmarketing surveillance, although subject to individual reporting biases, has noted 6 deaths due to infection in individuals receiving etanercept. These patients all had significant comorbid risk factors for infection, including chronic cutaneous ulcers, diabetes, congestive heart failure, renal insufficiency, and extra-articular manifestations of RA. Other reports document injection or infusion site reactions with both etanercept and infliximab; these have been mild and generally not led to cessation of treatment.
Clinical guidelines and precautions have been developed for administering infliximab and handling infusion reactions, including the use of trained personnel, a dedicated area for infusion, and the availability of emergency equipment, including life support. Protocols in the event of a reaction have also been established (Figure 5a, 5b, 5c). Ongoing phase 4 trials (ACCENT for patients with Crohn disease and PROMPT for patients with active RA) continue to investigate the efficacy and safety of infliximab in the clinic setting. For example, the PROMPT trial involves physicians in more than 100 community rheumatology practices who will enroll up to 1000 patients with active RA despite MTX therapy. These patients will receive 3 mg/kg of infliximab at weeks 0, 2, 6, and 14 and will be monitored for clinical response and possible adverse effects. This trial will provide rheumatologists in private practice with an opportunity to gain experience with infliximab.
Clinical studies have demonstrated that combination therapy with MTX and infliximab prevents radiologic progression of joint damage in patients who would have likely progressed taking MTX alone. Whether these encouraging results will persist in longer-term follow-up remains unknown, but such a prospect is exciting and provides a new perspective for the future development of RA therapies. However, while we await this longer-term follow-up data, our optimism must be tempered by unanswered questions about the long-term safety of these agents.
Another serious concern relates to cost. Etanercept and infliximab are more expensive than conventional DMARDs, and their routine use would have major economic implications for managed care organizations, other insurers, and society as a whole. Whether appropriate use of these biologics can produce ultimate cost savings remains an important question. Identifying patient-related factors that predict responsiveness to anti-TNF therapies will be an area of future research and may potentially allow these agents to be used more cost-effectively. Meanwhile, clinicians and their patients have embraced these new agents, and the agents are likely to assume a prominent role in the treatment of RA. A reasoned perspective of their true impact awaits further clinical experience and study over the next few years.
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