Changing Management


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
  Cytokines and the Inflammatory Response 

Rationale for Anti-TNF Therapies

Clinical Trials of TNF-alpha Antagonist Therapies

ATTRACT Outcomes

Radiographic Data

Anti-TNF Therapy in the Clinic

Reimbursement Issues


Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting 1% of the US population (approximately 2.1 million people). Three quarters of those affected are women. Rheumatoid arthritis exacts a considerable toll on a patient's quality of life, causing pain and functional disability, with associated restrictions on household, family, and recreational activities. Limitations in work capacity and in some cases, unemployment, can have substantial economic ramifications for both individuals and society. Combined direct and indirect costs from RA in the United States are estimated at $19 billion per year.[1]   Rheumatoid arthritis is typically characterized by symmetrical pain and swelling of the small joints of the hands and feet. Virtually any other joint in the body may become affected by inflammation, including the large joints, such as the shoulders, knees, and hips, jaws, and cervical spine. Persistent joint inflammation often produces articular cartilage and bone destruction as well as permanent deformities.[2] The natural history of disease is described in years, but joint damage may occur as early as 3 to 6 months after onset. Although RA predominantly affects the joints, it is a systemic disease and may cause fatigue, low-grade fever, and involve other organ systems, including the eyes, lungs, and blood vessels. For example, RA may cause scleritis (inflammatory eye disease), pleuritis, interstitial pulmonary fibrosis, and vasculitis.


The diagnosis of RA is based on clinical manifestations and the results of selected laboratory tests.[3] 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.[4] 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.[5]


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.[5]


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.[6] 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.[7] 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[8]; 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.[9] 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.[10]


Overactivity of TNF has been associated with synoviocyte proliferation, neo-angiogenesis, the recruitment of inflammatory cells, and the production of degradative enzymes.[11] 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.[12]


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.[16]



Cytokines and the Inflammatory Response
Marc Feldmann, MD, of the Kennedy Institute of Rheumatology, London, England, reviewed the biology of cytokines. Cytokines are hormone-like molecules secreted by a variety of cell types. However, while hormones circulate in blood and primarily act at tissue sites across a distance, cytokines diffuse between cells, bind to receptors on cells of a different type, and modulate the activity of those cells, a so-called paracrine effect.   TNF-alpha is an important proinflammatory cytokine produced mainly by macrophages and, to a lesser extent, T cells. Most of the actions of TNF-alpha overlap with IL-1, another key proinflammatory cytokine. TNF-alpha is among the first cytokines secreted during an inflammatory response and it may influence the production and release of other proinflammatory mediators as well as inhibitory factors. The inflammatory response observed in RA creates a "cytokine disequilibrium" in which the proinflammatory forces outweigh the compensatory mechanisms attempting to keep the inflammation in check. Such cytokine dysregulation leads to the pathological changes associated with RA.


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
The importance of TNF-alpha in the pathogenesis of synovial inflammation -- and the less-than-optimal effectiveness of current treatments -- has made this cytokine an attractive target for antirheumatic drug therapy. Studies have shown that synovial inflammation is characterized by the upregulation of both TNF-alpha and its membrane-bound receptors, with the consequent biological responses listed above.[17] When synovial cells from RA patients are incubated in culture, they produce increased quantities of the proinflammatory cytokines TNF-alpha, IL-1, IL-8, and GM-CSF,[18,19] and neutralizing the TNF-alpha in culture by the addition of anti-TNF-alpha antibodies decreases the production of IL-1, IL-8, and GM-CSF. Thus, it was hypothesized and subsequently demonstrated that neutralization of a single cytokine, TNF-alpha, could profoundly suppress synovial inflammation.   In addition to its proinflammatory effects, TNF-alpha also stimulates the production of cytokine inhibitors.[20] These inhibitory factors are not sufficient to neutralize the abundant levels of proinflammatory cytokines, which dominate the synovial milieu. These endogenous inhibitors include receptor antagonists (IL-1RA), soluble receptors (sIL-1R, sTNF-alphaR), cytokine-binding proteins, and anti-inflammatory cytokines (IL-4, IL-10, TGF-alpha).[21] In RA, the synovial tissue has been shown to produce increased levels of IL-1RA and soluble TNF-alpha receptors. The synthesis of these endogenous inhibitors is blocked by anti-TNF, showing that TNF-alpha is also involved in the control of these counterregulatory responses.[22]


Clinical trials of anti-TNF therapies have demonstrated clinical efficacy in the treatment of RA.[13] These clinical benefits include a reduction in acute phase reactants and rheumatoid factor titers as well as normalization of hemoglobin and platelet counts.[11] These improvements in clinical laboratory parameters result directly or indirectly from neutralization of excessive TNF-alpha.



Clinical Trials of TNF-alpha Antagonist Therapies
Etanercept, a recombinant TNF-alpha receptor:Fc fusion protein, was the first anti-TNF drug approved for the treatment of RA. Etanercept binds to soluble TNF-alpha and prevents its interaction with the cell surface TNF-alpha receptor. The soluble TNF-alpha receptor would not be expected to recognize TNF-alpha once it binds to the cell surface. Proof that etanercept blocks soluble TNF-alpha in vivo comes from several clinical trials of patients with RA. In these studies, treatment with etanercept significantly reduced the signs and symptoms of RA, reduced functional disability, and improved quality of life.[4] Etanercept begins to diminish joint inflammation within 2 weeks of starting therapy, and maximal benefits are observed after approximately 3 months of treatment. Clinical improvement has been sustained using etanercept for up to 3 years.[23]   These clinical effects were exemplified by the results of a clinical trial in which etanercept therapy was compared with placebo in 234 patients with active RA who were not receiving conventional DMARDs.[24] Twice-weekly subcutaneous injections of 25 mg of etanercept produced an ACR 20% response (eg, at least a 20% reduction in the number of tender and swollen joints) in 62% of patients at 3 months compared with a 23% response rate in the placebo group. At 6 months, the ACR 20% response rate was 59% in the group receiving 25 mg of etanercept and 11% in placebo-treated patients, while 45% and 5% of patients, respectively, reached an ACR 50% response. Similar results were observed in a 6-month trial[20] in which 25 mg of etanercept twice weekly or placebo were added to maintenance MTX therapy in 89 patients who continued to show active RA.


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.[20]


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.[13] 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%.[13]


Although TNF-alpha is the focus here, promising results have also been obtained with antagonists of IL-1 and IL-6.[15] In contrast, investigations of anti-T cell strategies have largely been disappointing.[25] Further trials with other anti-inflammatory cytokines and anti-adhesion molecules are awaited.[25]



ATTRACT Outcomes
Peter E. Lipsky, MD, from the University of Texas Southwestern Medical Center in Dallas presented data from the Anti-TNF-alpha Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) at the ACR meeting.   Previous trials[13,26,27] have demonstrated the efficacy of infliximab infusions both with and without MTX therapy. The primary objective of ATTRACT was to investigate the long-term benefits of infliximab in combination with MTX. Patients received a minimum MTX dose of 12.5 mg per week; this design feature was meant to avoid the potential criticism that benefits attributed to infliximab could be achieved by increasing the dose of MTX. The optimal dose and dosing interval for infliximab would also be further evaluated in this trial. An important aim of the trial was to ascertain whether treatment with infliximab would significantly retard radiographic progression of joint disease, a determination requiring at least 12 months of treatment.


ATTRACT enrolled 428 patients from 34 centers in the United States, Canada, and Europe.[12] 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).




Figure 1.




Figure 2a.




Figure 2b.




   Figure 2c. At the end of the 54 weeks, 52% of the infliximab-treated patients had achieved an ACR 20% response, compared with 17% of MTX-only controls (P<.001). Improvement with infliximab treatment was also evident when comparing patient outcomes in terms of ACR 50% (33% vs 18%) and ACR 70% (18% vs 3%). Overall results are provided in Table 3.



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.




Figure 4.


Radiographic Data
Desiree van der Heijde, MD, from Maastricht University Hospital in the Netherlands presented radiographic results from the ATTRACT trial. Radiographs of hands and feet were obtained at baseline, week 30, and week 54. The radiographs were centrally digitized and scored independently for erosions and joint space narrowing (using the van der Heijde modification of the Sharp method) by 2 experienced readers who were unaware of the patient's identity, treatment allocation, film sequence, or any other clinical data. Radiographic data were obtained in 81% of the cases, and the data showed that infliximab in combination with MTX significantly slowed the progression of joint damage compared with MTX alone. All the infliximab dosage schedules were associated with superior radiologic outcomes compared with MTX alone. In fact, most patients receiving infliximab and MTX showed no radiographic progression of joint damage, demonstrating, perhaps for the first time, that prevention of joint damage is a realistic goal.


Anti-TNF Therapy in the Clinic
Current treatment regimens for RA using NSAIDs, corticosteroids and several DMARDs (MTX, cyclosporine, and sulfasalazine, among others) are only partially effective and associated with potential toxic effects. The anti-TNF therapies, while not free of adverse effects, have emerged as an important advance in RA therapy. Michael H. Weisman, MD, from the Cedars-Sinai Medical Center in Los Angeles, Calif, summarized the practical applications and comparative advantages of anti-TNF therapy at the ACR meeting. At the moment, clinical trial data suggest that infliximab and etanercept are similar in reducing clinical signs and symptoms and in safety profiles. No data have yet established that the addition of etanercept to therapeutic doses of MTX produces the same radiologic benefits as adjunctive treatment with infliximab.   In making treatment decisions, rheumatologists will need to weigh a variety of ancillary factors, including advantages and disadvantages of possible routes of drug administration, the patient's insurance benefits, staff expertise in administering infusions, and their ability to appropriately treat the rare emergencies that can occur during infusions and safety monitoring. Although no specific laboratory studies have been recommended for safety monitoring of patients during infliximab or etanercept therapy, these agents may potentially make infections worse or result in life-threatening infectious complications. Thus, physicians should avoid TNF-alpha therapy for patients at high risk for infection (eg, uncontrolled diabetes mellitus and cutaneous ulcers) and remain vigilant for signs of infection during this therapy. TNF-alpha blockade treatments should be temporarily halted in patients who develop a serious bacterial infection. Physicians would be wise to manage patients receiving anti-TNF-alpha therapy with caution until more information is available regarding the long-term risks of infection and malignancy.


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.




Figure 5a.




Figure 5b.




Figure 5c.


Reimbursement Issues
Neal S. Birnbaum, MD, of the University of California in San Francisco discussed reimbursement issues related to the use of these new drugs, particularly in managed care settings. The cost of these novel anti-TNF-alpha agents is considerably higher than conventional treatments, which range from approximately $25 to $300 per month. However, Dr Birnbaum suggested that this higher cost should be viewed in the context of potential reductions in hospitalizations, joint replacement surgeries, and the costs of treating medical complications of RA. Average medical care costs for RA have been estimated at $5919 per year,[28] which is somewhat lower than the annual cost of an approved anti-TNF therapy. Clearly, these expensive biologic therapies must also achieve a reduction in indirect costs to fully justify their routine use.   In the United States, about 70% of patients with RA have health insurance through managed care organizations. The nature of a patient's health plan determines who covers the cost of therapy. One concern is whether individuals in lower socioeconomic groups will have access to these newer agents. A recent study found that patients with socioeconomic deprivation had an almost 2-fold higher mortality rate from RA than more affluent patients.[29] Infliximab -- which costs approximately $7000 to $11,000 annually -- may be the only option for some Medicare patients who cannot afford oral and injectable drugs, such as etanercept, which are not now covered under this government plan. The indications are that infliximab will be covered under Medicare. Like RA, Crohn disease costs the economy more than $1.7 billion per year (of which hospitalizations and surgery account for 80%). TNF-alpha blockade therapy may not only increase quality of life in this clinical setting, but result in substantial cost savings.[30]



In an aging society, the incidence of arthritis will continue to rise, as will the toll that resulting functional disabilities exact on the quality of life of those affected by this disease. Elucidation of the role of cytokines in the proinflammatory cascade has stimulated a new wave of drug development aimed at lessening this toll, with TNF-alpha emerging as an important therapeutic target in RA.   Clinical studies have convincingly shown that inhibition of TNF-alpha significantly reduces the signs and symptoms of joint disease. These anticytokine strategies work by downregulating the production of proinflammatory cytokines, inhibiting angiogenesis, and interfering with leukocyte recruitment to joints. Etanercept and infliximab are both approved by the Food and Drug Administration for the treatment of RA and appear to be equivalent in controlling disease manifestations for up to 3 years, with excellent tolerability.


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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