Recent Advances in the Treatment of Rheumatoid Arthritis
Vibeke Strand, MD FACP,Clinical Associate Professor, Division of Immunology, Clinical Faculty, Stanford University, Palo Alto, California
[Clinical Cornerstone 2(2):38-47, 1999]
AbstractRheumatoid arthritis (RA) affects about 0.5% to 1% of the population worldwide. Because there is no cure for this disease, the goal of therapy is to control the underlying inflammatory process and maintain or improve function. This article reviews 4 new treatments for patients with RA: leflunomide, etanercept, infliximab, and the protein A immunoadsorption column with plasmapheresis therapy.
IntroductionRheumatoid arthritis (RA) affects approximately 0.5% to 1% of the population worldwide. Over time, RA results in significant disability due to persistent inflammation, involvement of periarticular tissue, and joint deformity. As no cure exists, the therapeutic goal is to control the underlying inflammatory process and maintain or improve function. Because it compromises or prevents patients from engaging in desired physical activities, RA impacts most aspects of daily living.
RA generally has been regarded as a "nonfatal" disease in most patients; however, studies of life expectancy have revealed that survival among patients with RA is approximately 3 to 18 years shorter than that of the general population[1,2]. A prospective analysis of the long-term outcomes of 112 RA patients treated with disease-modifying antirheumatic drugs (DMARDs) over a 20-year period showed higher mortality rates than those for the general population. A 25-year follow-up of survival and cause of death in 209 patients with RA reported median life expectancy to be shortened by 7 years in men and 3 years in women.
The treatment of RA has been influenced by a "therapeutic pyramid" for the past 25 years. Initial treatment choices included education, rest alternating with activity, occupational as well as physical therapy, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs), which are also analgesic and have a rapid onset of effect. Over time patients usually try many different NSAIDs. If beneficial, they are continued until side effects or lack of efficacy limit further use. Low-dose corticosteroids (<=10 mg prednisone daily) are also frequently used, and often patients continue taking these for many years. The traditional pyramid suggests the use of DMARDs as the next approach. However, following documentation of poor long-term outcomes observed in patients treated with NSAIDs alone, DMARDs have progressively been used earlier in the disease course, making the term "second-line treatment agents" obsolete[5,6].
The "step-down bridge" approach to RA management focuses on early introduction of DMARD therapy. Using this philosophy, patients receive aggressive DMARD therapy (ie, combination therapy) early in the course of their disease, followed by less aggressive regimens (eg, dose tapering or discontinuation of more toxic agents) to maintain therapeutic benefit and prevent disease progression. A prototypic step-down bridge approach was evaluated in a 56-week, double-blind, randomized, multicenter trial that compared early combination therapy with sulfasalazine, prednisone, and methotrexate with sulfasalazine therapy alone in 155 patients with RA. Results of this trial indicated that early combined DMARD therapy immediately suppressed progression of radiologic damage, while sulfasalazine alone was less effective than combined therapy and had a more delayed onset of treatment effect (6 to 12 months).
The American College of Rheumatology (ACR) has established clinical guidelines for the management of RA. All patients whose RA remains active despite treatment with NSAIDs should be considered candidates for DMARD therapy. Initiation of therapy should not be delayed beyond 3 months for patients who have the following ongoing symptoms with NSAID therapy: joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels.
Given that the onset of RA peaks at ages 40 to 50 years, patients will suffer, on average, at least 20 to 30 years of active disease and its consequences. Currently available therapies are beneficial but not curative, and they can be safely and effectively administered for only a portion of this total disease duration. It is estimated that at a minimum, 50% of patients initiating DMARD therapy will discontinue treatment in <5 years; most are discontinued within 2 years. Using meta-analyses, the median time when 50% of patients have discontinued treatment with a given DMARD, excluding methotrexate, ranged from 1.1 to 2.3 years. The shortest treatment durations were reported with sulfasalazine and auranofin therapy; the longest was seen with azathioprine; hydroxychloroquine, penicillamine, and intramuscular gold produced intermediate duration times. Median survival time for treatment with methotrexate in this analysis was 4.6 years, longer than the other comparators, which confirmed the results of an earlier meta-analysis.
The relatively long treatment time with methotrexate administration reflects the perception that it is the "gold standard," the strongest DMARD currently available with the best risk-benefit profile. A recent survey of the preferences of rheumatologists from Canada and the United States regarding therapy of RA patients with moderate or aggressive disease confirms this impression. Frequently, methotrexate is used in combination with other DMARDs[13,14]. Despite the better apparent tolerability of methotrexate administration, treatment requires regular monitoring of hematologic variables and hepatic transaminase levels, and yearly chest radiographs. Treatment-associated toxicities specific to methotrexate are rare but include interstitial pneumonitis and reversible renal failure, usually in the context of concomitant NSAID administration.
Recognition of this large
"unmet need" led to renewed interest in developing new treatments for
RA. Over the past decade, an international consensus effort has developed a core
set of outcome measures for evaluation of all proposed therapies. The ACR
response criteria combine these measures into a single composite definition of a
patient as a "responder" or a "nonresponder." A minimum of
20% improvement is required in both the traditional measures of tender and
swollen joint counts, as well as in 3 of the following 5 items: patient and
physician global assessments of disease activity; patient assessment of pain;
CRP or ESR as an indicator of inflammation; and a measure of
function/disability, such as the Health Assessment Questionnaire. This measure
of response is termed the ACR >=20% (ACR20) response. Rather
than expressing outcomes in terms of mean improvement in joint counts, it is now
possible to compare treatments by ACR20 response rates, identifying the number
of responders with each therapeutic intervention.
Newly Approved Treatments for RAIn the past year, several new products have been introduced for the treatment of patients with RA, and more are expected. In contrast to only 2 approvals since 1986 (methotrexate and cyclosporine), patients can now be offered meaningful alternatives in treatment (Table). The first product, leflunomide, is a traditionally manufactured pharmaceutical agent with many similarities to methotrexate. The second, etanercept, is the first biologic agent to be approved for the treatment of RA. It is a recombinantly produced form of the natural soluble type II tumor necrosis factor- (TNF-) receptor, which binds TNF- and inhibits its proinflammatory effects. The third, celecoxib, is a cyclooxygenase-2 (COX-2)-specific, the first in this new class of NSAIDs. Fourth is the protein A immunoadsorption column, the first device approved for the treatment of RA. Rofecoxib, another COX-2-specific, is now approved for the treatment of acute pain and osteoarthritis and is expected to receive additional labeling for the treatment of active RA in the next year. Finally, another inhibitor of TNF-, infliximab, a chimeric monoclonal antibody to TNF-, is already approved for the treatment of severe, refractory Crohn's disease and is expected to receive labeling for the treatment of active RA in the near future.
The COX-2-specific NSAIDs are indicated for the treatment of osteoarthritis and will likely have the greatest impact in this clinical application. As reviewed above, NSAIDs are considered adjunctive treatment for the signs and symptoms of active RA. For this reason, both celecoxib and rofecoxib are omitted from this article. The reader is referred to the chapter by Simon (Osteoarthritis: A Review) for further information.
Leflunomide TherapyLeflunomide (Aravaź) is a new DMARD recently approved by the US Food and Drug Administration (FDA) for the treatment of RA. Leflunomide inhibits de novo pyrimidine synthesis, thereby inducing a reversible cell cycle arrest in rapidly dividing cell populations such as activated lymphocytes. Thus it acts as an antiproliferative agent, similar in mechanism of action to methotrexate, which, in low doses, inhibits de novo purine synthesis.
The approval of leflunomide was based on results of 3 phase 3 clinical studies. In US301, conducted in the United States and Canada, 482 methotrexate-naive patients with active RA received leflunomide 20 mg/d (n = 182), placebo (n = 118), or methotrexate 7.5 to 15 mg/wk (n = 182) for 52 weeks. MN301, conducted in Europe, Australia, and South Africa, treated 358 patients with active RA using leflunomide 20 mg/d (n = 133), placebo (n = 92), or sulfasalazine 2 g/d (n = 133) for 24 weeks. The third study, MN302, was conducted in Europe, Australia, and New Zealand; 999 methotrexate-naive patients with active RA were randomized to receive leflunomide 20 mg/d (n = 501) or methotrexate 7.5 to 15 mg/wk (n = 498) for 52 weeks.
ACR20 responses in the leflunomide, methotrexate, and sulfasalazine treatment groups across the 3 protocols ranged from 50% to 60%, compared with placebo responses at 6 and 12 months of 26% and 29%. The Health Assessment Questionnaires showed leflunomide, methotrexate, and sulfasalazine treatment effects to be equivalent and significantly superior to placebo in improving function and preventing disability. In the US protocol, analysis of the health-related quality-of-life measure showed fewer limitations due to pain and more energy in patients receiving leflunomide. The 3 active treatments also demonstrated equivalency in slowing disease progression, as measured by radiographs of the hands and feet at baseline, 6, or 12 months. The US protocol was the first 12-month, placebo-controlled trial to demonstrate slowing of disease progression by methotrexate administration, proving this long-suspected hypothesis.
As with methotrexate, leflunomide was well tolerated. Common adverse events included gastrointestinal complaints such as diarrhea, nausea and/or vomiting, and skin rash, as well as reversible alopecia. In the phase 3 trials, diarrhea was more common in patients receiving leflunomide but was generally mild to moderate, and few patients discontinued treatment due to this adverse effect. Nausea and/or vomiting were more prevalent with methotrexate treatment. On the other hand, abdominal pain was relatively equally distributed among the placebo and active-treatment groups; this finding may reflect the use of background NSAIDs. Methotrexate administration was associated with more oral ulcers. Skin rash was more frequent with leflunomide treatment; most rashes were mild to moderate in severity and did not require treatment discontinuation. Although reversible alopecia was more common in leflunomide-treated patients, all cases resolved, and few patients withdrew due to this complaint.
Leflunomide administration had no apparent adverse effects on hematocrit, hemoglobin, platelet or white blood cell counts, or on renal function . Leflunomide treatment was associated with elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). ALT was more sensitive to treatment effects with both methotrexate and leflunomide administration; all patients with AST elevations had concomitant ALT elevations, which frequently preceded abnormalities in ALT values. Nonetheless, most ALT elevations were mild (>1.2 the upper limit of normal [ULN] to <2 ULN), transient, and reversed with continuous treatment. Clinically significant elevations (>2 ULN) were generally asymptomatic and reversible, either with continued treatment or withdrawal. Marked elevations (>3 ULN) were less common and similarly reversible. To date, there has been no evidence to suggest leflunomide treatment results in cirrhosis and/or hepatic fibrosis, even when administered concurrently with methotrexate.
Based on these results, the
FDA has approved leflunomide for patients with active RA, even those who have
not failed prior DMARD therapies. Although there are no pharmacokinetic
interactions between concomitant leflunomide and methotrexate administration,
the safety and efficacy of this combination will require confirmation in a
randomized, placebo-controlled trial, which is currently under way.
Monitoring of leflunomide therapy, as recommended by the FDA, is more limited
than for methotrexate: ALT levels should be repeated monthly until stable and
then on a regular basis (every 2 to 3 months). Dose reductions are recommended
when repetitive values are >2
ULN (with concomitant administration of cholestyramine for 1 day to reduce blood
levels) and treatment discontinuation is warranted when repetitively >3
Introduction to Cytokine-Based TherapiesCytokines frequently have multiple biologic functions with overlapping effects. Often they have proinflammatory as well as anti-inflammatory activity, although in most cases they can be classified predominantly as proinflammatory or anti-inflammatory cytokines. The therapeutic effects of cytokine-targeted therapies also depend on the type of product, dose, dosing schedule, route of administration, mechanism of action, and patient population studied.
Interleukin-1 (IL-1) and TNF- are the key proinflammatory cytokines implicated in the pathogenesis of RA. Secreted by synovial macrophages, IL-1 and TNF- stimulate synovial cells to proliferate and produce collagenase, thereby inhibiting proteoglycan synthesis, degrading cartilage, and stimulating bone resorption. These cytokines induce the expression of adhesion molecules, resulting in further inflammatory cell recruitment and release of cytokines. As a prominent mediator of the inflammatory response, TNF- secretion stimulates release of IL-1 and IL-6 as well as other cytokines and metabolites of arachidonic acid. Unregulated overproduction of TNF- in transgenic mice results in the development of a chronic polyarthritis resembling RA.
A variety of proteins regulate the effector functions of cytokines in vivo and have been recombinantly constructed as therapeutic agents designed to inhibit IL-1 and IL-1. These include soluble-receptor antagonists and antibodies to cytokines. Soluble receptors are truncated forms of the cell surface receptor devoid of the transmembrane and intracytoplasmic domains that still retain binding affinity comparable to the full-length membrane-bound receptors. Soluble-receptor molecules bind free cytokine, inhibiting its binding to cell surface receptors. To be effective, they must be retained within the circulation. A variety of constructs have been generated by fusing the immunoglobulin G subclass (IgG1) Fc region sequences to soluble cytokine receptors, thereby increasing affinity for the cytokine and prolonging their half-life in the circulation. In comparison, anticytokine monoclonal antibodies have much higher (1000-fold) affinity and can bind cell surface-bound as well as free cytokine. They are smaller, possibly enabling a wider distribution, and often have a longer circulating half-life.
Etanercept TherapyEtanercept (EnbrelTM), the soluble p75 (type II) TNF- receptor conjugated to the Fc portion of IgG1 (rhuTNFR:Fc), was approved for the treatment of patients with moderate-to-severe RA who have responded inadequately to at least 1 DMARD. Etanercept was recently approved for the treatment of polyarticular juvenile rheumatoid arthritis.
Etanercept has been studied in 2 placebo-controlled trials. A phase 2 trial comparing 2 and 16 mg/m2 administered subcutaneously twice weekly in 180 patients demonstrated significant clinical improvement at 3 months by the ACR20 response criteria: 75% versus 14% placebo response. Onset of effect was rapid, and disease manifestations recurred within weeks of discontinuing treatment. A phase 2/3 trial examining 6 months of treatment in 234 patients reported 58% and 51% ACR20 responders compared with an 11% placebo response. Treatment in patients with active disease despite 3 to 5 years of therapy with methotrexate resulted in 71% ACR20 responders compared with 27% placebo responders at 6 months. Patients with long-standing RA (11 to 13 years' duration), having failed treatment with approximately 3 DMARDs, were enrolled in these trials, an indication that this treatment was effective in a population with relatively refractory disease.
Etanercept is well tolerated; most patients have little or no difficulty self-administering treatment. In controlled trials, approximately one third of patients developed injection-site reactions, all reported as mild to moderate. They occurred typically during the first month of treatment and lasted for 3 to 5 days; rotating the site of injection usually ameliorated the problem. In general, the incidence of infections has been similar across treatment groups; serious infections were reported in 22 (2.9%) of 745 patients. Recently, the label was updated to reflect the fact that 6 deaths have occurred due to infection in the estimated 25,000 patients treated to date with this agent. A new warning was added to closely monitor patients who develop a new infection while receiving therapy, as well as the recommendation to discontinue treatment in patients with serious infections or sepsis.
Infliximab TherapyInfliximab (RemicadeTM), the chimeric IgG1 monoclonal antibody to TNF-, was recently approved for the treatment of refractory Crohn's disease, including patients with fistula formation. Rapid and long-lasting improvement was observed in patients with this debilitating disease[33,34]. Infliximab is currently under review for approval in the treatment of active RA.
Initial controlled trials with this agent in patients with refractory RA demonstrated significant clinical responses with marked improvement in symptoms of malaise and fatigue that correlate with decreases in CRP levels. After single intravenous doses of monoclonal antibody, the onset of effect was rapid (within 1 to 3 days), with benefits lasting 4 to 8 weeks. Adverse effects of fever, rash, and nausea were mild and well tolerated. Repetitive treatment with the monoclonal antibody after disease relapse resulted in continued reduction in disease activity, although the magnitude and duration of response lessened with each successive administration.
Because infliximab is a chimeric monoclonal antibody, composed of murine as well as human sequences, antibody responses were detected in ~40% of patients, which may have contributed to the observed tachyphylaxis. In an effort to reduce these antibody responses, infliximab was administered in doses of 1, 3, and 10 mg/kg in combination with methotrexate. Although methotrexate administration appeared to have little effect on peak clinical responses, it prolonged duration of responses in most cases and decreased antibody responses. A subsequent clinical trial examined 3 and 10 mg/kg of infliximab administered on a monthly or bimonthly basis in 428 patients with active RA despite methotrexate treatment. Clinical effect as measured by ACR20 response criteria was rapid in onset and, at 30 weeks, similar in all active-treatment groups: 50% to 58% compared with a 20% placebo response.
Approximately 5% of patients discontinued treatment because of infusion reactions, such as urticaria, pruritus, chills, and fever. Serious infections have been reported in 3%. Anti-double-stranded DNA (dsDNA) antibodies were reported in 9% of patients; 2 patients with RA and 1 with Crohn's disease developed symptoms consistent with systemic lupus erythematosus (SLE), which resolved after treatment withdrawal. Three cases of lymphoproliferative disorders were reported in a total of 394 patients treated. In comparison, 16% of RA patients who received etanercept developed nonneutralizing antibodies to the soluble receptor. In etanercept-treated patients, 11% developed new positive antinuclear antibodies and 15% developed anti-dsDNA antibodies compared with 5% and 4% of patients taking placebo, respectively. To date, no cases of SLE or lymphoproliferative disorders have been reported.
Protein A Immunoadsorption Column with Plasmapheresis TherapyThis immunoadsorption column is composed of staphylococcus bacteria-derived protein A covalently bound to an inert silica matrix. Protein A is known to bind IgG, types I and IV, as well as antigen-bound IgG. Although the precise mechanism of action has yet to be identified, it is believed that plasmapheresis employing this immunoadsorption column allows binding and subsequent "remodeling" of immune complexes, thereby enhancing their in vivo clearance. Clinical benefit apparently requires multiple treatments; onset of effect is delayed; and to date, detailed studies have failed to demonstrate significant changes in IgG levels or circulating immune complexes as an explanation for efficacy.
This product has been approved for the treatment of idiopathic thrombocytopenic purpura for more than a decade. In the controlled clinical trial that supported approval of this product for the treatment of RA, patients were randomized to receive either 12 sham procedures (plasmapheresis without use of the column) or 12 active treatments once a week for 12 weeks. The primary efficacy analysis compared ACR20 responses at weeks 19 and 20 with the average of 3 baseline determinations. The trial was stopped after 91 patients were enrolled, when the Independent Data Safety Monitoring Board determined that efficacy had been demonstrated. Enrolled patients had a mean disease duration of 15.5 years and failed a mean of 5.4 DMARD regimens. Despite this patient population with long-standing, refractory disease, efficacy was evident in 33% of the active-treatment group compared with 9% of sham-treated patients. Patients with initial responses were more likely to respond with a second course of therapy.
Nonetheless, adverse effects
did occur with this treatment regimen. A total of 77% of the sham-treated
patients and 88% of active-treated patients experienced adverse events, most
self-limited, but the majority were moderate or severe. The most
common complaint was joint pain, followed by fatigue, hypotension, joint
swelling, nausea, and dizziness; the total of these complaints were experienced
by ~25% of patients. Many of the complaints of joint pain, fatigue, and/or joint
swelling were interpreted as posttreatment arthritic flares, which lasted from
12 to 72 hours. Other adverse effects included infectious complications due to
central line placement for venous access and decreases in hemoglobin and
hematocrit in a population already affected with anemia from chronic disease.
Thus, the label recommends against the use of central lines and suggests that
careful attention be paid to hemoglobin/hematocrit, with discontinuation of
treatment if hemoglobin levels fall below 8 g/dL.
Risk-Benefit AnalysisThese newly approved RA treatments have taught us much about the underlying disease as well as future directions for therapeutic interventions. Leflunomide can be added to a growing list of reversible purine/pyrimidine synthesis inhibitors that are effective in RA as well as in transplantation, and, by virtue of their mechanism of action, are immunomodulatory but not generally immunosuppressive. In addition to demonstrating significant improvement in function and delay of radiographic progression of disease, the leflunomide trials documented similar benefits with the current widely accepted DMARDs, methotrexate, and sulfasalazine.
Even more exciting for the treatment of RA are the new biologic agents designed to inhibit TNF-. These agents have a number of advantages over conventional pharmaceutical therapies. They have a rapid onset of action, and their effects are readily reversible. Used in combination therapy with other second-line agents, such as methotrexate, they appear to be safe and offer additional clinical benefit. Although it is difficult to determine whether autoimmune and lymphoproliferative disorders may be related to the underlying disease or could be a result of treatment with the biologic agent, at the present time potential risks appear to be outweighed by considerable clinical benefit.
Nonetheless, biologic agents have a number of disadvantages over conventional therapies. They require parenteral administration, may exhibit infusion or injection-related toxicities, and, in some cases, tachyphylaxis on retreatment, possibly related to immunogenicity. Presently, substantial cost is associated with their manufacture, and resulting high market prices limit patient access. To be considered cost-effective, these products must demonstrate substantial clinical benefit relative to conventional agents. Thus, initial use of biologic agents such as the TNF- antagonists will likely be confined to patients with moderate-to-severe RA who are partial responders to optimal doses of methotrexate, or patients who are unable to tolerate methotrexate after failing treatment with several DMARDs. A number of outstanding issues remain regarding their use in RA, including: (a) ability to slow radiographic progression; (b) utility in induction, maintenance, or flare of disease; (c) long-term adverse effects; and (d) utility in combination with other biologic agents[44,45]. Answers to many of these questions can be expected in the next several years, both with these and with newer products entering clinical trials.
Finally, treatment with the
protein A immunoadsorption column offers significant benefit in patients with
long-standing, refractory disease who have failed all other currently available
therapies. Based on current data, there is significant interest in examining
combination therapy in patients with persistently active RA despite maximally
tolerated doses of methotrexate.
ConclusionsThis is unquestionably an exciting time for rheumatology, now that multiple novel therapies are available to patients with RA. Only clinical use will determine their long-term efficacy and safety, and allow accurate assessment of their risks and benefits, as well as cost. Proof has been established that methotrexate and sulfasalazine slow radiographic progression of disease, and that agents with similar mechanisms of action are effective in treating patients with RA. Recent clinical trials have also shown that 6- and 12-month treatments result in meaningful improvement in function and health-related quality of life. The TNF-a cytokine antagonists have demonstrated that selective targeting of specific pathogenic elements of the underlying disease process can be an effective therapeutic strategy. They appear to offer effective and, at least in the short term, safe alternatives to conventional therapies, substantially augmenting our armamentarium. Whether these agents will demonstrate comparable disease-modifying effects as measured radiographically remains to be determined; data are eagerly awaited. Although these agents may not become the "gold standard" for the treatment of RA until long-term safety is clarified and cost issues are addressed, they have "raised the bar" for our expectations of efficacy for agents currently in development. Finally, the protein A immunoadsorption column offers a meaningful therapeutic alternative to patients with refractory disease who have failed multiple treatments. Further efforts to develop new therapies for this group of patients, previously overlooked, should be strongly encouraged.
As with well-accepted DMARDs
such as methotrexate, use of these newly approved treatments in RA requires
close monitoring and detailed knowledge of the underlying disease process and
its adverse effects as well as the risks of treatment. Hopefully, these new
therapeutic options will renew collaborative efforts between primary care
physicians and rheumatologist specialists in treating and comanaging our
patients with this aggressive and often underestimated autoimmune disease.
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