Recent Advances in the Treatment of Rheumatoid Arthritis

[Guest guest]

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]

Abstract

Rheumatoid 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.

Introduction

Rheumatoid 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[3]. 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[4].

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[7]. 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[8]. 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[9]. 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[10]. 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[9].

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[11]. 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[12]. 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[15].

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[16]. 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 RA

In 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 Therapy

Leflunomide (Arava®) 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[17].

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[18]. 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[19]. 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[20].

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[21]. 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[22]. 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[23]. 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 [23].

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[24]. 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 ULN.

Introduction to Cytokine-Based Therapies

Cytokines 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[25]. 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[26]. Unregulated overproduction of TNF- in transgenic mice

results in the development of a chronic polyarthritis resembling RA[27].

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[28]. 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 Therapy

Etanercept (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[29]. 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[30]. 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[31]. 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[32]. 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 Therapy

Infliximab (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[35]. 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[36].

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[37]. 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[38]. 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%[39]. 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[31]. 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 Therapy

This 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[40]. 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[41].

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[42].

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 Analysis

These 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[43].

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; (

utility in induction, maintenance, or flare of disease; © 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.

Conclusions

This 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.

Key Points

a.. Because no cure for RA exists, the therapeutic goal is to control the

underlying inflammatory process and maintain or improve function. RA impacts

most aspects of daily living.

b.. The US FDA has approved leflunomide for patients with active RA, even

those who have not failed prior disease-modifying antirheumatic drug therapies.

c.. Etanercept has been approved for the treatment of patients who have failed

to respond to 1 DMARD and the treatment of juvenile arthritis.

d.. Infliximab is expected to be approved for the treatment of RA in

combination with methotrexate.

e.. A new immunoadsorption column to be used with plasmapheresis has recently

been approved for the treatment of RA.

Table. Products Recently Introduced For the Treatment of Patients with

Rheumatoid Arthritis

Leflunomide

Etanercept

Celecoxib

Protein A immunoadsorption column

Rofecoxib

Infliximab

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