[Fwd: RA Clinical Management]

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Newsgroups: alt.support.arthritis

Changing Management of Rheumatoid Arthritis in Clinical Practice:

New Data, New Options  

Author: E. St. Clair, MD Writer: A. , PhD, FACSM

http://www.medscape.com/Medscape/Rheumatology/TreatmentUpdate/1999/tu02/public/t\

oc-tu02.html

The goal of this activity is to describe the most recent innovations in

rheumatoid arthritis treatment.

Introduction

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

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

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

All infliximab treatment regimens in combination with MTX effectively

reduced the signs and symptoms of RA for 54 weeks.

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.

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.

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

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. 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.

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]

Conclusion

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.