The Benefit/Risk Profile of TNF-Blocking Agents: Findings of a Consensus Panel

doi:10.1016/j.semarthrit.2004.11.006

Seminars in Arthritis and Rheumatism

Volume 34, Issue 6, June 2005, Pages 819-836

https://doi.org/10.1016/j.semarthrit.2004.11.006 Get rights and content

Objective

To review the benefits and risks associated with the use of the tumor necrosis factor (TNF)-blockers in various indications (eg, rheumatoid arthritis [RA], Crohn’s disease [CD], psoriasis).

Methods

The members of the consensus panel were selected based on their expertise. Centocor, Inc provided an educational grant to the Center for Health Care Education to facilitate the consensus panel. Peer-reviewed articles discussing clinical studies and clinical experiences with TNF-blockers form the basis of this review. Emerging data that have not been peer-reviewed are also included.

Results

The TNF-blockers infliximab, etanercept, and adalimumab are all approved for treatment of RA. All 3 are effective, and there are currently no published data from head-to-head clinical trials to support using 1 agent over another. Preliminary data from small, retrospective studies indicate that switching among agents to overcome inadequate efficacy or poor tolerability is beneficial in some patients. The only TNF-blocker currently approved for the induction and maintenance of remission in CD is infliximab. Preliminary data indicate that etanercept and infliximab are effective in treating psoriasis. Some risks associated with TNF-blockers have become apparent, including congestive heart failure, demyelinating diseases, and systemic lupus erythematosus, but in most cases can be identified and managed. Several of these risks (eg, lymphoma and serious infections) are associated with either the condition per se or the concomitant medication use. Simple screening procedures help manage the risk of tuberculosis infection; however, it is recommended that physicians and patients be alert to the development of any new infection so that appropriate treatment may be initiated promptly. Rare infusion reactions, particularly with infliximab, may also be effectively managed.

Conclusion

TNF-blockers are effective and may be safely used for short- and long-term management of RA or CD. TNF-blockers also show efficacy in other emerging indications.

Section snippets

Methods

This review is the product of a consensus panel meeting held by the authors on 16 July 2003 to discuss the benefits and risks associated with the use of TNF-blockers in approved and emerging indications. The members of the consensus panel were selected based on each member’s expertise in both clinical rheumatology and rheumatology research. Each specialty currently using anti-TNF therapy was represented on the panel to allow for a thorough review of the Benefit/Risk equation. Centocor, Inc

Clinical Pharmacology of the Approved TNF-Blockers

The routes of administration, approved doses, and basic pharmacokinetic properties of the 3 currently approved TNF-blockers are shown in Table 2 (1, 2, 3, 4).

Two distinct receptors for TNF (TNF-Rs), a 55-kDa protein (p55) and a 75-kDa protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble form (5). Binding of TNF to either cell surface TNF-R confers biological activity to the cytokine.

Etanercept (Enbrel®) is a dimeric fusion protein (approximately 150 kDa)

Monotherapy with TNF-Blockers

Data from several clinical studies indicate that monotherapy with the TNF-blockers is effective in the treatment of RA (6, 7, 8). For example, in a trial enrolling patients who had failed to respond to previous disease modifying antirheumatic drug (DMARD) therapy, a significantly higher proportion of patients treated with etanercept 25 mg achieved American College of Rheumatology (ACR) 20, 50, and 70 scores (9) within 6 months of onset of treatment compared with patients assigned to placebo (P

Risks Associated with TNF-Blocking Agents

Data from clinical trials are often the major sources of information about the risks associated with a new therapy. Clinicians tend to report adverse events associated with new treatments but, in general, such reporting does not continue as rigorously after the first 2 years of marketing (64). Underreporting of adverse events and a variety of other issues mean that long-term pharmacovigilance is not, at present, a complete source of information (64). Thus, most of the available safety data

Discussion

The availability of the TNF-blockers has dramatically affected the achievable goals in the management of RA, CD, and psoriasis. The 3 TNF-blockers (adalimumab, etanercept, and infliximab) are effective for the treatment of RA and, based on the published literature, there appears to be no clinical or scientific rationale for using 1 TNF-blocker over another. However, practical issues of administration and concomitant MTX therapy are factors for consideration. It is only in the treatment of CD

Acknowledgment

The faculty acknowledges the assistance of Dr. Gary Halpern, RPh, of Strategic Business Research, Horsham, PA, for his role as facilitator in the consensus meeting.

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: Conflicts of interest: Dr Hochberg acts as a consultant and/or serves on Advisory Boards for Abbott Laboratories, AstraZeneca, Aventis Pharmaceuticals Inc, Bristol-Myers Squibb, Eli Lilly, Genzyme, GlaxoSmithKline, Laboratories NEGMA, Merck & Co Inc, Novartis, Procter & Gamble, Roche Pharmaceuticals, Scios Inc, and Wyeth Pharmaceuticals Inc, and is currently receiving research support from the Arthritis Foundation, Department of Veterans Affairs, National Institutes of Health, GlaxoSmithKline, and Merck & Co Inc; Dr Lebwohl has received grants/research support and acted as a consultant for Amgen Inc, Biogen Inc, Centocor Inc, and Genentech Inc; Dr Plevy has acted as a consultant and received grants/research support from Centocor Inc; Dr Hobbs has received honorarium as a member of the Speaker’s Bureau for Abbott Laboratories, Amgen Inc, Centocor Inc, and Pfizer Inc; Dr Yocum has received grants/research support from Abbott Laboratories and Amgen Inc and acted as a consultant and received honoraria from Centocor Inc.

: This activity was supported by an unrestricted educational grant from Centocor, Inc.

¹: Chairpersons.

²: Faculty members of the consensus panel.

³: Medical reviewer.

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The Benefit/Risk Profile of TNF-Blocking Agents: Findings of a Consensus Panel

Objective

Methods

Results

Conclusion

Section snippets

Methods

Clinical Pharmacology of the Approved TNF-Blockers

Monotherapy with TNF-Blockers

Risks Associated with TNF-Blocking Agents

Discussion

Acknowledgment

Cell

Lancet

Lancet

Lancet

Lancet

Gastroenterology

Lancet

Am J Gastroenterol

Gastroenterology

Gastroenterology

Am J Gastroenterol

Am J Gastroenterol

Lancet

Lancet

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Best Pract Res Clin Rheumatol

Lancet Infect Dis

Am J Med

Eur J Cancer

Gastroenterology

Gastroenterology

Gastroenterology

Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy

J Rheumatol

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

Ann Intern Med

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis

Arthritis Rheum

Efficacy and safety of adalimumab (D2E7), the first fully human anti-TNF monoclonal antibody in patients with rheumatoid arthritis who failed previous DMARD therapy6-month results from a phase III study

Ann Rheum Dis

Guidelines for the management of rheumatoid arthritis2002 Update

Arthritis Rheum

Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritisresults of a multicenter, randomized, double-blind, placebo-controlled trial

Arthritis Rheum

A trial of etanercept, a recombinant tumor necrosis factor receptorFc fusion protein, in patients with rheumatoid arthritis receiving methotrexate

N Engl J Med

Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexatethe ARMADA trial

Arthritis Rheum

Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis

Ann Rheum Dis

Adalimumab (D2E7), a fully human anti-TNF—a monoclonal antibody, inhibits the progression of structural joint damage in patients with active RA despite concomitant methotrexate therapy

Arthritis Rheum

Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritisresults of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)

J Rheumatol

Infliximab and methotrexate in the treatment of rheumatoid arthritis

N Engl J Med

Treatment of early rheumatoid arthritis with infliximab plus methotrexate or methotrexate alone preliminary results of the ASPIRE trial

The dimensions of health outcomesthe health assessment questionnaire, disability and pain scales

J Rheumatol

102-week clinical and radiologic results from the ATTRACT triala 2 year randomized, controlled, phase 3 trial of infliximab (Remicade®) in patients with active rheumatoid arthritis despite methotrexate

Ann Rheum Dis

The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis

Arthritis Rheum

Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versadata from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense

Ann Rheum Dis

Do the clinical responses and complications following etanercept or infliximab therapy predict similar outcomes with the other tumor necrosis factor-alpha antagonists in patients with rheumatoid arthritis?

J Rheumatol

The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT)

Arthritis Rheum

International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis

Ann Rheum Dis

Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha

N Engl J Med

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease

N Engl J Med

Development and validation of an endoscopic index of the severity for Crohn’s diseasea prospective multicentre study