Indications

Individual patients differ in the aggressiveness of their disease and its concomitant structural damage, the effect of their disease on their quality of life, and the symptoms and signs engendered by their disease. All these factors must be examined when considering anti-TNF treatment for the patient, as must the toxicity of previous and/or alternative disease modifying antirheumatic drug (DMARD) use.

TNF blockers are recommended for the treatment of active RA after an adequate trial of another effective DMARD, of which methotrexate is a commonly used example2-16 (category A evidence). TNF blocking agents can be added to pre-existing treatment, or, when appropriate, may replace previous DMARDs7-16 (category A evidence). There is evidence that TNF blockers are effective for the treatment of RA in methotrexate naive patients2-9(category A evidence). The use of TNF blocking agents as the first DMARD for the treatment of RA2 (category A evidence) should, at present, be limited owing to considerations of long term safety and cost. However, patients in whom other DMARDs are relatively contraindicated may be considered for treatment with TNF blockers as the first DMARD (category D evidence).

At least one TNF blocking agent has been approved for juvenile idiopathic arthritis of the polyarticular type17 ,18(category A evidence). TNF blocking agents have been shown to be efficacious in psoriatic arthritis and ankylosing spondylitis18-22 (category A evidence). There is no evidence that any one TNF blocking agent should be used before another one can be tried, just as there is no credible evidence that one TNF blocker is more effective than another (category B evidence).

TNF blocking agents are being evaluated in Wegener's granulomatosis, adult onset Still's disease, polymyositis, and systemic sclerosis23-26 (category C evidence). These compounds may have potential in these diseases and in other conditions, but more work is needed in all cases.

Pharmacoeconomic data and long term safety data may change the circumstances when TNF blocking agents will be started, added to, or replace other DMARDs.

Clinical use

TNF blocking agents, when given in adequate doses and sufficiently frequent dosing regimens, should lead to significant, documentable improvement in symptoms, signs, and/or laboratory parameters within 8–12 weeks2-15 (category A evidence). Neither the American College of Rheumatology (ACR) response criteria nor the disease activity score (DAS) should be used in clinical practice as the sole measure to monitor individual response (category B evidence). Estimations of individual response require a combination of clinical judgment and quantitative measures, including the above and other validated quantitative measures, such as visual analogue scales (VAS) or Likert scales of global response or pain by the patient or global response by the doctor, joint tenderness and/or swelling counts, and laboratory data. Any may be used and may be the most appropriate measures for individual patients (category B evidence). These measures of response should be followed and individually important responses should be seen within 8–12 weeks2-15 (category A evidence). If such improvement occurs, treatment should be continued. If patients show no response to these agents, they should be stopped8 ,27 ,28 (category B evidence). In patients with an incomplete response, observations suggest that an increased dose or reduced dosing intervals may provide additional benefit. However, further study of this issue is required8 ,27 ,28 (category D evidence).

Data show that TNF blocking agents slow radiographic progression in RA11 ,28 (category A evidence). Although radiographic progression slows down in some patients without a clinical response, the long term clinical implications of these changes are unknown. Until the long term implications of slowing radiological damage are clear, radiological changes, alone, should not determine clinical decision-making.

Some patients have inadvertently become pregnant while being treated with TNF blocking agents and these pregnancies have resulted in the birth of normal infants (category D evidence). However, there are insufficient data to advise continuation of anti-TNF treatment if a patient becomes pregnant.

Rare cases of lupus-like disease have occurred in patients receiving TNF blocking agents, and treatment should be stopped if there is clinical evidence of a lupus-like syndrome9 ,12 ,29(category C evidence). There is no evidence that patients with RA who had, or develop, positive antinuclear antibodies (ANA), anticardiolipin antibodies (aCL), and/or dsDNA are at increased risk for the development of drug-induced lupus2-5 7-12 ,18 ,29 (category C evidence).

Warnings

TNF blocking agents should not be started or should be discontinued when serious infections occur, including septic arthritis, infected prostheses, acute abscess, osteomyelitis, sepsis, systemic fungal infections, Listeria, etc2-18 (category B evidence). Previous tuberculosis may be reactivated in patients given TNF blockers; screening and prophylaxis according to local recommendations should be undertaken in patients with previous tuberculosis or patients at risk for developing tuberculosis30 (category C evidence). Treatment with TNF blockers in such patients should only be resumed if the infections have been adequately treated (category D evidence).

Instances of demyelinating-like disorders have been reported in patients receiving TNF blockers30 ,31 (category C evidence). These agents should be stopped if a demyelinating-like disorder occurs. Patients with a history of definite demyelinating disease should not receive TNF blocking agents (category C evidence).

A very few instances of pancytopenia and aplastic anaemia have been reported30 ,31 (category C evidence). Because the incidence of these adverse effects is not known, specific recommendations about monitoring cannot be given at this time. If pancytopenia or aplastic anaemia, or both, occur, TNF blockers should be stopped and patients evaluated for evidence of other underlying disease and a potential relationship with the TNF blockade (category C evidence).

Precautionary statements

The safety of TNF blockade is unknown or has not been established in the following situations:

1

Lymphoma, lymphoproliferative disease, and other malignancies

2

Chronic infections, including HIV, hepatitis B or C, etc

3

During pregnancy or lactation

4

When considering primary vaccinations or live attenuated vaccines.

Other areas in which knowledge is lacking are highlighted in the recommendations of the consensus group for areas most urgently requiring further research.

Research

Among a number of potential areas requiring action or further research, or both, the consensus groups felt the following projects or directions were most important in each of three areas: registries, efficacy, and safety.

Summary

TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA.2-17Their use is expanding to other rheumatic diseases.18-26 ,32 However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.