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TNF antibodies and rheumatoid arthritis

NICE evidence
Early referral
Overall comment

A real difficulty with original treatments is that evidence emerges slowly. This is particularly the case for chronic diseases where treatments may have to be assessed over long periods. This slow emergence means that there can be some initial difficulty in assessing whether the treatment works, how well it works, in whom it works, and what the economics are if it does work.

There comes a point, though, when there is sufficient evidence on which to pass a judgement, which is one reason the UK government set up its National Institute for Clinical Excellence (NICE). As part of its work, NICE now publishes the evidence on which its judgements are based on its Internet site. The way in which it assessed the evidence on anti-TNF treatments for rheumatoid arthritis [1] demonstrates a growing quality and maturity in its processes.

NICE evidence

The 138-page report from Birmingham is a good background read on rheumatoid arthritis and its treatment. It examines the background, diagnosis, pathology, current service provision, the interventions, its search strategy, the results in the form of a meta-analysis of major outcomes, detailed summaries of the trials involved including adverse events, and the health economic arguments, as well as the implications for the NHS.


Infliximab and etanercept are partially humanised monoclonal antibodies aiming to reduce the actions of circulating tumour necrosis factor (TNF). Both exert their effects by removing TNF from the circulation, and consequently interrupt the inflammatory process.


With rheumatoid arthritis there are many possible outcomes, starting with the number of painful or swollen joints, through to health assessment questionnaires and quality of life. The most commonly used (though perhaps difficult to explain and use) measure is the American College of Rheumatology (ACR) response criteria, a composite measure of seven indices:

The ACR 20 response is defined as a 20% improvement in the first two of these, plus a 20% improvement in any three of the remaining five items. This is not an easy outcome to reach, though also being used now are ACR 50 and ACR 70, which are similar to the ACR 20 but at 50% and 70% improvements. These are very high hurdles of treatment efficacy and represent very significant clinical improvement.


To at least give a flavour of the results obtained with these two monoclonal antibodies, the results for ACR 20, 50 and 70 are looked at here. There are issues about dose, and about duration. The NICE evidence combines different doses and duration up to one year, but shows that, in the main, this is a reasonable thing to do, at least for now.

Results were consistent between trials comparing the new treatments with placebo. Those for the ACR 20 for etanercept are shown in Figure 1, and for infliximab in Figure 2. The results for ACR 20, 50 and 70 outcomes are in Table 1. NNTs were about 2-3 for ACR 20, about 4 for ACR 50, and about 8 for ACR 70.

Figure 1: ACR 20 with etanercept and placebo

Figure 2: ACR 20 with infliximab and placebo

Table 1: NNTs for etanercept and infliximab versus placebo at longest duration, and pooling all doses

[number/total (%)] with






Relative benefit



ACR 20 4 458/803
4.3 (3.1 to 5.9) 2.3 (2.0 to 2.6)
ACR 50 4 232/803
5.5 (3.3 to 9.2) 4.3 (3.6 to 5.2)
ACR 70 3 68/667
12 (3 to 47) 11 (8 to 15)


ACR 20 4 245/497
3.6 (2.3 to 5.4) 2.9 (2.4 to 3.6)
ACR 50 4 161/497
4.5 (2.4 to 8.3) 4.0 (3.2 to 5.3)
ACR 70 1 60/340
8 (2 to 31) 6.5 (4.9 to 9.7)

The analysis also shows that what happens with placebo depends on the difficulty of the outcome. With placebo about 14% of rheumatoid arthritis patients achieved ACR 20. As the hurdle was raised to ACR 50 and 70, the percentage of patients achieving the outcome fell to about 6% and 1% respectively (Table 1).

Good information about adverse events is also given in the report, though not recounted here.


Given the evidence outlined in the report, it is clear why the British Society for Rheumatology recommended that infliximab and etanercept should be used if the following criteria were met:

♦ Patients satisfy ACR classification for RA
♦ Patients have highly active RA
♦ Patients should have failed treatment on methotrexate and at least one other disease modifying agent
♦ Treated patients should be entered on a central register, with drugs, dose, outcomes and toxicity reported on a quarterly basis.

Early referral

An essential accompaniment to the NICE evidence is an evidence-based early referral recommendation for newly diagnosed rheumatoid arthritis [2]. Based on a wide literature search by an international group of influential rheumatologists, this review provides clear support for the observation that permanent structural damage occurs early in the course of active rheumatoid arthritis and that early disease modifying drug intervention slows the progression of structural joint damage and improves long term outcomes, as well as overall quality of life.

It provides an early referral algorithm for newly diagnosed rheumatoid arthritis. Early referral is advised in the event of clinical suspicion of RA, supported by the presence of any of the following:

1 At least three swollen joints
2 A positive "squeeze" test (composite compression test) that clinically evaluates a group of small adjacent joints such as metacarpophalangeal and metatarsophalangeal
3 Morning stiffness of at least 30 minutes

Important points were:

♦ Patients with RA have been shown to have an improved long term outcome, when treated by a rheumatologist
♦ There is evidence that delay of more than 12 weeks in treatment results in a missed opportunity to improve long term outcome
♦ RF positivity, a raised acute phase response, and erosions on X-ray are associated with poor outcome, but absence at presentation should not preclude diagnosis or referral
♦ NSAIDs can mask signs and symptoms at presentation
♦ Corticosteroids should not be prescribed without an accurate diagnosis.

The algorithm combines all these points with a diagram of the squeeze test, and it would make a useful guide for teaching, or a surgery wall, or computer aide.

Overall comment

There is much new in the field of rheumatoid arthritis, and probably much more to come, backed by good new evidence. Given that RA is the most common form of inflammatory arthritis affecting 0.5% to 1% of the population, and with a large economic impact because about 90% of patients have some form of disability with two decades, this is of increasing importance. Some or all of this could be incorporated into the delivery of a quality service.

A short review of new treatments can also be found in the STEER series from the Wessex Institute [3].


  1. P Jobanputra et al. The clinical effectiveness and cost-effectiveness of new drug treatments for rheumatoid arthritis: etanercept and infliximab. NICE 2002 ( )
  2. P Emery et al. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Annals of Rheumatic Disease 2002 61: 290-297.
  3. C de Vries. Effects of TNF-alpha antagonists in people with rheumatoid arthritis. ( )
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