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Anti-TNF therapy in early rheumatoid arthritis

Infliximab [1]
Etanercept [2]
Comment

Anti-TNF therapy for rheumatoid arthritis has a proven high degree of effectiveness (Bandolier 99) in clinical trials and the real world (Bandolier 104). In the main all these patients were already using disease-modifying drugs, or had failed to improve on them. Two new studies [1,2] suggest that earlier treatment can be as, or more, beneficial.

In the UK NICE adopted the British Society of Rheumatology (BSR) guidelines for treatment of rheumatoid arthritis, that anti-TNF agents should be used if the following criteria were met:

Starting anti-TNF agents earlier in the disease process was always going to be an issue, with good arguments for it. Simply put, since anti-TNF is so effective, why wait until patients have significant joint problems before ameliorating symptoms? It would be better to prevent the joint problems with an early start of anti-TNF treatments. Two studies, neither of which is a full randomised trial, add to the arguments.

Infliximab [1]

Information comes from a retrospective analysis of a large randomised trial of methotrexate alone and four schedules of infliximab (3 or 10 mg/kg every four or eight weeks) plus methotrexate for two years. The total trial size was 428, with 82 having rheumatoid arthritis for three years or less (the definition of early arthritis used).

Analysis was by original randomised allocation, and by all infliximab plus methotrexate regimens versus methotrexate alone.

One outcome was radiological progression in hands and feet. Ten of the 12 evaluable methotrexate-only patients had radiological progression, compared with 15/49 on additional infliximab (Figure 1). This is equivalent to an NNT of about 2 for infliximab to prevent radiological progression in early arthritis over two years.



Figure 1: Radiological progression or improvement of disease with infliximab or placebo in early rheumatoid arthritis





The second outcome was the proportion of patients whose erosion scores had improved using a definition of a minimum improvement, without a significant worsening in any one joint. No patient out of 12 on methotrexate alone had this degree of improvement, but 20/49 on additional infliximab did (Figure 1). This is equivalent to an NNT of about 2 for infliximab to improve erosion scores in early arthritis over two years.

Etanercept [2]

Here information comes from 207 patients in a long-term open label extension of a randomised trial in early (less than three years) rheumatoid arthritis, and 464 patients with established rheumatoid arthritis from a long term safety study who had poor response to previous disease modifying drugs, and some received etanercept for three years.

Recent onset patients had a mean duration of disease of one year, compared with 12 years for those with established rheumatoid arthritis. Both groups had similar improvements in tender and swollen joint counts, by more than 60-70% in each case.

The main differences were in responses to the health assessment questionnaire (HAQ), incorporating dimensions of physical function, disability, and ease of daily activities using the average of 20 questions scored 0 to 3. Scores of 0 indicate no difficulty, 1 some difficulty, 2 much difficulty, and 3 unable to perform. Low scores are better.

Patients with established rheumatoid arthritis had an initial average score of over 1.6, which fell to about 1 by three years. Patients with early rheumatoid arthritis had an average starting score of 1.5, falling to about 0.7 by three years. More of the early than established rheumatoid arthritis patients had three year scores below 1, or of 0 (Figure 2).



Figure 2: Percent of patients with good HAQ scores and early or established rheumatoid arthritis treated with etanercept for three years





Comment

In patients with early rheumatoid arthritis we know that etanercept is better than methotrexate in preventing radiological changes and at improving health assessment questionnaire scores [3]. Now we have strong suggestions of a similar effect with infliximab. In addition, it looks very much as if using anti-TNFs in early rheumatoid arthritis produces better results than using them when the disease has progressed.

Of course this is still a limited amount of information, but other studies in early rheumatoid arthritis are ongoing. Prediction is difficult, but it is unlikely that results of those trials will be very different from what we have now.

As Churchill said “...man will occasionally stumble over the truth, but usually manages to pick himself up, walk over or around it, and carry on.” The bills for early use of anti-TNF in rheumatoid arthritis (and perhaps other conditions) will be huge. The benefits for healthcare systems and society may also be huge.

The secret will be squaring a few circles rather than walking around the truth. We need some brainy health economists to begin looking at the implications of all this.

References:

  1. 1 FC Breedveld et al. Infliximab in active early rheumatoid arthritis. Annals of the Rheumatic Diseases 2004 63: 149-155.
  2. SW Baumgartner et al. Eternercept (Enbrel) in patients with rheumatoid arthritis with recent onset versus established disease: improvement in disability. Journal of Rheumatology 2004 31: 1532-1537.
  3. MC Genovese et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis. Two year radiological and clinical outcomes. Arthritis & Rheumatism 2002 46: 1442-1450.

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