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The new tumour necrosis factor α (TNFα) blockers are revolutionising the treatment of patients with resistant rheumatoid arthritis. Generally good response rates are seen and the treatments are well tolerated. These agents, however, are costly and questions about their long term side effects remain. In the UK, the administration of infliximab and etanercept has been reviewed by NICE, and guidelines were published in March, 2002.1 They recommend that “non-responders” discontinue treatment after 3 months. Non-responders are defined by a Disease Activity Score using a 28 joint count (DAS28) that remains greater than 3.2 or has not reduced by at least 1.2 from the score before treatment.
Anecdotal evidence suggests that patients become increasingly symptomatic towards the end of the 8 weeks between infusions. Therefore, despite an obvious sustained clinical improvement immediately after their infusion, their DAS28 may still be high at the eighth week. We have previously described a patient with active rheumatoid arthritis whose disease did not respond to the 8 weekly regimen but who has continued to have good disease control with a 6 weekly regimen.2 Does patient wellbeing deteriorate over the 8 weeks for patients already established on infliximab? We asked all our patients on such a regimen to rate their disease on a self administered patient global wellbeing visual analogue scale (VAS) for each of the 8 weeks between infusions.
Eighteen patients were identified and all successfully completed the VAS sheets. The Wilcoxon signed rank test using week 1 as comparator was used to detect significance. Figure 1 presents the results obtained.
This survey uses a simple but pragmatic outcome measure (patient global wellbeing VAS) to indicate that patients who receive infliximab do not have a uniform sustained response. There was a significant trend for patients to notice a general decrease in their wellbeing towards the end of the 8 week interval. It should be noted that a global patient VAS is a subjective measure that can be influenced by the patient’s expectations. A patient’s global VAS, however, is used as a component of the more objective DAS28. Clearly, the DAS28 will vary depending upon its temporal relationship with respect to the infusion.
Disease response to infliximab has been related to serum levels.3,4 Individual variations in pharmacodynamics mean that in a proportion of patients infliximab clears more rapidly. St Clair et al found that 26% of all patients had undetectable trough levels of serum infliximab at week 54 on a 3 mg/kg 8 weekly regimen.3 Maini et al noted that patients not treated with methotrexate cleared serum infliximab more rapidly. The role of new antibody production in this observation is unclear at present but may be relevant.4 Should patients have their trough serum infliximab levels measured before being classified as a “non-responder” in the current national guidelines?
If patients with undetectable trough serum infliximab levels are identified, how should they be treated? Should they have higher doses, such as 5 mg/kg and an 8 weekly regimen, or more frequent infusions? St Clair et al compared 3 mg/kg 6 weekly regimens with a dose increase of 100 mg using pharmacodynamic modelling and concluded that a 6 weekly regimen would yield a higher trough serum level.
In conclusion, TNFα antagonists are an effective but costly treatment for rheumatoid arthritis. We have performed a pragmatic survey demonstrating a decrease in patient wellbeing over the 8 weeks between infliximab infusions. Non-responders should not be defined by looking at the week 8 DAS28 without taking the clinical response over time into account. This finding has implications for the frequency of infliximab administration and the timing of DAS28 assessments.
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