Subsidised access to TNFα inhibitors: is the rationale for exclusion of rheumatoid-factor-negative patients defensible?

To the Editor: The tumour necrosis factor (TNFα) inhibitors etanercept, infliximab and adalimumab are new treatments for rheumatoid arthritis (RA) subsidised by the Pharmaceutical Benefits Scheme (PBS) under strict criteria. These are based on data supplied by the sponsors and protracted discussions between the stakeholders: the Pharmaceutical Benefits Advisory Committee (PBAC), the sponsors, rheumatologists and consumer representatives.1 One eligibility criterion is that adult patients must be or have been rheumatoid-factor positive. This requirement raises particular concerns.

Rheumatoid factor is not exclusively associated with RA. It is found in a number of other autoimmune and infectious diseases, and has been detected in healthy people. Rheumatoid factor is a serological criterion in the American College of Rheumatology classification for RA. However, its presence is not definitive for a clinical diagnosis of RA, with rheumatoid factor being absent in about 30% of patients with RA. Studies suggest that patients who test positive for rheumatoid factor at baseline are more susceptible to relatively severe expression of RA, with development of erosions and functional disability.2 As the PBS already limits access to TNFα inhibitors to patients with severe active RA, the predictive value of rheumatoid factor for severity is redundant.

We systematically reviewed 23 clinical trials of TNFα inhibitors available in the public domain (references available on request). The review showed that only the Early Rheumatoid Arthritis trial restricted recruitment to patients who tested positive for rheumatoid factor.3 The aim of this study was to examine the effect of etanercept on the rate of development of erosions in patients with early RA, not whether rheumatoid-factor status affected response.

We conclude that the evidence for an association between rheumatoid-factor status and response to TNFα inhibitors in patients with severe RA is inadequate to justify rheumatoid-factor status as a criterion for PBS subsidisation. Similarly, no evidence for an association between rheumatoid factor and response to disease-modifying anti-rheumatic drugs has been reported.4 Nevertheless, potential predictors of response to TNFα inhibitors and such drugs are emerging (eg, polymorphisms of HLA-DRB1, TNFα, and interleukin-10).5 Further analysis of the unpublished individual patient data held by the sponsors is needed to shed light on this question. Clinical studies specifically designed to evaluate the influence of rheumatoid-factor status on response would be helpful.

The PBAC may have been provided with these data, but patients and clinicians operating in the public domain have not. This gives rise to an ethical dilemma whereby prescribers cannot provide a plausible explanation for why rheumatoid-factor status is an access criterion. For example, if rheumatoid-factor-positive status was selected to exclude patients with rheumatoid-factor-negative psoriatic arthritis, then the rationale would not appear to be ethically sound. Greater transparency with respect to the rationale and the evidence for the criteria selected for targeting subsidised access to important high-cost pharmaceuticals will enhance confidence in the PBS process.