Tumour necrosis factor alpha inhibitors for the treatment of adult rheumatoid arthritis

Editor, – Professor McColl is to be congratulated for his admirable review of TNF-targeted antibodies (Aust Prescr 2004;27:43-6). These protein therapies may still need to be used as synergists with well-tried drugs such as methotrexate. They are very expensive and a real burden to both the Pharmaceutical Benefits Scheme (PBS) and to rheumatologists, who must provide much supportive data justifying the patient's need. Some of the criteria for their use may be suspect.¹

Two of these antibodies can bind cell-bound TNF, perhaps inducing apoptosis of the TNF-producing cells. In the long term, this may compromise natural defences against comorbidities, for example tumours, tuberculosis. (The third drug (etanercept) binds TNF after release from the cells.)

There are much cheaper drugs for controlling TNF production such as thalidomide and oxpentifylline (pentoxifylline).² Thalidomide may be in the 'too-hard basket', but oxpentifylline has been used for more than 30 years to treat poor circulation.³ Oxpentifylline is a proven alternative to steroids for controlling granulomatous inflammation in Hansen's disease.^4,5 So its safety is not an issue. Its short half-life³ permits rapid suspension of use should compromising situations such as infections arise. For optimal efficacy in treating chronic inflammation oxpentifylline may have to be used synergistically.⁶ One month's supply (400 mg tds) costs approximately $80 in Australia.

You will not read much about company-sponsored trials as the drug is out of patent and regulatory agencies do not favour drug combinations. The big question is whether support can be found for clinical trials of non-protein TNF-blockers. Positive outcomes might be much reduced costs to the PBS and widening the availability of TNF inhibition therapy.

Michael Whitehouse
Therapeutics Research Unit
Department of Medicine
Princess Alexandra Hospital
Woolloongabba, Qld

Professor G. McColl, the author of the article, comments:

I agree that the presence or absence of rheumatoid factor in patients treated with TNF inhibitors may not alter the likelihood of them responding. Studies subsequent to those used for the submission to the Australian Pharmaceutical Benefits Advisory Committee have shown that rheumatoid factor may not be a response-modifier, but further analysis of this information is required. I also agree about the increase of infectious risk when using TNF inhibitors and all clinicians using these agents must remain vigilant with regard to this risk.

Oxpentifylline and thalidomide do have anti-TNF effects, but the magnitude of their biological effect in rheumatoid arthritis appears modest, and certainly less than the TNF inhibitors described in my review, even when used in combination with methotrexate.1,2,3,4 Complications of thalidomide, especially neuropathy, also limit its clinical applicability in rheumatoid arthritis. The final comment about testing medications not protected by patent is reasonable and clearly work in this area will have to be investigator-driven and supported by institutions such as the National Health and Medical Research Council or the National Institutes of Health.