TNF-receptor-associated periodic syndrome (TRAPS) is an autoinflammatory condition and is the most common autosomal dominant hereditary periodic fever. Autoinflammatory syndromes are distinguished from autoimmune diseases by the fact that their disease immunopathology is largely played out by cells and molecules of the innate immune system.1 2

The pathogenesis of TRAPS is still not completely understood and treatment options are extremely limited. Prednisolone improves symptoms during attacks but the effect often wanes and patients may require increasing doses. Etanercept, a TNFR2 fusion protein, is reported to have a beneficial effect on many patients with TRAPS,3,–,6 whereas infliximab is not generally effective in most cases of TRAPS and may cause an overwhelming flare but occasional benefit has also been described.7,–,9 Anakinra, a recombinant interleukin 1 (IL-1) receptor antagonist, improves symptoms in some patients.10,–,12

Here we report our experience with biological agents in a large Irish family with TRAPS. This family consists of 15 affected family members with the T50M mutation in the TNFRSF1A gene. After informed consent, an interview, full clinical examination and chart reviews were performed. Data includes demographics, laboratory results and treatment. A summary of patient characteristics is shown in table 1.

A total of eight patients were treated with etanercept, six of whom were first treated for 6 months in 2001 (25 mg twice weekly) in the USA, as part of a clinical trial, with improvement in symptoms and reduced acute phase response (table 1); one of them did not require further treatment. Amyloidosis developed in two of these patients, reflecting their inadequate response to biological therapies, but the condition is stable since restarting etanercept, and inflammatory markers have remained normal in one of the patients under treatment. Two other patients had a partial response, with a reduction in inflammatory markers, and all four of these patients have remained on etanercept due to the lack of other efficacious medication; this has produced only limited symptomatic benefit and ongoing flares have persisted, despite an improvement in acute phase response. The remaining patients had a response on initiation of therapy but this was not sustained, with all of these patients reporting minimal or no efficacy after prolonged therapy.

Following the failure of etanercept therapy, three patients were started on anakinra but with no noticeable benefit and therapy was discontinued within 3 weeks. In fact, anakinra was very poorly tolerated due to disease flare characterised by injection site reactions occurring initially, followed by limb swelling, skin induration and fasciitis at injection sites which progressed further down the limb in association with raised C reactive protein present in all patients. This was typical of disease flares in these patients. Consequently, it is difficult to say whether anakinra would have had any beneficial effect if the treatment was continued.

Of the other seven members of this family, two refused treatment, one died due to concomitant multiple sclerosis, three have very mild disease and one is a 5-year-old child with very severe disease, who is already being considered for etanercept.

Contrary to many other published reports,3,–,6 10,–,12 our patients did not have a sustained response to etanercept and anakinra-caused disease flare; the treated patients had more severe and chronic disease. It is interesting to note that the T50M mutation is recognised as one of the most severe TNFRSF1A mutations in TRAPS. This poses questions as to whether the apparent inefficacy of medication is linked to the type of mutation or the severity of disease and also why etanercept-responsive patients lose efficacy with time? These dilemmas represent interesting aspects of TRAPS for exploration in future studies.