Rheumatology Advance Access originally published online on December 3, 2007
Rheumatology 2008 47(2):228-229; doi:10.1093/rheumatology/kem243
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Comment on: Failure of anti-TNF therapy in TNF receptor 1-associated periodic syndrome (TRAPS)
1Department of Rheumatology, School of Medicine, University of Wales Swansea, Swansea SA2 8PP, 2Department of Rheumatology, Princess of Wales Hospital, Bridgend CF31 1RQ and 3Department of Rheumatology, University Hospital of Wales, Cardiff C14 4XW, UK
Correspondence to: S. Siebert, School of Medicine, Grove Building, University of Wales Swansea, Swansea SA2 8PP, UK. E-mail: S.Siebert{at}swansea.ac.uk
SIR, We read with interest the report by Jacobelli et al. [1] about their experiences with anti-tumour necrosis factor (TNF) therapy in TNF receptor 1-associated periodic syndrome (TRAPS). In particular, they describe a severe paradoxical reaction following infliximab infusion, which has previously been noted in other patients [2, 3].
We report a patient with TRAPS who developed a similar inflammatory exacerbation following infliximab, but who subsequently responded well to etanercept, and discuss these apparently divergent responses to anti-TNF therapy. We have previously reported on the signalling effects in a 50-yr-old woman with the TRAPS phenotype and a C43S TNFRSF1A mutation [4]. This patient experienced recurrent attacks of inflammation every 4–5 weeks, characterized by high fevers, pharyngitis and arthritis, accompanied by a migrating skin rash and myalgia. These episodes were generally of 2 weeks duration, during which time she was largely confined to bed. Between episodes, she reported only minor musculoskeletal symptoms, although her inflammatory markers remained persistently elevated. As conventional immunosuppression with steroids and azathioprine had failed to control her disease, a trial of infliximab (3 mg/kg) was commenced. Within 12 h of her first infliximab infusion, she developed a severe exacerbation of her inflammatory illness, of sufficient severity to necessitate hospital admission. This episode was accompanied by marked increase in both the neutrophil and total white cell counts (Fig. 1A), as well as the C-reactive protein (CRP) (Fig. 1B). Extensive investigation did not reveal any evidence of infection. The episode settled spontaneously within a week with supportive treatment including intravenous fluids. Three months after the infliximab infusion, she was treated with etanercept (25 mg twice weekly), which she tolerated well. While this treatment did not abolish her background musculoskeletal symptoms or normalize the CRP (Fig. 1B), it prevented the severe episodic flares and CRP spikes, resulting in a marked functional improvement. This partial response to etanercept is consistent with that described in other patients with TRAPS [3].
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Therefore, these two anti-TNF agents appear to have divergent effects in our TRAPS patient. Other groups have also reported severe exacerbations of TRAPS following infliximab [1–3]. Interestingly, the only two published reports of TRAPS patients, who did not have reactions following infliximab, are in patients with the low-penetrance R92Q mutation [1, 5]. This suggests that exacerbation of TRAPS following the monoclonal antibody infliximab is a feature of this condition.
It has become increasingly evident that there are important differences between the various anti-TNF agents [6]. We postulate that these differences could account for the differential effects seen with etanercept and infliximab in our patient. Further study of these differential effects in TRAPS could help explain the underlying mechanisms of this condition and advance our understanding of how the anti-TNF agents work.
Furthermore, while there are no published reports on the use of the fully humanized anti-TNF monoclonal antibody adalimumab in TRAPS, the above responses to infliximab caution against its use in TRAPS. We suggest that the monoclonal anti-TNF antibodies, infliximab and adalimumab, should be avoided in TRAPS. While the results with etanercept are mixed, anakinra, a recombinant IL-1 receptor antagonist has shown promise and is undergoing further evaluation and could also yield interesting mechanistic information [3].
Disclosure statement: S.S. has previously received an unrestricted educational grant from Schering-Plough. All other authors have declared no conflicts of interest.
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References |
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 Top References |
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- Jacobelli S, Andre M, Alexandra JF, Dode C, Papo T. Failure of anti-TNF therapy in TNF receptor 1-associated periodic syndrome (TRAPS). Rheumatology (2007) 46:1211–2.
[Free Full Text] - Drewe E, Powell RJ. Novel treatments for tumour necrosis factor receptor-associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept. Clin Exp Rheum (2002) 4:S71.
- Church LD, Churchman SM, Hawkins PN, McDermott MF. Hereditary auto-inflammatory disorders and biologics. Springer Semin Immunopathol (2006) 27:494–508.[CrossRef][Web of Science][Medline]
- Siebert S, Amos N, Fielding CA, et al. Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant. Arthritis Rheum (2005) 52:1287–92.[CrossRef][Web of Science][Medline]
- Drewe E, Lanyon PC, Powell RJ. Emerging clinical spectrum of tumor necrosis factor receptor-associated periodic syndrome: comment on the articles by Hull et al. and Dode et al. Arthritis Rheum (2003) 48:1768–9.[CrossRef][Web of Science][Medline]
- Rigby WF. Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? Nat Clin Pract Rheumatol (2007) 3:227–33.[CrossRef][Web of Science][Medline]
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