Rheumatology Advance Access originally published online on August 25, 2006
Rheumatology 2007 46(7):1211-1212; doi:10.1093/rheumatology/kel298
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Failure of anti-TNF therapy in TNF Receptor 1-Associated Periodic Syndrome (TRAPS)
Internal Medicine department, Bichat Hospital, 46 rue Henri Huchard, 75018, Paris, 1Internal Medicine department Gabriel Montpied Hospital, 58 rue Montalembert, 63000 Clermont-Ferrand and 2Human Molecular Genetics, Cochin Hospital, 123 boulevard de Port-Royal, 75014 Paris, France
Correspondence to: T. Papo. E-mail: thomas.papo{at}bch.aphp.fr
SIR, Hereditary fevers are a group of multisystem disorders characterized by recurrent attacks of fever and organ-localized inflammation that mainly affect musculoskeletal system, skin and serosal cavities [1]. The acronym TRAPS (Tumour necrosis factor Receptor Associated Periodic Syndrome) designates a dominantly inherited disease, with mutations affecting the 55 KDa tumour necrosis factor (TNF) receptor gene. We report on two French patients suffering from TRAPS, treated with anti-TNF drugs (etanercept, infliximab).
Case 1: A 23-yr-old-woman was referred for recurrent fever with repeated sub-cutaneous inflammation of the trunk or limbs. The onset of recurrent fever was noted at the age of 3 yrs. A painful and swelling erythema of a limb with spasticity of adjacent joint was frequent. In February 1999, no mutation in MEFV—underlying FMF—was detected, but a C30S TNFRS1A mutation was found in the patient, her father and grandfather [2].
Colchicine was ineffective. From February 1999 to November 1999, self-medication by short steroids courses reduced the duration of the attacks. Continuous prednisone treatment was then tried to prevent relapses, which occurred when the daily dose dropped under 20 mg.
Etanercept was introduced in December 2000, 25 mg subcutaneously twice a week. The patient stopped the treatment at the end of January 2001 after a severe crisis. A second course of etanercept began in October 2001, after an interruption of 8 months, because of continuous attacks. In January 2003, under etanercept, severity and duration of attacks required methylprednisolone intravenous pulses. Etanercept was withdrawn and switched for infliximab in February 2003, 150 mg intravenously. Twelve hours after the end of the first infusion, a hyperacute paradoxical reaction occurred, resulting in a large extending painful oedema of the left arm, contra lateral to infusion. C-reactive protein (CRP) level was over 300 mg/l. Inflammation resolved under high-dose prednisolone. A second and third course of infliximab were administered at 2 and 6 weeks, respectively. Attacks were frequent with localized violent thoracic pain which was ascribed to recurrent intercostal myositis. Chronic anaemia (6.5 g/dl) required red blood cells transfusion. Infliximab was withdrawn in April 2003, before the fourth injection.
Case 2: A 27-yr-old woman was referred for periodic fever. The onset of recurrent fever was noted at the age of 5 yrs. At time of admission stereotyped attacks occurred weekly, lasting 24–48 h. High-grade fever could be accompanied with violent abdominal and thoracic pain, arthritis and maculous eruption. During flares, blood leucocytes count was 25 000/mm3 and CRP levels 100–150 mg/l. Between the attacks, CRP levels appeared still elevated around 50 mg/l. Haemoglobin level was never above 10.5 g/dl.
In March 2001, a R92Q TNFRS1A mutation was demonstrated. Her younger brother and mother had no periodic fever or other TRAPS manifestations and she did not know her father. No family member could be tested.
Previous treatments with colchicine or non-steroidal anti-inflammatory drugs were ineffective. Low-dose daily steroid therapy with 15 mg prednisone could not prevent attacks. Infliximab was then started in October 2002, without any efficacy on fever and joints inflammation. From November 2002 to May 2003, four other courses of infliximab 200 mg were administered intravenously. The frequency of feverish attacks did not diminish and other symptoms such as joint inflammation continued with the same intensity. Moreover, CRP and haemoglobin levels were unchanged.
Because TRAPS attacks are characterized by their variability in length, intensity and free intervals in the same individual, treatment efficacy may be extremely difficult to ascertain. Few patients have some symptomatic relief on fever with colchicine or non-steroidal anti-inflammatory drugs, but these treatments are unable to diminish musculoskeletal or abdominal symptoms and have no preventive effect. Inflammatory attacks respond to corticosteroids in some patients. Other agents (azathioprine, methotrexate, ciclosporin, tacrolimus, cyclophosphamide, thalidomide, chlorambucil and dapsone) have been tried empirically without clear benefit.
In the only detailed published report on anti-TNF therapy, seven TRAPS patients received subcutaneous etanercept 25 mg twice weekly during 24 weeks in order to prevent flares [3]. During a prospective follow-up, clinical activity evaluated with scores of well-being and pain, and CRP levels, clearly improved in five patients. Moreover, corticosteroids requirement was reduced. Interestingly, one of the five patients had a second course of etanercept after a 3 months wash-out, which was considered ineffective [4]. Another team published on 15 patients showing a global clinical and biological improvement in a 6 month etanercept trial (25 mg or 0.5 mg/kg twice or thrice weekly), with no reported failure (but no individual data is available in the latest abstract) [4, 5]. Two paediatric cases were also treated efficiently with etanercept [6, 7]. A short course of etanercept during 3 days has also been reported to be effective as curative treatment for acute attacks in two cases [6, 8]. Complete failure of etanercept occurred in only three patients, including our patient 1 [4, 9]. In contrast with rheumatoid arthritis, TNF-OC plasma levels may remain elevated in TRAPS patients under etanercept treatment [10].
Infliximab had also been tried to prevent attacks in three TRAPS patients. When including our two cases, treatment failure was obvious in five patients [4, 6, 9]. Three of them, including our patient 1, were previously treated by etanercept without any efficacy. Of note, as in patient 1, paradoxical inflammatory reaction was observed in three patients [4, 9].
In conclusion, failure of anti-TNF drugs (etanercept, infliximab) may be observed in TRAPS patients. Moreover, infliximab infusion can be followed by a severe paradoxical reaction and must be cautiously prescribed in this syndrome.
The authors have declared no conflicts of interest.
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[Abstract/Free Full Text] - Drewe E, Powell RJ. Novel treatments for tumor necrosis factor receptor-associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept. Clin Exp Rheum (2002) 4:S71.
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[Abstract/Free Full Text]
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