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Dramatic Improvement Following Interleukin 1ß Blockade in Tumor Necrosis Factor Receptor-1-Associated Syndrome (TRAPS) Resistant to Anti-TNF-α Therapy To the Editor: Tumor necrosis factor (TNF) receptor-1-associated-syndrome (TRAPS) is a chronic inherited autoinflammatory disorder. Typical features of TRAPS include recurrent fever, myalgia, rashes, and joint and abdominal pain associated with autosomal dominant mutations in the gene encoding the 55 kDa TNF receptor. Based upon a physiological rationale1, treatment with the p75 TNFR-Fc fusion protein etanercept has been found to be successful in many cases2. However, not all patients seem to benefit from anti-TNF-a therapy3. We describe dramatic improvement with interleukin 1ß (IL-1ß) blockade in a French patient with TRAPS who had failed to respond to anti-TNF-a therapy. A 26-year-old woman was followed for recurrent fever with persistent subcutaneous inflammation of the trunk or limbs. The onset of recurrent fever was noted at age 3 years. Stereotypic attacks occurred several times a year, lasting for 3 to 20 days. The fever was usually high-grade, with chills and sweats. Erythema with pain and swelling in a limb, together with stiffness in an adjacent joint, was frequent. This process moved distally down the limb during progression. There was no residual joint damage. Abdominal pain was also frequent, sometimes accompanied by diarrhea. The patient's family originated from the county of Normandy in France. Her grandfather had a similar history of sudden attacks between the ages of 30 and 55, consisting of high-grade fever, abdominal pain, and swelling and painful erythema in the trunk or limbs. The diagnosis of TRAPS was made in February 1999 when a missense mutation, C30S, was characterized in the first extracellular N-terminal cysteine-rich domain (CRD1) of the 55 kDa TNF receptor superfamily 1A (C30S TNFRSF1A mutation)4. She was initially treated with colchicine that was ineffective. From February 1999 to November 1999, self-medication by short courses of steroids attenuated the intensity and diminished the duration of the attacks. Continuous oral prednisone treatment was then tried to prevent relapses, which occurred when daily dose was under 20 mg. Over the last 8 years her condition had deteriorated, with increasing frequency and severity of attacks and chronic anemia. From December 2000 to March 2005, she was successively treated with etanercept, infliximab, and azathioprine, with no benefit. Clinical and biological remission was never achieved and C-reactive protein (CRP) had never normalized. The only way to reduce the intensity of attacks was to maintain prednisone at a minimal level of 20–25 mg (0.4 mg/kg) daily. As a beneficial response to IL-1ß blockade had been suggested in TRAPS3, treatment with daily subcutaneous injections of 100 mg anakinra was initiated in November 2006. The last attack had occurred 2 weeks before. At this time, the patient was treated with 20 mg daily oral prednisone. Blood tests showed a white blood cell count of 14,000 (85% neutrophils), CRP 75 mg/l, and hemoglobin 11.1 g/dl. Urinalysis was normal. From the day anakinra was started, she had no more clinical symptoms. CRP decreased to normal baseline values within 3 weeks and has remained in the normal range (Figure 1).
Inflammatory cytokine production was assessed before and under therapeutic IL-1ß blockade. Release of IL-1ß and TNF-a was measured from Ficoll-isolated unstimulated peripheral blood mononuclear cells as described5. A normal TNF-a level was observed both before (active disease) and under anakinra (inactive disease). Circulating levels of IL-1ß were under the detection threshold in both situations (data not shown). A mutation search was performed on genomic DNA after polymerase chain reaction amplification of exon 3 of CIAS1 gene as described6. No mutation was detected. Besides minor reactions at injection site, anakinra was well tolerated. Prednisone could be stopped after 3 months of anakinra treatment. At 9 months, the patient remains in complete clinical and biological remission. TRAPS is a rare autoinflammatory autosomal dominantly inherited condition associated with mutation of the 55 kDa TNFRSF1A. TRAPS usually shows a response to high doses of oral prednisone. However, the initial response may wane with time. Immunomodulators such as azathioprine, methotrexate, and cyclosporin have been tried, with disappointing results3. After the discovery of the genetic basis of TRAPS, anti-TNF-a treatment was introduced2. Not all patients benefit from this therapy, however. In our patient, both etanercept and infliximab failed to give satisfactory control of the disease7. Corticosteroids attenuated the intensity of attacks but did not diminish disease activity as assessed by the recurrence of attacks and the sustained high CRP blood level. The impact of the disease on the quality of life, corticosteroid-associated morbidity, and the potential occurrence of amyloidosis all emphasize the need to search for a novel treatment strategy in TRAPS. A dramatic improvement caused by the recombinant human IL-1ß receptor antagonist was observed in our patient with TRAPS. More than 40 different TNFRSF1A mutations have been identified8. Some patients do not express the TRAPS phenotype although they carry TRAPS-associated mutations. In addition, a previous study reported patients with symptoms highly suggestive of TRAPS with none of the mutations in the TNFRSF1A gene known to date9. Obviously, the genetic heterogeneity of TRAPS may affect treatment response. The TNFRSF1A receptor is a membrane protein with 4 cysteine-rich extracellular domains, a transmembrane domain, and a ~70-residue intracellular "death domain" involved in signal transduction10. Accordingly, our patient was known to have the C30S mutation that affects the CRD1 of TNFRSF1A4. Although the proinflammatory effects of TNF-a seemed to be mediated predominantly through binding of TNFRSF1A1, failure of anti-TNF-a therapy suggests that inflammation does not depend only on TNF-a-TNFRSF1A interaction, and that other mechanisms might be involved in the pathogenesis of TRAPS. A beneficial response to anakinra in TRAPS has been reported3. Both this report and ours point to the role of IL-1ß in the pathogenesis of TRAPS. Interestingly, efficacy of anakinra has recently been reported in other inherited autoinflammatory disorders, such as the cryopyrin-associated periodic syndromes (CAPS)11,12. CAPS include syndromes previously thought to be distinct — familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease — now linked to mutations in the CIAS1 gene13. The protein encoded by CIAS1 belongs to the inflammasome, a protein complex that contains cysteine-aspartate proteases involved in the proteolytic cleavage of IL-114. Hence, mutations in CIAS1 ultimately result in overproduction of IL-1ß. Because our observation suggests that IL-1ß could play a key role in the pathogenesis of TRAPS, we hypothesized the coexistence of 2 different autoinflammatory disease genes, meaning both mutations of the CIAS1 and TNFRSF1A genes in our patient. However, the plasma level of IL-1ß was under the detection threshold and we failed to find any mutation in the exon 3 of CIAS1. Our observation suggests that IL-1ß blockade with anakinra is safe and effective in controlling TRAPS refractory to anti-TNF-a agents. KARIM SACRÉ, MD; BENOIT BRIHAYE, MD; OLIVIER LIDOVE, MD; THOMAS PAPO, MD, Internal Medicine Department; MARIE-ANNICK POCIDALO, MD, PhD, Immunology Department, Bichat Hospital; LAURENCE CUISSET, PhD; CATHERINE DODÉ, PhD, Human Molecular Genetics Department, Cochin Hospital, Paris, France. Address reprint requests to Prof. T. Papo, Internal Medicine Department, Bichat Hospital, 46 rue Henri Huchard, 75018, Paris, France. E-mail: thomas.papo@bch.aphp.fr 2. Drewe E, McDermott EM, Powel PT, Isaacs JD, Powel RJ. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumor necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology Oxford 2003;42:235-9. [MEDLINE] 3. Simon A, Bodar EJ, van der Hilst JCH, et al. Beneficial response to interleukin-1 receptor antagonist in TRAPS. Am J Med 2004;117:208-10. [MEDLINE] 4. Dode C, Papo T, Fieschi C, et al. A novel missense mutation (c30s) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family. Arthritis Rheum 1999;43:1535-42. [MEDLINE] 5. Saito M, Fujisawa A, Nishikomori R, et al. Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic cutaneous articular syndrome. Arthritis Rheum 2005;52:3579-85. [MEDLINE] 6. Dode C, Le Dû N, Cuisset L, et al. New mutations of CIAS1 for Muckle Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 2002;70:1498-506. [MEDLINE] 7. Jacobelli S, Andre M, Alexandra JF, Dode C, Papo T. Failure of anti-TNF therapy in TNF-receptor-1-associated periodic syndrome (TRAPS). Rheumatology Oxford 2007;46:1211-2. [MEDLINE] 8. Infevers database. The Registry of Familial Mediterranean Fever and Hereditary Autoinflammatory Disorders Mutations. Touinou I, editor. Internet. Available from: http://fmf.igh.cnrs.fr/infevers. Accessed November 23, 2007. 9. Aganna E, Hammond L, Hawkins PN, et al. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum 2003;48:2632-44. [MEDLINE] 10. Banner DW, D'Arcy A, Janes W, et al. Crystal structure of the soluble human 55kd TNF receptor-human TNFb complex: implication for TNF receptor activation. Cell 1993;73:431-55. [MEDLINE] 11. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004;50:607-12. [MEDLINE] 12. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004;364:1779-85. [MEDLINE] 13. Arostegui JI, Aldea A, Modesto C, et al. Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheum 2004;50:4045-50. [MEDLINE] 14. Neven B, Callebaut I, Prieur AM, et al. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 2004;103:2809-15. [MEDLINE]
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