{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:05:44Z","timestamp":1792062344518,"version":"4.4.0"},"reference-count":22,"publisher":"AVES YAYINCILIK A.\u015e.","issue":"4","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Archives of Rheumatology"],"abstract":"<jats:p>Objectives: The study aimed to conduct a systematic literature review of the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of patients with deficiency of the interleukin-1 receptor antagonist (DIRA) and determine the practical contributions that the current scientific literature offers concerning the clinical and epidemiological aspects of DIRA.\r\nMaterials and methods: A systematic review of the literature was conducted in the PubMed, Scopus, Web of Science, and the Virtual Health Library databases between January 2009 and June 2024 in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. The following MeSH descriptors were used: \u201cinterleukin-1 receptor antagonist deficiency,\u201d \u201cepidemiology,\u201d \u201cclinical manifestations,\u201d \u201ctreatment,\u201d and \u201cphysiopathology.\u201d\r\nResults: Of the 3,749 articles, 18 met the eligibility criteria. The findings were divided by heuristic questions into three groups: \u201cepidemiological and genetic aspects of patients with DIRA,\u201d \u201cclinical and laboratory characterization in DIRA,\u201d and \u201ctherapeutic approach to patients with DIRA.\u201d\r\nConclusion: DIRA appears to be more common in males around four years of age. Several IL-1RN mutations were described, varying according to the geographic location. The most common symptoms were fever, followed by osteoarticular manifestations (arthralgia, muscle contracture, fracture, osteolytic lesions, and osteomyelitis), nail changes, pneumonia, venous thrombosis, and, in severe cases, multiple organ failure. There were no specific laboratory markers. Canakinumab was the drug of choice; however, glucocorticoids, rilonacept, and anakinra have been used.<\/jats:p>","DOI":"10.46497\/archrheumatol.2024.10882","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T07:56:27Z","timestamp":1740988587000},"page":"566-578","source":"Crossref","is-referenced-by-count":5,"title":["Deficiency of interleukin-1 receptor antagonist: A systematic review"],"prefix":"10.5152","volume":"39","author":[{"family":"W\u00e9rgila Ruana Gon\u00e7alves Barros","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Jucier Gon\u00e7alves J\u00fanior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"3111","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref-1","doi-asserted-by":"crossref","unstructured":"Kutukculer N, Puel A, Eren Akarcan S, Moriya K, Edeer Karaca N, Migaud M, et al. Deficiency of interleukin-1 receptor antagonist: A case with late onset severe inflammatory arthritis, nail psoriasis with onychomycosis and well responsive to Adalimumab therapy. Case Reports Immunol 2019;2019:1902817. doi: 10.1155\/2019\/1902817.","DOI":"10.1155\/2019\/1902817"},{"key":"ref-2","doi-asserted-by":"crossref","unstructured":"Romano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron K, et al. The 2021 EULAR\/ American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: Cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, Mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Arthritis Rheumatol 2022;74:1102-21. doi: 10.1002\/art.42139.","DOI":"10.1002\/art.42139"},{"key":"ref-3","doi-asserted-by":"crossref","unstructured":"Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med 2009;360:2467-70. doi: 10.1056\/NEJMe0811014.","DOI":"10.1056\/NEJMe0811014"},{"key":"ref-4","doi-asserted-by":"crossref","unstructured":"Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009;360:2426-37. doi: 10.1056\/NEJMoa0807865.","DOI":"10.1056\/NEJMoa0807865"},{"key":"ref-5","doi-asserted-by":"crossref","unstructured":"Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 2009;360:2438-44. doi: 10.1056\/ NEJMoa0809568.","DOI":"10.1056\/NEJMoa0809568"},{"key":"ref-6","doi-asserted-by":"crossref","unstructured":"Garg M, de Jesus AA, Chapelle D, Dancey P, Herzog R, Rivas-Chacon R, et al. Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight 2017;2:e94838. doi: 10.1172\/jci.insight.94838.","DOI":"10.1172\/jci.insight.94838"},{"key":"ref-7","doi-asserted-by":"crossref","unstructured":"Stenerson M, Dufendach K, Aksentijevich I, Brady J, Austin J, Reed AM. The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum 2011;63:4018-22. doi: 10.1002\/ art.30565.","DOI":"10.1002\/art.30565"},{"key":"ref-8","doi-asserted-by":"crossref","unstructured":"Mendonca LO, Malle L, Donovan FX, Chandrasekharappa SC, Montealegre Sanchez GA, Garg M, et al. Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the first Indian patient and a novel deletion affecting IL1RN. J Clin Immunol 2017;37:445-51. doi: 10.1007\/s10875-017-0399-1.","DOI":"10.1007\/s10875-017-0399-1"},{"key":"ref-9","doi-asserted-by":"crossref","unstructured":"Jesus AA, Osman M, Silva CA, Kim PW, Pham TH, Gadina M, et al. A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: Description of two unrelated cases from Brazil. Arthritis Rheum 2011;63:4007-17. doi: 10.1002\/art.30588.","DOI":"10.1002\/art.30588"},{"key":"ref-10","doi-asserted-by":"crossref","unstructured":"Minkis K, Aksentijevich I, Goldbach-Mansky R, Magro C, Scott R, Davis JG, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol 2012;148:747-52. doi: 10.1001\/ archdermatol.2011.3208.","DOI":"10.1001\/archdermatol.2011.3208"},{"key":"ref-11","doi-asserted-by":"crossref","unstructured":"Rivera-Sepulveda A, Col\u00f3n-Font\u00e1nez F, L\u00f3pez M, Puig-Ramos G. Deficiency of interleukin-1 receptor antagonist: New genetic autoinflammatory disease as a diagnostic challenge for pediatricians. J Pediatr Genet 2021;12:227-32. doi: 10.1055\/s-0041-1724113.","DOI":"10.1055\/s-0041-1724113"},{"key":"ref-12","doi-asserted-by":"crossref","unstructured":"Ulusoy E, Karaca NE, El-Shanti H, Kilicoglu E, Aksu G, Kutukculer N. Interleukin-1 receptor antagonist deficiency with a novel mutation; Late onset and successful treatment with canakinumab: A case report. J Med Case Rep 2015;9:145. doi: 10.1186\/ s13256-015-0618-4.","DOI":"10.1186\/s13256-015-0618-4"},{"key":"ref-13","doi-asserted-by":"crossref","unstructured":"Mendon\u00e7a LO, Grossi A, Caroli F, de Oliveira RA, Kalil J, Castro FFM, et al. A case report of a novel compound heterozygous mutation in a Brazilian patient with Deficiency of Interleukin-1 Receptor Antagonist (DIRA). Pediatr Rheumatol Online J 2020;18:67. doi: 10.1186\/s12969-020-00454-5.","DOI":"10.1186\/s12969-020-00454-5"},{"key":"ref-14","doi-asserted-by":"crossref","unstructured":"S\u00f6zeri B, Ger\u00e7eker-T\u00fcrk B, Y\u0131ld\u0131z-At\u0131kan B, Mir S, Berdeli A. A novel mutation of Interleukin-1 Receptor Antagonist (IL1RN) in a DIRA patient from Turkey: Diagnosis and treatment. Turk J Pediatr 2018;60:588- 92. doi: 10.24953\/turkjped.2018.05.020.","DOI":"10.24953\/turkjped.2018.05.020"},{"key":"ref-15","doi-asserted-by":"crossref","unstructured":"Schnellbacher C, Ciocca G, Menendez R, Aksentijevich I, Goldbach-Mansky R, Duarte AM, et al. Deficiency of interleukin-1 receptor antagonist responsive to anakinra. Pediatr Dermatol 2013;30:758-60. doi: 10.1111\/j.1525-1470.2012.01725.x.","DOI":"10.1111\/j.1525-1470.2012.01725.x"},{"key":"ref-16","doi-asserted-by":"crossref","unstructured":"Brau-Javier CN, Gonzales-Chavez J, Toro JR. Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: Excellent response to anakinra. Arch Dermatol 2012;148:301-4. doi: 10.1001\/ archdermatol.2011.2857.","DOI":"10.1001\/archdermatol.2011.2857"},{"key":"ref-17","doi-asserted-by":"crossref","unstructured":"Sakran W, Shalev SA, Sakran W, Shalev SA, El-Shanti H, Uziel Y, et al. Chronic recurrent multifocal osteomyelitis and deficiency of interleukin-1-receptor antagonist. Pediatr Infect Dis J 2013;32:94. doi: 10.1097\/INF.0b013e3182700cc1.","DOI":"10.1097\/INF.0b013e3182700cc1"},{"key":"ref-18","doi-asserted-by":"crossref","unstructured":"Thacker PG, Binkovitz LA, Thomas KB. Deficiency of interleukin-1-receptor antagonist syndrome: A rare auto-inflammatory condition that mimics multiple classic radiographic findings. Pediatr Radiol 2012;42:495-8. doi: 10.1007\/s00247-011- 2208-y.","DOI":"10.1007\/s00247-011-2208-y"},{"key":"ref-19","doi-asserted-by":"crossref","unstructured":"Ziaee V, Youssefian L, Faghankhani M, Jazayeri A, Saeidian AH, Vahidnezhad H, et al. Homozygous IL1RN mutation in siblings with Deficiency of Interleukin-1 Receptor Antagonist (DIRA). J Clin Immunol 2020;40:637-42. doi: 10.1007\/s10875- 020-00767-w.","DOI":"10.1007\/s10875-020-00767-w"},{"key":"ref-20","doi-asserted-by":"crossref","unstructured":"Kuemmerle-Deschner JB, Welzel T, Hoertnagel K, Tsiflikas I, Hospach A, Liu X, et al. New variant in the IL1RN-gene (DIRA) associated with late-onset, CRMO-like presentation. Rheumatology (Oxford) 2020;59:3259-63. doi: 10.1093\/rheumatology\/ keaa119.","DOI":"10.1093\/rheumatology\/keaa119"},{"key":"ref-21","doi-asserted-by":"crossref","unstructured":"Altiok E, Aksoy F, Perk Y, Taylan F, Kim PW, Il\u0131kkan B, et al. A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset. Clin Immunol 2012;145:77-81. doi: 10.1016\/j. clim.2012.08.003.","DOI":"10.1016\/j.clim.2012.08.003"},{"key":"ref-22","doi-asserted-by":"crossref","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. 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