A Unique Pathognomic Skin Manifestation of Familial Mediterranean Fever: Erysipelas-Like Erythema

Öz

Background: The present study aimed to describe the differences between patients with and with-out ELE in patients with Familial Mediterranean Fever (FMF) and to determine the relationship between erysipelas-like erythema (ELE) and demographic, clinical, genetic and treatment character-istics of the patients. Materials and Methods: The medical files of patients who were followed up with a diagnosis of FMF in the Pediatric Rheumatology Department of Gaziantep City Hospital between October 2023 and October 2024 were retrospectively analysed. Results: Of 409 patients with FMF, 205 (50.1%) were male. The median age at diagnosis was 6 (min-imum:1-maximum:18) years. FMF attack was accompanied by fever in 325 (79.5%), abdominal pain in 302 (73.8%), arthralgia in 121 (29.6%), arthritis in 56 (13.7%), chest pain in 62 (15.6%) and ELE in 55 (13.4%) patients. When comparing patients with ELE to those without, the frequencies of chest pain, arthralgia, and arthritis were significantly higher in the ELE group (p=0.014, p<0.001, p<0.001, respectively). Pathological mutations were significantly more common in FMF with ELE than those without one (p<0.001). Additionally, among FMF patients, the use of anti-interleukin-1 (anti-IL-1) treatment combinations due to colchicine resistance was significantly higher in those with ELE (p<0.001). Conclusions: The present study showed that ELE may be associated with subclinical inflammation, arthritis, colchicine resistance, pathogenic mutations, and severe disease scores in FMF patients. Based on these findings and existing literature, we believe that the presence of ELE in FMF patients is significant in terms of diagnosis, prognosis, and predicting the course of the disease.

Anahtar Kelimeler

• anti-interleukin-1
• colchicine resistance
• erysipelas-like erythema
• familial mediterranean fever

Ailevi Akdeniz Ateşinin Eşsiz Patognomik Cilt Bulgusu: Erizipel Benzeri Eritem

Öz

Amaç: Bu çalışmanın amacı erizipel benzeri eritemi olan ve olmayan Ailevi Akdeniz Ateşi (AAA) has-taları arasındaki farklılıkları tanımlamak ve erizipel benzeri eritem ile hastaların demografik, klinik, genetik ve tedavi özellikleri arasındaki ilişkiyi ortaya koymaktır. Materyal ve Metod: Ekim 2023 ve Ekim 2024 tarihleri arasında Gaziantep Şehir Hastanesi Çocuk Romatoloji bölümünde AAA tanısıyla takip edilen hastaların dosyaları retrospektif olarak incelendi. Bulgular: Ailevi Akdeniz Ateşi olan 409 hastanın 205'i (%50,1) erkekti. Hastaların tanı yaşı ortanca 6 (minimum:1-maksimum:18) yıldı. Hastaların 325'inde (%79,5) ateş, 302'sinde (%73,8) karın ağrısı, 121'inde (%29,6) artralji, 56'sında (%13,7) artrit, 62'sinde (%15,6) göğüs ağrısı ve 55'inde (%13,4) erizipel benzeri eritem FMF atağına eşlik ediyordu. Erizipel benzeri eritemi olan hastalar olmayanlarla karşılaştırıldığında, göğüs ağrısı, artralji ve artrit sıklıkları erizipel benzeri eritemi olan grupta anlamlı olarak daha yüksekti (sırasıyla p=0.014, p<0.001, p<0.001). Ailevi Akdeniz Ateşi hastalarında patolojik mutasyonlar ELE’si olanlarda ELE’si olmayanlardan daha yaygındı (p<0,001). Ayrıca AAA hastaları arasında kolşisin direnci nedeniyle anti-interlökin-1 tedavi kombinasyonlarının kullanımı erizipel benzeri eritemili hastalarda anlamlı derecede daha yüksekti (p<0.001). Sonuç: Bu çalışma erizipel benzeri eritemin AAA hastalarında subklinik inflamasyon, artrit, kolşisin direnci, patojenik mutasyonlar ve ciddi hastalık skorları ile ilişkili olabileceğini göstermiştir. Bu bulgulara ve mevcut literatüre dayanarak AAA hastalarında erizipel benzeri eritem varlığının tanı, prognoz hem de hastalık seyrinin öngörülmesi açısından öneme sahip olduğana inanıyoruz.

Anahtar Kelimeler

• ailevi akdeniz ateşi
• anti-interlökin-1
• erizipel benzeri eritem
• kolşisin direnci

Kaynakça

1. 1. Tufan A, Lachmann HJ. Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci. 2020;50(SI-2):1591-1610.
2. 2. Arpacı A, Doğan S, Erdoğan HF, El Ç, Cura SE. Presentation of a new mutation in FMF and evaluating the frequency of distri-bution of the MEFV gene mutation in our region with clinical findings. Mol Biol Rep. 2021;48(3):2025-2033.
3. 3. Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38(1):67-74.
4. 4. Varan Ö, Kucuk H, Babaoglu H, Guven SC, Ozturk MA, Hazneda-roglu S et al. Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amy-loidosis. Mod Rheumatol. 2019;29(2):363-366.
5. 5. Batu ED, Basaran O, Bilginer Y, Ozen S. Familial Mediterranean Fever: How to Interpret Genetic Results? How to Treat? A Quarter of a Century After the Association with the Mefv Gene. Curr Rheumatol Rep. 2022;24(6):206-212.
6. 6. Van Gijn ME, Ceccherini I, Shinar Y, Carbo EC, Slofstra M, Arostegui JI et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflamma-tory Diseases (INSAID). J Med Genet. 2018;55(8):530-537.
7. 7. Gezgin Yildirim D, Seven MB, Gönen S, Söylemezoğlu O. Ery-sipelas-like erythema in children with familial Mediterranean fever. Clin Exp Rheumatol. 2020;38 Suppl 127(5):101-104.
8. 8. Koker O, Aktay Ayaz N. Autoimmune and autoinflammatory diseases with mucocutaneous manifestations: A pediatric rheumatology perspective. Int J Dermatol. 2023;62(6):723-736.

9. 9. Sag E, Demirel D, Demir S, Atalay E, Akca U, Bilginer Y et al. Performance of the new 'Eurofever/PRINTO classification cri-teria' in FMF patients. Semin Arthritis Rheum. 2020;50(1):172-175.
10. 10. Tanatar A, Sönmez HE, Karadağ ŞG, Çakmak F, Çakan M, Demir F et al. Performance of Tel-Hashomer, Livneh, pediatric and new Eurofever/PRINTO classification criteria for familial Medi-terranean fever in a referral center. Rheumatol Int. 2020;40(1):21-27.
11. 11. Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M et al. P. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998;75(2):216-9.
12. 12. Ozen S, Demirkaya E, Amaryan G, Koné-Paut I, Polat A, Woo P, Uziel Y et al. Paediatric Rheumatology International Trials Or-ganisation; Eurofever Project. Results from a multicentre in-ternational registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children. Ann Rheum Dis. 2014;73(4):662-7.
13. 13. Öner N, Çelikel E, Güngörer V, Ekici Tekin Z, Coşkun S, Karagöl C et al. The Effect of Clinical and Genetic Variables of Familial Mediterranean Fever Patients: Real Life Data. J Clin Rheu-matol. 2023;29(7):326-331.
14. 14. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G et al. EULAR recommendations for the management of fa-milial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644-51.
15. 15. Hentgen V, Grateau G, Kone-Paut I, Livneh A, Padeh S, Rozen-baum M et al. Evidence-based recommendations for the prac-tical management of Familial Mediterranean Fever. Semin Ar-thritis Rheum. 2013;43(3):387-91.
16. 16. Parmaksız G, Noyan ZA. Can RDW be used as a screening test for subclinical inflammation in children with FMF? Is RDW re-lated to MEFV gene mutations? Clin Rheumatol. 2023;42(1):197-202.
17. 17. Gezgin Yıldırım D, Esmeray Senol P, Söylemezoğlu O. Predic-tors of persistent inflammation in children with familial Medi-terranean fever. Mod Rheumatol. 2022;32(4):803-807.
18. 18. Bayram MT, Çankaya T, Bora E, Kavukçu S, Ülgenalp A, Soylu A et al. Risk factors for subclinical inflammation in children with Familial Mediterranean fever. Rheumatol Int. 2015;35(8):1393-8.
19. 19. Çakmak F, Arık SD, Kayaalp G, Çağlayan Ş, Ulu K, Coşkuner T ve ark. Erysipelas-like Erythema: A Pathognomonic Rash in Chil-dren with Familial Mediterranean Fever. Med J Bakirkoy. 2023;19(2):217-221.
20. 20. Ozturk K, Cakan M. The analysis of genotype-phenotype corre-lation in familial Mediterranean fever. Pediatr Int. 2022;64(1):e15017. PMID: 34606655. doi: 10.1111/ped.15017.
21. 21. Moradian MM, Sarkisian T, Amaryan G, Hayrapetyan H, Yeghiazaryan A, Davidian N et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014;16(3):258-63.
22. 22. Avar-Aydın PÖ, Ozcakar ZB, Aydın F, Karakaş HD, Çakar N, Yalçınkaya F. Erysipelas-Like Erythema: A Manifestation of Se-vere Disease Phenotype in Pediatric Patients with Familial Mediterranean Fever. Turk Arch Pediatr. 2022;57(6):599-602.
23. 23. Yaşar Bilge NŞ, Bodakçi E, Bilgin M, Kaşifoğlu T. Comparison of clinical features in FMF patients according to severity scores: An analysis with the ISSF scoring system. Eur J Rheumatol. 2020;7(2):68-70.
24. 24. Maggio MC, Corsello G. FMF is not always "fever": from clinical presentation to "treat to target". Ital J Pediatr. 2020;46(1):7. PMID: 31941537. doi: 10.1186/s13052-019-0766-z
25. 25. Özen S, Batu ED, Demir S. Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommen-dations for Management. Front Immunol. 2017;8:253. PMID: 28386255. doi: 10.3389/fimmu.2017.00253.
26. 26. Mosad Mosa D, Shokry D, Ahmed DB, Sobh A. Early predictors of colchicine resistance in familial Mediterranean fever. Mod Rheumatol. 2023;33(4):830-835.
27. 27. Batu ED, Şener S, Arslanoglu Aydin E, Aliyev E, Bagrul İ, Türk-men Ş et al. A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry. Rheumatology (Oxford). 2024;63(3):791-797.
28. 28. Avar Aydın PÖ, Özçakar ZB, Aydın F, Karakaş HD, Çakar N, Yalçınkaya F. The Characteristics of Pediatric Patients with Familial Mediterranean Fever Treated with Anti-Interleukin-1 Treatment. Turk Arch Pediatr. 2022;57(4):448-452.
29. 29. Aktay Ayaz N, Demirkan FG, Coşkuner T, Demir F, Tanatar A, Çakan M et al. PREDICT-crFMF score: A novel model for pre-dicting colchicine resistance in children with familial Medi-terranean fever. Mod Rheumatol. 2023;34(1):220-225.