Immunological Evaluation of Children with Behçet's Disease

Abstract

Objective: Behçet's disease (BD) is a rare, chronic, systemic inflammatory condition characterized by features of both autoinflammation and vasculitis. This study aimed to investigate the clinical manifestations, laboratory findings, and immunological features of children with BD, and to evaluate their treatment response. Methods: A retrospective analysis was conducted of the medical records of 50 children with BD, aged 0–18 years, followed at a single pediatric rheumatology center between January 2011 and 2023. Demographic, clinical, laboratory, and immunological data were collected, including serum immunoglobulin levels (interpreted according to age-specific reference values), lymphocyte subsets, and treatment response. Results: The cohort comprised 24 males (48%) and 26 females (52%). The mean age at diagnosis was 11.12±4.24 years, with an average diagnostic delay of 2.08 years. A family history of BD was present in 20 patients (40%). Oral aphthous ulcers were the most common manifestation (96%), followed by gastrointestinal involvement and genital ulcers (each 34%), musculoskeletal involvement (58%), uveitis (18%), neurological (18%), and vascular involvement (10%). HLA-B51 was positive in 39 patients (78%), and MEFV variants in 5 of 16 tested (31.2%). Before treatment, 13 of 34 patients (38.2%) showed a reduction in at least one serum immunoglobulin (IgG in 5, IgM in 6, and IgA in 2, all below −2 SD); one patient with low IgG developed multisystem inflammatory syndrome in children (MIS-C) after COVID-19 and received intravenous immunoglobulin for 6 months. Decreased T, B, and/or natural killer (NK) cells in the lymphocyte subset were detected in 15 out of 30 patients (50%). Although changes in lymphocyte subgroup counts and/or decreased immunoglobulin levels were detected in patients with oral aphthous ulcers and gastrointestinal involvement, immune tests were normal in most patients with neurological or vascular involvement. Colchicine was the most frequently prescribed medication (90%), followed by systemic corticosteroids (24%) and biological agents (18%); clinical improvement was observed in 32 patients (64%), and of the nine patients with uveitis, eight received treatment, of whom five achieved complete recovery. Conclusion: In our study, we observed antibody deficiencies and alterations in lymphocyte subsets, particularly in patients with gastrointestinal mucosal involvement and oral and genital aphthous ulcers. These findings suggest that immunological assessment may contribute to the monitoring of children with BD; however, controlled studies are needed to determine whether it can inform treatment decisions.

Keywords

• Behçet's disease
• Children
• Immunoglobulins
• Lymphocytes

Ethical Statement

Ethical approval was obtained from the Bursa Uludag University Faculty of Medicine Medical Research Ethics Committee for the study (2022–11/23).

Behçet Hastalığı olan Çocukların İmmünolojik Değerlendirilmesi

Abstract

Amaç: Behçet hastalığı (BH), hem otoinflamasyon hem de vaskülit özellikleriyle karakterize, nadir, kronik, sistemik inflamatuar bir hastalıktır. Bu çalışma, Behçet hastalığı olan çocukların klinik bulgularını, laboratuvar bulgularını ve immünolojik özelliklerini araştırmayı ve tedavi yanıtlarını değerlendirmeyi amaçlamıştır. Yöntemler: Ocak 2011 ile 2023 yılları arasında tek bir çocuk romatolojisi merkezinde takip edilen, 0–18 yaş aralığındaki BH tanılı 50 çocuğun tıbbi kayıtları retrospektif olarak analiz edildi. Demografik, klinik, laboratuvar ve immünolojik veriler toplandı; bunlara serum immünoglobulin düzeyleri (yaşa uygun referans değerlerine göre yorumlandı), lenfosit alt grupları ve tedavi yanıtı dâhildi. Bulgular: Kohort 24 erkek (%48) ve 26 kız (%52) hastadan oluşuyordu. Tanı anındaki ortalama yaş 11,12±4,24 yıl olup, ortalama tanı gecikmesi 2,08 yıldı. Yirmi hastada (%40) ailede Behçet hastalığı öyküsü mevcuttu. Oral aftöz ülserler en sık görülen bulguydu (%96); bunu gastrointestinal tutulum ve genital ülserler (her biri %34), kas-iskelet sistemi tutulumu (%58), üveit (%18), nörolojik (%18) ve vasküler tutulum (%10) izledi. HLA-B51, 39 hastada (%78) pozitifti ve MEFV varyantları test edilen 16 hastanın 5'inde (%31,2) saptandı. Tedavi öncesinde, 34 hastanın 13'ünde (%38,2) en az bir serum immünoglobulin düzeyinde azalma görüldü (5 hastada IgG, 6 hastada IgM, 2 hastada IgA; tümü −2 SD altında); düşük IgG'si olan bir hastada COVID-19 sonrası MIS-C gelişti ve 6 ay boyunca intravenöz immünoglobulin tedavisi aldı. Lenfosit alt grubunda T, B ve/veya NK hücrelerinde azalma 30 hastanın 15'inde (%50) saptandı. Lenfosit alt grubu sayılarındaki değişiklikler ve/veya immünoglobulin düzeylerindeki azalmalar oral aftöz ülser ve gastrointestinal tutulumu olan hastalarda saptanırken, nörolojik veya vasküler tutulumu olan hastaların çoğunda immün testler normaldi. Kolşisin en sık reçete edilen ilaçtı (%90); bunu sistemik kortikosteroidler (%24) ve biyolojik ajanlar (%18) izledi. Otuz iki hastada (%64) klinik düzelme gözlendi ve üveit nedeniyle tedavi edilen 8 hastanın 5'inde biyolojik ajanlarla tam iyileşme sağlandı. Sonuç: Çalışmamızda, özellikle gastrointestinal mukozal tutulumu ve oral ile genital aftöz ülserleri olan hastalarda antikor eksiklikleri ve lenfosit alt gruplarında değişiklikler gözlemledik. Bu bulgular, immünolojik değerlendirmenin Behçet hastalığı olan çocukların takibine katkı sağlayabileceğini düşündürmektedir; ancak tedaviyi yönlendirip yönlendiremeyeceğini belirlemek için kontrollü çalışmalara ihtiyaç vardır.

Keywords

• Behçet hastalığı
• Çocuklar
• İmmünoglobulinler
• Lenfositler

References

1. 1.Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçetsyndrome: a contemporary view. Nat RevRheumatol. 2018 Feb;14(2):107-19.
2. 2.Kone-Paut I. Behçet's disease in children, anoverview. Pediatr Rheumatol Online J. 2016;14:10.
3. 3.Yildiz M, Haslak F, Adrovic A, et al. PediatricBehçet's Disease. Front Med (Lausanne). 2021 Feb3;8:627192.
4. 4.Yıldız M, Köker O, Adrovic A, et al. PediatricBehçet's disease - clinical aspects and currentconcepts. Eur J Rheumatol. 2020 Feb;7(Suppl1):S38-S47.
5. 5.Maldini C, Druce K, Basu N, LaValley MP, Mahr A.Exploring the variability in Behçet's diseaseprevalence: a meta-analytical approach.Rheumatology (Oxford). 2018;57(1):185-95.
6. 6.Hu YC, Chiang BL, Yang YH. Clinical Manifestationsand Management of Pediatric Behçet’s Disease. ClinRev Allergy Immunol. 2021 Oct;61(2):171-80.
7. 7.Lavalle S, Caruso S, Foti R, et al. Behçet's Disease,Pathogenesis, Clinical Features, and TreatmentApproaches: A Comprehensive Review. Medicina(Kaunas). 2024;60(4):562.
8. 8. Seyahi E. Phenotypes in Behçet’s syndrome. InternEmerg Med. 2019;14:677-89.

9. 9.Tong B, Liu X, Xiao J, Su G. Immunopathogenesis of Behcet's Disease. Front Immunol. 2019 Mar29;10:665.
10. 10.Koné-Paut I, Shahram F, Darce-Bello M, et al.Consensus classification criteria for paediatricBehçet's disease from a prospective observationalcohort: PEDBD. Ann Rheum Dis. 2016Jun;75(6):958-64.
11. 11.International Study Group for Behçet's Disease.Criteria for diagnosis of Behçet's disease. Lancet.1990;335(8697):1078-80.
12. 12.Bayram RO, Özdemir H, Emsen A, Türk Dağı H,Artaç H. Reference ranges for serumimmunoglobulin (IgG, IgA, and IgM) and IgGsubclass levels in healthy children. Turk J Med Sci.2019;49(2):497-505.
13. 13.Besci Ö, Başer D, Öğülür İ, et al. Reference valuesfor T and B lymphocyte subpopulations in Turkishchildren and adults. Turk J Med Sci.2021;51(4):1814-24.
14. 14.Kalra S, Silman A, Akman-Demir G, et al.Diagnosis and management of Neuro-Behçet'sdisease: international consensus recommendations.J Neurol. 2014;261(9):1662-76.
15. 15.Abacar K, Macleod T, Direskeneli H, McGonagleD.How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparateautoimmune disorders. Front Immunol.2024;15:1439371.
16. 16.Tekgöz N, Tekgöz E, Çolak S, et al. Age-relateddifferences in the clinical phenotypes of Behçet'sdisease: The experience of two referral centres. ModRheumatol. 2023;34(1):194-200.
17. 17.Çirkinoğlu MS, Demir S, Bilginer Y, Özen S.Behçet's disease in children: single-centerexperience. Turk Pediatri Ars. 2019 Sep25;54(3):179-84.
18. 18.Maldini C, Lavalley MP, Cheminant M, deMenthon M, Mahr A. Relationships of HLA-B51 or B5genotype with Behcet's disease clinicalcharacteristics: systematic review and meta-analyses of observational studies. Rheumatology(Oxford). 2012 May;51(5):887-900.
19. 19.de Menthon M, Lavalley MP, Maldini C, GuillevinL, Mahr A. HLA-B51/B5 and the risk of Behçet'sdisease: a systematic review and meta-analysis ofcase-control genetic association studies. ArthritisRheum. 2009 Oct 15;61(10):1287-96.
20. 20.Wu Z, Zhang S, Li J, et al. Association betweenMEFV Mutations M694V and M680I and Behçet'sDisease: A Meta-Analysis. PLoS One.2015;10(7):e0132704.
21. 21.Parsaei A, Moradi S, Masoumi M, et al. Predictivevalue of erythrocyte sedimentation rate and C-reactive protein in Behcet's disease activity andmanifestations: a cross-sectional study. BMCRheumatol. 2022 Feb 11;6(1):9.
22. 22.Sota J, Vitale A, Rigante D, et al. Correlation ofSerum Amyloid-A Levels, Clinical Manifestations,Treatment, and Disease Activity in Patients withBehçet's Disease. Isr Med Assoc J. 2018Aug;20(8):517-21.
23. 23.Bettiol A, Alibaz-Oner F, Direskeneli H, et al.Vascular Behçet syndrome: from pathogenesis totreatment. Nat Rev Rheumatol. 2023 Feb;19(2):111-26.
24. 24.Tanacan E, Dincer D, Erdogan FG, Gurler A. Acutoff value for the Systemic Immune-InflammationIndex in determining activity of Behçet disease. ClinExp Dermatol. 2021 Mar;46(2):286-91.
25. 25.Hasan MS, Ryan PL, Bergmeier LA, Fortune F.Circulating NK cells and their subsets in Behçet'sdisease. Clin Exp Immunol. 2017 May;188(2):311-22.
26. 26.Yamaguchi Y, Takahashi H, Satoh T, et al. Naturalkiller cells control a T-helper 1 response in patientswith Behçet's disease. Arthritis Res Ther.2010;12(3):R80.
27. 27.Djaballah-Ider F, Djaballah A, Djeraba Z, Chaib S,Touil-Boukoffa C. Auto-immunity profile evaluationduring different clinical manifestations of Behçet disease in Algerian patients: effect of corticosteroid treatment. Inflammopharmacology. 2019 Dec;27(6):1113-22.
28. 28.Scully C, Boyle P, Yap PL. Immunoglobulins G, M,A, D, and E in Behçet’s syndrome. Clin Chim Acta1982; 20:37-42.
29. 29.van der Houwen TB, van Hagen PM,Timmermans WM, et al. Chronic signs of memory Bcell activation in patients with Behçet's disease arepartially restored by anti-tumour necrosis factortreatment. Rheumatology (Oxford). 2017Jan;56(1):134-44.
30. 30.Lim E, Tao Y, White AJ, French AR, Cooper MA.Hypogammaglobulinemia in pediatric systemiclupus erythematosus. Lupus. 2013;22(13):1382-7.
31. 31.Moradinejad MH, Rafati AH, Ardalan M, et al.Prevalence of IgA deficiency in children withjuvenile rheumatoid arthritis. Iran J Allergy AsthmaImmunol. 2011;10(1):35-40.
32. 32.Giani T, Luppino AF, Ferrara G. TreatmentOptions in Pediatric Behçet's Disease. PaediatrDrugs. 2023;25(2):165-91.
33. 33.Hatemi G, Christensen R, Bang D, et al. 2018update of the EULAR recommendations for themanagement of Behçet's syndrome. Ann Rheum Dis.2018 Jun;77(6):808-18.
34. 34.Nanthapisal S, Klein NJ, Ambrose N, EleftheriouD, Brogan PA. Paediatric Behçet's disease: a UKtertiary centre experience. Clin Rheumatol. 2016Oct;35(10):2509-16.