Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children18310.24287/1726-1708-2018-17-2-114-120ШКОЛА ИММУНОЛОГАClinical case of IgG4-related diseaseКлинический случай IgG4-ассоциированного заболеванияhttps://orcid.org/0000-0002-7846-3473SagoyanG. B.СагоянГ.Б.
Russian Federation
https://orcid.org/0000-0003-3664-2876AbramovD. S.АбрамовД.С.
Russian Federation
https://orcid.org/0000-0002-8208-2075DeordievaE. A.ДеордиеваЕ.А.
Russian Federation
BurlakovV. I.БурлаковВ.И.
Russian Federation
https://orcid.org/0000-0001-7317-7104TereshchenkoG. V.ТерещенкоГ.В.
Russian Federation
https://orcid.org/0000-0002-2869-6535KozlovaA. L.КозловаА.Л.
Russian Federation

MD, PhD, Department of immunology

Russia 117997, Moscow, Samory Mashela st., 1

annamax-99@mail.ruDmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, ImmunologyФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России2009201817211412020092018Copyright ©; 1970, «D. Rogachev NMRCPHOI»Copyright ©; 1970, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России1970«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/183

IgG4-related disease is an extremely rare disorder, сcharacterized by the inflammatory infiltration of various organs, with predominance of IgG4-positive plasma cells, fibrosis and high IgG4 plasma concentration. Treatment regiments have not been optimized, especially in children. Here we discuss a case of IgG4-related disease of the orbit in a 13 year old boy and our new treatment approach involving JAK-kinase inhibitor ruxolitininb. The article also presents analysis of the state of the problem of IgG4-related disease it he world, including terminology, historical references, pathogenesis, diagnostic problems  and clinical manifestations.

IgG4-связанное заболевание - крайне редкое, характеризующееся воспалительной инфильтрацией различных органов с преобладанием IgG4-положительных плазмоцитов, фиброзом и повышением концентрации IgG4 в крови. Подходы к его терапии не оптимизированы, особенно в педиатрической группе пациентов. В статье обсуждается случай IgG4-связанного заболевания орбиты у мальчика 13 лет, рассмотрен новый вариант терапевтического подхода при этой патологии с применением ингибитора JAK-киназ - руксолитиниба. Представлен анализ современного состояния проблемы IgG4-связанного заболевания в мире, затрагивающий аспекты терминологии, исторические справки, патогенез, проблемы диагностики и клинические проявления.

IgG4-related diseasechildrenorbitatreatmentJAK-inhibitorIgG4-связанное заболеваниедетиорбиталечениеингибитор JAK-киназKamisawa T., Zen Y., Pillai S., et al. IgG4-related disease. Lancet 2015; 385 (9976): 1460-71.Okazaki K., Uchida K., Ikeura T. Current concept and diagnosis of IgG4-related disease in the hepato-bilio-pancreatic system. J Gastroenterol 2013; 48 (3): 303-14.Mikulicz J. Uber eine eigenartige symmetrishe Erkrankung der Tranen und Mundspeicheldrusen. Stuttgart: Beitr z Chir Fesrschrf Theodor Billroth 1892: p. 610-30.Kuttner H. Uber entzundiche Tumoren der submaaxilla ren Speicheldruse. Beitr Klin Chir 1896; 15: 815-34.Comings D.E., Skubi K.B., Van Eyes J., Motulsky A.G. Familial multifocal fibrosclerosis. Ann Intern Med 1967; 66: 884-92.Okamoto T., Kamisawa A. Autoimmune pancreatitis: proposal of IgG4related sclerosing disease. J Gastroenterol 2006; 41: 613-25.Masaki Y., Dong L., Kurose N., Kitaga-wa K, Morikawa Y., Yamamoto M., et al. Proposal for a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68: 1310-5.Yamamoto M., Takahashi H., Ohara M., Suzuki C., Naishiro Y., Yamamoto H., et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol 2006; 16: 335-40.Umehara H., Okazaki K., Masaki Y., Kawano M., Yamamoto M., Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012; 22 (1): 1-14.Uchida K., Masamune A., Shimose-gawa T., Okazaki K., et. al. Prevalence of IgG4-related disease in Japan based on nationwide survey in 2009. Int J Rheumatol 2012; e358371.Stone J.H., Patel V.I., Oliveira G.R., Stone J.Rl. Case records of the Massachusetts General Hospital. Case 38-2012. A 60-year-old man with abdominal pain and aortic aneurysms. N Engl J Med 2012; 367 (24): 2335-46.Karim F., Loeffen J., Bramer W., Westernberg L., Verdijk R., Haden M, et. al. IgG4-related disease: a systematic review of this unrecognized disease in pediatrics. Pediatric Rheumatology 2016; 14: 18.Kawa S., Ota M., Yoshizawa K., Horiu-chi A., Hamano H., Ochi Y., et. al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 2002; 122 (5): 1264-9.Chang M.C., Chang Y.T., Tien Y.W., Lian P.C., Jan I.S., Wei S.C., et.al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem 2007; 53 (9): 1700-5.Umemura T., Ota M., Hamano H., Katsuyama Y., Kiyosawa K., Kawa S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut 2006; 55 (9): 1367-8.Umemura T., Ota M., Hamano H., Katsuyama Y., Muraki T., Arakura N., et. al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 2008; 103 (3): 588-94.Masaki Y., Dong L., Kurose N., Kitaga-wa K., Morikawa Y., Yamamoto M., et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68: 1310.Guarneri F., Guarneri C., Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med 2005; 9(3): 741-4.Yadlapati S., Verheyen E., Efthimiou P. IgG4-related disease: a complex under diagnosed clinical entity. Rheumatol Int 2018; 38 (2): 169-77.Frulloni L., Lunardi C., Simone R., Dolcino M., Scattolini C., Falconi M., et. al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med 2009; 361 (22): 2135-42.Zen Y., Fujii T., Harada K., Kawano M., Yamada K., Takahira M., et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007; 45: 1538.Björnsson E. Immunoglobulin G4-associated cholangitis. Curr Opin Gastroenterol 2008; 24: 389.Mattoo H., Mahajan V.S., Maehara T., Deshpande V., Della-Torre E., Wallace Z., et al. Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy Clin Immunol 2016; 138: 825.Kalapesi F.B., Garrott H.M., Moldovan C. IgG4 Orbital Inflammation in a 5-Year-Old Child Presenting as an Orbital Mass. Informa Healthcare USA 2013; 32 (2): 137-40.Lee C.S., Harocopos G.J., Kraus C.L., Lee A.Y., Van Stavern G. P., Couch S. M., et. al. IgG4-associated orbital and ocular inflammation. Journal of ophthalmic inflammation and infection 2015; 5: 15.Soliotis F., Mavragani C.P., Plastiras S.C., Rontogianni D., Skopouli F.N., Moutsopoulos H.M. IgG4-related disease: a rheumatologist’s perspective. Clin Exp Rheumatol 2014; 32: 724.Nakano S., Takeda I., Kitamura K., Watahiki H., Iimura Y., Takenaka M. Vanishing tumor of the abdomen in patient with Sjogren’s syndrome. Am J Dig Dis 1978; 23 (5): 75-9.Kamisawa T., Shimosegawa T., Okaza-ki K., Nishino T., Watanabe H., Kanno A., et. al. Standard steroid treatment for autoimmune pancreatitis. Gut 2009; 58 (11): 1504-7.Umehara H., Okazaki K., Masaki Y., Kawano M., Yamamoto M., Saeki T., et al. Comprehensive diagnostic criteria for IgG4-relataed disease, 2011. Mod Rheumatol 2012; 22 (1): 21-30.Kim H.M., Chung M.J., Chung J.B. Remission and relapse of autoimmune pancreatitis: focusing on corticosteroid treatment. Pancreas 2010; 39 (5): 555-60.Kim H.M., Chung M.J., Chung J.B. Remission and relapse of autoimmune pancreatitis: focusing on corticosteroid treatment. Pancreas 2010; 39 (5): 555-60.Kamisawa T., Okazaki K., Kawa S., Ito T., Inui K., Irie H., et al. Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis. J Gastroenterol 2014; 49 (6): 961-70.Saeki T., Kawano M., Mizushima I., Yamamoto M., Wada Y., Nakashima H., et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int. 2013; 84 (4): 826-33.Hirano K., Tada M., Isayama H., Yagioka H., Sasaki T., Kogure H., et. al. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut 2007; 56 (12): 1719-24.Wu A., Andrew N.H., Tsirbas A., Tan P., Gajdatsy A., Selva D., et. al. Rituximab for the treatment of IgG4-related orbital disease: experience from five cases. Eye (Lond) 2015; 29 (1): 122-8.Khosroshahi A., Bloch D.B., Deshpande V., Stone J.H. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum 2010; 62 (6): 1755-62.Hart P.A., Topazian M.P., Witzig T.E., Clain J.E., Gleeson F.C., Klebig R.R., et. al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut 2013; 62 (11): 1607-15.Della-Torre E., Campochiaro C., Bozzo-lo E.P., Dagna L., Scotti R., Nicoletti R., et. al. Methotrexate for maintenance of remission in IgG4-related disease. Rheumatology (Oxford) 2015; 54 (10): 1934-6.Carruthers M.N., Topazian M.P., Khos-roshahi A., Witzig T., Wallace Z., Hart P., et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis 2015; 74 (6): 1171-7.Kozlova A., Burlakov V., Abramov D., Sagoyan G., Shcherbina A. A case report of a pediatric patient with orbital IgG4-related disease. PRES 2017, RPeS-ABS-1402.Aalberse R.C., Stapel S.O., Schuurman J., Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009; 39: 469.Liu L.J., Chen M., Yu F.,Zhao M., Wang H. IgG subclass distribution, affinity of anti-myeloperoxidase antibodies in sera from patients with Wegener's granulomatosis and microscopic polyangiitis. Nephrology (Carlton) 2008; 13: 629.Zen Y., Nakanuma Y. Pathogenesis of IgG4-related disease. Curr Opin Rheumatol 2011; 23: 114.Horvath C.M. The JAK-STAT pathway stimulated by interferon gamma. Sci STKE 2004: 260.Frank D.A., Robertson M.S., Bonni A., Ritz J., Greenberg M. Interleukin 2 signaling involves the phosphorylation of STAT proteins. Proc Natl Acad Shi USA 1995; 92 (17): 7779-83.Busch-Dienstfertig M., Gonzalez-Rod-riguez S. IL-4, JAK-STAT signaling and pain. JAK STAT 2013; 2 (4): е27638.Siang H., Harris M. B., Rothman P. IL4/IL13 signaling beyong JAK/STAT. J Allergy Clin Immunol 2000; 105 (6 Pt. 1): 1063-70.Razdrak K., Stafford S., Alam R. The activation of the Jak-STAT1 signaling pathway by IL - in eosinophils. J Immunol 1995; 155 (1): 397-402.