Abstract
Blau syndrome is a rare genetic granulomatosis affecting children. It could be responsible for vision-threatening complications and articular deformation. Due to the rarity of this disease, there are no standardized guidelines for its management. This work aimed to provide an updated overview of the different therapeutic options for Blau syndrome. We conducted research in the PubMed database for the different treatments used in Blau syndrome patients, and we proposed a therapeutic algorithm for disease management. High doses of corticosteroids are considered as a bridging therapy in Blau syndrome. Methotrexate should be initiated if the patient has articular or ocular involvement. An anti-tumor necrosis factor α should be added for patients with uveitis or residual arthritis. If the patient remains symptomatic, a switch to another anti-tumor necrosis factor α is the best option. In non-responders to the first- and second-line biotherapies, a switch to an anti-interleukin 1, an anti-interleukin 6, or tofacitinib is necessary.
Conclusion: This article suggested an algorithm for the treatment of Blau syndrome. Other studies are necessary to confirm the efficacy of these treatments.
What is Known: • Blau syndrome is a rare but severe granulomatosis that could be responsible for vision-threatening complications and articular deformation. • Blau syndrome seems to be refractory to treatments. | |
What is New: • High doses of corticosteroids are usually insufficient and should be considered only as a bridging therapy. • Blau syndrome could be considered as a poor factor for uveitis, thus, an anti-tumor necrosis factor α should be initiated for patients with uveitis or with residual arthritis. |
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References
Kaufman KP, Becker ML (2021) Distinguishing Blau syndrome from systemic sarcoidosis. Curr Allergy Asthma Rep 21(2):10
Takada S, Saito MK, Kambe N (2020) Blau syndrome: NOD2-related systemic autoinflammatory granulomatosis. G Ital Dermatol Venereol 155(5):537–541
Chiu B, Chan J, Das S, Alshamma Z, Sergi C (2019) Pediatric sarcoidosis: a review with emphasis on early onset and high-risk sarcoidosis and diagnostic challenges. Diagnostics (Basel) 9(4):160
Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L (2012) Blau syndrome, clinical and genetic aspects. Autoimmun Rev 12(1):44–51
Sidiqi A, Pegado V (2020) Blau syndrome following a bacterial infection. J AAPOS 24(2):118–120
Okazaki F, Wakiguchi H, Korenaga Y, Nakamura T, Yasudo H, Uchi S et al (2021) A novel mutation in early-onset sarcoidosis/Blau syndrome: an association with Propionibacterium acnes. Pediatr Rheumatol Online J 19(1):18
Arakawa A, Kambe N, Nishikomori R, Tanabe A, Ueda M, Nishigori C et al (2021) NOD2 mutation-associated case with Blau syndrome triggered by BCG vaccination. Children (Basel) 8(2):117
Rosé CD, Pans S, Casteels I, Anton J, Bader-Meunier B, Brissaud P et al (2015) Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford) 54(6):1008–1016
Poline J, Bourrat E, Meinzer U (2020) Camptodactlyly in pediatric practice: Blau syndrome. J Pediatr 221:257–259
Poline J, Fogel O, Pajot C, Miceli-Richard C, Rybojad M, Galeotti C et al (2020) Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome. J Eur Acad Dermatol Venereol 34(2):340–348
Maccora I, Marrani E, Mastrolia MV, Abu-Rumeileh S, Maniscalco V, Fusco E et al (2021) Ocular involvement in monogenic autoinflammatory disease. Autoimmun Rev 20(11):102944
Saini SK, Rose CD (1996) Liver involvement in familial granulomatous arthritis (Blau syndrome). J Rheumatol 23(2):396–399
Ting SS, Ziegler J, Fischer E (1998) Familial granulomatous arthritis (Blau syndrome) with granulomatous renal lesions. J Pediatr 133(3):450–452
Jabs DA, Houk JL, Bias WB, Arnett FC (1985) Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 78(5):801–804
Sinharay R, McKeown L, Phillips C, Li A, Duckworth A, Hall F et al (2021) First report of liver transplantation in Blau syndrome: the challenges faced in this rare granulomatous liver disease. Transpl Immunol 65:101378
Wu D, Shen M (2018) Two Chinese pedigrees of Blau syndrome with thirteen affected members. Clin Rheumatol 37(1):265–270
Su J, Liu D (2021) Blau syndrome with pulmonary nodule in a child. Australas J Dermatol 62(2):217–220
Sarens IL, Casteels I, Anton J, Bader-Meunier B, Brissaud P, Chédeville G et al (2018) Blau Syndrome-associated uveitis: preliminary results from an international prospective interventional case series. Am J Ophthalmol 187:158–166
Wu S, Zhong L, Sun Z, Zhu T, Song H, Sui R (2020) Ocular features in Chinese patients with Blau syndrome. Ocul Immunol Inflamm 28(1):79–85
Iriqat S, Safieh MA, Fatouleh M, Alkaiyat A (2021) Blau syndrome: a case report from Palestine. Pediatr Rheumatol Online J 19(1):138
Jindal AK, Pilania RK, Suri D, Gupta A, Gattorno M, Ceccherini I et al (2021) A young female with early onset arthritis, uveitis, hepatic, and renal granulomas: a clinical tryst with Blau syndrome over 20 years and case-based review. Rheumatol Int 41(1):173–181
Matsuda T, Kambe N, Takimoto-Ito R, Ueki Y, Nakamizo S, Saito MK et al (2022) Potential benefits of TNF targeting therapy in Blau syndrome, a NOD2-associated systemic autoinflammatory granulomatosis. Front Immunol 13:895765
Nascimento H, Sousa JM, Fernández DG, Salomão GHA, Sato EH, Muccioli C et al (2018) Blau-Jabs syndrome in a tertiary ophthalmologic center. Ophthalmic Surg Lasers Imaging Retina 49(1):70–75
Marín-Noriega MA, Muñoz-Ortiz J, Mosquera C, de-la-Torre A (2020) Ophthalmological treatment of early-onset sarcoidosis/Blau syndrome in a Colombian child: a case report. Am J Ophthalmol Case Rep 18:100714
PaÇ Kisaarslan A, SÖzerİ B, Şahİn N, Özdemİr ÇİÇek S, GÜndÜz Z, Demİrkaya E et al (2020) Blau syndrome and early-onset sarcoidosis: a six case series and review of the literature. Arch Rheumatol 35(1):117–127
Shetty AK, Gedalia A (1998) Sarcoidosis: a pediatric perspective. Clin Pediatr (Phila) 37(12):707–717
Millington GWM, Dobson J, Holden S, Waters G, Puvanachandra N, Close R et al (2019) Sporadic Blau syndrome treated with adalimumab. Clin Exp Dermatol 44(7):811–813
Kumrah R, Pilania RK, Menia NK, Rawat A, Sharma J, Gupta A et al (2022) Blau syndrome: lessons learned in a tertiary care centre at Chandigarh. North India Front Immunol 13:932919
Chen J, Luo Y, Zhao M, Wu D, Yang Y, Zhang W et al (2019) Effective treatment of TNFα inhibitors in Chinese patients with Blau syndrome. Arthritis Res Ther 21(1):236
Yasui K, Yashiro M, Tsuge M, Manki A, Takemoto K, Yamamoto M et al (2010) Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism. Arthritis Rheum 62(1):250–257
Wang W, Wang W, Zhong LQ, Li WD, Wu SJ, Song HM (2022) Thalidomide may be an effective drug for Blau syndrome: a case report. Ann Palliat Med 11(7):2538–2543
Soper JR, Bonar SF, O’Sullivan DJ, McCredie J, Willert HG (2019) Thalidomide and neurotrophism. Skeletal Radiol 48(4):517–525
Lu L, Shen M, Jiang D, Li Y, Zheng X, Li Y et al (2018) Blau syndrome with good reponses to tocilizumab: a case report and focused literature review. Semin Arthritis Rheum 47(5):727–731
Nagakura T, Wakiguchi H, Kubota T, Yamatou T, Yamasaki Y, Nonaka Y et al (2017) Tumor necrosis factor inhibitors provide longterm clinical benefits in pediatric and young adult patients with Blau syndrome. J Rheumatol 44(4):536–538
Matsuda T, Kambe N, Ueki Y, Kanazawa N, Izawa K, Honda Y et al (2020) Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. Ann Rheum Dis 79(11):1492–1499
Raiji VR, Miller MM, Jung LK (2011) Uveitis in Blau syndrome from a de novo mutation of the NOD2/CARD15 gene. J AAPOS 15(2):205–207
Bravo-Ljubetic L, Peralta-Calvo J, Noval S, Pastora-Salvador N, Abelairas-Gómez J, Merino R (2013) Adalimumab therapy for refractory childhood uveitis. J AAPOS 17(5):456–459
Simonini G, Xu Z, Caputo R, De Libero C, Pagnini I, Pascual V et al (2013) Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum 65(2):513–518
Caracseghi F, Izquierdo-Blasco J, Sanchez-Montanez A, Melendo-Perez S, Roig-Quilis M, Modesto C (2011) Etanercept-induced myelopathy in a pediatric case of blau syndrome. Case Rep Rheumatol 2011:134106
Martin TM, Zhang Z, Kurz P, Rosé CD, Chen H, Lu H et al (2009) The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum 60(2):611–618
Godfrey MS, Friedman LN (2019) Tuberculosis and biologic therapies: anti-tumor necrosis factor-α and beyond. Clin Chest Med 40(4):721–739
Barbati F, Marrani E, Volpi B, Ferrara G, Lodi L, Mastrolia MV et al (2022) Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study. Eur J Pediatr 181(9):3439–3448
Zhang S, Cai Z, Mo X, Zeng H (2021) Tofacitinib effectiveness in Blau syndrome: a case series of Chinese paediatric patients. Pediatr Rheumatol Online J 19(1):160
Aróstegui JI, Arnal C, Merino R, Modesto C, Antonia Carballo M, Moreno P et al (2007) NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum 56(11):3805–3813
Lopalco G, Schiraldi S, Venerito V, Guerriero S, Iannone F (2020) Effectiveness and safety profile of anakinra in a HLA-B27 positive patient with multiple sclerosis-associated uveitis. Mult Scler Relat Disord 42:102152
Fabiani C, Vitale A, Emmi G, Lopalco G, Vannozzi L, Guerriero S et al (2017) Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol 36(1):191–197
Maccora I, Abu Rumeileh S, Curci F, de Libero C, Marrani E, Mastrolia MV et al (2022) Tocilizumab and abatacept for the treatment of childhood chronic uveitis: a monocentric comparison experience. Front Pediatr 10:851453
Brunner HI, Wong R, Nys M, Kou TD, Dominique A, Martini A et al (2020) Abatacept: a review of the treatment of polyarticular-course juvenile idiopathic arthritis. Paediatr Drugs 22(6):653–672
Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA (2021) JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Ann Rheum Dis 80(7):865–875
Álvarez-Reguera C, Prieto-Peña D, Herrero-Morant A, Sánchez-Bilbao L, Martín-Varillas JL, González-López E et al (2022) Clinical and immunological study of tofacitinib and baricitinib in refractory Blau syndrome: case report and literature review. Ther Adv Musculoskelet Dis 14:1759720X221093211
Angeles-Han ST, Ringold S, Beukelman T, Lovell D, Cuello CA, Becker ML et al (2019) 2019 American College of Rheumatology/Arthritis Foundation guideline for the screening, monitoring, and treatment of juvenile idiopathic arthritis-associated uveitis. Arthritis Care Res (Hoboken) 71(6):703–716
Foeldvari I, Maccora I, Petrushkin H, Rahman N, Anton J, de Boer J et al (2023) New and updated recommendations for the treatment of juvenile idiopathic arthritis-associated uveitis and idiopathic chronic anterior uveitis. Arthritis Care Res (Hoboken) 75(5):975–982
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Dr. Hanene Ferjani: writing — review and editing. Dr. Lobna Kharrat: writing — original draft. Dr. Dorra Ben Nessib and Dr. Kaouther Maatallah: data analysis. Dr. Dhia Kaffel and Dr. Wafa Hamdi: supervision and validation.
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Lassoued Ferjani, H., Kharrat, L., Ben Nessib, D. et al. Management of Blau syndrome: review and proposal of a treatment algorithm. Eur J Pediatr 183, 1–7 (2024). https://doi.org/10.1007/s00431-023-05204-9
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DOI: https://doi.org/10.1007/s00431-023-05204-9