EXTRA-ARTICULAR MANIFESTATIONS ASSOCIATED WITH HLA-B27 IN PEDIATRIC PATIENTS, INCLUDING UVEITIS, INFLAMMATORY BOWEL DISEASE AND DERMATOLOGICAL INVOLVEMENT: A SYSTEMATIC REVIEW

Zuzanna Przybylska; Bartłomiej Przystaś; Sebastian Podeszwa; Wiktor Rolski; Mikołaj Piotr Hobot; Paweł Michalski; Aleksandra Anna Purpura; Paulina Michalska; Magdalena Grzechowiak; Gabriela Patrycja Dobosz

doi:10.31435/ijitss.2(50).2026.5583

Authors

Zuzanna Przybylska Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland; Department of Clinical Genetics and Rare Diseases, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-055 Katowice, Poland https://orcid.org/0009-0001-3329-4602
Bartłomiej Przystaś Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0009-6121-3839
Sebastian Podeszwa Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0000-2973-5324
Wiktor Rolski Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0005-1439-4842
Mikołaj Piotr Hobot Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0001-2829-6005
Paweł Michalski SP ZOZ Miejski Szpital Zespolony w Częstochowie: 42-200 Częstochowa, Poland https://orcid.org/0009-0002-8935-7171
Aleksandra Anna Purpura Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0006-3893-7730
Paulina Michalska Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0007-4141-5906
Magdalena Grzechowiak Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0001-8486-0352
Gabriela Patrycja Dobosz Medical University of Silesia in Katowice, 15 Poniatowskiego Street, 40-055 Katowice, Poland https://orcid.org/0009-0009-4012-9101

DOI:

https://doi.org/10.31435/ijitss.2(50).2026.5583

Keywords:

HLA-B27, Uveitis, Extra-Articular Manifestations, Psoriasis, Inflammatory Bowel Disease, Pediatric Population

Abstract

Background: HLA-B27 is strongly associated with spondyloarthritis and related conditions. While extra-articular manifestations (EAMs) are well characterized in adults, their prevalence and clinical relevance in pediatric populations remain less clearly defined.

Aim: To systematically review and quantitatively synthesize evidence on the association between HLA-B27 positivity and extra-articular manifestations, including uveitis, inflammatory bowel disease (IBD), and dermatological involvement, in pediatric patients.

Material and methods: A systematic literature search of PubMed, Embase, Scopus, and Google Scholar was performed. Observational studies reporting extra-articular manifestations in HLA-B27–positive pediatric patients were included.

Results: Twenty-five studies met the inclusion criteria and were included in the qualitative synthesis. Uveitis was the most frequently reported manifestation, with consistently higher occurrence in HLA-B27–positive pediatric patients across cohorts. Inflammatory bowel disease and dermatological manifestations were reported less frequently but remained consistent components of the disease spectrum.

Conclusions: HLA-B27 positivity in pediatric patients is associated with a significant burden of extra-articular disease. Early recognition and multidisciplinary management may improve long-term outcomes. Integration of digital health tools and improved healthcare system strategies may play a key role in optimizing early detection and management.

References

Rosenbaum, J. T., Harrington, C. A., Searles, R. P., Fei, S. S., Zaki, A., Arepalli, S., Paley, M. A., Hassman, L. M., Vitale, A. T., Conrady, C. D., Keath, P., Mitchell, C., Watson, L., Planck, S. R., Martin, T. M., & Choi, D. (2021). Revising the diagnosis of idiopathic uveitis by peripheral blood transcriptomics. American Journal of Ophthalmology, 222, 15–23. https://doi.org/10.1016/j.ajo.2020.09.012

Fisher, C., Ciurtin, C., Leandro, M., Sen, D., & Wedderburn, L. R. (2021). Similarities and differences between juvenile and adult spondyloarthropathies. Frontiers in Medicine, 8, Article 681621. https://doi.org/10.3389/fmed.2021.681621

Barut, K., Adrovic, A., Şahin, S., & Kasapçopur, Ö. (2017). Juvenile idiopathic arthritis. Balkan Medical Journal, 34(2), 90–101. https://doi.org/10.4274/balkanmedj.2017.0111

Lazăr, C., Crișan, M., Man, O. I., Sur, L. M., Samașca, G., & Bolunduț, A. C. (2025). Juvenile spondyloarthropathies: Diagnostic and therapeutic advances—A narrative review. Journal of Clinical Medicine, 14(9), Article 3166. https://doi.org/10.3390/jcm14093166

Gritz, D. C., & Wong, I. G. (2004). Incidence and prevalence of uveitis in Northern California: The Northern California Epidemiology of Uveitis Study. Ophthalmology, 111(3), 491–500. https://doi.org/10.1016/j.ophtha.2003.06.014

Durrani, O. M., Meads, C. A., & Murray, P. I. (2004). Uveitis: A potentially blinding disease. Ophthalmologica, 218(4), 223–236. https://doi.org/10.1159/000078612

Shin, Y., Kang, J. M., Lee, J., Lee, C. S., Lee, S. C., & Ahn, J. G. (2021). Epidemiology of pediatric uveitis and associated systemic diseases. Pediatric Rheumatology Online Journal, 19(1), Article 48. https://doi.org/10.1186/s12969-021-00516-2

Angeles-Han, S. T., & Rabinovich, C. E. (2016). Uveitis in children. Current Opinion in Rheumatology, 28(5), 544–549. https://doi.org/10.1097/BOR.0000000000000316

Agrawal, M., Shah, S., Patel, A., Pinotti, R., Colombel, J.-F., & Burisch, J. (2019). Changing epidemiology of immune-mediated inflammatory diseases in immigrants: A systematic review of population-based studies. Journal of Autoimmunity, 105, Article 102303. https://doi.org/10.1016/j.jaut.2019.07.002

Sandberg, K., Yarger, E., & Saeed, S. (2020). Updates in diagnosis and management of inflammatory bowel disease. Current Problems in Pediatric and Adolescent Health Care, 50(5), Article 100785. https://doi.org/10.1016/j.cppeds.2020.100785

Scarallo, L., Maniscalco, V., Marrani, E., Aloi, M., Alvisi, P., Arrigo, S., Bramuzzo, M., Cardile, S., Dilillo, D., Felici, E., Graziano, F., Martinelli, M., Norsa, L., Romano, C., Pochesci, S., Zuin, G., Simonini, G., & Lionetti, P. (2025). Prevalence and outcomes of arthritis in pediatric IBD: A multicenter study from the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition. Digestive and Liver Disease, 57(3), 716–723. https://doi.org/10.1016/j.dld.2024.12.010

Generali, E., Ceribelli, A., Massarotti, M., Cantarini, L., & Selmi, C. (2015). Seronegative reactive spondyloarthritis and the skin. Clinics in Dermatology, 33(5), 531–537. https://doi.org/10.1016/j.clindermatol.2015.05.004

Kearsley-Fleet, L., Klotsche, J., van Straalen, J. W., Costello, W., D’Angelo, G., Giancane, G., Horneff, G., Klein, A., Láday, M., Lunt, M., de Roock, S., Ruperto, N., Schoemaker, C., Vijatov-Djuric, G., Vojinovic, J., Vougiouka, O., Wulffraat, N. M., Hyrich, K. L., Minden, K., & Swart, J. F. (2022). Burden of comorbid conditions in children and young people with juvenile idiopathic arthritis: A collaborative analysis of 3 JIA registries. Rheumatology, 61(6), 2524–2534. https://doi.org/10.1093/rheumatology/keab641

Foster, H. E., Minden, K., Clemente, D., Leon, L., McDonagh, J. E., Kamphuis, S., Berggren, K., van Pelt, P., Wouters, C., Waite-Jones, J., Tattersall, R., Wyllie, R., Stones, S. R., Martini, A., Constantin, T., Schalm, S., Fidanci, B., Erer, B., Demirkaya, E., Ozen, S., & Carmona, L. (2017). EULAR/PReS standards and recommendations for the transitional care of young people with juvenile-onset rheumatic diseases. Annals of the Rheumatic Diseases, 76(4), 639–646. https://doi.org/10.1136/annrheumdis-2016-210112

Angeles-Han, S. T., Ringold, S., Beukelman, T., Lovell, D., Cuello, C. A., Becker, M. L., Colbert, R. A., Feldman, B. M., Holland, G. N., Ferguson, P. J., Gewanter, H., Guzman, J., Horonjeff, J., Nigrovic, P. A., Ombrello, M. J., Passo, M. H., Stoll, M. L., Rabinovich, C. E., Sen, H. N., Schneider, R., & Reston, J. (2019). 2019 American College of Rheumatology/Arthritis Foundation guideline for the screening, monitoring, and treatment of juvenile idiopathic arthritis-associated uveitis. Arthritis Care & Research, 71(6), 703–716. https://doi.org/10.1002/acr.23871

Hollander, J. E., & Carr, B. G. (2020). Virtually perfect? Telemedicine for Covid-19. The New England Journal of Medicine, 382(18), 1679–1681. https://doi.org/10.1056/NEJMp2003539

Whitelaw, S., Mamas, M. A., Topol, E., & Van Spall, H. G. C. (2020). Applications of digital technology in COVID-19 pandemic planning and response. The Lancet Digital Health, 2(8), e435–e440. https://doi.org/10.1016/S2589-7500(20)30142-4

Shih, Y. J., Yang, Y. H., Lin, C. Y., Chang, C. L., & Chiang, B. L. (2019). Enthesitis-related arthritis is the most common category of juvenile idiopathic arthritis in Taiwan and presents persistent active disease. Pediatric Rheumatology Online Journal, 17(1), Article 58. https://doi.org/10.1186/s12969-019-0363-0

Arkachaisri, T., Teh, K. L., Book, Y. X., Hoh, S. F., Gao, X., & Das, L. (2021). Enthesitis related arthritis in a longitudinal Southeast Asian registry: High prevalence of HLA-B27, different sacroiliitis risk factors and less common drug-free remission. Journal of Clinical Medicine, 10(4), Article 568. https://doi.org/10.3390/jcm10040568

Gmuca, S., Xiao, R., Brandon, T. G., Pagnini, I., Wright, T. B., Beukelman, T., Morgan, E. M., & Weiss, P. F. (2017). Multicenter inception cohort of enthesitis-related arthritis: Variation in disease characteristics and treatment approaches. Arthritis Research & Therapy, 19(1), Article 84. https://doi.org/10.1186/s13075-017-1297-x

Yıldız, M., Haşlak, F., Adroviç, A., Şahin, S., Barut, K., & Kasapçopur, Ö. (2022). Juvenile spondyloartropathies. European Journal of Rheumatology, 9(1), 42–49. https://doi.org/10.5152/eurjrheum.2021.20235

Böhm, M. R., Tappeiner, C., Breitbach, M. A., Zurek-Imhoff, B., Heinz, C., & Heiligenhaus, A. (2017). Ocular hypotony in patients with juvenile idiopathic arthritis-associated uveitis. American Journal of Ophthalmology, 173, 45–55. https://doi.org/10.1016/j.ajo.2016.09.018

Kothari, S., Foster, C. S., Pistilli, M., Liesegang, T. L., Daniel, E., Sen, H. N., Suhler, E. B., Thorne, J. E., Jabs, D. A., Levy-Clarke, G. A., Nussenblatt, R. B., Rosenbaum, J. T., Lawrence, S. D., & Kempen, J. H. (2015). The risk of intraocular pressure elevation in pediatric noninfectious uveitis. Ophthalmology, 122(10), 1987–2001. https://doi.org/10.1016/j.ophtha.2015.06.041

Twilt, M., & Tzaribachev, N. (2015). Juvenile idiopathic arthritis: A frequent cause for chronic joint inflammation in childhood. Seminars in Orthodontics, 21, 72–76. https://doi.org/10.1053/j.sodo.2015.02.002

Constantin, T., Foeldvari, I., Anton, J., de Boer, J., Czitrom-Guillaume, S., Edelsten, C., Gepstein, R., Heiligenhaus, A., Pilkington, C. A., Simonini, G., Uziel, Y., Vastert, S. J., Wulffraat, N. M., Haasnoot, A. M., Walscheid, K., Pálinkás, A., Pattani, R., Györgyi, Z., Kozma, R., Boom, V., & Ramanan, A. V. (2018). Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: The SHARE initiative. Annals of the Rheumatic Diseases, 77(8), 1107–1117. https://doi.org/10.1136/annrheumdis-2018-213131

Hayworth, J. L., Turk, M. A., Nevskaya, T., & Pope, J. E. (2020). Fréquence de l’uvéite chez les patients présentant une arthrite chronique juvénile. Revue du Rhumatisme. https://doi.org/10.1016/j.rhum.2020.01.022

Gaur, P., Misra, R., & Aggarwal, A. (2015). Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis. Clinical Immunology, 161(2), 163–169. https://doi.org/10.1016/j.clim.2015.07.012

Sahin, S., Acari, C., Sonmez, H. E., Kilic, F. Z., Sag, E., Dundar, H. A., Adrovic, A., Demir, S., Barut, K., Bilginer, Y., Sozeri, B., Unsal, E., Ozen, S., & Kasapcopur, O. (2021). Frequency of juvenile idiopathic arthritis and associated uveitis in pediatric rheumatology clinics in Turkey: A retrospective study, JUPITER. Pediatric Rheumatology Online Journal, 19(1), Article 134. https://doi.org/10.1186/s12969-021-00613-2

Haasnoot, A. J., van Tent-Hoeve, M., Wulffraat, N. M., Schalij-Delfos, N. E., Los, L. I., Armbrust, W., Zuithoff, N. P., & de Boer, J. H. (2015). Erythrocyte sedimentation rate as baseline predictor for the development of uveitis in children with juvenile idiopathic arthritis. American Journal of Ophthalmology, 159(2), 372–377.e1. https://doi.org/10.1016/j.ajo.2014.11.007

Bou Antoun, M., Adamsbaum, C., Semerano, L., Koné-Paut, I., & Rossi-Semerano, L. (2017). Clinical predictors of magnetic resonance imaging-detected sacroiliitis in children with enthesitis related arthritis. Joint Bone Spine, 84(6), 699–702. https://doi.org/10.1016/j.jbspin.2017.07.003

Oliveira Pinheiro, F., Leuzinger-Dias, M., Fernandes, B. M., Fonseca, D., Vilaça, J., Figueira, L., & Brito, I. (2023). Outcome of uveitis in juvenile idiopathic arthritis and spondyloarthritis patients: A 5-year follow-up study. ARP Rheumatology, 2(1), 17–21. https://pubmed.ncbi.nlm.nih.gov/36842134/

Suelves, A. M., Lamba, N., Meese, H. K., Foster, C. S., González-Martín, J. M., Díaz-Llopis, M., & Christen, W. G. (2016). Nuclear cataract as an early predictive factor for recalcitrant juvenile idiopathic arthritis-associated uveitis. Journal of AAPOS, 20(3), 232–238.e1. https://doi.org/10.1016/j.jaapos.2016.02.010

Pers, Y.-M., Le Blay, P., Ludwig, C., Rittore, C., Tejedor, G., Foliwe, R., Rodiere, M., Jorgensen, C., & Touitou, I. (2017). Association of TRAF1-C5 with risk of uveitis in juvenile idiopathic arthritis. Joint Bone Spine, 84(3), 305–308. https://doi.org/10.1016/j.jbspin.2016.04.014

Standardization of Uveitis Nomenclature (SUN) Working Group. (2021). Classification criteria for juvenile idiopathic arthritis-associated chronic anterior uveitis. American Journal of Ophthalmology, 228, 192–197. https://doi.org/10.1016/j.ajo.2021.03.055

Osswald, D., Rameau, A. C., Speeg-Schatz, C., Terzic, J., & Sauer, A. (2018). Profil clinique et épidémiologique des uvéites pédiatriques, évolution des uvéites inflammatoires sous anti-TNF alpha [Clinical and epidemiological profile of pediatric uveitis, course of inflammatory uveitis treated with anti-TNF alpha]. Journal Français d’Ophtalmologie, 41(5), 447–452. https://doi.org/10.1016/j.jfo.2017.09.016

Stoll, M. L., Duck, L. W., Chang, M. H., Colbert, R. A., Nigrovic, P. A., Thompson, S. D., & Elson, C. O. (2020). Identification of Prevotella oralis as a possible target antigen in children with enthesitis related arthritis. Clinical Immunology, 216, Article 108463. https://doi.org/10.1016/j.clim.2020.108463

Gulati, R., Kavadichanda, G. C., Mariaselvam, C. M., Kumar, G., & Negi, V. S. (2021). Association of HLA-G, HLA-E and HLA-B*27 with susceptibility and clinical phenotype of enthesitis related arthritis (ERA). Human Immunology, 82(9), 615–620. https://doi.org/10.1016/j.humimm.2021.06.006

Boeskorova, S., Afonskaya, M., Argunova, V., Sleptsova, P., Leonteva, L., Burtseva, T., & Kostik, M. M. (2025). Ethnic heterogeneity of juvenile arthritis in the Republic of Sakha (Yakutia) related to a high human leukocyte antigen B27 frequency. World Journal of Clinical Pediatrics, 14(2), Article 101873. https://doi.org/10.5409/wjcp.v14.i2.101873

Khawaja, K., & Al-Maini, M. (2017). Access to pediatric rheumatology care for juvenile idiopathic arthritis in the United Arab Emirates. Pediatric Rheumatology Online Journal, 15(1), Article 41. https://doi.org/10.1186/s12969-017-0170-4

Esteva, A., Robicquet, A., Ramsundar, B., Kuleshov, V., DePristo, M., Chou, K., Cui, C., Corrado, G., Thrun, S., & Dean, J. (2019). A guide to deep learning in healthcare. Nature Medicine, 25(1), 24–29. https://doi.org/10.1038/s41591-018-0316-z

Davenport, T., & Kalakota, R. (2019). The potential for artificial intelligence in healthcare. Future Healthcare Journal, 6(2), 94–98. https://doi.org/10.7861/futurehosp.6-2-94

Topol, E. J. (2019). High-performance medicine: The convergence of human and artificial intelligence. Nature Medicine, 25(1), 44–56. https://doi.org/10.1038/s41591-018-0300-7

Heiligenhaus, A., Minden, K., Tappeiner, C., Baus, H., Bertram, B., Deuter, C., Foeldvari, I., Föll, D., Frosch, M., Ganser, G., Gaubitz, M., Günther, A., Heinz, C., Horneff, G., Huemer, C., Kopp, I., Lommatzsch, C., Lutz, T., Michels, H., Neß, T., & Lehmann, H. W. (2019). Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Seminars in Arthritis and Rheumatism, 49(1), 43–55. https://doi.org/10.1016/j.semarthrit.2018.11.004

Shenoi, S., Hayward, K., Curran, M. L., Kessler, E., Mehta, J. J., Riebschleger, M. P., & Foster, H. E. (2020). Telemedicine in pediatric rheumatology: This is the time for the community to embrace a new way of clinical practice. Pediatric Rheumatology Online Journal, 18(1), Article 85. https://doi.org/10.1186/s12969-020-00476-z

Ting, D. S. W., Pasquale, L. R., Peng, L., Campbell, J. P., Lee, A. Y., Raman, R., Tan, G. S. W., Schmetterer, L., Keane, P. A., & Wong, T. Y. (2019). Artificial intelligence and deep learning in ophthalmology. British Journal of Ophthalmology, 103(2), 167–175. https://doi.org/10.1136/bjophthalmol-2018-313173

Gulshan, V., Peng, L., Coram, M., Stumpe, M. C., Wu, D., Narayanaswamy, A., Venugopalan, S., Widner, K., Madams, T., Cuadros, J., Kim, R., Raman, R., Nelson, P. C., Mega, J. L., & Webster, D. R. (2016). Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs. JAMA, 316(22), 2402–2410. https://doi.org/10.1001/jama.2016.17216