Abstract
Behçet’s disease (BD) is a multi-systemic, chronic inflammatory disease of unknown etiology, with a multisystemic recurrent course and variable vasculitis. Although the disease onset is usually between the second and fourth decades of life, the preliminary symptoms and signs may appear under the age of 16 years. The prevalence of BD in children is unknown, but it is probably very low. The most common ocular manifestations of pediatric BD include anterior and posterior uveitis, panuveitis, retinal vasculitis, and retinitis. The pathogenesis, treatment, and future directions for pediatric BD are also briefly discussed.
Behçet’s disease (BD) is a multi-systemic, chronic inflammatory disease of unknown etiology, with a multisystemic recurrent course and variable vasculitis, affecting any type and size of vessels, predominantly the veins, and thereby causing considerable morbidity and mortality.1-6 The term pediatric BD is used for cases diagnosed during childhood before the age of 16 years.1,4,7 Oral and genital mucosa, skin, and eyes are initially involved in pediatric BD.2 In addition, involvement can occur in other systems, such as the musculoskeletal, neurological, vascular, gastrointestinal, pulmonary, nephrourological, and cardiac systems.1
Ocular Manifestations of Pediatric Behçet’s Disease
Ocular involvement in pediatric BD is often observed 2–3 years after the onset of the disease; however, in 10%–20% of patients, it is present from the onset.4,7 Conflicting results have been found regarding ocular involvement in BD in children versus adults.4 For example, pediatric ocular involvement was found to occur less commonly and at a later stage than in adults; however, they had a worse prognosis, especially in males.7 Another study also found BD was not a common source of pediatric uveitis, even in countries with a high prevalence of this disease.8 The rate of ocular involvement was found to be similar between children and adults (30.9% and 29.1%, respectively) in another report.9 In contrast, other studies found ocular involvement was more common in children.10,11
A national cohort study using cross-sectional data on pediatric BD in Italy found ocular involvement was the second most common (43.6%) clinical result after oral ulcers.3 In a cohort of Iranian patients with pediatric BD, ocular involvement was more frequent (66.2%) and more severe than those in other reports.12 A prospective epidemiological study of BD in children and young people in the United Kingdom (UK) and Republic of Ireland found ocular involvement in 17.9% (10/56) of cases.6 Retrospective reviewed data of patients with BD aged 16 years or younger in a tertiary hospital in Taiwan found ocular involvement in 27.3% of cases.5 Therefore, the rate of ocular involvement is highly variable in pediatric BD, from 8.7% in the UK,13 66.2% in an Iranian pediatric cohort,12 and 81% in Turkey,14 although the latter result was obtained from an ophthalmology department.
The most common ocular manifestations of pediatric BD consist of anterior and posterior uveitis, panuveitis, retinal vasculitis, and retinitis,2,9,15,16 the prevalence of which varies considerably from 8.7% in the UK13 to 66.2% in an Iranian pediatric cohort.12 Uveitis may be the presenting symptom of BD in 10% of patients.2 The mean (±SD) age of onset of uveitis was 10.94 ± 3.62 years in children with BD.16
Anterior uveitis was found to be more common in patients younger than 10 years-of-age and was associated with familial aggregation,2 whereas panuveitis occurred later in the disease course.16 Intermediate uveitis was rare.2 Bilateral posterior uveitis with retinal vasculitis was found to be the most representative attribute of ocular BD.17 Iridocyclitis, keratitis, episcleritis, scleritis, vitritis, vitreous hemorrhage, optic neuritis, cataract, glaucoma, and retinal detachment can be other ocular manifestations of BD.4
A single-center retrospective study in Turkey found ocular findings in 35% of 34 children with BD.18 Panuveitis was reported as the most common ocular complication (67%) in this study,18 while posterior and anterior uveitis were observed at rates of 25% and 8%, respectively.18 The rates of panuveitis, posterior uveitis, and anterior uveitis have been reported to be 54%, 29%, and 17%, respectively, when uveitis was categorized in another study.7 The occurrence and severity of uveitis were reported to be related to male gender, commonly after the age of 10 years.7,10,15,19 Complications can vary and include cataracts, maculopathy, posterior synechiae, retinal detachment, and optic atrophy.15 In a recent prospective pediatric BD cohort, vision loss due to severe uveitis and enucleation has been recorded.6 After 5 years of follow-up in one study,16 visual acuity decreased to less than 20/200 by the Snellen test in 16.6% (26/156) of children with BD, which included 33.3% (26/78) of patients with ocular involvement.16
Regional Bias
Referral bias, as a form of selection bias, can considerably affect the reported estimations of ocular involvement in BD in different populations and contexts. Referral bias is due to the fact that individuals with particular traits, such as those with more severe or progressive ocular diseases, are more likely to seek medical attention and then be referred to dedicated ophthalmology departments for diagnosis and management. This can result in a skewed account of the actual prevalence of ocular involvement in the general population.20
Particular care protocols, healthcare strategies, and socioeconomic factors can also influence referral patterns. For example, in areas with limited access to medical resources, patients are less likely to be referred for assessment, potentially resulting in underestimation of ocular involvement. Increased access to focused care departments or new treatment guidelines can cause apparent changes in the reported rates of ocular involvement, which may not reproduce the true changes in the disease course or prevalence. Therefore, comparing ocular involvement rates across different populations or contexts without accounting for referral bias can mislead conclusions regarding the natural history or severity of BD in different regions of the world.20
Pathogenesis
The rate of familial aggregation in pediatric BD is higher than in adults,7,21 which may explain the difference in the clinical phenotype of adult and pediatric BD patients.22 The pathogenesis of BD is multifactorial, where a range of genetic, autoimmune, autoinflammatory, environmental, cytokine-related, dysfunctional T cell-dependent, non-infectious, and infectious factors, and changes in the gut microbiome may interact with each other to drive the potential sources of the disease.1,2,4,20,22-37
Human leukocyte antigen (HLA) genes, including HLA-B15, HLA-A26, HLA-B27, HLA-B51, and HLA-B5701, have been reported to be pivotal sources of genetic susceptibility.1-3,18,20,35,38-49 Outside the HLA region, an array of susceptibility forms can be strongly associated with the interleukin (IL)-23/IL-17 pathway,5,30,32,35,42,49-57 tumor necrosis factor (TNF) signaling, and pattern recognition receptor systems.37 Genome wide association probes have found associations between BD and several non-HLA genes, such as ERAP1,49,58-60 IL23 receptor (IL-23R), IL-23R/IL-12RB2, IL-10, and STAT4.22,34,43,49,61-65
Microbial infections, such as Streptococcus sanguinis22,34,66,67 and Mycobacterium tuberculosis, as well as viruses, such as herpes simplex virus (HSV), may trigger the disease in immunogenetically predisposed cases.37 Indeed, its association with both HLA-B51 and infectious factors, such as S. sanguinis, indicates BD can be the consequence of uncontrolled activation of the immune system driven by an exogenous trigger, with a mechanism of molecular mimicry.22,68
Treatment
Since non-infectious uveitis entities are supposed to be immune-related dysfunctions, typically designated as autoinflammatory or autoimmune diseases, which signify a self-directed pathological mechanism within the body, these entities are principally managed with immunosuppressive medications to suppress autoinflammatory or autoimmune responses.35,69 Because of the prominent relapsing-remitting route of ocular BD, the prevention of recurrent ocular inflammatory incidents is the most important therapeutic aim, as each relapse may induce a possible danger for irreversible vision loss and everlasting ocular complications.2,37,49,70,71
There are no published internationally approved recommendations concerning the management and treatment of pediatric BD.5,18,49 In addition, our understanding of therapeutic responses in pediatric BD is chiefly based on investigations performed in adult patients with BD.49 Considering the complex mechanisms underlying BD, treatment is mainly based on the affected site and disease severity.5 Given the rapid response to systemic corticosteroids and inadequate data regarding other medications administered to patients with pediatric BD, corticosteroids remain a good option for short-term therapy.5 However, the European Alliance of Associations for Rheumatology (EULAR) recommendations signify any patient with BD and inflammatory posterior uveitis should be treated with either azathioprine, cyclosporine, interferon-alpha, or monoclonal anti-TNF-alpha antibodies, and systemic glucocorticosteroids should not be used alone to control eye involvement.57 Although the EULAR recommendations are based on adult studies, they can be generalized to pediatric BD patients due to limited evidence in children.36 The combination of corticosteroids and immunomodulatory medications, such as anti-TNF agents (e.g., etanercept, infliximab, and adalimumab), interferon alpha, and conventional immunosuppressants (e.g., cyclosporine, azathioprine, and cyclophosphamide), comprises the main therapy for the disease.1-4,20,36,37,49
Future directions
Future studies should be conducted for a better understanding of the risk factors, pathogenesis, clinical course and manifestations, and treatment options of BD based on patients’ age, gender, medical history, and individual preferences according to the type and severity of affected organs.1,5,20,37,57 Randomized controlled trials are needed to specifically examine pediatric populations.20 Targeting specific pathological signaling pathways should be emphasized for better therapeutic results associated with fewer side effects.20 In addition, since the administration of corticosteroids and immunosuppressants can lead to considerable side effects or intolerance, which mainly limit their long-term use, follow-up should carefully address these possible effects.20
In this review, the author’s goal is to highlight ocular manifestations of pediatric BD to increase awareness of this rare disease among medical professionals, helping patients obtain a faster diagnosis, better coordination of management, and improve access to specialist advice, care, and drugs.
Acknowledgements
The author would like to express his honest gratitude and high respect for the lifetime support of his father, Mohammad Nouraeinejad.
Footnotes
Disclosures: This research did not receive any grant funding in the public, commercial, or nonprofit sectors. The author declares no conflicts of interest related to this work.
- Received March 1, 2024.
- Revision received May 14, 2025.
- Accepted June 10, 2025.
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