HLA-B5 prevalence in patients with spondyloarthritis and impact on disease phenotype: a multicentric case-control study.

OBJECTIVE: The study aimed to estimate the prevalence of HLA-B51 and HLA-B52 in Lebanese patients with spondyloarthritis (SpA) compared to healthy controls (HC). We further aimed to evaluate the impact of HLA-B51 on phenotype and identify the distribution of the alleles in the HLA-B locus. METHODS: A case-control study enrolled consecutive SpA patients from three rheumatology clinics in Lebanon, including axial (axSpA), peripheral SpA (pSpA), and psoriatic arthritis (PsA) and HC from blood donors. Demographic and disease data were collected through interviews and file reviews, with testing of the entire HLA-B locus using molecular techniques. The prevalence of HLA-B51 and B52 was estimated in SpA patients versus controls. Prevalence comparisons were made, and logistic regression identified factors associated with HLA-B51 in patients. RESULTS: Data from 120 HC and 86 SpA patients (65 axSpA, 15 pSpA, 6 PsA), mean age 25.6 and 46.4 years, respectively, showed a higher HLA-B51 prevalence in SpA (25.6%), especially axSpA (29.2%) versus HC (12.5%), p = 0.016, and a numerically higher HLA-B52 prevalence (8.1% versus 4.2%, p = 0.230). HLA-B51 correlated with recurrent oral ulcerations (OR 7.99(95%CI 2.14-29.84) and radiographic juxta-articular erosions (OR 7.65(95%CI 1.14-38.03)). HLA-B35 was the most dominant allele in both groups (18.7%), followed by HLA-B27 (15.7%) and HLA-B51 (13.4%) in SpA. CONCLUSION: HLA-B51 was identified more frequently in patients with SpA compared to HC and was associated with recurrent oral ulcerations and juxta-articular radiographic erosions. Longitudinal studies are needed to determine whether this association indicates a disease overlap or might correlate with a specific SpA phenotype.

Impact of HLA-B51 on Uveitis and Retinal Vasculitis: Data from the AIDA International Network Registries on Ocular Inflammatory Disorders.

PURPOSE: The clinical relevance of human leukocyte antigen (HLA) subtypes such as HLA-B51 on Behçet's disease (BD)-related uveitis and non-infectious uveitis (NIU) unrelated to BD remains largely unknown. METHODS: Data were prospectively collected from the International AIDA Network Registry for BD and for NIU. We assessed differences between groups (NIU unrelated to BD and positive for HLA-B51, BD-related uveitis positive for HLA-B51 and BD-related uveitis negative for HLA-B51) in terms of long-term ocular complications, visual acuity (VA) measured by best corrected visual acuity (BCVA), anatomical pattern, occurrence of retinal vasculitis (RV) and macular edema over time. RESULTS: Records of 213 patients (341 eyes) were analyzed. No differences in complications were observed (p = 0.465). With regard to VA, a significant difference was detected in median BCVA (p = 0.046), which was not maintained after Bonferroni correction (p = 0.060). RV was significantly more prevalent in NIU-affected patients who tested positive for HLA-B51, irrespective of the systemic diagnosis of BD (p = 0.025). No differences emerged in the occurrence of macular edema (p = 0.99). CONCLUSIONS: Patients with NIU testing positive for HLA-B51 exhibit an increased likelihood of RV throughout disease course, irrespective of a systemic diagnosis of BD. The rate of complications as well as VA are comparable between NIU cases unrelated to BD testing positive for HLA-B51 and uveitis associated with BD. Therefore, it is advisable to perform the HLA-B typing in patients with NIU or retinal vasculitis, even in the absence of typical BD features.

Significant association of HLA-A26 with uveitis and gastrointestinal involvement in patients with Behçet's disease in a multicenter study.

OBJECTIVES: Specific HLA haplotypes are associated with Behçet's disease (BD). Because the effects of HLA-A26 and its combination with HLA-B51 on organ involvement in BD have not been well demonstrated, we aimed to examine them. METHODS: This multicenter, cross-sectional, observational study enrolled patients with BD who visited Kyoto University Hospital between 2018 and 2021 or Kurashiki Central Hospital between 2006 and 2016 (n = 200). Disease severity was evaluated using the Krause score. RESULTS: Uveitis and gastrointestinal involvement were observed in 95/196 and 57/167 patients, respectively. The HLA alleles identified were HLA-B51 (n = 52/106), HLA-A26 (n = 25/88), and HLA-B51 and HLA-A26 (n = 6/88). In patients harboring HLA-B51, the presence of HLA-A26 was associated with higher frequencies of uveitis (p = 0.03) and coexistence of uveitis and gastrointestinal involvement (p = 0.002), and higher Krause scores (p = 0.02). Furthermore, the presence of HLA-A26 was associated with a higher frequency of uveitis in patients with gastrointestinal involvement (p = 0.001) and gastrointestinal involvement in patients with uveitis (p = 0.001). CONCLUSIONS: Since specific HLA haplotypes and their combinations are associated with organ involvement, both HLA-A and HLA-B haplotypes should be confirmed when screening for affected organs.

The novel HLA-B*51:389 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*51:389 differs from HLA-B*51:02:01:01 by one nucleotide in exon 2.

Next generation sequencing identifies two novel HLA alleles, HLA-B*51:395 and HLA-DQB1*06:478.

We identified two novel HLA alleles by NGS, HLA-B*51:395 and HLA-DQB1*06:478.

Characterization of the novel HLA-B*51:394Q allele by sequencing-based typing.

HLA-B*51:394Q differs from HLA-B*51:01:01:05 by one nucleotide substitution in codon 339 in exon 7.

Characterization of the novel HLA-B*51:01:01:109 allele by next generation sequencing in a Greek individual.

HLA-B*51:01:01:109 differs from HLA-B*51:01:01:01 by one nucleotide substitution in intron 5.

Case report: Deep vein thrombosis as the sole clinical feature of Behcet's syndrome.

Introduction: Behcet's syndrome is a rare, chronic, systemic condition often categorized within the group of vasculitides. It presents a diagnostic challenge due to its varied clinical manifestations and the absence of a definitive laboratory test. Its etiology remains unclear but may involve genetic, infectious, and environmental factors. Case presentation: We report the case of a 16-year-old male who presented with deep vein thrombosis, followed by recurrent episodes of breakthrough thrombosis, despite adequate anticoagulant therapy. The patient did not meet the International Study Group (ISG) criteria nor the International Criteria for Behcet's syndrome (ICBD) due to the absence of characteristic features such as oral aphthous ulcers, genital ulcers, and uveitis. Later in the disease course, after ruling out other causes of breakthrough thrombosis, he tested positive for HLA-B51, an allele associated with Behcet's syndrome, and exhibited a pathergy reaction. Discussion: The patient's clinical course underlines the diagnostic complexity associated with Behcet's syndrome and highlights the importance of maintaining a broad differential diagnosis in cases of recurrent thrombosis. Although HLA-B51 testing is not routinely recommended, it played a pivotal role in our case, underscoring the value of an integrated diagnostic approach. Furthermore, this case reinforces the potential for atypical presentations of Behcet's syndrome, necessitating vigilant clinical awareness. After establishing the diagnosis, we successfully treated the patient with immunosuppressive therapy, significantly improving his condition.

Neuro-Behçet's Disease Onset in the Context of Tuberculous Meningoencephalitis: A Case Report.

Behçet's disease (BD) is a systemic vasculitis that frequently presents with a relapsing-remitting pattern. CNS involvement (Neuro-Behçet) is rare, affecting approximately 10% of patients. Its etiological mechanisms are not yet fully understood. The most commonly accepted hypothesis is that of a systemic inflammatory reaction triggered by an infectious agent or by an autoantigen, such as heat shock protein, in genetically predisposed individuals. Mycobacterium tuberculosis is known to be closely interconnected with BD, both affecting cell-mediated immunity to a certain extent and probably sharing a common genetic background. We present the case of a 34-year-old Caucasian woman who had been diagnosed with tuberculous meningitis 15 months prior, with significant neurological deficits and lesional burden on MRI with repeated relapses whenever treatment withdrawal was attempted. These relapses were initially considered as reactivation of tuberculous meningoencephalitis, and symptoms improved after a combination of antituberculous treatment and corticosteroid therapy. After the second relapse, the diagnosis was reconsidered, as new information emerged about oral and genital aphthous lesions, making us suspect a BD diagnosis. HLA B51 testing was positive, antituberculous treatment was stopped, and the patient was started on high doses of oral Cortisone and Azathioprine. Consequently, the evolution was favorable, with no further relapses and slow improvements in neurological deficits. To our knowledge, this is the first report of Neuro-Behçet's disease onset precipitated by tuberculous meningitis. We include a review of the available literature on this subject. Our case reinforces the fact that Mycobacterium tuberculosis infection can precipitate BD in genetically predisposed patients, and we recommend HLA B51 screening in patients with prolonged or relapsing meningoencephalitis, even if an infectious agent is apparently involved.

The relationship between HLA-B*51 subtypes, clinical manifestations and severity of Behçet's syndrome: a large Italian cohort study.

Objectives: Behçet's syndrome (BS) is a chronic multisystemic inflammatory disorder of unclear aetiology. The predominant BS susceptibility locus was identified within HLA-B*51. HLA-B*51 subtypes were previously studied as disease susceptibility markers. Few data are now available about the relationship between B*51 subtypes and clinical phenotype. The aim of this study was to genotype HLA-B*51 subtypes in a series of Italian BS patients and to test the association with clinical manifestations and disease severity (Krause's index). Methods: HLA-B*51 subtype genotyping for 63 alleles (B*51:01-B*51:63) was performed by PCR after DNA extraction from whole blood of BS patients. The correlation of disease clinical manifestations and severity (Krause's index) with the HLA-B*51 allele and its subtypes was analysed. Results: We enrolled 241 (140 male and 101 female) BS patients, and HLA-B*51 frequency was 62.7% (151 of 241). One hundred and eight of the HLA-B*51-positive patients carried the B*51:01 subtype (108 of 151, 71.5%), 39 of 151 (25.8%) the B*51:08 subtype, 2 of 151 (1.3%) the B*51:02 subtype, 1 of 151 (0.7%) the B*51:05 subtype, and 1 of 151 (0.7%) the B*51:07 subtype. We found that ocular involvement was statistically associated with HLA-B*51 positivity and with B*51:01 and B*51:08 subtypes (P < 0.05). We also found that disease severity was higher in HLA-B*51-positive patients than in negative patients, but without statistical significance (median Krause's index 5.1 vs 4.1, P > 0.05). Conclusion: Here, we confirm a high frequency of the HLA-B*51 allele in our group of BS patients. B*51:01 and B*51:08 were found to be the most common subtypes, and an association of both subtypes with ocular involvement was also underlined.

Behçet's Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade.

Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, γδ T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.

Pediatric Behçet's disease: Experience of a single tertiary center.

Objectives: The aim of this study was to examine the clinical and phenotypic features of pediatric Behçet's disease (PEDBD) in our clinic and present the rates of fulfilling the diagnostic criteria. Patients and methods: Thirty-four patients (20 males, 14 females; mean age: 16.0±2.1 years; range, 10 to 18 years) diagnosed with PEDBD between January 2010 and December 2019 were retrospectively evaluated. Patients were reclassified according to 1990 International Study Group (ISG) criteria, 2014 International Criteria for Behçet's Disease (ICBD), and PEDBD criteria. Results: The mean age at diagnosis was 12.6±3.1 years, the median diagnosis delay time was 12.0 (range, 4.5 to 27.0) months, and the mean age at symptom onset was 10.8±2.9 years. The mean follow-up period was 31.9±20.9 months. Oral aphthous ulcer was observed in 33 (97.1%), genital ulcer in 16 (47.0%), ocular involvement in 15 (44.1%), skin lesion in 11 (32.3%), joint involvement in nine (26.4%), both vascular and neurological involvement in six (17.6%) patients. The pathergy test was positive in 11 (37.8%) patients, and human leukocyte antigen (HLA)-B51 was positive in 11 (78.5%) of 14 patients. The rates of patients meeting the criteria for ISG, ICBD, and PEDBD were 52.9%, 82.4%, and 50.0%, respectively. Conclusion: Pathergy and HLA-B51 can be used as supportive findings in patients who do not meet the diagnostic criteria. However, expert opinion is still the gold standard in diagnosis.

Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency.

OBJECTIVE: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. METHODS: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. RESULTS: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. CONCLUSIONS: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.

Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency / Enfermedad de Behçet en países de Latinoamérica: Revisión sistemática de la literatura sobre datos demográficos, hallazgos clínicos y frecuencia del alelo HLA-B*51

Objective: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. Methods: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. Results: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. Conclusions: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.(AU)

Objetivo: Describir las características demográficas, clínicas y la frecuencia del alelo HLA-B*51 en pacientes con enfermedad de Behçet (EB) en países de América Latina. Métodos: Se llevó a cabo una revisión sistemática de la literatura (RSL) según la guía PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) sin realizar un metaanálisis final. Se incluyeron estudios observacionales (transversales o de cohortes) de pacientes con EB que cumplieron con los criterios de clasificación del Grupo Internacional de Estudio de la EB e informaron las características demográficas, clínicas y de laboratorio en pacientes adultos con EB. Resultados: Doce estudios fueron incluidos para la RSL. La información de 532 pacientes provenientes de 5 países de América Latina se incluyó para el análisis. La edad media al diagnóstico fue de 33 años, el 58,3% fueron mujeres y el 41,7% hombres; la mayoría de los pacientes fueron no caucásicos. Las manifestaciones clínicas más comunes fueron las úlceras orales y genitales recurrentes, seguidas del compromiso cutáneo, ocular, articular, neurológico, gastrointestinal, vascular y cardíaco. La prevalencia de la EB fue descrita en 2 estudios, uno realizado en Brasil que reportó una prevalencia de 0,3/100.000 habitantes, y otro en Colombia con una prevalencia de 1,1/100.000 habitantes. La frecuencia del HLA-B*51 en pacientes con EB fue del 38%, 30,1% y 9% en Argentina, Brasil y México, respectivamente. Conclusiones: La prevalencia de la EB en los países latinoamericanos parece ser baja, así como la frecuencia del alelo HLA-B*51. Sin embargo, la fuerza de asociación entre el HLA-B*51 y la EB sigue siendo alta en nuestra población. Las características clínicas claves de la EB son similares a las reportadas en países/regiones donde es endémica.(AU)

Characterization of the novel HLA-B*51:384 allele by sequencing-based typing.

HLA-B*51:384 differs from HLA-B*51:01:01:01 by one nucleotide substitution in codon 267 in exon 4.

HLA-B*51:380, a novel HLA-B allele with one exonic mutation identified in a Greek individual.

Characterization of the novel HLA-B*51:380 allele in a Greek individual using next-generation sequencing.

Rheumatologist's Perspective on Non-Infectious Uveitis: Patterns from Tertiary Referral Rheumatologic Clinics in Italy.

Non-infectious uveitis (NIU) can be an early or even the first extra-articular manifestation of systemic rheumatic diseases, or the first one; thus, rheumatologists are often involved in the diagnostic and therapeutic assessment of NIU. We evaluated 130 patients with a diagnosis of NIU who were admitted to two Italian rheumatologic clinics (Tor Vergata University Hospital in Rome, and Federico II University in Naples) from January 2018 to December 2021. Anterior uveitis (AU) occurred in 75.4% of patients, followed by posterior uveitis (PU, 21.5%); acute (54.6%) and recurrent (35.4%) NIU were more documented than chronic NIU (10%), and a bilateral involvement was observed in 38.7% of cases. Half of NIU cases were associated with spondyloarthritis (SpA); the remaining were affected by Behçet disease (BD)-related uveitis (13.9%) and idiopathic NIU (9.2%). HLA-B27+ patients (34.8%) had a higher prevalence of anterior and unilateral NIU (p = 0.005) with acute course (p = 0.04) than HLA-B27- patients. On the contrary, HLA-B51+ patients (19.6%) had mostly PU and bilateral NIU (p < 0.0001) and recurrent course (p = 0.04) than HLA-B51- patients. At the first rheumatologic referral, 117 patients (90%) received systemic treatments. Findings from this study demonstrate that rheumatologic referral has a pivotal role in the diagnostic work-up of NIU and may dramatically influence NIU-treatment strategies.

Immunopathogenesis of Behçet's disease.

Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure. Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors. Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.

The novel HLA-B*51:381 allele, identified in a Chinese individual through Sanger dideoxy nucleotide sequencing.

HLA-B*51:381 differs from HLA-B*51:01:01:01 by one nucleotide in exon 5.

Identification of the novel HLA-B allele, B*51:01:101, by next-generation sequencing.

The novel HLA-B*51:01:101 allele was characterized using next generation sequencing technology.