HLA-B*51 Beyond Behcet’s Disease: Topography of Symptoms, Associated Diagnoses, and Characterization of Chronic Inflammatory Arthritis Phenotypes

In the clinical context of the new medical concept of diseases related to the Major Histocompatibility Complex class I (MHC-I-opathy), contrasting data are available on the possible association among HLA-B*51, Behcet’s disease (BD), and spondyloarthritis (SpA). The aim of this retrospective study on a cohort of HLA-B*51-positive patients who were clinically observed for almost 5 years is primarily to evaluate which classification criteria they satisfy among BD, axial (ax) or peripheral (p) SpA, and psoriatic arthritis (PsA). Furthermore, we characterized the possible impact of different arthritis phenotypes on the most frequent extra-articular clinical manifestations in BD, ax-SpA, p-SpA, and PsA. A comparison with HLA-B*51-negative patients (matched with HLA-B*51-positive patients for age, gender, and diagnosis, by mean propensity score) was also performed to evaluate the true impact on clinical manifestations of HLA-B*51. We conducted a monocentric retrospective study from 2013 to 2025. The inclusion criteria were HLA-B*51 positivity, the availability of the entire MHC-I class test, and rheumatological clinical follow-up of at least 5 years. The exclusion criterion was positivity for clinically important MCH-I loci other than HLA-B*51. A total of 105 patients met the inclusion criteria in an average clinical observation period of 8.4 ± 2.9 years. All patients were Apulian and were HLA-B* 51 positive. During the follow-up, 32 patients (31%) met the BD criteria, 17 (16%) met the PsA criteria, 25 (24%) met the p-SpA criteria, and 13 (12%) met the ax-SpA criteria. Of note, 16% and 34% of BD patients met the ax-SpA and p-SpA ASAS criteria, respectively. Prevalent articular phenotypes in this HLA-B*51 cluster of patients are a polyarticular pattern and enthesis involvement in all disease groups. In BD patients, axial involvement was associated with a significantly higher percentage of neurological manifestations (40% vs. 7%, p = 0.043) and inflammatory bowel disease (IBD) (100% vs. 15%, p = 0.0001), compared to patients with exclusive peripheral joint involvement. This latest data on IBD remains significant, even in comparison with HLA-B*51 negative patients (33%; p = 0.035). In the p-SpA group, a significantly higher rate of uveitis (28%) was observed compared to both ax-SpA with HLA-B*51-positive (0%, p = 0.035) and p-SpA with HLA-B*51-negative patients (4%, p = 0.030). A high percentage of multi-drug failures was highlighted in patients with PsA (60%) and p-SpA (40%). This study provides new data on the association between HLA-B*51 and the onset of BD and/or SpA or PsA, and its possible impact on extra-articular manifestations. We confirm the higher prevalence of the peripheral articular phenotype in BD, but we also highlight a specific association between the rarer axial involvement and gastrointestinal involvement in HLA-B*51 patients. In SpA, the peripheral articular phenotype appears to be associated with a higher occurrence of uveitis in the presence of HLA-B*51.