Changes in the proportion of clinical clusters contribute to the phenotypic evolution of Behçet’s disease in Japan

Abstract

Background We hypothesized that Behçet’s disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD. Methods A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups. Results A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters. Conclusions In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely “mucocutaneous”, “mucocutaneous with arthritis”, “neuro”, “GI”, and “eye.”

Behçet’s Disease—Do Microbiomes and Genetics Collaborate in Pathogenesis?

“…Second, certain demographic analysis does not support a link between manifestations of BD form FIGURE 1 | Systemic inflammation leading to clinical features in Behcȩt's disease may either be initiated by of causing changes in the gut microbiome in patients who are genetically predisposed to the condition. example ocular involvement not associated with intestinal BD (13). Thirdly, many patients with BD do not have intestinal-BD, therefore there is no direct association between gut inflammation, the microbiome and other manifestations of BD.…”

“…To identify the clinical clusters of BD, Soejima and associates investigated the clinical phenotype of 657 patients with BD from the Yokohama City Hospital database and 6754 patients with BD from the Japanese Ministry of Health, Labour and Welfare database. They identified that gastrointestinal BD was associated with vascular but not eye involvement, while a second cluster had high incidence of eye involvement but no vascular or neurological involvement (13). Chronological analyses showed expansion of the gastrointestinal cluster in BD patients over 27 years in a relatively stable genetic cohort in Japan, indicating that environmental factors might be involved in the disease manifestation of BD.…”

The association of Behçet's syndrome with HLA-B51 as understood in 2021

“…There is accumulating evidence that HLA-B∗51 positivity differs among the clinical subtypes of Behçet's syndrome [ 14 ▪ , 21 , 22 , 23 ▪ ]. Maldini et al conducted meta-analyses to determine the relationship of the HLA-B5 or B∗51 genotype with each clinical symptom in patients with Behçet's syndrome [ 14 ▪ ].…”

“…Recently, the frequency of HLA-B51 has been declining in Japanese patients with Behçet's syndrome [ 21 , 23 ▪ ]. This decline has been associated with an increased ratio of female patients, increased gastrointestinal involvement, and decreased ocular disease.…”

“…This decline has been associated with an increased ratio of female patients, increased gastrointestinal involvement, and decreased ocular disease. Our recent study showed that these epidemiological changes were associated with altered proportions of each clinical cluster in Japanese patients with Behçet's syndrome [ 23 ▪ ]. Our cohort included at least five independent clusters characterized by mucocutaneous dominant, mucocutaneous with arthritis, ocular involvement, neurological involvement, and gastrointestinal involvement.…”