-
Annals of the Rheumatic Diseases Jul 2023The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong... (Review)
Review
The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
Topics: Humans; Genetic Predisposition to Disease; Uveitis; Behcet Syndrome; Histocompatibility Antigens Class I; Spondylarthritis; Aminopeptidases; Minor Histocompatibility Antigens
PubMed: 36987655
DOI: 10.1136/ard-2022-222852 -
Proceedings of the National Academy of... Jun 2022Behçet's disease (BD) is a chronic vasculitis characterized by systemic immune aberrations. However, a comprehensive understanding of immune disturbances in BD and how...
Behçet's disease (BD) is a chronic vasculitis characterized by systemic immune aberrations. However, a comprehensive understanding of immune disturbances in BD and how they contribute to BD pathogenesis is lacking. Here, we performed single-cell and bulk RNA sequencing to profile peripheral blood mononuclear cells (PBMCs) and isolated monocytes from BD patients and healthy donors. We observed prominent expansion and transcriptional changes in monocytes in PBMCs from BD patients. Deciphering the monocyte heterogeneity revealed the accumulation of C1q-high (C1q) monocytes in BD. Pseudotime inference indicated that BD monocytes markedly shifted their differentiation toward inflammation-accompanied and C1q monocyte-ended trajectory. Further experiments showed that C1q monocytes enhanced phagocytosis and proinflammatory cytokine secretion, and multiplatform analyses revealed the significant clinical relevance of this subtype. Mechanistically, C1q monocytes were induced by activated interferon-γ (IFN-γ) signaling in BD patients and were decreased by tofacitinib treatment. Our study illustrates the BD immune landscape and the unrecognized contribution of C1q monocytes to BD hyperinflammation, showing their potential as therapeutic targets and clinical assessment indexes.
Topics: Behcet Syndrome; Complement C1q; Humans; Monocytes; RNA-Seq; Single-Cell Analysis
PubMed: 35727985
DOI: 10.1073/pnas.2204289119 -
Genes and Immunity Apr 2022Uveitis is the most common form of intraocular inflammatory disease and is a significant cause of visual impairment worldwide. Aetiologically, uveitis can also be... (Review)
Review
Uveitis is the most common form of intraocular inflammatory disease and is a significant cause of visual impairment worldwide. Aetiologically, uveitis can also be classified into infectious uveitis and non-infectious uveitis. The common non-infectious forms of uveitis include acute anterior uveitis (AAU), Behçet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, birdshot chorioretinopathy (BSCR), sarcoid uveitis. In addition, a few monogenic autoinflammatory disorders can also cause uveitis, such as Blau Syndrome and haploinsufficiency of A20 (HA20). Although the exact pathogenesis of non-infectious uveitis is still unclear, it is well-recognised that it involves both genetic and environmental risk factors. A hallmark of uveitis is its strong associations with human leucocyte antigens (HLA). For examples, AAU, BD and BSCR are strongly associated with HLA-B27, HLA-B51, and HLA-A29, respectively. In uveitis studies, multiple GWAS have successfully been conducted and led to identification of novel susceptibility loci, for example, IL23R has been identified in BD, VKH and AAU. In this review, we summarize the latest progress on the genetic associations of both HLA and non-HLA genes with major forms of uveitis, including AAU, BD, VKH, BSCR, sarcoid uveitis, Blau Syndrome and HA20, and potential future research directions.
Topics: Arthritis; Behcet Syndrome; HLA Antigens; HLA-B27 Antigen; Humans; Sarcoidosis; Synovitis; Uveitis; Uveitis, Anterior
PubMed: 35379982
DOI: 10.1038/s41435-022-00168-6 -
Turkish Journal of Medical Sciences Nov 2020We still do not know the cause(s) of Behçet syndrome. Most probably several, separate disease mechanisms are involved. I, like some others, propose we call it not a... (Review)
Review
We still do not know the cause(s) of Behçet syndrome. Most probably several, separate disease mechanisms are involved. I, like some others, propose we call it not a disease but a syndrome, a construct with a list of strong and weak elements. I like to think that this frank admission of our ignorance of its cause(s) will be an important semantic stimulus for more meaningful research.
Topics: Behcet Syndrome; Humans; Male; Syndrome
PubMed: 32222123
DOI: 10.3906/sag-2002-145 -
Journal of the Belgian Society of... 2022Although Behçet disease is a multisystemic and chronic vasculitis, it can be superimposed with a variety of acute vasculitis.
Although Behçet disease is a multisystemic and chronic vasculitis, it can be superimposed with a variety of acute vasculitis.
PubMed: 36415211
DOI: 10.5334/jbsr.2949 -
American Journal of Clinical Dermatology Sep 2023Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure)...
BACKGROUND
Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure) worldwide across approved indications of plaque psoriasis, psoriatic arthritis, and Behçet's syndrome; however, long-term exposure across these indications has not been reported.
OBJECTIVE
The aim of this study was to conduct a pooled analysis of apremilast data from 15 clinical studies with open-label extension phases, focusing on long-term safety.
METHODS
We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of special interest, including thrombotic events, malignancies, major adverse cardiac events (MACE), serious infections, and depression. Data were pooled across 15 randomized, placebo-controlled studies and divided into placebo-controlled or all-apremilast-exposure groups. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS
Overall, 4183 patients were exposed to apremilast (6788 patient-years). Most TEAEs were mild to moderate in the placebo-controlled period (96.6%) and throughout all apremilast exposure (91.6%). TEAE rates of special interest were similar between treatment groups in the placebo-controlled period and remained low throughout all apremilast exposure. Exposure-adjusted incidence rates per 100 patient-years during all apremilast exposure were MACE, 0.30; thrombotic events, 0.10; malignancies, 1.0; serious infections, 1.10; serious opportunistic infections, 0.21; and depression, 1.78. Safety findings were consistent across indications and regions. No new safety signals were identified.
CONCLUSIONS
The incidence of serious TEAEs and TEAEs of special interest was low despite long-term exposure, further establishing apremilast as a safe oral option for long-term use across indications with a favorable benefit-risk profile.
CLINICAL TRIAL REGISTRATION
NCT00773734, NCT01194219, NCT01232283, NCT01690299, NCT01988103, NCT02425826, NCT03123471, NCT03721172, NCT01172938, NCT01212757, NCT01212770, NCT01307423, NCT01925768, NCT00866359, NCT02307513.
Topics: Humans; Arthritis, Psoriatic; Behcet Syndrome; Neoplasms; Psoriasis; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37316690
DOI: 10.1007/s40257-023-00783-7 -
Atencion Primaria Apr 2020
Topics: Adult; Behcet Syndrome; Colchicine; Glucocorticoids; Humans; Male; Prednisone; Stomatitis, Aphthous
PubMed: 31351751
DOI: 10.1016/j.aprim.2019.05.013 -
Clinical and Experimental Rheumatology 2020Ocular involvement in Behçet's syndrome still represents a challenge for both rheumatologists and ophthalmologists; over the past 20 years the availability of new... (Review)
Review
Ocular involvement in Behçet's syndrome still represents a challenge for both rheumatologists and ophthalmologists; over the past 20 years the availability of new diagnostic tools and the concomitant introduction of biologic drugs led to a significant improvement in the management of these patients. The lack of uniform definitions and the diversity of the outcome measures still represent an obstacle for the prompt and correct management of ocular manifestations. The aim of the present review is to summarise the current evidences related to correct diagnosis and proper management of patients with Behçet's syndrome and ocular involvement.
Topics: Behcet Syndrome; Humans
PubMed: 33253088
DOI: No ID Found -
Journal of the European Academy of... Sep 2021
Topics: Behcet Syndrome; COVID-19; Humans; SARS-CoV-2
PubMed: 33914986
DOI: 10.1111/jdv.17325 -
JAMA Ophthalmology Apr 2021Although experimental studies support the hypothesis that exposure of infectious agents may trigger an aberrant immune response and contribute to noninfectious uveitis,...
IMPORTANCE
Although experimental studies support the hypothesis that exposure of infectious agents may trigger an aberrant immune response and contribute to noninfectious uveitis, the association of a definite pathogen with human noninfectious uveitis conditions appears not to have been well established in a population.
OBJECTIVE
To evaluate associations of tuberculosis infection with risk of several noninfectious uveitis conditions.
DESIGN, SETTING, AND PARTICIPANTS
These mendelian randomization and observational analyses were conducted with the genetic data of a Chinese cohort enrolled between April 2008 and January 2018 and a Japanese cohort enrolled between January 2002 and June 2009. We recruited participants for T-SPOT.TB (Oxford Immunotec) assays between July and November 2019. The Chinese cohort included patients with uveitis associated with Behçet disease or other uveitis conditions and control participants. The Japanese cohort and the group given T-SPOT.TB assays included individuals with Behçet disease and control participants. Data analyses for this study were completed from July 2019 to January 2020.
EXPOSURES
Genetic variants associated with tuberculosis as natural proxies for tuberculosis exposure.
MAIN OUTCOMES AND MEASURES
The primary outcome was the odds ratio (OR) for Behçet disease, estimated by an inverse variance weighted mean of associations with genetically determined tuberculosis susceptibility. The T-SPOT.TB positivity rate was examined in individuals with Behçet disease and compared with that of control participants.
RESULTS
The Chinese cohort included 999 patients with uveitis associated with Behçet disease, 1585 with other uveitis conditions, and 4417 control participants. The Japanese cohort included 611 individuals with Behçet disease and 737 control participants. The group given T-SPOT.TB assays included 116 individuals with Behçet disease and 121 control participants. Of the Chinese individuals with Behçet disease and control participants, 2257 (41.7%) were female and the mean (SD) age was 35.4 (12.5) years. In the Japanese cohort, 564 (41.8%) were female and the mean (SD) age was 39.1 (12.7) years. Genetically determined tuberculosis susceptibility was associated with an increased risk for Behçet disease. The OR for Behçet disease per 2-fold increase in tuberculosis incidence was 1.26 (95% CI, 1.12-1.43; P = 1.47 × 10-4). Replication using the Japanese cohort yielded similar results (OR, 1.16 [95% CI, 1.08-1.26]). In T-SPOT.TB assays, having a positive result, indicating a history of tuberculosis infection, was found to be an independent risk factor for Behçet disease (OR, 2.26 [95% CI, 1.11-4.60]).
CONCLUSIONS AND RELEVANCE
These human genetic and biomarker data demonstrated that tuberculosis exposure was a risk factor for Behçet disease. This study provides novel evidence linking an infectious agent to the risk of a noninfectious uveitis condition.
Topics: Adult; Behcet Syndrome; Female; Humans; Interferon-gamma Release Tests; Male; Tuberculosis; Tuberculosis, Ocular; Uveitis
PubMed: 33599689
DOI: 10.1001/jamaophthalmol.2020.6985