Investigation of the acute pathogenesis of spondyloarthritis/HLA-B27-associated anterior uveitis based on genome-wide association analysis and single-cell transcriptomics.

BACKGROUND: Patients with spondyloarthritis (SpA)/HLA-B27-associated acute anterior uveitis (AAU) experience recurring acute flares, which pose significant visual and financial challenges. Despite established links between SpA and HLA-B27-associated AAU, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. METHODS: To investigate the acute pathogenesis of SpA/HLA-B27-associated AAU, Mendelian randomization (MR) and single-cell transcriptomic analyses were employed. The MR incorporated publicly available protein quantitative trait locus data from previous studies, along with genome-wide association study data from public databases. Causal relationships between plasma proteins and anterior uveitis were assessed using two-sample MR. Additionally, colocalization analysis was performed using Bayesian colocalization. Single-cell transcriptome analysis utilized the anterior uveitis dataset from the Gene Expression Omnibus (GEO) database. Dimensionality reduction, clustering, transcription factor analysis, pseudotime analysis, and cell communication analysis were subsequently conducted to explore the underlying mechanisms involved. RESULTS: Mendelian randomization analysis revealed that circulating levels of AIF1 and VARS were significantly associated with a reduced risk of developing SpA/HLA-B27-associated AAU, with AIF1 showing a robust correlation with anterior uveitis onset. Colocalization analysis supported these findings. Single-cell transcriptome analysis showed predominant AIF1 expression in myeloid cells, which was notably lower in the HLA-B27-positive group. Pseudotime analysis revealed dendritic cell terminal positions in differentiation branches, accompanied by gradual decreases in AIF1 expression. Based on cell communication analysis, CD141+CLEC9A+ classic dendritic cells (cDCs) and the APP pathway play crucial roles in cellular communication in the Spa/HLA-B27 group. CONCLUSIONS: AIF1 is essential for the pathogenesis of SpA/HLA-B27-associated AAU. Myeloid cell differentiation into DCs and decreased AIF1 levels are also pivotal in this process.

How to translate genetic findings into clinical applications in spondyloarthritis?

Spondyloarthritis (SpA) is characterized by a strong genetic predisposition evidenced by the identification of up to 50 susceptibility loci, in addition to HLA-B27, the major genetic factor associated with the disease. These loci have not only deepened our understanding of disease pathogenesis but also offer the potential to improve disease management. Diagnostic delay is a major issue in SpA. HLA-B27 testing is widely used as diagnostic biomarker in SpA but its predictive value is limited. Several attempts have been made to develop more sophisticated polygenic risk score (PRS). However, these scores currently offer very little improvement as compared to HLA-B27 and are still difficult to implement in clinical routine. Genetics might also help to predict disease outcome including treatment response. Several genetic variants have been reported to be associated with radiographic damage or with poor response to TNF blockers, unfortunately with lack of coherence across studies. Large-scale studies should be conducted to obtain more robust findings. Genetic and genomic evidence in complex diseases can be further used to support the identification of new drug targets and to repurpose existing drugs. Although not fully driven by genetics, development of IL-17 blockers has been facilitated by the discovery of the association between IL23R variants and SpA. Development of recent approaches combining GWAS findings with functional genomics will help to prioritize new drug targets in the future. Although very promising, translational genetics in SpA remains challenging and will require a multidisciplinary approach that integrates genetics, genomics, immunology, and clinical research.

Prevalence of HLA B27 in Patients Diagnosed with Ankylosing Spondylitis (AS) in Diyarbakir, Southeastern Region of Turkey.

AIM: The research to be conducted on human leukocyte antigen (HLA)-B27 in patients diagnosed with ankylosing spondylitis (AS) in Diyarbakir between 2019-2021 is to contribute to the understanding of the prevalence and effect of this genetic marker in the local population. As a researcher working on HLA-B27 and AS, our focus is to research the following. HLA-B27 Prevalence: To determine the prevalence of HLA-B27 in patients diagnosed with AS during the specified period in Diyarbakir. This information can provide insight into the genetic factors associated with the disease in the local population. Disease Severity: Investigate the relationship between HLA-B27 positivity and severity of AS symptoms. To examine factors such as disease progression, pain levels, functional impairment, and quality of life in HLA-B27 positive patients compared to HLA-B27 negative patients. By Genetic Associations: To enable the discovery of potential genetic relationships between HLA-B27 and other genetic markers known to be associated with AS. To investigate whether there are any specific genetic variants associated with HLA-B27 that contribute to disease susceptibility or severity. Researchers: We recommend considering the following approaches to generate knowledge on this topic globally: Literature Review: Conducting a comprehensive review of the available scientific literature on HLA-B27 and AS. It is to describe relevant studies conducted globally and summarize their findings to provide a broader understanding of the subject. Collaboration and Data Sharing: To encourage cooperation with researchers from other regions or countries doing similar studies on HLA-B27 and ASs. By sharing our data and collaborating on analysis, we can improve the global perspective and generalizability of your findings. International Conferences and Journals: Presenting our research findings at international conferences focusing on rheumatology, genetics or related fields. To disseminate our findings globally is to submit your research articles to reputable journals specializing in AS or genetic studies. Online Platforms: Using online platforms such as Researchgate.net, academia.edu or social media networks to share our research findings, connect with other researchers in the field and participate in discussions on a global scale. By using these fields, it is possible to contribute to the global knowledge and understanding of the relationship between HLA-B27 and AS. It is also to obtain insights from studies carried out in other regions. MATERIALS AND METHODS: 198 (104 male and 94 female) patients who applied to Dicle University Faculty of Medicine Physical Therapy and Rehabilitation Clinic with AS symptoms between 2019-2021 and were referred to Dicle University Medical Biology and Genetics Department for evaluation. HLA-B27 positivity was included in our study as a case group. As the control group, 50 people (25 males, 25 females) were selected among the unrelated people who applied to our laboratory to be a bone marrow donor. In both groups, DNA isolation was performed from peripheral blood using the salt precipitation method. Rotar Gene Q device was used for real-time PCR analysis. As a statistical method in analysis; The prevalences of the variables of interest were calculated. The lower and upper limits of 95% were determined as the confidence interval. According to the presence of HLA 27 positivity, the mean of ESR, CRP, and age variables were compared. Mann-Whitney U test was used due to the small number of subjects. Also, correlations between ESR and CRP were calculated. Spearman rho correlation statistics were used as a statistical method. Analyzed. RESULT: Radiological examinations and laboratory tests were performed on 198 patients with suspicion AS and 50 healthy control group of 248 subjects. The prevalence of those with a definite diagnosis of AS was calculated as statistical analysis recalculated 20.16 (95% CI: 0.76-0.9552). The prevalence of HLA-B27 in 50 patients diagnosed with AS as a result of radiological examinations and laboratory tests was calculated as 92%. CONCLUSION: Our study is the first study covering the province of Diyarbakir in the Southeastern Anatolia Region, which we think will contribute to the literature in the evaluation of HLA-B27 positivity in AS patients. The prevalence of HLA-B27 in our region is higher than the prevalence in Turkey.

A Review of Laboratory Practices Using the HLA-B27 Survey by the College of American Pathologists: How Important Is Allele-Level Typing?

CONTEXT.­: Ankylosing spondylitis (AS) is an autoimmune disorder with a strong genetic risk, especially with HLA-B27. Clinical testing for HLA-B27 has been used to help diagnose patients with signs and symptoms of AS. Testing methods used by clinical laboratories for HLA-B27 fall into the broad categories of serologic/antibody- or molecular-based methods and have evolved over time. The College of American Pathologists (CAP) offers a proficiency testing survey for HLA-B27. OBJECTIVE.­: To analyze HLA-B27 testing trends and their performance in the past decade, using the proficiency testing survey data submitted to CAP. DESIGN.­: We analyzed the HLA-B27 CAP proficiency testing data from 2010 to 2020 for the method used, participant concordance, and error rates. Results from case scenarios to understand evolving scientific data around HLA-B27 risk alleles were also analyzed. RESULTS.­: Antibody-based flow cytometry is the most common method, though it has decreased from 60% in 2010 to 52% in 2020, with a corresponding increase in molecular methods. Among the molecular methods, real-time polymerase chain reaction has increased from 2% to 15%. Flow cytometry had the highest error rate (5.33%), and sequence-specific oligonucleotide (0%) is the most accurate (0%). Results of case scenarios demonstrated that most participants understood that allele-level HLA-B27 typing results inform clinical interpretation, for example HLA-B*27:06 is not associated with AS. CONCLUSIONS.­: These data demonstrated the changing trends for HLA-B27 testing during the past decade. HLA-B27 allelic typing provides a better understanding of AS association. This is possible by testing for the second field with methods like next-generation sequencing.

Shared and Distinct Gut Microbiota in Spondyloarthritis, Acute Anterior Uveitis, and Crohn's Disease.

OBJECTIVE: Spondyloarthritis (SpA) is a group of immune-mediated diseases highly concomitant with nonmusculoskeletal inflammatory disorders, such as acute anterior uveitis (AAU) and Crohn's disease (CD). The gut microbiome represents a promising avenue to elucidate shared and distinct underlying pathophysiology. METHODS: We performed 16S ribosomal RNA sequencing on stool samples of 277 patients (72 CD, 103 AAU, and 102 SpA) included in the German Spondyloarthritis Inception Cohort and 62 back pain controls without any inflammatory disorder. Discriminatory statistical methods were used to disentangle microbial disease signals from one another and a wide range of potential confounders. Patients were naive to or had not received treatment with biological disease-modifying antirheumatic drugs (DMARDs) for >3 months before enrollment, providing a better approximation of a true baseline disease signal. RESULTS: We identified a shared, immune-mediated disease signal represented by low abundances of Lachnospiraceae taxa relative to controls, most notably Fusicatenibacter, which was most abundant in controls receiving nonsteroidal antiinflammatory drug monotherapy and implied to partially mediate higher serum C-reactive protein. Patients with SpA showed an enrichment of Collinsella, whereas human leukocyte antigen (HLA)-B27+ individuals displayed enriched Faecalibacterium. CD patients had higher abundances of a Ruminococcus taxon, and previous conventional/synthetic DMARD therapy was associated with increased Akkermansia. CONCLUSION: Our work supports the existence of a common gut dysbiosis in SpA and related inflammatory pathologies. We reveal shared and disease-specific microbial associations and suggest potential mediators of disease activity. Validation studies are needed to clarify the role of Fusicatenibacter in gut-joint inflammation, and metagenomic resolution is needed to understand the relationship between Faecalibacterium commensals and HLA-B27.

HLA-B27-positive anterior uveitis : Clinical aspects, diagnostics, interdisciplinary management, and treatment.

Acute anterior uveitis (AAU) associated with human leukocyte antigen (HLA) B27 is the most common form of noninfectious intraocular inflammation and is considered to be a separate clinical entity. Young adults between the ages of 20 and 40 years are predominantly affected. The HLA-B27 positive AAU typically presents as a unilateral, fulminant disruption of the blood-aqueous humor barrier, which is accompanied by pronounced cellular infiltration and fibrinous exudation. Other characteristics are reduced intraocular pressure and a high tendency to relapse, which can also involve the partner eye. Patients with HLA-B27 positive AAU share a high risk for other genetically associated diseases, especially spondylarthritis, chronic inflammatory bowel diseases and psoriasis. As up to 40% of those affected have a systemic disease that has not yet been diagnosed, the ophthalmologist is of major importance for early detection.

[The role of HLA-B27 in the pathogenesis and diagnosis of axial spondyloarthritis : 50 years after discovery of the strong genetic association]. / Zur Rolle von HLA-B27 in der Pathogenese und Diagnostik der axialen Spondyloarthritis : 50 Jahre nach Entdeckung der starken genetischen Assoziation.

BACKGROUND: The association of the human lymphocyte antigen B27 (HLA-B27) with ankylosing spondylitis (AS), also now called axial spondylarthritis (axSpA), was first described 50 years ago. OBJECTIVE: This article gives an overview of the available knowledge on the topic. MATERIAL AND METHODS: This is a narrative review based on the experience of the authors. RESULTS: The HLA-B27 is a member of the HLA class I family of genes of the major histocompatibility complex (MHC). The prevalence of HLA-B27 in the central European population is approximately 8 %, i.e., the vast majority of carriers of HLA-B27+ remain healthy. The frequency of HLA-B27 shows a decline from north to south. The HLA-B27 explains only 30 % of the genetic burden of axSpA. The prevalence of the disease correlates with the frequency of HLA-B27 in the population, i.e., there are geographic differences. Approximately 60-90 % of patients with axSpA worldwide are HLA-B27+. Some 200 subtypes of HLA-B27 can be differentiated using the polymerase chain reaction (PCR). In Thailand and Sardinia two subtypes were found that are not associated with axSpA. The physiological function of HLA class I molecules is the defence of the organism against microbes. Microbial peptides are presented to the immune system, which can be specifically attacked by CD8+ T­cells. Genetic polymorphisms of the enzyme endoplasmic reticulum aminopeptidase 1 (ERAP1), which breaks down peptides in the endoplasmic reticulum, are associated only with HLA-B27+ diseases. DISCUSSION: The pathogenesis of axSpA is unclear but a major hypothesis is that of the arthritogenic peptides. In this it is assumed that potentially pathogenic foreign or autologous peptides can be presented by HLA-B27. If nothing else, HLA-B27 plays an important role in the diagnosis, classification and determination of the severity of axSpA.

Predominant ligament-centric soft-tissue involvement differentiates axial psoriatic arthritis from ankylosing spondylitis.

Since the original description of spondyloarthritis 50 years ago, results have demonstrated similarities and differences between ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA). HLA-B27 gene carriage in axial inflammation is linked to peri-fibrocartilaginous sacroiliac joint osteitis, as well as to spinal peri-entheseal osteitis, which is often extensive and which provides a crucial anatomical and immunological differentiation between the AS and PsA phenotypes. Specifically, HLA-B27-related diffuse bone marrow oedema (histologically an osteitis) and bone marrow fatty corners detected via magnetic resonance imaging, as well as radiographic changes such as sacroiliitis, vertebral squaring, corner erosions and Romanus lesions, all indicate initial bone phenotypes in HLA-B27+ axial disease. However, in much of PsA with axial involvement, enthesitis primarily manifests in ligamentous soft tissue as 'ligamentitis', with characteristic lesions that include para-syndesmophytes and sacroiliac joint bony sparing. Like axial PsA, diffuse idiopathic skeletal hyperostosis phenotypes, which can be indistinguishable from PsA, exhibit a thoracic and cervical spinal ligamentous soft-tissue tropism, clinically manifesting as syndesmophytosis that is soft-tissue-centric, including paravertebral soft-tissue ossification and sacroiliac soft-ligamentous ossification instead of joint-cavity fusion. The enthesis bone and soft tissues have radically different immune cell and stromal compositions, which probably underpins differential responses to immunomodulatory therapy, especially IL-23 inhibition.

Pathophysiology and immunolgical basis of axial spondyloarthritis.

Over the recent years the wider availability and application of state-of-the-art immunological technologies greatly advanced the insight into the mechanisms that play an important role in axial spondyloarthritis (axSpA) pathophysiology. This increased understanding has facilitated the development of novel treatments that target disease relevant pathways, hereby improving outcome for axSpA patients. In axSpA pathophysiology genetic and environmental factors as well as immune activation by mechanical or bacterial stress resulting in a chronic inflammatory response have a central role. The TNF and IL-23/IL-17 immune pathways play a pivotal role in these disease mechanisms. This review provides an outline of the immunological basis of axSpA with a focus on key genetic risk factors and their link to activation of the pathological immune response, as well as on the role of the gut and entheses in the initiation of inflammation with subsequent new bone formation in axSpA.

HLA-B*27 and Ankylosing Spondylitis: 50 Years of Insights and Discoveries.

PURPOSE OF REVIEW: To commemorate the 50th anniversary of the groundbreaking discovery of a remarkably strong association between HLA-B*27 and ankylosing spondylitis (AS). RECENT FINDINGS: In addition to HLA-B*27, more than 116 other recognized genetic risk variants have been identified, while epigenetic factors largely remain unexplored in this context. Among patients with AS who carry the HLA-B*27 gene, clonally expanded CD8 + T cells can be found in their bloodstream and within inflamed tissues. Moreover, the α and ß chain motifs of these T-cell receptors demonstrate a distinct affinity for certain self- and microbial-derived peptides, leading to an autoimmune response that ultimately results in the onset of the disease. These distinctive peptide-binding and presentation characteristics are a hallmark of the disease-associated HLA-B*27:05 subtype but are absent in HLA-B*27:09, a subtype not associated with the disease, differing by only a single amino acid. This discovery represents a significant advancement in unraveling the 50-year-old puzzle of how HLA-B*27 contributes to the development of AS. These findings will significantly accelerate the process of identifying peptides, both self- and microbial-derived, that instigate autoimmunity. This, in return, will pave the way for the development of more accurate and effective targeted treatments. Moreover, the discovery of improved biomarkers, in conjunction with the emerging technology of electric field molecular fingerprinting, has the potential to greatly bolster early diagnosis capabilities. A very recently published groundbreak paper underscores the remarkable effectiveness of targeting and eliminating disease-causing T cells in a HLA-B*27 patients with AS. This pivotal advancement not only signifies a paradigm shift but also bolsters the potential for preventing the disease in individuals carrying high-risk genetic variants.

HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Development and validation of a machine learning-based nomogram for predicting HLA-B27 expression.

BACKGROUND: HLA-B27 positivity is normal in patients undergoing rheumatic diseases. The diagnosis of many diseases requires an HLA-B27 examination. METHODS: This study screened totally 1503 patients who underwent HLA-B27 examination, liver/kidney function tests, and complete blood routine examination in First Affiliated Hospital of Guangxi Medical University. The training cohort included 509 cases with HLA-B27 positivity whereas 611 with HLA-B27 negativity. In addition, validation cohort included 147 cases with HLA-B27 positivity whereas 236 with HLA-B27 negativity. In this study, 3 ML approaches, namely, LASSO, support vector machine (SVM) recursive feature elimination and random forest, were adopted for screening feature variables. Subsequently, to acquire the prediction model, the intersection was selected. Finally, differences among 148 cases with HLA-B27 positivity and negativity suffering from ankylosing spondylitis (AS) were investigated. RESULTS: Six factors, namely red blood cell count, human major compatibility complex, mean platelet volume, albumin/globulin ratio (ALB/GLB), prealbumin, and bicarbonate radical, were chosen with the aim of constructing the diagnostic nomogram using ML methods. For training queue, nomogram curve exhibited the value of area under the curve (AUC) of 0.8254496, and C-value of the model was 0.825. Moreover, nomogram C-value of the validation queue was 0.853, and the AUC value was 0.852675. Furthermore, a significant decrease in the ALB/GLB was noted among cases with HLA-B27 positivity and AS cases. CONCLUSION: To conclude, the proposed ML model can effectively predict HLA-B27 and help doctors in the diagnosis of various immune diseases.

Comparison of clinical characteristics between adult-onset and juvenile-onset non-radiographic axial spondyloarthritis in Chinese patients: results from the COCAS cohort.

BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. We aimed to describe the clinical characteristics of patients with non-radiographic axSpA (nr-axSpA) in China and compare the differences between adult- and juvenile-onset cases. METHODS: A cross-sectional study was conducted using data from 776 patients with nr-axSpA in the Clinical Characteristic and Outcome in Chinese Axial Spondyloarthritis (COCAS) study cohort. Patients were divided into two groups including the adult-onset group (n = 662) and the juvenile-onset group (n = 114) according to age at disease onset. Baseline demographics and clinical characteristics were compared between patients with adult-onset and juvenile-onset nr-axSpA. RESULTS: Overall, the male-to-female ratio was 1.26:1, the prevalence of HLA-B27 positivity was 72.2%, and the median age at disease onset of nr-axSpA was 22 years. Nearly 75% of nr-axSpA patients had peripheral arthritis in the disease course, and the prevalence of extra-articular manifestations was 10.4%. The juvenile-onset group contained a higher proportion of men (66.7% vs. 53.9%, P = 0.011) and a longer baseline disease duration (4.0 [4.0] vs. 1.6 [3.5], P < 0.001) than the adult-onset group. A family history of spondyloarthritis was more frequent in the juvenile-onset group than in the adult-onset group (23.7% vs. 15.4%, P = 0.028), but no significant difference in the prevalence of HLA-B27 positivity was observed between the two groups (P = 0.537). Regarding initial symptoms, peripheral arthritis occurred more often in patients with juvenile-onset nr-axSpA, whereas patients with adult-onset nr-axSpA presented more frequently with axial involvement. The prevalence of inflammatory back pain (IBP) was higher in the adult-onset group than in the juvenile-onset group (85.0% vs. 75.4%, P = 0.010), whereas the juvenile-onset group showed a higher prevalence of peripheral arthritis and enthesitis than the adult-onset group (67.5% vs. 48.5%, P < 0.001; 35.1% vs. 23.3%, P = 0.007, respectively). CONCLUSIONS: Compared with adult-onset nr-axSpA, juvenile-onset nr-axSpA was more common in men and those with a family history of spondyloarthritis. Juvenile-onset nr-axSpA presents with a "peripheral predominant" mode at disease onset and a higher frequency of peripheral arthritis and enthesitis during the disease course.

Identification of the first signs or symptoms in different spondyloarthritis subtypes and their association with HLA-B27: data from REGISPONSER and RESPONDIA registries.

OBJECTIVE: To describe and analyse the initial symptoms attributable to patients with spondyloarthritis (SpA) and their association with HLA-B27 status. METHODS: This was an observational, cross-sectional and multicentre study with patients who fulfilled the European Spondyloarthropathy Study Group criteria for SpA from the Registry of Spondyloarthritis of Spanish Rheumatology (REGISPONSER) and Ibero-American Registry of Spondyloarthropathies (RESPONDIA) united registries. Differences in the first sign(s) or symptom(s) were compared across diagnoses and between HLA-B27 status. The diagnostic delay between patients who start the disease with musculoskeletal manifestations (MMs) and extra-MMs (EMMs) was compared. RESULTS: A total of 4067 patients were included (2208 from REGISPONSER and 1859 from RESPONDIA) (ankylosing spondylitis (AS): 68.3%, psoriatic arthritis (PsA): 19.9%, undifferentiated SpA: 11.8%). Overall, 3624 (89.1%) patients initiated the disease with MMs and 443 (10.9%) with EMMs. Low back pain (61.7%) and lower-limb arthritis (38.5%) were the most frequent initial symptoms. In AS patients, the absence of HLA-B27 seems to be related to an increase in the probability of starting the disease with cervical pain and peripheral manifestations. In PsA, the onset of arthritis and psoriasis was more prevalent in HLA-B27-negative patients, while initiation with axial manifestations was more predominant in HLA-B27-positive patients. The diagnostic delay was longer in patients with initial MMs than in those with EMMs (7.2 (34.8) vs 4.5 (7.6) years, respectively). CONCLUSION: In this SpA population, MMs were the most prevalent initial symptoms, with differences across diagnoses and depending on the presence of the HLA-B27 antigen.

Disease characteristics of HLA-B27 positive and negative finnish patients with juvenile idiopathic arthritis - results of the 18-year cohort follow-up study.

BACKGROUND: The aim of this long-term follow-up study was to compare the disease characteristics of HLA-B27 positive and negative patients with juvenile idiopathic arthritis (JIA). METHODS: The study is a cohort study with consecutive cases of newly diagnosed Finnish patients with JIA according to the International League of Associations for Rheumatology (ILAR) criteria [1]. Patients were enrolled between 1997 and 2000 from a defined area of Southern Finland. Clinical data including disease activity and serology were registered during a mean period of 17.5 years. RESULTS: 159 patients completed the 18-year follow-up study. HLA-B27 was available for 151 patients, of which 25% were HLA-B27 positive. Chronic uveitis was diagnosed in 30% of HLA-B27 positive and 29% of HLA-B27 negative patients. HLA-B27 positive patients had a lower prevalence of temporomandibular (TMJ) involvement than the antigen negative ones, 19% versus 28%. None of the HLA-B27 positive patients had cervical spine affected compared to 11% of antigen negative patients (p = 0.022). Of the HLA-B27 positive patients, 54% had had biological medication at some point during follow-up versus 25% in the negative group (p = 0.003). At last follow-up, 32% of antigen positive patients were not in remission compared to 18% of the antigen negative (p = 0.017). CONCLUSIONS: The use of biological medication was more common in HLA-B27 positive patients with JIA. At the 18-year follow-up, more antigen positive patients had active disease compared HLA-B27 negative patients. This real-world follow-up study indicates that the prospects for worse outcome with HLA-B27 positivity in long-term should be taken into consideration.

Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis.

The human lymphocyte antigen B27 (HLA B27) is a member of the HLA class I family of genes in the major histocompatibility complex whose name goes back to its discovery in studies of transplanted tissue compatibility. Its prevalence in the mid-European population is about 8%. The association of HLA B27 alleles with ankylosing spondylitis (AS), a highly heritable disease, which is part of the spectrum of axial spondyloarthritis (axSpA), was discovered 50 years ago. HLA B27 explains less than 30% of the total genetic load. About 60%-90% of axSpA patients worldwide carry HLA B27. The prevalence of the disease is linked to the frequency of HLA B27 in the population which implies that there are relevant differences. Among the roughly 200 subtypes known there are two which are not disease associated. The function of HLA class I molecules is to present peptides to the immune system to defend the organism against microbes targeted by CD8+T cells. This is much supported by the role of the endoplasmic reticulum aminopeptidase 1 (ERAP 1) in AS, an enzyme that is responsible for the intracellular trimming of peptides, since polymorphisms of this gene are only associated with HLA-B27+ disease. The arthritogenic peptide hypothesis trying to explain the pathogenesis of AS is based on that very immune function assuming that also self peptides can be presented. HLA-B27 also plays an important role in classification, diagnosis and severitiy of axSpA.

Development of ankylosing spondylitis in patients with ulcerative colitis: A systematic meta-analysis.

BACKGROUND: Ulcerative colitis (UC) is a manifestation of inflammatory bowel disease (IBD), which can cause inflammation of the intestinal tract. Ankylosing spondylitis (AS) is an inflammatory disease of the sacroiliac joints. Many studies have found that some UC patients progress to AS. In this study, we conducted a literature search and meta-analysis to investigate the prevalence of AS among UC patients during follow-up. METHODS: The studies related to the AS among patients with UC were obtained from PubMed, Web of Science, Embase, and Cochrane Library databases since its inception-December 2022. The literature was screened strictly according to inclusion and exclusion criteria. Forest plots were used to detect the overall incidence of AS in UC and to compare the risk ratios for the development of AS in the UC. The heterogeneity of studies was assessed using I2 statistical methods. RESULTS: 1) 17 studies with 98704 UC patients were included. 2)700 UC patients developed AS during follow-up (1.66%, 95% CI: 0.89-2.62%). Human leukocyte antigen B27 (HLA-B27) was reported in 3 studies. HLA-B27 positivity was significantly higher than the incidence of HLA-B27 negativity in AS patients (68.29% vs 31.71%, P < 0.0001). There was significantly increased risk of AS development in HLA-B27 positive IBD patients (RR: 22.17, 95% CI: 11.79-41.66, P < 0.0001). 3)The definite follow-up time was reported in 12 studies (range: 0.3-40 years). After follow-up for ≥5 years, the incidence of AS among patients with UC was 1.75% (95% CI: 0.62-3.37%). Meanwhile, after follow-up for <5 years, the incidence of AS among patients with UC was 1.41% (95% CI: 0.65-2.37%) which was significant. CONCLUSION: Patients with UC are more likely to develop AS in the future. Furthermore, the IBD patients are at a higher risk of AS who have positive HLA-B27. The incidence of AS increased with longer follow-up time.

Clinical profile and treatment utilisation based on HLA-B*27 status in axial spondyloarthritis: results from ASAS-PerSpA study.

OBJECTIVE: We aimed to characterize differences of clinical features, extra-musculoskeletal manifestations and treatment utilizations based on the patients' HLA-B*27 status in a global axSpA cohort and identify predictors of HLA-B*27 negativity in these patients. METHODOLOGY: In post-hoc analysis of the ASAS-PerSpA study, patients fulfilling the 2009 ASAS classification criteria for axSpA and typed for HLA-B*27 were included. The patient characteristics cwere compared between the HLA-B*27(+) and HLA-B*27(-) subgroups. Multivariablete logistic regression was conducted to identify predictors of HLA-B*27 negativity. RESULTS: Of 2910 patients with axSpA from 24 countries, 2269 were tested for HLA-B*27 [1753 HLA-B*27(+) and 516 HLA-B*27(-)]. The proportion of males was higher in the HLA-B*27 (+) compared to the HLA-B*27 (-) subgroup (72.1 vs 54.3%). Patient population with HLA-B*27 (+) more often had positive family history for axSpA (29.8 vs 15.3%), and younger age at diagnosis, 31.6 years (SD 10.9) vs 37.7 years (SD 12.1). HLA-B*27 (-) patients had significantly higher peripheral arthritis (47.5 vs 42.1%, p<0.05), psoriasis (19.4 vs 10.2), enthesitis (56.6 vs 49.8%) and IBD (12.8 vs 3.4) (p<0.001). The exposure to csDMARDS in HLA-B*27 (-) patients was higher (61.2 vs 55.0%, p< 0.05). On multivariable analysis, HLA-B*27 (-) status was positively associated with enthesitis, psoriasis and IBD with an OR 1.27 (1.02-1.57), 1.84 (1.36-2.48) and 4.84 (3.23-7.30) respectively, and inversely associated with uveitis, OR 0.37 (0.27-0.50). CONCLUSION: HLA-B*27 (-) axSpA patients had a longer delay in diagnosis, more frequently had peripheral arthritis, enthesitis, IBD, psoriasis, and were more often treated with csDMARDs compared to HLA-B*27 (+) subgroup.

Human leukocyte antigen - B27 and antibodies to Klebsiella pneumoniae in Ankylosing Spondylitis: associations and clinical outcome.

Ankylosing spondylitis (AS) is a chronic disabling rheumatic disease with indefinite etiology. Human leukocyte antigen-B27 (HLA-B27) carriage and Klebsiella pneumoniae (K. pneumoniae) infections may contribute to the etiopathogenesis of AS. The objective of this study was to determine the association of HLA-B27 carriage, serum immunoglobulin G (IgG) to K. pneumoniae with AS, and its clinical outcome. In a case-control study, HLA-B27 carriage was detected by polymerase chain reaction, serum IgG to K. pneumoniae was measured by ELISA, and K. pneumoniae was isolated from the stool of 40 AS patients who were compared to age and sex-matched 40 normal individuals. Clinical findings, disease activity, and functional ability were evaluated for all AS patients. HLA-B27, serum IgG to K. pneumoniae, and fecal carriage of Klebsiella were significantly higher in AS patients when compared to controls (p < 0.001 for all). Disease activity and functional score categories were significantly higher in HLA-B27 positive AS patients with an elevated titer of K. pneumoniae IgG than in HLA-B27 negative patients with low titer of K. pneumoniae IgG (p < 0.012 and p < 0.001, respectively). In conclusion, HLA-B27 carriage and K. pneumoniae infections could play a significant role in the development and clinical outcome of AS patients.