Gut microbiota in axial spondyloarthritis : genetics, medications and future treatments.

Axial spondyloarthritis, also referred to as ankylosing spondylitis, is a chronic inflammatory condition that predominantly affects the axial spine but may also present with peripheral arthritis. It falls within the umbrella of disorders known as spondyloarthropathies. In addition to axial spondyloarthritis, this group includes psoriatic arthritis, enteropathic arthritis, reactive arthritis, and undifferentiated spondyloarthropathy, with axial spondyloarthritis being one of the most common. The overall mechanisms underlying the development of axial spondyloarthritis are complex and multifactorial. There is a significant and well-recognized association between axial spondyloarthritis and the HLA-B27 gene, but there have also been non-HLA genes identified in the disease process, as well as certain inflammatory cytokines that play a role in the inflammatory process, such as tumor necrosis factor (TNF). More recently, there has been research and new evidence linking changes in the gut microbiota to the disease process of axial spondyloarthritis. Research into the role of the gut microbiota and gut dysbiosis is a large, ever-growing field. It has been associated with a multitude of conditions, including axial spondyloarthritis. This mini-review highlights the symbiotic relationship of the gut microbiota with the pathogenesis, therapeutic agents and future treatments of axial spondyloarthritis.

Bacterial amyloid curli activates the host unfolded protein response via IRE1α in the presence of HLA-B27.

Salmonella enterica serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA; activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1α branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. In vivo, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA.

Illuminating the impact of γδ T cells in man and mice in spondylarthritides.

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.

Advances in Psoriatic Disease Research: Insights From GRAPPA Pilot Research Awardees.

Research progress from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) pilot award program was presented and discussed at the GRAPPA 2023 annual meeting. Topics included identification of protein biomarkers associated with enthesitis in psoriatic arthritis (PsA), the role of HLA-B27 on gut microbial dysbiosis in PsA, single-cell profiling of synovial fluid vs psoriatic skin lesions in PsA, and the role of mechanotransduction in hyperactivation of transforming growth factor-ß via αVß6 integrin in psoriatic epidermis.

CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis.

HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human ß2m (hß2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.

Increased risk of malignancy in HLA-B27-positive patients with ankylosing spondylitis requiring biologics for sustained inflammation: A long-term, single-center retrospective study.

OBJECTIVES: To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. METHODS: Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. RESULTS: During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. CONCLUSIONS: HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.

Changes in HLA-B27 Transgenic Rat Fecal Microbiota Following Tofacitinib Treatment and Ileocecal Resection Surgery: Implications for Crohn's Disease Management.

The therapeutic management of Crohn's disease (CD), a chronic relapsing-remitting inflammatory bowel disease (IBD), is highly challenging. Surgical resection is sometimes a necessary procedure even though it is often associated with postoperative recurrences (PORs). Tofacitinib, an orally active small molecule Janus kinase inhibitor, is an anti-inflammatory drug meant to limit PORs in CD. Whereas bidirectional interactions between the gut microbiota and the relevant IBD drug are crucial, little is known about the impact of tofacitinib on the gut microbiota. The HLA-B27 transgenic rat is a good preclinical model used in IBD research, including for PORs after ileocecal resection (ICR). In the present study, we used shotgun metagenomics to first delineate the baseline composition and determinants of the fecal microbiome of HLA-B27 rats and then to evaluate the distinct impact of either tofacitinib treatment, ileocecal resection or the cumulative effect of both interventions on the gut microbiota in these HLA-B27 rats. The results confirmed that the microbiome of the HLA-B27 rats was fairly different from their wild-type littermates. We demonstrated here that oral treatment with tofacitinib does not affect the gut microbial composition of HLA-B27 rats. Of note, we showed that ICR induced an intense loss of bacterial diversity together with dramatic changes in taxa relative abundances. However, the oral treatment with tofacitinib neither modified the alpha-diversity nor exacerbated significant modifications in bacterial taxa induced by ICR. Collectively, these preclinical data are rather favorable for the use of tofacitinib in combination with ICR to address Crohn's disease management when considering microbiota.

Exploring the unifying concept of spondyloarthritis: a latent class analysis of the REGISPONSER registry.

OBJECTIVES: The aim of our study was to identify the potential distinct phenotypes within a broad SpA population. METHODS: We conducted a cross-sectional study using the REGISPONSER registry, which has data from 31 specialist centres in Spain, including patients with SpA who have fulfilled the ESSG criteria. A latent class analysis (LCA) was performed to identify the latent classes underlying SpA according to a set of predefined clinical and radiographic features, independently of expert opinion. RESULTS: In a population of 2319 SpA patients, a five-classes LCA model yielded the best fit. Classes named 'Axial with spine involvement' and 'Axial with isolated SI joint involvement' showed a primarily axial SpA phenotype defined by inflammatory back pain and high HLA-B27 prevalence. Patients in class 'Axial + peripheral' showed a similar distribution of manifest variables to previous classes but also had a higher likelihood of peripheral involvement (peripheral arthritis/dactylitis) and enthesitis, therefore representing a mixed (axial and peripheral) subtype. Classes 'Peripheral + psoriasis' and 'Axial + peripheral + psoriasis' were indicative of peripheral SpA (and/or PsA) with high likelihood of psoriasis, peripheral involvement, dactylitis, nail disease, and low HLA-B27 prevalence, while class 'Axial + peripheral + psoriasis' also exhibited increased probability of axial involvement both clinically and radiologically. CONCLUSION: The identification of five latent classes in the REGISPONSER registry with significant overlap between axial and peripheral phenotypes is concordant with a unifying concept of SpA. Psoriasis and related features (nail disease and dactylitis) influenced the phenotype of both axial and peripheral manifestations.

HLA-B*58 and HLA-B*27 Play a Role in the Development of Acute Leukemia: A Case Control Study.

BACKGROUND: Acute leukemia (AL) constitutes a group of malignant hematological diseases with multifactor origins. Some human leukocyte alleles (HLA) may be important genetic risk factors for development of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It is still unknown whether there is a relationship between ALL and AML with some alleles of the major histocompatibility complex. Our study looks specifically at western and southwest Algerian populations. METHOD: Using the polymerase chain reaction with the sequence specific probe (PCR- SSP) method, we investigated the relationship of HLA-B alleles in 163 Algerian AL patients and 293 controls from the same ethnic origin. The study ran from 2013 - 2020. RESULTS: Allele frequencies of HLA-B*27 and HLA-B*58 was higher in AL patients compared with control individuals; p=0.05 and p=0.03 respectively. Interestingly, all patients carrying HLA-B*27 allele and 88% of patients carrying HLA-B*58 allele had AML. However, there were no significant differences when we compared these results with the rest of AL group (HLA-B*X allele) (p=0.387). Response to induction chemotherapy treatment were comparable between the two patient groups 67% and 65% (p=0.978) respectively. CONCLUSION: These results suggest that the HLA-B*27 and HLA-B*58, may be factors predisposing individuals to acute leukemia, in west and southwest Algerian patients. A large-scale study is still needed to confirm these findings.

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.

The Presence of Pigmentation on Central Anterior Lens Capsule in the Human Leukocyte Antigen B27-Associated Anterior Uveitis and Its Value in Clinical Diagnosis.

PURPOSE: To report on the value of presence of pigmentation on central anterior lens capsule (PioLe) in HLA B27- associated anterior uveitis (HLA B27-AU). METHODS: 268 patients (320 eyes) with AU were reviewed. Two diagnostic models to predict probability of HLA-B27-AU were developed. The first model included 6 variables (age, gender, unilaterality, presence of non-granulomatous keratic precipitates, hypopyon, and intraocular pressure (IOP). The second model was developed to investigate the added value of PioLe into the first model. RESULTS:      Unilaterality, presence of hypopyon, IOP <21 mmHg and PioLe were characteristic for HLA-B27 positive patients (P≤0.003 for all). All of 6 variables had area under receiver operating characteristic curves (AuROC) ≤ 60, but PioLe reached even higher value (65.5). Diagnostic model I and II had AuROC 76.3% (95%CI, 68.4%-84.2%) and 80.0% (95%CI, 72.6%-87.5%), respectively. CONCLUSIONS: Unilaterality, hypopyon, IOP <21 mmHg and presence of PioLe are clinical signs suggesting HLA B27- AU.

The association between refractory plantar fasciitis and insertional Achilles tendinopathy and peripheral spondyloarthritis: a report of human leukocyte antigen B-27 investigation and treatment outcome.

PURPOSE: This study aimed to determine the presence of peripheral spondyloarthritis and investigate the clinical characteristics of patients with concurrent peripheral spondyloarthritis in those presenting with refractory plantar fasciitis and Achilles tendinopathy by conducting human leukocyte antigen B-27 (HLA-B27) testing. METHODS: This retrospective study aimed to investigate patients who complained of persistent pain and significant limitations in daily activities due to their respective foot pain, despite receiving conservative treatment for over one year under the diagnosis of plantar fasciitis or insertional Achilles tendinopathy. The study included 63 patients who underwent HLA-B27 testing. The patients were classified into two groups based on the presence or absence of HLA-B27 positivity. The Mann-Whitney U test assessed significant relationships between continuous variables, and the chi-square test was used to compare categorical variables. RESULTS: Among the 63 included patients, HLA-B27 positivity was confirmed in 11 patients (17.5%), which was significantly associated with a lower average age (22.8 years versus 31.7 years, P = 0.01) and a substantially lower proportion of females compared to HLA-B27-negative patients (9.1% vs. 25.0%, P = 0.001). Ten of the 11 patients initiated treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) combined with oral steroids as the first-line medication after being diagnosed as HLA-B27 positive. Six patients experienced pain relief with the first-line medication (60%). Four patients who did not achieve pain control with the first-line medication received tumour necrosis factor-alpha inhibitors as the second-line medication. Two patients experienced pain relief, while two experienced reduced but persistent pain. CONCLUSIONS: Among the patients with "refractory" plantar fasciitis and insertional Achilles tendinopathy, 17.5% were diagnosed with peripheral spondyloarthritis. Patients diagnosed with peripheral spondyloarthritis had a higher proportion of men and relatively younger mean age compared to those without the diagnosis. Approximately 70% of these patients achieved symptom improvement in foot and ankle joints by taking conventional synthetic DMARDs, TNF-α inhibitors, or both appropriate for spondyloarthritis.

[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.

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 did not protect against COVID-19 in patients with axial spondyloarthritis - data from the ReumaCov-Brasil Registry.

BACKGROUND: Some studies have suggested the HLA-B27 gene may protect against some infections, as well as it could play a benefit role on the viral clearance, including hepatitis C and HIV. However, there is lack of SARS-CoV-2 pandemic data in spondyloarthritis (SpA) patients. AIM: To evaluate the impact of HLA-B27 gene positivity on the susceptibility and severity of COVID-19 and disease activity in axial SpA patients. METHODS: The ReumaCoV-Brasil is a multicenter, observational, prospective cohort designed to monitor immune-mediated rheumatic diseases patients during SARS-CoV-2 pandemic in Brazil. Axial SpA patients, according to the ASAS classification criteria (2009), and only those with known HLA-B27 status, were included in this ReumaCov-Brasil's subanalysis. After pairing them to sex and age, they were divided in two groups: with (cases) and without (control group) COVID-19 diagnosis. Other immunodeficiency diseases, past organ or bone marrow transplantation, neoplasms and current chemotherapy were excluded. Demographic data, managing of COVID-19 (diagnosis, treatment, and outcomes, including hospitalization, mechanical ventilation, and death), comorbidities, clinical details (disease activity and concomitant medication) were collected using the Research Electronic Data Capture (REDCap) database. Data are presented as descriptive analysis and multiple regression models, using SPSS program, version 20. P level was set as 5%. RESULTS: From May 24th, 2020 to Jan 24th, 2021, a total of 153 axial SpA patients were included, of whom 85 (55.5%) with COVID-19 and 68 (44.4%) without COVID-19. Most of them were men (N = 92; 60.1%) with mean age of 44.0 ± 11.1 years and long-term disease (11.7 ± 9.9 years). Regarding the HLA-B27 status, 112 (73.2%) patients tested positive. There were no significant statistical differences concerning social distancing, smoking, BMI (body mass index), waist circumference and comorbidities. Regarding biological DMARDs, 110 (71.8%) were on TNF inhibitors and 14 (9.15%) on IL-17 antagonists. Comparing those patients with and without COVID-19, the HLA-B27 positivity was not different between groups (n = 64, 75.3% vs. n = 48, 48%, respectively; p = 0.514). In addition, disease activity was similar before and after the infection. Interestingly, no new episodes of arthritis, enthesitis or extra-musculoskeletal manifestations were reported after the COVID-19. The mean time from the first symptoms to hospitalization was 7.1 ± 3.4 days, and although the number of hospitalization days was numerically higher in the B27 positive group, no statistically significant difference was observed (5.7 ± 4.11 for B27 negative patients and 13.5 ± 14.8 for B27 positive patients; p = 0.594). Only one HLA-B27 negative patient died. No significant difference was found regarding concomitant medications, including conventional or biologic DMARDs between the groups. CONCLUSIONS: No significant difference of COVID-19 frequency rate was observed in patients with axial SpA regarding the HLA-B27 positivity, suggesting a lack of protective effect with SARS-CoV-2 infection. In addition, the disease activity was similar before and after the infection. TRIAL REGISTRATION: This study was approved by the Brazilian Committee of Ethics in Human Research (CONEP), CAAE 30186820.2.1001.8807, and was registered at the Brazilian Registry of Clinical Trials - REBEC, RBR-33YTQC. All patients read and signed the informed consent form before inclusion.

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.

HLA-B27 status and inflammatory MRI lesions of the sacroiliac joints: a post hoc analysis in patients without axial spondyloarthritis.

OBJECTIVE: The assessment of inflammatory and structural lesions in the sacroiliac joint (SIJ) is crucial in axial spondyloarthritis (axSpA). HLA-B27 status plays an important role in axSpA diagnosis and has been linked to MRI lesion burden in the general population. We aimed to investigate the sex-specific influence of HLA-B27 status on inflammatory and structural MRI findings in patients with low back pain of non-inflammatory origin. METHODS: This post hoc analysis included 139 non-axSpA patients (90 women) with chronic low back pain. Two readers scored MRIs of the SIJ for the presence of sclerosis, erosion, fat metaplasia, bone marrow oedema (BMO) and ankylosis. Frequencies and extent of lesions were compared regarding the HLA-B27 status using χ2 tests and t-tests. Regression models to assess the sex-dependent influence of HLA-B27 on lesion burden were computed. RESULTS: HLA-B27 was positive in 33 women (36.7%) and 23 men (46.9%). The overall occurrence of all SIJ lesions did not differ in HLA-B27 negative and positive individuals. There were no significant differences in the extent of lesions considering the HLA-B27 positivity, for erosion (mean sum score (MSS) of 0.91 vs 0.48; p=0.144), sclerosis (MSS 1.65 vs 1.88; p=0.576), fat metaplasia (MSS 0.56 vs 0.27; p=0.425), BMO (MSS 0.75 vs 0.59; p=0.460) and ankylosis (MSS 0.06 vs 0.04; p=0.659). CONCLUSION: HLA-B27 status has no significant influence on the occurrence and extent of SIJ lesions in patients with low back pain of non-inflammatory origin in either men or women.

Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/- mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II ß-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.

Associations between family history of psoriatic disease and clinical characteristics on patients with psoriatic arthritis: a nationwide study from the Chinese Registry of Psoriatic Arthritis (CREPAR II).

OBJECTIVES: The study aimed to identify clinical characteristics in Chinese patients with psoriatic arthritis (PsA) with or without a family history of psoriasis and/or PsA. METHODS: Patients with PsA were recruited based on Chinese REgistry of Psoriatic ARthritis (CREPAR) between December 2018 and June 2021. The demographics, clinical information relating to PsA, laboratory variables and comorbidities were collected. The association between family history of psoriatic disease and clinical characteristics on PsA was analysed using logistic regression analysis. RESULTS: Among 1074 eligible patients with PsA, 313 (29.1%) had a family history of psoriasis and/or PsA. Compared with patients without a family history, notably, patients with a family history of psoriasis and/or PsA had an earlier age of onset of psoriasis and PsA, higher proportions of enthesitis and nail involvement, a higher prevalence of positive human leukocyte antigen-B27 (HLA-B27), lower disease activity score 28-erythrocyte sedimentation rate, higher proportions of hyperlipidaemia, lower proportions of hypertension and diabetes. Furthermore, after adjusting for confounding factors, logistic regression analysis demonstrated that a positive family history of psoriasis and/or PsA was associated with more females (OR 1.514, 95% CI 1.088-2.108, p=0.014), earlier age at psoriasis onset (OR 0.971, 95%CI 0.955-0.988, p=0.001), a higher prevalence of HLA-B27 (OR 1.625 95%CI 1.089-2.426, p=0.018), more presence of nail involvement (OR 1.424, 95%CI 1.007-2.013, p=0.046) and enthesitis (OR 1.393, 95%CI 1.005-1.930, p=0.046), a higher proportion of hyperlipidaemia (OR 2.550, 95%CI 1.506-4.317, p=0.001) in PsA patients. CONCLUSIONS: This was first nationwide study to characterize patients with and without a family history of psoriatic disease in China. The findings from the present study revealed that family history of psoriasis and/or PsA had greater effects on disease phenotypes of PsA, especially nail disease and enthesitis.