Differences in Cellular Clearing Mechanisms of Aggregates of Two Subtypes of HLA-B27

Ankylosing spondylitis (AS) belongs to a group of diseases, called spondyloarthropathies (SpA), that are strongly associated with the genetic marker HLA-B27. AS is characterized by inflammation of joints and primarily affects the spine. Over 160 subtypes of HLA-B27 are known, owing to high polymorphism. Some are strongly associated with disease (e.g., B*2704), whereas others are not (e.g., B*2709). Misfolding of HLA-B27 molecules [as dimers, or as high-molecular-weight (HMW) oligomers] is one of several hypotheses proposed to explain the link between HLA-B27 and AS. Our group has previously established the existence of HMW species of HLA-B27 in AS patients. Still, very little is known about the mechanisms underlying differences in pathogenic outcomes of different HLA-B27 subtypes. We conducted a proteomics-based evaluation of the differential disease association of HLA B*2704 and B*2709, using stable transfectants of genes encoding the two proteins. A clear difference was observed in protein clearance mechanisms: whereas unfolded protein response (UPR), autophagy, and aggresomes were involved in the degradation of B*2704, the endosome–lysosome machinery was primarily involved in B*2709 degradation. These differences offer insights into the differential disease association of B*2704 and B*2709.

Epidemiology and Clinical Features of Anterior Uveitis: a Prospective Study

Purpose: To report the pattern, epidemiology, and clinical features of anterior uveitis (AU) in southern TaiwanMethods: A prospective case series was performed to recruit patients with AU at two medical centers (Kaohsiung Chang Gung Memorial Hospital and Kaohsiung Veterans General Hospital) in southern Taiwan from December 1, 2018 to March 31, 2020. These patients enrolled were reviewed for clinical diagnoses, ocular presentations, and laboratory data, including aqueous polymerase chain reaction tests.Results: A total of 112 patients were included. The most common clinical diagnoses were idiopathic AU (37.5%), HLA-B27-associated acute AU (25.0%), and herpetic AU (18.8%); among herpetic etiology, cytomegalovirus (CMV) was the most common pathogen. Hypertensive AU was associated with older age, more males, and greater numbers of corneal edema, and fewer iris posterior synechiae. Compared with HLA-B27-associated acute AU, CMV AU was associated with older age, high intraocular pressure, more keratic precipitates, greater iris atrophy, more pseudophakia, and fewer pupil posterior synechiae. Conclusion: This prospective study identified the epidemiological and clinical features of AU in southern Taiwan. The most common etiologies were idiopathic AU, HLA-B27-associated acute AU, and herpetic (most CMV) AU.

HLA-B27 and not variation in MICA is responsible for genotype by sex interaction in risk of Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus. The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors' report is unlikely to be a result of variation in MICA, but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.

HLA-B27 assoziierte anteriore Uveitis: Herausforderung für eine interdisziplinäre Zusammenarbeit

ZusammenfassungDie akute anteriore Uveitis (AAU) ist die häufigste Form intraokularer Entzündungen, die v. a. Personen im erwerbsfähigen Alter betrifft und mit erheblichen sozioökonomischen Auswirkungen verbunden ist. Etwa die Hälfte der AAU-Patienten sind HLA-B27 positiv und teilen ein hohes Risiko zu HLA-B27-assoziierten Erkrankungen, insbesondere zur Spondyloarthritis (SpA). Sowohl die SpA als auch die AAU sind komplexe entzündliche Erkrankungen, deren genaue Pathogenese unbekannt ist. Da bei bis zu 40% der AAU-Patienten eine nicht diagnostizierte SpA vorliegt, bietet die AAU die Möglichkeit einer frühzeitigen Erkennung der zugrundeliegenden rheumatologischen Erkrankung. Die klinische Präsentation der AAU bei SpA weist eine Reihe typischer Augenbefunde auf, die diagnostisch wegweisend sind und auf eine systemische Grunderkrankung hindeuten können. Daher ist eine abgestimmte Überweisungsstrategie zur zügigen Diagnostik und Behandlung notwendig. Dieser Beitrag fokussiert daher auf die interdisziplinäre Zusammenarbeit und bietet gleichzeitig Hinweise für die differentialdiagnostische Abklärung.

Spinal Radiographic Progression and Predictors of Progression in Patients With Radiographic Axial Spondyloarthritis Receiving Ixekizumab Over 2 Years

Objective To evaluate the long-term effect of ixekizumab on radiographic changes in the spine in patients with radiographic axial spondyloarthritis (r-axSpA) by measuring change from baseline through 2 years in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and to identify potential predictors of progression. Methods This study evaluates patients from COAST-V (NCT02696785, bDMARD-naive) and COAST-W (NCT02696798, TNFi-experienced) who had mSASSS data at baseline in the originating studies and 108 weeks after baseline in the extension study COAST-Y (NCT03129100). We examined the proportion of patients who did not have spinal radiographic progression through 2 years (108 weeks) of treatment with ixekizumab (80 mg every 2 or 4 weeks) and the change from baseline to year 2 in mSASSS. Potential predictors of spinal radiographic progression were also evaluated. Results Among patients with evaluable radiographs who were originally assigned to ixekizumab (N=230), mean (SD) change in mSASSS from baseline at year 2 was 0.3 (1.8). The proportion of non-progressors over 2 years was 89.6% if defined as mSASSS change from baseline <2 and 75.7% if defined as mSASSS change from baseline ≤0. Predictors of structural progression at year 2 (mSASSS change >0) were age ≥40, baseline syndesmophytes, HLA-B27 positivity and male gender. Week 52 inflammation in SPARCC spine was also a predictor of radiographic progression at year 2 in patients with MRI-data in COAST-V (N=109). Conclusion The majority of patients with r-axSpA receiving ixekizumab had no radiographic progression in the spine through 2 years of treatment. Predictors were generally consistent with previous studies.

Comparison of ankylosing spondylitis patients with and without fibromyalgia syndrome according to the disease activation scores and response to treatment

Objectives: The aim of this study was to investigate the association of fibromyalgia (FM) syndrome with ankylosing spondylitis (AS) and to compare the AS patients with and without FM according to the disease activity, clinical and laboratory findings, and response to treatment. Patients and methods: Between September 2016 and September 2020, a total of 511 patients (312 males, 119 females; mean age: 43.0±11.2 years; range, 18 to 77 years) who were diagnosed with AS were retrospectively analyzed. Age, sex, disease duration, disease onset age, and extra-articular findings were recorded. Medical treatments used by the patients for the treatment of AS and FM were noted. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), human leukocyte antigen-B27 (HLA-B27) status, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) with ESR (ASDAS-ESR) and ASDAS-CRP values were recorded. Results: The frequency of FM in AS patients was 23.2%. Totally, 75.4% of the FM patients were female. The HLA-B27 positivity, extra-articular involvement frequency, disease duration, and acute phase reactants levels were similar between AS patients with and without FM (p=0.118, p=0.154, p=0.829, p=0.113, and p=0.763, respectively). The AS patients with FM had lower rates of achieving remission or low disease activity, compared to those without FM. The mean of all three disease activity scores between these two groups was also higher in the AS patients with FM (p<0.001). The rate of use of biological therapy was significantly higher in the AS patients with FM than those without FM (p=0.037). Conclusion: Since the treatment plan of AS is made based on the disease activity scores, unnecessary biological therapy may be initiated for patients or the biological therapies they use may be switched unnecessarily. Therefore, it should be kept in mind that FM may present with AS in patients who do not respond to treatment clinically, and this may be misinterpreted as treatment unresponsiveness.

Intraocular dendritic cells characterize HLA-B27-associated acute anterior uveitis

Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. Uveitis associated with the HLA haplotype B27 (HLA-B27) is a common subtype of uveitis and a prototypical ocular immune-mediated disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations. Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27-positive (n = 4) and -negative (n = 2) anterior uveitis and an infectious endophthalmitis control (n = 1) by combining single-cell RNA-sequencing with flow cytometry and protein analysis. Ocular cell infiltrates consisted primarily of lymphocytes in both subtypes of uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27-positive uveitis exclusively featured a plasmacytoid and classical dendritic cell (cDC) infiltrate. Moreover, cDCs were central in predicted local cell-cell communication. This suggests a unique pattern of ocular leukocyte infiltration in HLA-B27-positive uveitis with relevance to DCs.