Comparison of SARS-COV-2 humoral response between rheumatoid arthritis, psoriatic arthritis and spondyloarthritis patients and controls in two unvaccinated cohorts.

OBJECTIVES: To compare the humoral response after a SARS-CoV-2 infection in an inflammatory rheumatic disease population with a healthy control population in a case-control study. METHODS: Cases: between March and September 2021, all consecutive unvaccinated patients followed for rheumatoid arthritis (RA), spondyloarthritis (SpA) or psoriatic arthritis (PsA) in 16 hospitals in France were systematically screened with a SARS-CoV-2 serological test. Patients with a positive test were included in the COVID-RIC-2 cohort. CONTROLS: between June and July 2020, healthcare professionals working in the Toulouse University Hospital were screened with a SARS-CoV-2 serological test. Those with a positive test were included in the COVID-BIOTOUL cohort and matched to those from COVID-RIC-2 by age, sex and time-sampling on infection date. ANALYSES: total SARS-CoV-2 antibody titres were centrally measured and compared. RESULTS: 95 patients from COVID-RIC-2 (mean age 49 years, 76% females, median delay of COVID infection: 149 days) including 48 RA, 33 SpA and 14 PsA were compared to 95 matched controls. Globally, there was no significant difference of SARS-CoV-2 antibody titres between both populations: 155 Binding Antibody Units (BAU) (IQR:7-376) in COVID-RIC-2 vs. 120 BAU (IQR:35-320) in COVID-BIOTOUL. There was a trend towards higher antibody titres in patients from COVID-RIC-2 with severe COVID-19 symptoms. In COVID-RIC-2, there was no impact of age, sex, time-sampling or underlying disease on antibody titres and patients taking glucocorticoids, abatacept or rituximab trended toward having lower antibody titres after COVID-19 infection. CONCLUSIONS: This study provides reassuring data on humoral response after COVID-19 infection in patients treated with disease-modifying anti-rheumatic drugs.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Characteristics of patients with difficult-to-treat rheumatoid arthritis in a French single-centre hospital.

OBJECTIVES: To compare the features of difficult-to-treat rheumatoid arthritis (D2TRA) patients using two different definitions according to the previous failure of targeted therapies. METHODS: We stratified consecutive RA patients treated at Cochin Hospital into two groups, a D2TRA group and a non-D2TRA group, according to two definitions of D2TRA. Both definitions defined D2TRA as RAs failing at least two targeted therapies, with a different mechanism of action for the EULAR-D2TRA definition or without prejudging the mechanism of action and for the Alternative D2TRA definition. RESULTS: We included 320 consecutive RA patients. We identified 76 EULAR-D2TRA and 244 non-DTRA patients, and 120 Alternative D2TRA and 200 non-DTRA patients. Compared with non-D2TRA, D2TRA patients from both definitions were more likely to have lower socioeconomic level, positive rheumatoid factor, interstitial lung disease, higher DAS28-CRP and were more likely to respond to rituximab and Janus kinase inhibitors. Although EULAR and Alternative D2TRA patients displayed similar clinical and biological features, they were characterized by different therapeutic profiles. We observed fewer patients receiving methotrexate in the Alternative D2TRA group (53% vs 64%, P = 0.046). Patients with Alternative D2TRA not fulfilling the EULAR definition (n = 44) had all received two successive first-line TNF inhibitors, a monoclonal antibody and a soluble receptor, and were comparable to EULAR-D2TRA patients with regards to all other characteristics. CONCLUSION: Low socioeconomic status, diabetes, interstitial lung disease and absence of combination with methotrexate allow identification of D2TRA. In addition, the inclusion as 'early-D2TRA' of patients failing two TNF inhibitors in the EULAR definition of D2TRA would facilitate the rapid identification of D2TRA patients.

Should complete B-cell depletion be maintained in patients treated long-term with rituximab for rheumatoid arthritis?

OBJECTIVE: To determine whether persistent complete B cell (BC) depletion was associated with a better clinical response in rheumatoid arthritis (RA) patients long-term treated with rituximab (RTX). METHODS: We conducted a retrospective study including RA patients admitted for a new infusion between 2019 and 2021. The primary end point was the comparison of the mean DAS28-CRP at each of the 4 last infusion visits between patients with persistent complete BC depletion (mean CD19 counts <18/µL at each of the last 4 visits) or without persistent complete BC depletion (mean CD19 counts of the last 4 visits ≥18/µL). Secondary endpoints included DAS28, pain/fatigue VAS, CRP, gammaglobulins and the frequency of self-reported RA flares. RESULTS: Of the 126 patients in maintenance therapy with RTX (exposure period: 76 ± 5 months, n 14 ± 7 infusions received), 43 (34%) had persistent complete BC depletion at each of the 4 last infusions. The mean DAS28-CRP calculated at each of the 4 last infusion visits did not significantly differ according to persistence or not of complete BC depletion. This result remained unchanged after adjusting for antibody status, number of previous therapies, number of RTX infusion and cumulative RTX dose. All secondary outcomes were also not significantly different between both groups. CONCLUSION: Maintaining complete BC depletion does not appear to be a therapeutic target to achieve in RA patients in long-term maintenance therapy with RTX. There is a limited benefit of monitoring CD19 in RA patients long term treated with RTX and having achieved low disease activity/remission.

Risk factors of impaired humoral response to COVID-19 vaccination in rituximab-treated patients.

OBJECTIVE: To identify which factors influence humoral response to coronavirus disease 2019 (COVID-19) vaccination in rituximab (RTX)-treated patients. METHODS: This was an observational, prospective, usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a two-dose regimen COVID-19 vaccination. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured at the time of the new RTX infusion. RESULTS: From the recruited patients, 16/45 (36%) produced antibodies reaching the assay cut-off value of 15 AU/ml and 29/45 (64%) had a negative serology. Within RTX-treated patients, 25 (56%) had undetectable B cells. Negative serology was associated with undetectable B cells (24/25 vs 5/20, P < 0.001). Moreover, SARS-CoV-2 spike antibodies correlated with CD19 counts (r = 0.86, P < 0.001). The effect of RTX and MTX was additive in terms of seroconversion rates (23% vs 50% in patients receiving RTX in monotherapy, P = 0.12) and SARS-CoV-2 spike antibody levels [3.80 (95% CI 3.80, 7.50) vs 75 (95% CI 3.8, 353) AU/ml in patients receiving RTX in monotherapy; P = 0.025]. Multivariate analyses including demographics, disease characteristics, gammaglobulin levels, RTX and other therapies used, CD19 counts, and the time between the last RTX infusion and vaccination identified detectable B cells as the only variable independently associated with seropositivity [odds ratio 35.2 (95% CI 3.59, 344.20)]. CONCLUSIONS: B cell depletion is the main independent contributing factor of antibody response to SARS-CoV-2 vaccination in RTX-treated patients. Monitoring CD19 may be of interest to identify the most appropriate period to perform vaccination.

Bone Involvement in Patients with Spondyloarthropathies.

Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.

Hip Pain Associated with Acetabular Dysplasia in Patients with Suspected Axial Spondyloarthritis: DESIR Cohort Data.

OBJECTIVES: To determine whether acetabular dysplasia is associated with hip pain at physical examination among adults with recent-onset inflammatory back pain (IBP) suggesting axial spondyloarthritis (axSpA). METHODS: This cross-sectional ancillary study was conducted on the prospective DESIR cohort, which enrolled patients aged 18-50 years who had recent-onset IBP. Two readers used antero-posterior pelvic radiographs to assess the Tönnis angle, acetabular angle (AA), lateral centre-edge angle (LCEA), and femoral head extrusion index (FHEI). Abnormality of one or more of these four variables defined acetabular dysplasia. Hip pain upon physical examination was assessed based on Ritchie's articular index. RESULTS: The overall prevalence of acetabular dysplasia was 22% (139/636). The proportion of females was higher in the group with acetabular dysplasia. Hip pain was found in 21% (29/139) of patients with versus 12% (59/497) without acetabular dysplasia (OR, 1.96; 95% CI, 1.20 to 3.20); the association was significant in males (OR, 3.14; 95% CI, 1.44 to 6.86) but not females (OR, 1.39; 95% CI, 0.74 to 2.62). Results were similar when acetabular dysplasia was defined on the basis of LCEA alone (OR, 2.15; 95% CI, 1.18 to 2.62). CONCLUSION: Among patients with recent-onset IBP suggesting axSpA, acetabular dysplasia was significantly associated with hip pain in males. Hip pain related to acetabular dysplasia might result in overdiagnosis of hip involvement by axSpA.

Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo.

OBJECTIVES: Antitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi. METHODS: Immune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays. RESULTS: Anti-TNF therapy induced profound changes in patients' innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF. CONCLUSIONS: We show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

Secukinumab and ustekinumab treatment in psoriatic arthritis: results of a direct comparison.

OBJECTIVES: To evaluate the characteristics of patients (pts) with PsA treated by ustekinumab (UST) or secukinumab (SEK) and to compare real-world persistence of UST and SEK in PsA. METHODS: In this retrospective, national, multicentre cohort study, pts with PsA (CASPAR criteria or diagnosis confirmed by the rheumatologist) initiating UST or SEK with a follow-up ≥6 months were included from January 2011 to April 2019. The persistence between SEK and UST was assessed after considering the potential confounding factors by using pre-specified propensity-score methods. Causes of discontinuation and tolerance were also collected. RESULTS: A total of 406 pts were included: 245 with UST and 161 with SEK. The persistence rate was lower in the UST group compared with the SEK group [median persistence 9.4 vs 14.7 months; 26.4% vs 38.0% at 2 years; weighted hazard ratio (HR) = 1.42; 95% CI: 1.07, 1.92; P =0.015]. In subgroup analysis, the persistence rate of SEK associated with MTX was significantly higher than that of UST associated with MTX: HR = 2.20; 95% CI: 1.30, 3.51; P =0.001, in contrast to SEK vs UST monotherapy: HR = 1.06; 95% CI: 0.74, 1.53; P =0.75. Discontinuation due to inefficacy was reported in 91.7% (SEK) and 82.4% (UST) of pts. Discontinuation due to an adverse event was reported in 12.2% (SEK) and 7.7% (UST) of pts. CONCLUSION: In this first study comparing UST and SEK, the persistence of SEK was higher than that of UST in PsA. In subgroup analysis, this difference was only found in association with MTX.

Doctor's aptitude for switching from innovator etanercept to biosimilar etanercept in inflammatory rheumatic diseases: experience from a single French rheumatology tertiary care center.

OBJECTIVES: To describe the switch to biosimilar etanercept (bETN), evaluate factors associated with this switch, and evaluate the efficacy of this switch in a real-life setting METHODS: We included patients, from October 2016 to April 2017, with rheumatoid arthritis (RA) and spondyloarthritis (SpA) who received innovator ETN (iETN) for at least 6 months. After receiving information on biosimilars, all physicians were invited to propose a switch from iETN to bETN. Factors associated with bETN discontinuation were explored by univariate and multivariate analyses. We estimated the proportion of patients still on bETN over time by Kaplan-Meier survival analysis. We assessed serum trough concentrations of iETN and bETN and anti-drug antibodies to ETN. RESULTS: Overall, 183 outpatients were eligible for a potential switch; 94 (51.6%) switched from iETN to bETN. The probability of a switch was greater with an older than younger aged physician (mean [SD] age 50.4 [14.3] with a switch vs 44.8 [11.3] with no switch, p = 0.005) and the physician having a full-time academic position than other position (56.4% with a switch vs 13.5% with no switch, p < 0.001). After a 6-month follow-up, bETN retention rate was 83% (95% CI: 0.76-0.92). The first cause of bETN discontinuation was inefficacy (50%). On multivariate analysis, no factor was independently associated with a bETN switch or discontinuation. Drug trough levels did not significantly differ by discontinuation or continuation of bETN. No patient showed anti-drug antibodies. CONCLUSION: The probability of switching from iETN to bETN was likely related to physician characteristics.

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib.

Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.

Role of the IL-12/IL-35 balance in patients with Sjögren syndrome.

BACKGROUND: An interferon signature is involved in the pathogenesis of primary Sjögren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of TH1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. OBJECTIVE: We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. METHODS: The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. RESULTS: We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. CONCLUSION: Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.

The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelter's syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fisher's exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fisher's exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA.

Disease activity is longitudinally related to sacroiliac inflammation on MRI in male patients with axial spondyloarthritis: 2-years of the DESIR cohort.

OBJECTIVES: To investigate the longitudinal relationship between inflammatory lesions in sacroiliac joints on MRI (MRI-SI) and clinical disease activity measures (DA) in patients with axial spondyloarthritis (axSpA). METHODS: Two-year follow-up data from 167 patients (50% males, mean (SD) age 33 (9) years) fulfilling the Assessment of SpondyloArthritis international Society axSpA criteria in the DEvenir des Spondylarthopathies Indifférenciées Récentes cohort with MRI-SI at baseline, 1 year and 2 years were analysed. The relationship between MRI-SI (as dependent variable) and DA (Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), patient's global DA, night pain, C reactive protein and erythrocyte sedimentation rate, as independent variables) was investigated using two types of generalised estimating equations (GEE) models: model of absolute scores and model of change scores. RESULTS: In the model of absolute scores, the relationship between DA and MRI-SI was different for males and females: in males, but not in females, a statistically significant relationship with MRI-SI was found for all DA except BASDAI. In the model of changes, only ASDAS (beta (95% CI): 2.79 (0.85 to 4.73) and pain at night (0.97 (0.04 to 1.90)) were significantly associated in males while again in females no significant relationship was found. ASDAS fitted the data best. CONCLUSIONS: In male patients, but not in female patients, with axSpA, clinical DA, especially if measured by ASDAS, is longitudinally associated with MRI-SI inflammatory lesions.

Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjögren's syndrome.

BACKGROUND: Beyond genetics, epigenetics alterations and especially those related to DNA methylation, play key roles in the pathogenesis of autoimmune diseases such as primary Sjögren's syndrome (pSS) and systemic lupus erythematosus. This study aimed to assess the role of methylation deregulation in pSS pathogeny through a genome-wide methylation approach. PATIENTS AND METHODS: 26 female patients with pSS and 22 age-matched controls were included in this study. CD4+ T cells and CD19+ B cells were isolated from peripheral blood mononuclear cells by magnetic microbeads and their genome-wide DNA methylation profiles were analysed using Infinium Human Methylation 450 K BeadChips. Probes with a median DNA methylation difference of at least 7% and p<0.01 between patients and controls were considered significantly differentially methylated. RESULTS: Methylation alterations were mainly present in B cells compared with T cells. In B cells, an enrichment of genes with differentially methylated probes in genetic at-risk loci was observed, suggesting involvement of both genetic and epigenetic abnormalities in the same genes. Methylation alterations in B cells were more frequent in some specific pathways including Interferon Regulated Genes, mainly among patients who were autoantibody positive. Moreover, genes with differentially methylated probes were over-represented in B cells from patients with active disease. CONCLUSIONS: This study demonstrated more important deregulation of DNA methylation patterns in B cells compared with T cells, emphasising the importance of B cells in the pathogenesis of the disease. Overlap between genes with differentially methylated probes in B lymphocytes and genetic at-risk loci is a new finding highlighting their importance in pSS.

Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma.

BACKGROUND AND OBJECTIVE: A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association. PATIENTS AND METHODS: The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts. RESULTS: The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively). CONCLUSIONS: This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma.