anti-SSA Autoantibodies Research Articles

Association between anti-SSA autoantibodies and conduction disturbances in heart failure

BackgroundConduction disturbances play an important role in the occurrence and development of heart failure (HF). Studies suggest autoantibodies may attack the conduction system. However, whether autoantibodies are associated with conduction disturbances in patients with HF is unclear. ObjectiveThe purpose of this study was to assess whether anti-SSA, anti-Ro/Sjögren syndrome-related antigen A antibodies known for congenital atrioventricular block (AVB), is associated with conduction disturbances in patients with HF. MethodsThis retrospective observational study used data from patients with HF who were admitted to Beijing Anzhen Hospital between January 2018 and June 2022. Patients who were tested for anti-SSA and had undergone electrocardiographic examination during hospitalization were included. Conduction disturbances, including AVB, bundle branch block (BBB), and intraventricular conduction delay, were confirmed by a cardiologist blinded to anti-SSA status. Univariate and multivariable logistic regression analyses were performed to assess the association between anti-SSA and conduction disturbances. ResultsA total of 766 patients were included in this study, of whom 70 (9.1%) were anti-SSA positive. Subjects who were anti-SSA positive showed a higher prevalence of AVB (20% vs 10.6%) and BBB (27.3 % vs 10.9 %), including both left BBB and right BBB (all P <.05). After adjusting for known risk factors, anti-SSA was independently associated with AVB (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.18–5.43; P = .03) and BBB (OR 3.15; 95% CI 1.68–5.89; P <.001). ConclusionAnti-SSA is independently associated with AVB and BBB in patients with HF. Further study of the role of autoantibodies in the development of conduction abnormalities in patients with HF to generate possible targeted treatments is required.

Anti-SSA Ro52 and anti-Ro60 autoantibodies: association with clinical phenotypes.

Anti-SSA autoantibodies can be differentiated according to their antigenic target proteins as anti-Ro60 (60 kDa) or anti-Ro52 (52 kDa). Anti-SSA(Ro60) antibodies are clearly associated with connective tissue diseases (CTD), but the clinical significance of anti-SSA(Ro52) antibodies remains unclear. The aim of the present study was to analyse the disease phenotype of patients with anti-Ro52 and/or anti-Ro60 antibodies. A multicentre, cross-sectional study was carried out of positive anti-Ro52 and/or Ro60 antibodies patients followed at 10 Rheumatology centres from January 2018 until December 2021. Patients were categorised into 3 groups: group 1 (Ro52+/Ro60-); group 2 (Ro52-/Ro60+); group 3 (Ro52+/Ro60+). Antinuclear antibodies were evaluated by indirect immunofluorescence assay and further screened for anti-extractable nuclear antigen (ENA) antibodies. Demographicsand clinical data were compared between the 3 groups, by patients' medical chart review. Univariate analysis was performed and subsequently logistic regression was used to identify intergroup differences and calculate the odds ratio with a 95% confidence interval (95% CI). We included 776 patients [female: 83.1%; median age: 59 (46-71) years]. Groups 1, 2, and 3 comprised 31.1%, 32.6%, and 36.3% of the patients, respectively. Anti-Ro52 antibody alone was more frequently associated with non-rheumatic diseases, older age, and men (p<0.05). Among patients with CTD, the diagnosis of systemic lupus erythematosus is 3 and 2 times more prevalent in groups 2 and 3, respectively, than in group 1 [OR 2.8 (95% CI 1.60, 4.97), p<0.001; OR 2.2 (95% CI 1.28, 3.86), p<0.01]. In group 2, the diagnosis of undifferentiated CTD is more frequent than in the other groups. Group 1 was more frequently associated with inflammatory myositis than group 2 [OR 0.09 (95% CI 0.01, 0.33), p<0.001] or group 3 [OR 0.08 (95% CI 0.01, 0.29), p<0.001]. Group 1 was also more frequently associated with arthritis (p<0.01), interstitial lung disease (p<0.01), and myositis (p<0.01). Anti-Ro52+ antibody alone is frequently found in patients with non-rheumatic diseases. In addition, anti-Ro52+ antibody is also prevalent in patients with CTD and associated with clinical phenotypes that are different from anti-Ro60+ antibody.

Phenotypic Profiles Among 72 Caucasian and Afro-Caribbean Patients with Antisynthetase Syndrome Involving Anti-PL7 or Anti-PL12 Autoantibodies

ObjectivesAntisynthetase syndrome (ASyS) is a rare autoimmune disease. We aimed to determine clinical, biological, radiological, and evolutive profiles of ASyS patients with anti-PL7 or anti-PL12 autoantibodies. MethodsWe performed a retrospective study that included adults with overt positivity for anti-PL7/anti-PL12 autoantibodies and at least one Connors’ criterion. ResultsAmong 72 patients, 69% were women, 29 had anti-PL7 and 43 anti-PL12 autoantibodies, median age was 60.3 years, and median follow-up period was 52.2 months. At diagnosis, 76% of patients had interstitial lung disease, 61% had arthritis, 39% myositis, 25% Raynaud's phenomenon, 18% mechanic's hands, and 17% had fever. The most frequent pattern on initial chest computed tomography was non-specific interstitial pneumonia and 67% had fibrosis at last follow-up. During follow-up, 12 patients had pericardial effusion (18%), 19 had pulmonary hypertension (29%), 9 (12.5%) had neoplasms, and 14 (19%) died. Sixty-seven patients (93%) received at least one steroid or immunosuppressive drug. Patients with anti-PL12 autoantibodies were younger (p=0.01) and more frequently exhibited anti-SSA autoantibodies (p=0.01); patients with anti-PL7 autoantibodies had more severe weakness and higher maximum creatine kinase levels (p=0.03 and 0.04, respectively). Initial severe dyspnoea was more common in patients from the West Indies (p=0.009), with lower predicted values of forced vital capacity, forced expiratory volume in 1s, and total lung capacity (p=0.01, p=0.02, p=0.01, respectively) contributing to a more severe ‘respiratory’ initial presentation. ConclusionsThe high mortality and significant numbers of cardiovascular events, neoplasms and lung fibrosis in anti-PL7/12 patients justify close monitoring and question addition of antifibrotic drugs.

P094 “Neonatal lupus”: a unique name for very different realities

Abstract Background Neonatal lupus is a rare condition linked to the maternal-fetal transmission of maternal anti-SSA and/or anti-SSB antibodies, more rarely anti-U1-RNP. The most frequent clinical manifestations are cardiac and cutaneous, more rarely hematological (thrombocytopenia, leuco-neutropenia), hepatic (cholestasis), neurological (spastic paresis, lymphocytic meningitis) or renal. We report two observations of neonatal lupus: a classic form, and a rare form. Observations First case: A female newborn, premature of 37 weeks, from a first-degree consanguineous marriage, having a mother followed for systemic lupus erythematosus, with poor therapeutic compliance, presented at H1 of life with neonatal respiratory distress. The clinical examination revealed severe bradycardia at 67 Bpm. The electrocardiogram showed complete atrioventricular block, with a moderate pericarditis on the echocardiography, minimal tricuspid insufficiency, interatrial communication, and a 6 mm foramen oval with LR shunt. The immunological test had objectified positive antinuclear, anti-SSA and anti-SSB antibodies. An implementation of a pacemaker with inter-atrial communication ligation were performed successfully. The evolution was marked by the appearance of a malar erythema with generalized lesions of discoid lupus at the age of 14 months, treated with local corticosteroid therapy, with good outcomes. The control immunological workup was negative at 18 months. Second case: A 2-month-old boy from a non-consanguineous marriage with a mother followed for Sjögren's syndrome was admitted for a symptomatology dating back to birth marked by the appearance of diffuse petechial purpura. Clinically, the infant presented diffuse discoid macules throughout the body. The somatic examination, particularly cardiovascular, was normal. The biological workup showed haemolytic anaemia with a positive coombs test and severe thrombocytopenia. The electrocardiogram and echocardiography were normal. The immunological workup had objectified positive anti-SSA, anti-SSB and anti-nuclear antibodies. The infant was treated by oral corticosteroids (prednisolone) for 4 months, with good outcomes. The control immunological workup was negative at 6 months. Conclusion The clinical manifestations of neonatal lupus are polymorphic, and the only one that may expose to life threat is complete atrioventricular block. All mothers with known lupus or with positive anti-SSA autoantibodies should be monitored during pregnancy with repeated ultrasounds.

The Transcriptomic Profile of Monocytes from Patients With Sjögren's Syndrome Is Associated With Inflammatory Parameters and Is Mimicked by Circulating Mediators.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by infiltration of the exocrine glands and prominent B cell hyperactivity. Considering the key role of monocytes in promoting B cell hyperactivity, we performed RNA-sequencing analysis of CD14+ monocytes from patients with pSS, non-Sjögren’s sicca (nSS), and healthy controls (HC). We demonstrated that the transcriptomic profile of pSS patients is enriched in intermediate and non-classical monocyte profiles, and confirmed the increased frequency of non-classical monocytes in pSS patients by flow-cytometry analysis. Weighted gene co-expression network analysis identified four molecular signatures in monocytes from pSS patients, functionally annotated for processes related with translation, IFN-signaling, and toll-like receptor signaling. Systemic and local inflammatory features significantly correlated with the expression of these signatures. Furthermore, genes highly associated with clinical features in pSS were identified as hub-genes for each signature. Unsupervised hierarchical cluster analysis of the hub-genes identified four clusters of nSS and pSS patients, each with distinct inflammatory and transcriptomic profiles. One cluster showed a significantly higher percentage of pSS patients with higher prevalence of anti-SSA autoantibodies, interferon-score, and erythrocyte sedimentation rate compared to the other clusters. Finally, we showed that the identified transcriptomic differences in pSS monocytes were induced in monocytes of healthy controls by exposure to serum of pSS patients. Representative hub-genes of all four signatures were partially inhibited by interferon-α/β receptor blockade, indicating that the circulating inflammatory mediators, including type I interferons have a significant contribution to the altered transcriptional profile of pSS-monocytes. Our study suggests that targeting key circulating inflammatory mediators, such as type I interferons, could offer new insights into the important pathways and mechanisms driving pSS, and holds promise for halting immunopathology in Sjögren’s Syndrome.

Combination of anti-early apoptotic cell autoantibodies and anti-SSA autoantibodies in lupus nephritis

The aim of this study was to investigate the association of anti-early apoptotic cell autoantibodies, anti-SSA, and anti-SSB with clinical features of lupus nephritis (LN). Multiparameter flow cytometry was used to determine early apoptotic cells and for measuring the simultaneous binding of annexin V, 7-AAD, and IgG from LN patients (n = 39). The association between clinical features of LN and autoantibodies against early apoptotic cells, and between the autoantibodies and anti-SSA and anti-SSB, were further investigated. Thirteen LN patients (33.3 %) were positive for autoantibodies against early apoptotic cells. The prevalence of anti-SSA and anti-SSB were similar in patients with anti-early apoptotic cell autoantibodies and those without (anti-SSA: 9/13 versus 15/26; anti-SSB: 3/13 versus 4/26). Anti-early apoptotic cell antibody-positive patients had lower C3 levels (0.34 ± 0.22) than the antibody-negative patients (0.47 ± 0.17, p = 0.059); and significantly higher anti-dsDNA levels (502.99 ± 275.48 versus 214.13 ± 229.29, p = 0.001). In univariate logistic regression analysis, the presence of anti-early apoptotic cell antibody could predict poor short-term prognosis (HR 7.500, 95 % CI: 1.210 - 46.504, p = 0.030), while patients who were double positive for anti-SSA and anti-early apoptotic cell antibody had significantly increased risk of poor short-term outcome (HR 17.500, 95 % CI: 2.500 - 122.500, p = 0.004). The combination of anti-early apoptotic cell autoantibodies and anti-SSA might be of predictive value in LN.

Association between anti-Ro 60 kDa (SS-A) autoantibodies and hypocomplementemia in systemic lupus erythematosus patients from Algiers prefectures

BackgroundSystemic lupus erythematosus (SLE) is characterized by a vicious cycle maintaining systemic inflammation. It starts by autoantibody production, immune complex formation and complement activation that contribute to inflammation, tissue damage and further autoantibody production. Aim of the workTo evaluate the association between the auto-antibodies (abs), circulating immune complexes (CIC), and complement activity in SLE patients. Patients and methodsThis study involved 30 female SLE patients analyzed for autoantibodies, complement profile including complement hemolytic 50 (CH50), alternative pathway 50, factor B, C1q, C2, C3 and C4 as well as C1q-CIC. SLE disease activity was assessed by the SLE Disease Activity Index (SLEDAI). ResultsThe age of patients was 34±12.8years, disease duration was 5.2±3.2years and their mean SLEDAI was 9.96±4.2. Anti-SSA, anti-dsDNA, anti-C1q abs, and CIC were detected in 36.7%, 50%, 50% and 30% of patients, respectively. Anti-SSA were higher in patients with lower compared to normal CH50 activity and C3 level (24.7 vs 88.6U/ml; p=0.002 and 118.6±25.18U/ml vs 15.9±7.3; p<0.0001 respectively) than the other autoantibodies. Increased CIC were higher in patients with lupus nephritis and were associated with anti-SSA, anti-SSB, anti-C1q, anti-Sm and in patients with low CH50 activity. The CIC significantly correlated with anti-C1q (r=0.69, p<0.0001), anti-SSA (r=0.5, p=0.005) and negatively with CH50 (r=−0.4, p=0.046). ConclusionsThe current study confirms that the etiopathogenic anti-SSA autoantibodies are the most associated with hypocomplementemia in SLE. This would stimulate future researches for validation of predictive biomarkers earlier than hypocomplementemia which is still the major unmet need in lupus research and patient care.

Intracranial hemodynamic changes in primary Sjögren syndrome: a transcranial Doppler case-control study.

The aim of this case-control study is to evaluate the cerebral hemodynamic parameters in primary Sjögren syndrome patients by means of transcranial Doppler and the possible relationship with neuroimaging structural alteration, immunological markers and subclinical neurological involvement. 87 consecutive treatment-naïve outpatients with primary Sjögren syndrome and 86 age- and sex-matched healthy controls underwent transcranial Doppler for bilateral measurement of mean flow velocities, pulsatility index and systolic-diastolic ratio, brain magnetic resonance imaging, clinical evaluation with neuropsychological test and serological assessment. 28 patients and 4 controls (32 vs. 4 %, p .001) had executive function disorders at neuropsychological tests. Mean pulsatility index and systolic-diastolic ratio were significantly higher in both mean cerebral arteries of the patients than in controls (1.3 ± 0.6 vs. 0.9 ± 0.6, p .01 and 3.4 ± 1.7 vs. 1.6 ± 0.7, p .001, respectively). White matter hyperintensities were present in 21 patients and 18 controls. Only age was significantly associated with WMHs in both groups (p < .0001). The increase in systolic-diastolic ratio significantly correlates with neuropsychological impairment. Anti-SSA autoantibodies positively correlate with impaired systolic-diastolic ratio and with neuropsychiatric symptoms. The correlation between haemodynamic changes and anti-SSA autoantibodies suggests a role for the autoimmune response in determining early cerebral hemodynamic dysfunctions. The functional impairment of the endothelium may play a pivotal role in vasomotor dysfunction before any organic damage. The subsequent structural damage of the arterial wall may be responsible for the increase in resistances in small cerebral arteries and sustained hypoperfusion.

Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial.

Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited. To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue. From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012. Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48. The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue. At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group. Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes. clinicaltrials.gov Identifier: NCT00632866.

OP0114 Inefficacy of Hydroxychoroquine in Primary Sjögren’s Syndrome: Results at 12 Months of the Randomized Placebo-Controlled Trial of Plaquenil in Primary Sjögren’s Syndrome

BackgroundHydroxychloroquine (HQ, Plaquenil) is often prescribed in patients with primary Sjögren’s syndrome (pSS). However, except a crossover trial, no controlled trial has ever evaluated HQ versus placebo.ObjectivesMethods120 patients with pSS...

Increased serum levels of high-mobility group box 1 (HMGB1) in primary Sjögren's syndrome

Objective: To determine serum levels of high-mobility group box 1 (HMGB1) in patients with primary Sjögren’s syndrome (pSS) as compared to healthy volunteers and patients with sicca symptoms, and to determine whether serum HMGB1 levels are correlated with disease activity in pSS.Methods: Serum HMGB1 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 101 patients with pSS, 13 patients with sicca symptoms, and 40 healthy volunteers. Clinical and laboratory variables were also analysed and serum HMGB1 levels were correlated with the Sjögren’s Syndrome Disease Activity Index (SSDAI).Results: The serum levels of HMGB1 were significantly increased in pSS patients as compared to patients with sicca symptoms and healthy controls (p = 0.04 and p = 0.01, respectively). In the subgroups of patients with anti-SSA autoantibodies, the serum levels of HMGB1 were significantly higher than those in the subgroup of pSS patients who were anti-SSA negative and in healthy controls and patients with sicca symptoms (p < 0.001, p < 0.001, and p = 0.004, respectively). There was no significant correlation between serum HMGB1 levels (in pSS patients with anti-SSA autoantibodies) and SSDAI score (r = 0.03, p = 0.83). Patients with active disease had higher HMGB1 levels than patients with low disease activity (p = 0.04), but HMGB1 levels did not correlate with the SSDAI.Conclusion: Serum HMGB1 levels are increased in pSS patients and more specifically in patients with SSA autoantibodies. There was, however, no correlation of HMGB1 with the SSDAI.

Cerebrospinal Fluid Anti-SSA Autoantibodies in Primary Sjögren’s Syndrome with Central Nervous System Involvement

Background: Central nervous system involvement in primary Sjögren’s syndrome is a matter of controversy, and its diagnosis remains difficult. Methods: We report 3 patients with primary Sjögren’s syndrome and central nervous system involvement in whom we assessed intrathecal immunoglobulin G synthesis and the presence of cerebrospinal fluid anti-SSA and anti-SSB autoantibodies. Results: We found intrathecal immunoglobulin G synthesis and presence of cerebrospinal fluid anti-SSA autoantibodies in all patients, with demonstration for the first time of specific anti-SSA autoantibody intrathecal synthesis in 2 patients. Conclusion: We suggest that cerebrospinal fluid anti-SSA autoantibodies could serve as a biomarker for Sjögren’s-syndrome-related central nervous system involvement.

Re: Traditional cardiovascular risk factors in primary Sjogren's syndrome: role of dyslipidaemia

SIR, we would like to thank Gerli et al. [1] for their reply and the post hoc analysis of their recent Sjogren’s syndrome (SS) study [2] performed. This analysis confirmed our findings [3] in relation to the presence of anti-SSA/B autoantibodies and lower total and HDL cholesterol levels. In addition, Gerli et al.’s study showed anti-SSA antibodies, but not lipid levels, to be an independent predictor of mean carotid arterial thickening [2]. As referenced in our article, in RA and SLE several possible factors, including autoantibodies, can lead through vascular damage to a dysfunctional vasculature more susceptible to traditional cardiovascular risk factors, such as cholesterol levels, than in general. In addition, decreased lipid levels tended to predict cardiovascular morbidity and mortality in RA [4]. An association between intima-media thickening and altered lipid levels in SS patients could perhaps, as Gerli and co-authors had suggested, be detected in larger population-based studies with longer follow-up. Gerli et al. believe that the presence of anti-SSA/B autoantibodies is better for disease diagnosis than as a reflection of disease activity. As they indicate, these autoantibodies are thought to be a marker of autoimmune dysregulation characterizing an SS patient’s subset with more severe disease [5, 6]. Indeed, anti-SSA autoantibodies are detected in virtually all SS patients with coexistent vasculitis and in some of these patients it may be the only detectable antibody [7]. Again, this vasculitis can subsequently result in cardiovascular morbidity [8]. Moreover, anti-SSB autoantibody proved to be a highly significant marker of organ involvement in a large cohort of primary SS patients [5]. Interestingly, during an SS outcome measures workshop, Soloman et al. showed in a meta-analysis identifying predictive biomarkers in SS clinical trials that anti-SSB autoantibody may be a promising biomarker, in addition to IgG levels [9]. We agree immune-mediated mechanisms can play a role, but the relative contribution of each of the mechanisms needs to be further elucidated. Precocious atherosclerosis, dyslipidemia and autoimmune dysregulation could all be involved in a potential atherosclerotic risk and subsequently cardiovascular events. Gerli et al.’s and our studies provide the rationale for further research. B. M. LODDE, V. SANKAR, M. R. KOK, R. A. LEAKAN, P. P. TAK, S. R. PILLEMER Gene Therapy and Therapeutics Branch/National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA and Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands Accepted 8 September 2006 Correspondence to: Dr Beatrijs M. Lodde, GTTB/NIDCR, National Institutes of Health, 10 Center Drive, Room 1N114, MSC 1190, Bethesda, MD 20892-1190, USA. E-mail: blodde@mail.nih.gov

Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C

We present the case of a 53-year-old woman who developed systemic lupus erythematosus (SLE) after being treated with interferon-alpha (IFN-alpha) for cryoglobulinemic vasculitis associated with hepatitis C virus (HCV) infection. Her cryoglobulinemic vasculitis resolved rapidly with IFN-alpha treatment. However, after 10 months of IFN-alpha therapy, she developed a photosensitive malar rash, oral ulcers, arthralgias, lymphopenia, and anti-SSA autoantibodies. She was diagnosed with SLE induced by IFN-alpha therapy. IFN-alpha was discontinued, she was treated with a short course of prednisone and hydroxychloroquine, and she improved rapidly. This is the first report of IFN-alpha-induced SLE complicating treatment of cryoglobulinemic vasculitis associated with HCV infection. The development of SLE during therapy with IFN-alpha could be due to direct immunomodulation by IFN-alpha, and review of experimental data and prior case reports suggests a pathogenic role for IFN-alpha in SLE.