Autoantibodies In Systemic Sclerosis Research Articles

Application of Immunoblot assay (ANA 23 Profile) for detection of autoantibodies in systemic sclerosis

Objective: Examine the clinical and subclinical characteristics and the rate of autoantibodies in systemic sclerosis (SSc) using Immunoblot technique (ANA 23 Profile). Research subjects and methods: Cross-sectional descriptive study of 57 patients diagnosed with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria and were tested for autoantibodies using the Immunoblot technique (ANA 23 Profile) at the National Hospital of Dermatology and Venereology. Results: Among 57 SSc patients, the female/male ratio was 5/1. The average age of disease onset was 49.3±13.3, with 57.9% of patients over the age of 50. Diffuse SSc was the most common (70%). Raynaud was the most common symptom (98.2%), followed by gastroesophageal reflux (86%), and pulmonary fibrosis (70.2%). Heart and kidney damage were less frequently observed, accounting for 15.8 and 5.3%, respectively. Positive rates of the three major antibodies in SSc included anti-Scl-70 antibody (63.2%), anti-centromere antibody (17.5%), and anti-RNA polymer III antibody (12.3%), respectively. Scl-70 autoantibodies were mainly found in diffuse skin types (91.7%) while CENP autoantibodies were mainly found in localised skin types (90%) with p<0.05. RNAP III antibodies were mainly found in diffuse skin types (85.7%), however, this difference was not statistically significant (p>0.05). Conclusion: The presence of Scl-70 was related to the diffuse skin types while the presence of CENP was related to localised skin types.

Nouveaux auto-anticorps dans la myosite auto-immune et la sclérodermie systémique

AbstractAntinuclear antibodies support the diagnosis of autoimmune myositis and systemic sclerosis. Recently, a new anti-synthetase antibody has been described as well as several new autoantibodies in systemic sclerosis. Immunoprecipitation mass spectrometry played a decisive role in uncovering these new antigenic targets. In this short report, novel autoantibodies (and their HEp-2 indirect immunofluorescence profile) are summarized.

Prognostic value of anti-IFI16 autoantibodies in pulmonary arterial hypertension and mortality in patients with systemic sclerosis

ObjectivesTo determine the diagnostic value of anti-interferon gamma inducible protein 16 (IFI16) autoantibodies in systemic sclerosis (SSc) patients negative for all tested SSc-specific autoantibodies (SSc-seronegative patients) and to evaluate the clinical significance of these autoantibodies, whether isolated or in the presence of anti-centromere autoantibodies (ACA). MethodsOverall, 58 SSc-seronegative and 66 ACA-positive patients were included in the study. All patients were tested for anti-IFI16 autoantibodies by an in-house direct ELISA. Associations between clinical parameters and anti-IFI16 autoantibodies were analysed. ResultsOverall, 17.2% of SSc-seronegative and 39.4% of ACA-positive patients were positive for anti-IFI16 autoantibodies. Anti-IFI16 autoantibodies were found only in patients within the limited cutaneous SSc (lcSSc) subset. A positive association between anti-IFI16 positivity and isolated pulmonary arterial hypertension (PAH) was found (odds ratio [OR]=5.07; p=0.014) even after adjusting for ACA status (OR=4.99; p=0.019). Anti-IFI16-positive patients were found to have poorer overall survival than negative patients (p=0.032). Cumulative survival rates at 10, 20 and 30 years were 96.9%, 92.5% and 68.7% for anti-IFI16-positive patients vs. 98.8%, 97.0% and 90.3% for anti-IFI16-negative-patients, respectively. Anti-IFI16-positive patients also had worse overall survival than anti-IFI16-negative patients after adjusting for ACA status in the multivariate Cox analysis (hazard ratio [HR]=3.21; p=0.043). ConclusionAnti-IFI16 autoantibodies were associated with isolated PAH and poorer overall survival. Anti-IFI16 autoantibodies could be used as a supplementary marker of lcSSc in SSc-seronegative patients and for identifying ACA-positive patients with worse clinical outcome.

Pulmonary manifestations and prognosis of a cohort of patients with interstitial lung disease and positive to anti-Th/To autoantibodies

IntroductionTh/To autoantibody may be relevant in evaluating patients with interstitial lung disease (ILD) because the clinical diagnosis of systemic sclerosis (SSc) may not be evident. The study's objective was to describe manifestations and evolution of pulmonary function in a cohort of ILD patients positive for Th/To autoantibodies. MethodsILD patients positive for anti-Th/To autoantibody were enrolled in this protocol. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. ResultsFifty-two patients positive for anti-Th/To autoantibodies with ILD were included. Only 21% of the patients fulfilled the ACR/EULAR 2013 systemic sclerosis classification criteria, and 63.4% fulfilled the IPAF ATS/ERS 2015 criteria. Twenty-five percent of the patients died during follow-up. Respiratory failure was the principal cause of death. Twenty-nine patients (56%) were positive for other hallmark SSc autoantibodies. The most frequent HRCT pattern was nonspecific interstitial pneumonia (NISP). Survival was strongly associated to the systolic pulmonary arterial pressure (sPAP), male sex and the extent of fibrosis in HRCT; besides, patients positive for other hallmark SSc autoantibodies had worse survival compared to those positive only to anti-Th/To. Seventy-six percent of them behaved as fibrotic progressive pulmonary disease, with an absolute decline of the FVC of at least 5%. ConclusionsOnly a small proportion of ILD patients positive for Th/To meet the criteria to be classified as SSc; however, most met criteria for IPAF. A high proportion of patients behave as progressive fibrotic pulmonary disease. Survival is associated with sPAP, the extent of lung disease, and the presence of other hallmark SSc autoantibodies.

Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis.

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways.

The role of B cells in systemic sclerosis.

Systemic sclerosis (SSc) is a rare and refractory systemic disease characterized by fibrosis and vasculopathy in the presence of autoimmune abnormalities. While the exact cause of SSc is incompletely understood, the specific autoantibodies identified in SSc are closely linked to disease severity and prognosis, indicating a significant role of autoimmune abnormalities in the pathogenesis of SSc. Although the direct pathogenic mechanisms of autoantibodies in SSc are not fully elucidated, numerous prior investigations have demonstrated the involvement of B cells in the pathogenesis of SSc through various mechanisms. Additionally, several clinical trials have explored the efficacy of B-cell depletion therapy for SSc, with many reporting positive outcomes. However, the role of B cells in SSc pathogenesis is multifaceted, as they can both promote inflammation and exert inhibitory functions. This article provides an overview of the involvement of B cells in SSc development, incorporating the latest research findings.

The Autoantibody Array Assay: A Novel Autoantibody Detection Method.

Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune collagen diseases. Specific autoantibodies are known to be involved in their pathogeneses, each presenting with a different clinical manifestation. Although immunoprecipitation is the gold standard method for detecting autoantibodies, it is difficult to perform in all cases owing to the use of radioisotopes. In this study, we developed a new detection method for SSc and DM autoantibodies (A-cube) using cell-free protein synthesis and examined its validity. Proteins were synthesized using wheat germ cell-free protein synthesis. A total of 100 cases of SSc, 50 cases of DM, and 82 healthy controls were examined. The validity of the method was examined by a comparison with existing test results. Anti-centromere antibody, anti-topoisomerase I antibody, anti-RNA polymerase III antibody, anti-U1RNP anti-body, anti-Jo-1 antibody, anti-TIF1γ antibody, anti-Mi-2 antibody, and anti-ARS antibody were tested for. The results suggested that A-cube is comparable with existing testing methods or has a high sensitivity or specificity. In addition, there was a case in which the diagnosis was reconsidered using the A-cube. The quality of the A-cube was ensured, and its usefulness for a comprehensive analysis was demonstrated. The A-cube can therefore contribute to the clinical assessment and treatment of SSc and DM.

Proteomic aptamer analysis reveals serum biomarkers associated with disease mechanisms and phenotypes of systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that affects multiple organs, leading to elevated morbidity and mortality with limited treatment options. The early detection of organ involvement is challenging as there is currently no serum marker available to predict the progression of SSc. The aptamer technology proteomic analysis holds the potential to correlate SSc manifestations with serum proteins up to femtomolar concentrations. This is a two-tier study of serum samples from women with SSc (including patients with interstitial lung disease - ILD - at high-resolution CT scan) and age-matched healthy controls (HC) that were first analyzed with aptamer-based proteomic analysis for over 1300 proteins. Proposed associated proteins were validated by ELISA first in an independent cohort of patients with SSc and HC, and selected proteins subject to further validation in two additional cohorts. The preliminary aptamer-based proteomic analysis identified 33 proteins with significantly different concentrations in SSc compared to HC sera and 9 associated with SSc-ILD, including proteins involved in extracellular matrix formation and cell-cell adhesion, angiogenesis, leukocyte recruitment, activation, and signaling. Further validations in independent cohorts ultimately confirmed the association of specific proteins with early SSc onset, specific organ involvement, and serum autoantibodies. Our multi-tier proteomic analysis identified serum proteins discriminating patients with SSc and HC or associated with different SSc subsets, disease duration, and manifestations, including ILD, skin involvement, esophageal disease, and autoantibodies.

Molecular typing of HLA-class II alleles reveals an association with autoantibodies and disease subsets of systemic sclerosis in a North Indian (Kashmir) population

To identify specific human leukocyte antigen (HLA)-Class II (DRB/DQB1/DPB1) alleles associated with systemic sclerosis (SSc) and to explore their relation with SSc autoantibodies, clinical manifestations, and disease subsets. HLA-class II alleles (DRB1/DRB3/DRB4/DRB5/DQB1) were determined by DNA typing in 80 SSc cases and 60 matched controls and HLA-DPB1 in 40 SSc patients and 30 controls by allele-specific-polymerase chain reaction with sequence-specific primers (PCR-SSP). The mean age of SSc patients was 36.9 ± 9.4 years; 76 females and 4 males (F:M 19:1) and a disease duration of 5.3 ± 3.3 years, they were 43(53.7%) limited and 37(46.2%) diffuse subtypes. SSc was significantly associated with DRB1*11, DRB1*01, DQB1*04, and DQB1*03*03 in a >4-fold manner, whereas DPB1*04 had a >7-fold increased risk compared to controls. There was a strong association between DRB1*11 (p = 0.04), DQB1*03*03 (p = 0.005), and DPB1*13 (p = 0.009) with anti-topoisomerase I (anti-topoI) whereas the frequency of DRB1*01 (p < 0.0001) was increased in patients with anti-centromere (ACA) positive SSc compared those negative (56% vs 25%; p < 0.0001). DRB1*03, DRB1*15, and DQB1*03*01 were SSc protective alleles in patients with positive ACA. Anti-topo I was associated with interstitial lung disease (ILD) (p < 0.01), whereas ACA with pulmonary arterial hypertension (PAH) (p = 0.01) and protection against ILD (p < 0.001). In addition, HLA-DRB1*03, DQB1*03*01and DPB1*03 were more frequent in patients with ILD than in patients without. Associations between specific HLA-class II alleles with certain SSc-specific autoantibodies (anti-topo I and ACA) were identified. Specific HLA associations with clinical and serological subtypes could serve as biomarkers of disease severity and progression in SSc.

Autoantibody Profile and Lung HRCT Scan in Systemic Sclerosis with Restrictive Lung Disease

Objective: To identify auto-antibodies in systemic sclerosis with interstitial lung disease (ILD). Method: This was a descriptive categorical study on auto-antibody profile in systemic sclerosis patients visiting the Rheumatology Clinic of Dr. Hasan Sadikin General Hospital, West Java, and Bandung during the period of January 2018 to December 2019 who were registered in the West Java Systemic Sclerosis Registry. Auto-antibody identification was performed using the Euroline immunoblot assays.Results: Thirty six cases were identified during the study period with most of the cases involved women (n=35, 97.2%). The average age of patients participating in this study was 40 years, with an average duration of disease of 18 months. Diffuse cutaneous systemic sclerosis was found in 22 (61.1%) cases and limited cutaneous systemic sclerosis was observed in 14 (38.9%) cases. Specific autoantibodies were positive in 33 (91.6%) cases, with anti-topoisomerase I as the largest group, positive in 22 (52.9.3%) cases. This was followed by anti-Th/To in eight (15.7%) cases; anti-Ro52 in four (7.8%) cases; anti-centromere in three (5.9%) cases; anti-RNA polymerase in three (5.9%) cases; anti-fibrillarin in three (5.9%) cases; anti-Ku in two (3.9%) cases; and anti-PDGF in one (2.0%) case. High-resolution computed tomography of the lung showed 34 (94.4%) cases with ILD and 22 (61.1%) cases with severe lung fibrosis. Usual interstitial pneumonia was seen in 19 (52.8%) cases and non-specific interstitial pneumonia in 15 (41.7%) cases.Conclusion: Anti-topoisomerase I, anti-Th/To, and anti-Ro52 are the most common autoantibodies observed in systemic sclerosis patients with ILD as the most prevalent feature detected with lung HRCT.

Detection of anti-eIF2B autoantibodies in systemic sclerosis by immunoprecipitation-mass spectrometry.

Dear Editor, Anti-eukaryotic initiation factor 2B (eIF2B) autoantibodies are a recently described autoantibody specificity in SSc associated with diffuse cutaneous involvement, interstitial lung disease (ILD) and a cytoplasmic pattern on HEp-2 indirect immunofluorescence (HEp-2 IIF) [1–3]. Hitherto only 19 patients have been identified, all by radiolabelled protein immunoprecipitation [1–3]. Here we describe immunoprecipitation-mass spectrometry (IP-MS) as a detection method for anti-eIF2B autoantibodies and further characterize the precipitation pattern of the eIF2B complex as precipitated by various anti-eIF2B sera. We also further document the clinical associations of anti-eIF2B autoantibodies. The study was approved by the following Ethical Committees: University Hospitals Leuven (S60347/B32220071204) (Leuven) and Hospices civils de Lyon, Lyon (CT 69HCL21_0501) (Lyon). This was a retrospective study using left-over material of samples submitted to the clinical laboratory (secondary use) for which an informed consent waiver was authorized by the Ethical Committee of the University Hospitals Leuven, Belgium, and Hospices civils de Lyon, France. Patients were notified of the content and aim of the study. The patient data have been anonymized.

Nanoimmunosensor for the electrochemical detection of oncostatin M receptor and monoclonal autoantibodies in systemic sclerosis

Systemic sclerosis (SSc) is a chronic, autoimmune disease that primarily affects connective tissue. SSc can be classified into limited cutaneous (lSSc) and diffuse cutaneous (dSSc). Oncostatin M receptor (sOSMR) is an important inflammatory biomarker expressed in the serum of patients with autoimmune diseases. A nanoengineered immunosensor surface was developed. The biosensor was composed of a conductive layer of polypyrrole, electrodeposited gold nanoparticles, and sOSMR protein for anti-human OSMR monoclonal antibody biorecognition. The electrochemical response evaluated by cyclic voltammetry and electrochemical impedance spectroscopy indicated the detection of the target analyte present in clinical samples from lSSc and dSSc patients. The voltammetric anodic shift for lSSc specimens was 82.7% ± 0.9–93.6% ± 3.2, and dSSc specimens was 118.7 ± 2.6 to 379.6 ± 2.6, revealing a differential diagnostic character for SSc subtypes. The sensor platform was adapted for identifying sOSMR, using anti-OSMR antibodies as bioreceptors. With a linear response range estimated from 0.005 to 500 pg mL−1 and a limit of detection of 0.42 pg mL−1, the sensing strategy demonstrated high sensitivity in identifying the human OSMR protein in clinical samples. The proposed biosensor is a promising and innovative tool for SSc-related biomarker research.

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis.

Systemic sclerosis (SSc) belongs to the group of connective tissue diseases and is associated with the occurrence of disease-specific autoantibodies. Although it is still controversial whether these antibodies contribute to pathogenesis, there are new insights into the development of these specific antibodies and their possible pathophysiological properties. Interestingly, they are associated with specific clinical manifestations, but for some rarer antibodies this association is not fully clarified. The aim of this study is a comprehensive analysis of the serum autoantibody status in patients with SSc followed by correlation analyses of autoantibodies with the clinical course of the disease. Serum from SSc patients was analyzed using a line blot (EUROLINE, EUROIMMUN AG) for SSc-related autoantibodies. Autoantibodies to centromere, Topo-1, antimitochondrial antibodies (AMA) M2 subunit, angiotensin II type 1 receptors (AT1R) and endothelin-1 type-A-receptors (ETAR) were also determined by ELISA. We formed immunological clusters and used principal components analysis (PCA) to assign specific clinical characteristics to these clusters. A total of 372 SSc patients were included. 95.3% of the patients were antinuclear antibody positive and in 333 patients at least one SSc specific antibody could be detected. Four immunological clusters could be found by PCA. Centromere, Topo-1 and RP3 all formed own clusters, which are associated with distinct clinical phenotypes. We found that patients with an inverted phenotype, such as limited cutaneous SSc patients within the Topo-1 cluster show an increased risk for interstital lung disease compared to ACA positive patients. Anti-AT1R and anti-ETAR autoantibodies were measured in 176 SSc patients; no association with SSc disease manifestation was found. SSc patients with AMA-M2 antibodies showed an increased risk of cardiovascular events. In our in large cluster analysis, which included an extended autoantibody profile, we were able to show that serologic status of SSc patients provides important clues to disease manifestation, co-morbidities and complications. Line blot was a reliable technique to detect autoantibodies in SSc and detected rarer autoantibodies in 42% of our patients.

Scleroderma specific autoantibodies in rheumatoid arthritis and Sjögren's syndrome patients with interstitial lung disease: Prevalence and associations

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients’ sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2–94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach.

Thyroid dysfunction and anti-thyroid antibodies in systemic sclerosis patients

Aim of the workTo assess the frequency of thyroid dysfunction and thyroid auto-antibodies in systemic sclerosis (SSc) patients. Patients and methodsThis study included thirty-three SSc patients and 30 matching controls. Thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti thyroglobulin (ATG) and anti thyroid peroxidase autoantibodies (ATPO) were measured in the sera of patients and controls. ResultsThe mean age of the patients was 45.9 ± 13.05 years; 28 females and 5 males (F: M 5.6:1) and a disease duration of 4.58 ± 3.84 years. The FT3, FT4, TSH tended to be higher in patients (T3: 2.8 ± 0.66 pg/ml; T4: 1.5 ± 0.65 ng/ml; TSH: 1.9 ± 2.1ul/ml) than in controls (p = 0.07, p = 0.21 and p = 0.24 respectively) while the ATG level in patients was 40 ± 21.3 IU/ml and ATPO 36.7 ± 88.2 IU/ml. Four patients had hypothyroidism (12 %); 3 (9 %) subclinical hypothyroidism (SCHT) and 1 (3 %) clinical hypothyroidism (CHT). ATG was positive in one patient and in 2 controls while ATPO was positive in two patients compared to one control. Both antibodies were positive in one patient. ATPO was associated with SCHT in one (3 %) and with overt hypothyroidism in another (3 %). The thyroid profile, ATG and ATPO were comparable between females and males (p = 0.34, p = 0.23, p = 0.96, p = 0.77 and p = 0.35 respectively) and all were similar between lcSSc and dcSSc except TSH (lower in dcSSc; p = 0.03). Muscle weakness was significantly higher among ATPO positive patients (p = 0.005) while thyroid dysfunction was significantly associated with arthralgia (p = 0.007). ConclusionThyroid dysfunction mainly hypothyroidism is more frequent among SSc patients.

Functional autoantibodies in systemic sclerosis: influence of autologous stem cell transplantation and correlation with clinical outcome.

To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I (topo-I) in SSc-patients and to analyse their prognostic relevance. Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients' sera were tested for anti-AT1R and anti-topo-I antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4-217 months, median 28 months). Anti-topo-I antibodies were also analysed for their capacity to inhibit enzyme function. A total of 70% of the SSc patients had anti-topo-I- and 51% anti-AT1R antibodies in the ELISA before aSCT. In all instances, anti-topo-I antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2 patients than in group 1 patients (P < 0.001), while there was no difference between both groups for anti-AT1R antibodies detected by ELISA. Stimulatory anti-AT1R antibodies detected by LA were confined to group 1-patients. Reactivity of functionally active anti-AT1R antibodies was not influenced by aSCT, while anti-topo-I antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.

Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies. In this review, we present mechanisms of the innate immune system leading to the generation of autoantibodies, alterations of the B-cell compartment in SSc, autoantibodies as biomarkers and autoantibody-mediated pathologies in SSc as well as potential therapeutic approaches to target these.

Clinical significance of serum ferritin in patients with systemic sclerosis.

ObjectiveThe purpose of this study was to explore the clinical significance of serum ferritin (SF) in patients with systemic sclerosis (SSc).MethodsThe levels of SF were measured in 115 patients with SSc and 117 healthy controls (HCs). Clinical characteristics and laboratory indexes between the high ferritin SSc group and the normal ferritin SSc group were analyzed.ResultsThe level of SF in SSc patients was significantly higher than that in HCs (319.78 [179, 554.33] ng/ml vs. 99 [49.03, 164.29] ng/ml, p < 0.01). Compared with the normal ferritin SSc group, the high ferritin SSc group was more likely to develop skin diffuse cutaneous SSc, fingertip arthralgia, and cardiac involvement. In addition, the levels of glutamine transaminase (GGT), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase isoenzyme‐MB (CK‐MB), lactate dehydrogenase (LD), immunoglobulin G (IgG), immunoglobulin A (IgA), C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the positive rate of anti‐Scl70 antibody in the high ferritin SSc group were significantly higher (each p < 0.05). SF was positively correlated with GGT, ALT, CK, CK‐MB, LD, IgA, CRP, and ESR (each p < 0.05). Multiple linear regression analysis showed that cardiac involvement, ALT, and ESR were independent influencing factors of SF in SSc.ConclusionOur study shows that the level of SF in patients with SSc is increased, and the elevated SF is related to abnormal liver function, myocardial involvement, inflammatory status, and production of autoantibodies in SSc. Cardiac involvement, ALT, and ESR are independent factors affecting SF in SSc.

Systemic Sclerosis-Specific Antibodies: Novel and Classical Biomarkers

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad’s phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of “seronegative” SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients’ stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns’ interpretation. The gold-standard technique for autoantibodies’ identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.

AB0653 The association of autoantibodies with morbidity and mortality of scleroderma renal crisis in Japan

BackgroundThe morbidity of scleroderma renal crisis (SRC) and autoantibodies in systemic sclerosis (SSc) vary by races and regions. Anti-RNA polymerase III is associated with SRC in America and European countries. However, the association of autoantibodies with SRC had not been elucidated in Japan.ObjectivesWe aimed to investigate the association of autoantibodies with morbidity and mortality of SRC in Japan.MethodsThe clinical characteristics and mortality of 330 patients with systemic sclerosis (SSc) at Kyoto University Hospital were retrospectively analyzed, focusing on anti-centromere, anti-RNA polymerase III, anti-topoisomerase I, and anti-U1-RNP. Logistic regression analyses were performed to examine the association of autoantibodies with the development and mortality of SRC. Kaplan-Meier survival analysis was performed comparing the groups classified by autoantibodies.ResultsAnti-centromere (n = 177/318, 56%), anti-topoisomerase I (n = 80/311, 26%), anti-RNA polymerase III (n = 27/204, 13%), and anti-U1-RNP (n = 24/305, 8%) were found in SSc patients (n = 330). SRC was observed in 24 out of 330 SSc patients, including anti-topoisomerase I (n = 12/24, 50%), anti-RNA polymerase III (n = 7/24, 29%), anti-U1-RNP (n = 5/24, 21%), and anti-centromere (n = 3/24, 13%). Anti-U1-RNP (odds ratio [95% confidence interval], 3.63 [1.11–10.2]), anti-RNA polymerase III (3.29 [1.16–8.70]), and anti-topoisomerase I (3.22 [1.37–7.57]) were associated with the development of SRC. All patients with SRC were treated with ACE inhibitors and the 1-year survival rate was 54%. Anti-topoisomerase I was associated with the 1-year mortality of SRC (6.00 [1.11–41.1]). When the survival rate was compared between the patients positive for anti-topoisomerase I (n=12) and negative for anti-topoisomerase I (n=12), the 1-year survival rate was 33% vs 75% (p=0.041), respectively (Figure 1A). Furthermore, the 1-year survival of anti-centromere (100%), anti-RNA polymerase III (83%), and others/not detected (50%) were shown in patients negative for anti-topoisomerase I (Figure 1B).Figure 1.Overall survival of patients with SRC according to the type of autoantibodies.(A) The survival rates in SRC patients who were positive for anti-topoisomerase I (solid line, n = 12) and those who were negative for anti-topoisomerase I (dotted line, n = 12).(B) SRC patients negative for anti-topoisomerase I were classified as patients with anti-RNA polymerase III (dotted line, n = 6), anti-centromere (broken line, n = 2), and others/not detected (chain line, n = 4).ConclusionSpecific SSc-related autoantibodies were associated with the morbidity and mortality in SRC.