Risk Factor For Systemic Sclerosis Research Articles

Are there more acute cardiac hospitalizations in winter in patients with systemic sclerosis? An analysis from the National Inpatient Sample

Objective: Cold-induced transient myocardial ischemia has been described in patients with systemic sclerosis. The clinical impact of cold exposure in systemic sclerosis patients with acute cardiac conditions is unknown. We compared the seasonal variation of acute cardiac hospitalizations in patients with and without systemic sclerosis. Methods: We performed a retrospective cross-sectional study using the National Inpatient Sample from 2016 to 2019. The primary outcome was acute cardiac hospitalization primarily due to heart failure, acute myocardial infarction, or cardiac arrhythmias. We compared the proportion of acute cardiac hospitalizations in each season in patients with and without systemic sclerosis. We also performed a subgroup analysis by US geographic region (Northeast, Midwest, South, West). Results: There were a total of 10,118,002 acute cardiac hospitalizations over the 4-year study period. Compared to those without systemic sclerosis, patients with systemic sclerosis who were hospitalized for acute cardiac care were younger (mean age 67 ± 13 vs 70 ± 14 years, p < 0.01), a greater proportion were female (82% vs 45%, p < 0.01), and a smaller proportion were Caucasian (68% vs 71%, p < 0.01). There was a lesser proportion of traditional cardiovascular risk factors in systemic sclerosis compared to non-systemic sclerosis patients. There was no significant difference in the proportion of winter admissions between systemic sclerosis and non-systemic sclerosis patients for total acute cardiac hospitalizations (26.4% vs 25.9%, p = 0.51), heart failure (27.0% vs 26.5%, p = 0.64), acute myocardial infarction (26.9% vs 25.5%, p = 0.50), or arrhythmias (24.3% vs 25.0%, p = 0.68). The results were consistent across all four US geographic regions. Conclusion: Our study did not support that patients with systemic sclerosis had a disproportionally higher risk of acute cardiac hospitalization in winter compared to the general population. We found that systemic sclerosis patients hospitalized for acute cardiac care had a lower burden of traditional cardiovascular risk factors than their non-systemic sclerosis counterparts.

Pregnancy-associated risk factors and incidence of systemic sclerosis in primiparous women: A nationwide population-based cohort study.

To evaluate the pregnancy-related risk factors and incidence rate (IR) of systemic sclerosis (SSc) in primipara using the Health Insurance Review and Assessment database, covering all medical claims in South Korea. From the database, 2,260,952 primipara aged 18-49 years from 2008 to 2018 were identified. The patients were followed up after their index delivery until December 2019. A Cox proportional hazard analysis was performed to identify the association of pregnancy-related factors with SSc development. The SSc IR was 0.62 cases per 100,000 patient-years. Primipara had a higher risk of developing SSc after 3 years postpartum than in the first 3 years of delivery (OR = 1.98, 95% CI: 1.36-2.78, p < .001). A multivariate analysis showed that older age (35-49 years) (HR = 2.14, 95% CI: 1.05-4.35, p = .037) and a Caesarean section (CS) (HR = 1.86, 95% CI: 1.10-3.15, p = .021) are risk factors for SSc. At 3 years postpartum, CS (HR = 2.97, 95% CI: 1.39-6.32, p = .005) and a female infant (HR = 2.28, 95% CI: 1.11-4.71, p = .026) were associated with SSc development. Having a CS, late childbirth, and a female infant are the risk factors for SSc in primipara. This study establishes the IR of SSc in primipara.

Toward Understanding of Environmental Risk Factors in Systemic Sclerosis [Formula: see text

Systemic sclerosis (SSc) is a severe, chronic, and incurable autoimmune fibrotic skin disease with significant extracutaneous involvement. Low concordance rate in twin studies and unequal geographic distribution of SSc argues for importance of environment in disease initiation and progression. In this manuscript we provide a summary of all investigated potential external risk factors for SSc. A literature search in PubMed and EMBASE database was performed for studies published until January 1, 2020 by 2 reviewers (EN and LO) independently. Occupational and/or environmental exposures to silica and organic solvents are associated with increased incidence and severity of SSc. Exposure to epoxy resins, asbestos, and particulate air pollution favors increased risk of SSc, but data are based on limited number of observational studies. There is insufficient evidence to conclude an association between SSc development and other occupational (eg, welding fumes) or personal exposures (eg, smoking, vitamin D deficiency). Association of SSc with silicone breast implants has been disproven. Infectious pathogens (eg, Helicobacter pylori and angiotropic viruses) and dysbiosis seem to play a role in SSc development and severity, but their role remains to be clarified. It may be prudent to counsel our patients with SSc (or those at risk of SSc) to avoid occupations with exposure to silica, organic solvents, asbestos and epoxy resins; restraint from smoking, using cocaine or drugs with pro-fibrotic potential. While the association between low vitamin D and SSc remains to be confirmed, we believe that SSc patients should be encouraged to maintain healthy vitamin D levels as benefits outweigh the risks.

Survival rate, causes of death, and risk factors in systemic sclerosis: a large cohort study.

To investigate the clinical pattern, survival rate, causes of death and risk factors in a large cohort of Chinese Han patients with systemic sclerosis (SSc). Inpatients treated from 2002 to 2014 were included in this study. Patients were classified into diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc-overlap syndrome groups. Data were analyzed using Chi-squared tests, Kaplan-Meier curves, log-rank tests, and Cox proportional hazards modeling. Among a total of 201 patients, dcSSc (50.2%) was the major subtype, followed by lcSSc (30.3%) and SSc-overlap (19.4%). Interstitial lung disease (ILD, 148/201, 74%) was the most frequent organ involvement. The overall survival rates were 98% and 95% at 5 and 10years, respectively. The overall standard mortality ratio (SMR) was 2.22. The most common cause of death was ILD combined with infection (8/16, 50%), followed by kidney failure (2/16, 12.5%). On crude analysis, pulmonary hypertension, ILD, cardiac involvements, renal involvements, and digital ischemia were associated with poor prognosis. On multivariate analysis, pericardial effusion (p = 0.000) and digital ischemia (p = 0.016) were independent prognostic factors of death. The mortality rate of patients with SSc is mildly increased in comparison with the general population. ILD is the most common systemic involvement and the principal cause of death in SSc. Pericardial effusion and digital ischemia are independent factors associated with death.

Mapping and predicting mortality from systemic sclerosis

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes...

Systemic sclerosis due to crystalline silica exposure among jewelry workers in Korea: two case reports

BackgroundOccupational exposure to crystalline silica is a potential risk factor for various systemic autoimmune diseases including systemic sclerosis. The etiology of systemic sclerosis is not conclusively known, but there are epidemiological studies that show the relationship between exposure to crystalline silica and risk of systemic sclerosis. Here we report, for the first time, two cases of crystalline silica-related systemic sclerosis in patients who worked in crystal processing in the jewelry-manufacturing field.Case presentationCase 1 is a 57-year-old man who had worked mainly in crystal processing for multiple jewelry-processing companies for 17 years, since the age of 15 years. He contracted tuberculosis at the age of 25 years and showed Raynaud’s phenomenon of both the hands and feet at age 32 years. Digital cyanosis and sclerosis developed at approximately age 41 years. The patient was diagnosed with systemic sclerosis at age 48 years.Case 2 is a 52-year-old man who worked in crystal processing for various jewelry-processing companies for 7 years, since the age of 23 years. He first showed signs of cyanosis in the third and fourth digits of both hands at age 32 years, was diagnosed with Raynaud’s syndrome at age 37 years, and was diagnosed with systemic sclerosis at age 38 years.Crystal processing is a detailed process that involves slabbing and trimming the selected amethyst and quartz crystals, which requires close proximity of the worker’s face with the target area. In the 1980s and 1990s, the working hours were 12 h per day, and the working environment involved 15 workers crowded into a small, 70-m2 space with poor ventilation.ConclusionTwo workers who processed crystals with a maximum crystalline silica content of 56.66% developed systemic sclerosis. Considering the epidemiological and experimental evidence, exposure to crystalline silica dust was an important risk factor for systemic sclerosis. An active intervention is necessary to reduce exposure in similar exposure groups in the field of jewelry processing.

Identification of Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis by Whole-Exome Sequencing.

To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc). We performed whole-exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case-control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls. The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 2.77 × 10(-7)). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence of association (P = 9.35 × 10(-10), odds ratio [OR] 6.11), which was confirmed in the replication cohort (P = 0.012, OR 1.86) and meta-analysis (P = 1.92 × 10(-7), OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10(-5)). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005). ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications.

FRI0260 Survival, causes of death and mortality risk factors in systemic sclerosis

BackgroundAmong the rheumatic diseases, Systemic Sclerosis (SSc) stands out as a severely incapacitating and life-threatening disease.ObjectivesTo analize the causes of death, survival and risk factors for mortality in SSc patients.MethodsDemographic,...

STAT4 is a Genetic Risk Factor for Systemic Sclerosis in a Chinese Population

Systemic sclerosis (SSc) is an immune-mediated and complex genetic disease. An association of single-nucleotide polymorphisms (SNPs) in the STAT4 gene with SSc has been reported in European Caucasians, North Americans and Japanese. We undertook the current study to examine whether the STAT4 SNPs are also associated with susceptibility to SSc and SSc subsets in a Han Chinese population. A total of 453 Han Chinese patients with SSc and 534 healthy controls were examined in the study. The SNPs rs7574865, rs10168266 and rs3821236 of the STAT4 gene were examined with SNP TaqMan assays. The T-allele carriers of rs7574865 and rs10168266 were strongly associated with the presence of anti-topoisomerase I (ATA) and pulmonary fibrosis in SSc patients, as well as with diffuse cutaneous SSc (dcSSc). The presence of anti-centromere (ACA) and limited cutaneous SSc (lcSSc) did not show significant association with any of the examined SNPs. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc. It also revealed different genetic aspects of SSc subsets in a Han Chinese population.

Environmental risk factors in systemic sclerosis

Environmental risk factors have been implicated in the pathogenesis of systemic sclerosis (SSc). Recent evidence further supports this relationship and constitutes the focus of this review article. Exposure to silica through various occupations remains one of the main environmental risk factors for SSc. Emerging evidence has also implicated organic solvents in the development of this difficult-to-manage condition. The individual role of these toxins is, however, difficult to ascertain due to methodological limitations in study design. Other occupational agents, such as epoxy resins, welding fumes and hand-arm vibration, have been investigated, but no definitive associations may be made due to small sample sizes. The controversial association between silicone breast surgery and SSc has not been proven and, amongst other non-occupational factors, smoking does not increase the risk of development but does appear to impact upon the severity of disease. A number of environmental exposures are likely to play an important role in the development of the disease; however, current evidence consists mainly of heterogeneous studies with relatively small sample sizes. In the future, multicentre collaborations may help inform preventive strategies.

Evaluation of a Shared Autoimmune Disease-associated Polymorphism of TRAF6 in Systemic Sclerosis and Giant Cell Arteritis

We evaluated whether a single-nucleotide polymorphism (SNP) of the TRAF6 gene previously associated with systemic lupus erythematosus and rheumatoid arthritis may be a common risk factor for systemic sclerosis (SSc) and giant cell arteritis (GCA). A total of 1185 patients with SSc, 479 patients with biopsy-proven GCA, and 1442 unrelated healthy controls of white Spanish origin were genotyped for the rs540386 variant using a specifically designed TaqMan(©) allele discrimination assay. No significant associations of this SNP with global SSc or GCA were found. This was also the case when the potential associations of the TRAF6 polymorphism with the main clinical phenotypes of the 2 diseases (e.g., limited cutaneous and diffuse cutaneous SSc, or presence of polymyalgia rheumatica and visual ischemic manifestations in GCA) were assessed. Our data do not support a role of the rs540386 TRAF6 variant as a key component of the genetic network underlying SSc and GCA.

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of ≤ 1 was a significant risk factor for SSc (OR=1.55 (1.13-2.14), P=0.007) relative to CN ≥ 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

Epidemiology of systemic sclerosis

To identify the recent data regarding prevalence, incidence, survival, and risk factors for systemic sclerosis (SSc) and to compare these data to previously published findings. SSc disease occurrence data are now available for Argentina, Taiwan, and India and continue to show wide variation across geographic regions. The survival rate is negatively impacted by older age of onset, male sex, scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer, and antitopoisomerase and anti-U1 antibodies. It appears that silica exposure confers an increased risk for developing scleroderma, but this exposure accounts for a very small proportion of male patients. Smoking is not associated with increased SSc susceptibility. Malignancies are reported in scleroderma at an increased rate, but the magnitude of this risk and the type of cancer vary among reports. Prevalence and incidence of SSc appears to be greater in populations of European ancestry and lower in Asian groups. Exposure to silica dust appears to be an environmental trigger, but this only accounts for a small proportion of male cases. Evidence for increased risk of neoplasia is suggestive, but the magnitude of the risk and the types of malignancies vary among reports.

Biological ageing is a key determinant in systemic sclerosis

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation and fibrosis of the skin and internal organs, occurring mainly in females. Although a lot of progress has been made in the discovery of genetic risk factors for SSc, environmental factors triggering onset of SSc have not been identified. This provides a foundation for the involvement of processes related to biological ageing to trigger SSc onset and perpetuation in the genetically susceptible host. Consequently, we have investigated key determinants of biological ageing, namely telomere attrition and the role of telosome proteins in the pathology of systemic sclerosis and how it impacts on individual leukocyte cell subsets. Epigenetic processes, such as telomere attrition have been implicated in SSc [1]. The length of telomeric DNA repeats shortens during replicative ageing of peripheral blood lymphocytes. This process is exacerbated by psychological, sociological and biological determinants [2,3]. As a consequence, telomere length reflects the “miles on the clock” of a given cell type. Proteinaceous components of the associatedtelosome arecomplicit in the sensing, signaling and repair of DNA damage [3]. These have a critical role inprotectingthe cell from excessive DNA damage, by facilitating cellular senescence and apoptosis. This study aimed to evaluate telosome biologyin an independent, clinically well-defined SSc cohorts. Moreover, we aimed to investigate whether there are differences in telomere attrition between different immune cell subsets and if these differences are accompanied by changes in expression of genes involved in telomere functioning.

Cigarette smoking is not a risk factor for systemic sclerosis

To investigate the association of cigarette smoking with susceptibility to systemic sclerosis (SSc) in a large, well-defined patient population. We conducted a review of 1,379 patients with SSc enrolled in the Scleroderma Family Registry and DNA Repository and/or the Genetics versus Environment in Scleroderma Outcome Study cohort. Smoking history was obtained from chart review or via telephone interview. Patients with SSc were subsequently categorized as never smokers or ever smokers. Patients with SSc for whom smoking data were available were matched 2:1 by age, sex, ethnicity, and state of residence to control subjects, using the Behavioral Risk Factor Surveillance System. The majority of patients were white (74.2%), with Hispanics and blacks representing 11.3% and 9.7%, respectively. Most patients had limited cutaneous involvement (54%). For our comparative analyses, 621 patients were matched with control subjects. There was no significant difference in age, sex, ethnicity, and SSc subtype between matched versus unmatched patients. The majority of patients had never smoked (57%), while 43% of patients were classified as ever smokers. The patients with SSc did not differ from control subjects in terms of their smoking behavior (odds ratio [OR] 1.020, 95% confidence interval [95% CI] 0.839-1.240, P=0.842). Anti-topoisomerase I antibody-positive patients were more likely to be never smokers (OR 0.648, 95% CI 0.421-0.998, P=0.049), whereas no such association was observed with anticentromere and anti-RNA polymerase III antibodies. Unlike its role in rheumatoid arthritis, smoking does not confer a risk for development of SSc, although it may impact disease severity.

Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition

Endothelial dysfunction and inflammation are pathogenic mechanisms common to systemic sclerosis (SSc) and atherosclerosis. This study was undertaken to examine the relationship between coronary atherosclerosis, as assessed by the coronary artery calcium score (CACS), and conventional cardiovascular and disease-specific risk factors in SSc patients. The CACS was measured by computed tomography, and cardiovascular risk factors were examined in SSc patients and compared with controls matched for age, sex, and glycemic status. Disease activity score, antiphospholipid antibodies, high-sensitivity C-reactive protein level, and erythrocyte sedimentation rate were measured in SSc patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. We recruited 53 SSc patients (50 women and 3 men) and 106 controls. The patients had a mean ± SD age of 53.1 ± 12.9 years and a median disease duration of 9 years. Compared to controls, SSc patients had significantly lower low-density lipoprotein (LDL) cholesterol levels (P = 0.001), high-density lipoprotein cholesterol levels (P = 0.01), diastolic blood pressure, waist circumference, and body mass index and were more likely to be receiving vasodilators (all P < 0.001). There was a significantly higher proportion of SSc patients among subjects with more severe coronary calcification (CACS ≥ 101) compared to those with lesser severity (CACS <100) (56.5% versus 29.4%; P = 0.01). Multiple logistic regression analysis revealed SSc to be an independent determinant for a CACS ≥ 101 (OR 10.89 [95% CI 2.21-53.75], P = 0.003) together with age and LDL cholesterol level after adjustment for other cardiovascular risk factors. Among disease-specific factors, only disease duration (OR 1.14 [95% CI 1.02-1.27], P = 0.02) was independently associated with more severe coronary calcification (CACS ≥ 101). Our findings indicate that SSc is an independent risk factor for coronary calcification, in addition to the conventional risk factors for coronary atherosclerosis, such as age and hypertension.

Patient subgroups and potential risk factors in systemic sclerosis: is there a possibility of an early diagnosis?

Systemic sclerosis is often well established at diagnosis, when the disease has already evolved to an obliterative vasculopathy with fibrosis and significant end-organ damage. The present classification criteria perform poorly when attempting to make an early diagnosis, limiting the possibility of early treatment and of preventing disease evolution and tissue damage, leading to loss of function and impairment of quality of life. Recently, experts have identified Raynaud’s phenomenon, antinuclear antibodies and puffy fingers as ‘red flags’ that can be used as signs of suspected early systemic sclerosis. The positivity of other signs such as specific antibodies (anticentromere antibodies and anti-topoisomerase I) and capillaroscopy may allow a diagnosis of very early systemic sclerosis and prompt further investigation at the internal organ level. These red flags can help to track patients in the earliest phase of the disease and those at risk of progressing to overt disease. This ‘window of opportunity’ may...

Separate influences of birth order and gravidity/parity on the development of systemic sclerosis

Birth order has been valuable in revealing the role of environmental influences on the risk of developing certain diseases such as allergy and atopy. In addition, pregnancy has profound effects on the immune system such as short-term effects that permit fetal survival as well as longer-term effects that could influence late-onset diseases. In order to better evaluate these influences, we studied the association of birth order and gravidity/parity as risk factors for systemic sclerosis (SSc; scleroderma). Data regarding SSc cases and their unaffected sibling controls were obtained from the Scleroderma Family Registry and DNA Repository. The case-sibling design was used to minimize confounding due to differences in age, race, ethnicity, or calendar time. The gravidity/parity analysis was based on sibships with at least one SSc-affected and one unaffected sister. Birth order was examined in 974 sibships, comparing SSc cases (n = 987) with their unaffected siblings (n = 3,088). The risk of scleroderma increased with increasing birth order (odds ratio [OR] 1.25, 95% confidence interval [95% CI] 1.06-1.50 for birth order 2-5; OR 2.22, 95% CI 1.57-3.15 for birth order 6-9; and OR 3.53, 95% CI 1.68-7.45 for birth order 10-15). Gravidity/parity was analyzed in 168 sibships (256 unaffected sisters, 172 SSc cases). We found an association between a history of one or more pregnancies and SSc (OR 2.8). Birth order and pregnancy were independently associated with a higher risk of developing SSc. These findings suggest that immune development in early childhood and/or pregnancy-associated events, including but not limited to microchimerism, plays a role in SSc susceptibility.

Occupational silica exposure as a risk factor for scleroderma: a meta-analysis

Among potential environmental risk factors for systemic sclerosis (SSc), occupational exposures have received some attention. In this meta-analysis, we examined the association between SSc and occupational exposure to silica. We searched Medline, Toxline, BIOSIS, and Embase (1949 and November 2009) for original articles published in any language. Sixteen studies are included in the analysis, of which, 3 are cohort studies, 9 case-control and 4 are of other designs. The combined estimator of relative risk (CERR) and 95% confidence interval (CI) were calculated using fixed or random effect models. Significant heterogeneity was detected (I (2) = 97.2%; P < 0.01), and the CERR was 3.20 (95% CI, 1.89-5.43). The CERR for studies in females was 1.03 (95% CI, 0.74-1.44) and was 3.02 (95% CI, 1.24-7.35) for males. The CERR for case-control studies was 2.24 (95% CI, 1.65-3.31) and was 15.49 (95% CI, 4.54-52.87) for cohort studies. The findings suggest that silica exposure may be a significant risk factor for developing SSc and specifically in males. Further observational studies examining the role of occupational silica exposure in the context of other risk factors are needed.

HLA-DRB1*11: a Strong Risk Factor for Acquired Severe ADAMTS13 Deficiency-Related Idiopathic Thrombotic Thrombocytopenic Purpura in Caucasians.

Abstract 2412Poster Board II-387Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from excessive von Willebrand factor (VWF)-mediated platelet clumping and capillary occlusion in relation with an autoantibody-mediated defect in the VWF-cleaving protease ADAMTS13. So far, the mechanisms leading to the loss of tolerance of the immune system against ADAMTS13 remain unknown. The usually switched isotype of the secreted anti-ADAMTS13 antibodies implies a cooperation between T lymphocytes and B lymphocytes and thus a recognition by T cell receptors of ADAMTS13 epitopes bound to human leukocyte antigen (HLA) molecules. We therefore hypothesized that particular HLA alleles may be involved in the process leading to a loss of tolerance of the immune system against ADAMTS13. Particularly, alleles within class I A and B loci and class II DRB1 and DQB1 loci are those most frequently associated with susceptibility to autoimmune diseases.We have compared medium resolution typing of HLA class I (HLA-A, B) and II (HLA-DRB1, DQB1) loci in 61 Caucasian patients with idiopathic TTP and a documented severe (<5%) acquired, autoantibody-mediated, ADAMTS13 deficiency to 132 healthy Caucasian volunteer donors Caucasian individuals and to 42 Caucasian patients with atypical hemolytic uremic syndrome (HUS) who displayed a detectable ADAMTS13 activity.The frequency of HLA-A, -B and -DQB1 alleles was comparable between patients with acquired idiopathic TTP, healthy individuals and patients with other forms of TMA. By contrast, the HLA DRB1*11 allele was observed in 62% of patients with acquired idiopathic TTP, whereas the usually reported incidence of this allele ranges from 13.5% to 24.5%, with the lower incidence in Asian/Pacific Islanders and Caucasians and the greater incidence in Afro-Caribbeans (http://www.allelefrequencies.net). Comparison to our group of healthy individuals confirmed this striking difference, which was statistically significant (20%, P = 10-7, odd ratio [OR] = 6.43, CI95% =2.3-12.7). The increased incidence of DRB1*11 in acquired idiopathic TTP was also significant when compared to patients with a diagnosis of atypical HUS (17%, P= 6×10-5). By contrast, DRB1*11 frequency in this latter group was comparable to this observed in healthy individuals (P = n.s). All patients were heterozygous for this allele. We also observed a decreased incidence of the DRB1*04 allele in acquired idiopathic TTP when compared to healthy individuals (10% versus 30%, respectively, Pcorr = 0.025). DRB1*04, resulting in the DR53 antigen when associated with DRB4, could thus be involved as a protective allele in acquired idiopathic TTP, as suggested in a previous work. We found no association between DRB1*11 and clinical features of autoimmunity, central nervous system involvement, antinuclear antibodies, anti-ADAMTS13 inhibitors, flare-up and relapse episodes and survival. Of note, the association between DRB1*11 with acquired idiopathic TTP was not observed in Afro-Caribbeans (3/12, 25%, p=0.04). High resolution typing of DRB1*11 allele revealed that both DRB1*1101 and DRB1*1104 alleles were significantly over-represented, suggesting that the generic DRB1*11 (and not the DRB1*11 alleles) is the predisposing factor.The DRB1*11 was reported to be a risk factor for systemic sclerosis, early-onset juvenile chronic arthritis and sarcoidosis, and protective against multiple sclerosis and pemphigus vulgaris. Accordingly, we found no patient with one of those 2 latter diseases in our French National TTP registry, whereas a past history of systemic sclerosis, sarcoidosis and juvenile chronic arthritis was observed in 1 case each.Our findings propose DRB1*11 as a strong risk factor for acquired idiopathic TTP in Caucasians. Indeed, the autoimmune response in acquired idiopathic TTP may involve the recognition by T cells of a class II region of DRB1*11, bound to a peptide fragment of ADAMTS13. We also suggest that acquired idiopathic TTP represents a subset of TMA with specific genetic risk factors, distinguishing it from the other forms of idiopathic TMA. The incomplete rate of concordance may be explained by other yet unexplored mechanisms, including additional predisposing genes and environmental triggers. Forthcoming genomewide association studies should lead to the identification of additional alleles associated with the risk of acquired idiopathic TTP. Disclosures:No relevant conflicts of interest to declare.