Do ethnoracial differences exist among antiphospholipid antibody-positive patients with no other systemic autoimmune diseases: results from the APS ACTION registry.

Background/PurposeAPS ACTION Registry was created to study the natural course of antiphospholipid syndrome (APS) over 10 years in persistently antiphospholipid antibody (aPL) positive patients with or without systemic autoimmune rheumatic diseases (SARDs). Our primary objective was to compare the characteristics of aPL-positive patients with or without thrombocytopenia (TP) and/or autoimmune hemolytic anemia (AIHA).MethodsThe registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within 1year prior to enrollment. For the primary comparison of demographic, clinical, and serologic characteristics in this retrospective study, we divided patients into two groups: TP/AIHA ever and never. Thrombocytopenia was defined as a platelet count of <100,000 x 109/L tested twice at least 12 weeks apart, and AIHA was defined as anemia with hemolysis and a positive direct antiglobulin test (DAT). For the secondary analysis, we compared patients with TP versus AIHA, and the immunosuppressive use stratified by systemic lupus erythematosus (SLE) classification.ResultsAs of April 2022, of 1,039 patients (primary aPL/APS: 618 [59%]; SLE classification: 334 [31%]) included in the registry, 228 (22%) had baseline (historical or current) TP and/or AIHA (TP only: 176 [17%]; AIHA only: 35 [3%], and both: 17 [2%]). Thrombocytopenia and/or AIHA was significantly associated with Asian race, SLE classification, cardiac valve disease, catastrophic/microvascular APS, triple aPL (lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein-I antibody) positivity, and SLE-related serologic and inflammatory markers. When 101/618 (16%) primary aPL/APS patients and 101/334 (34%) SLE patients with TP and/or AIHA were compared, azathioprine and mycophenolate mofetil were more commonly reported in lupus patients, however corticosteroid, intravenous immunoglobulin, and rituximab use were similar between groups.ConclusionIn our large multi-center international cohort of persistently aPL-positive patients, approximately one-fifth had active or historical TP and/or AIHA at registry entry; half of these patients had additional SLE. Cardiac valve disease, catastrophic/microvascular APS, and triple aPL-positivity were aPL-related clinical and laboratory manifestations associated with TP and/or AIHA, suggesting a more severe APS clinical phenotype in aPL-patients with TP and/or AIHA.

There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimoto's thyroiditis (HT) and Graves' disease (GD) with systemic autoimmune diseases. One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren's syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90-, 160-, 220-, 556-, 176- and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.

The objective was to determine the mortality rate as well as the causes and predictors of death in antiphospholipid antibody (aPL)-positive patients with and without antiphospholipid syndrome (APS) classification. The inclusion criterion for the multicenter international Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) registry is positive aPLs according to the Revised Sapporo Classification Criteria tested within one year before enrollment. Patients are observed every 12 ± 3 months with clinical data and blood collection. For this prospective analysis, we first analyzed the causes of death for patients reported as "deceased." Secondly, we analyzed risk factors for death using the adjusted Cox proportional hazards model and calculated survival probability using the Kaplan-Meier model based on different age groups. Of 967 patients, 43 (5%) were deceased after a median follow-up of 5.3 years. Based on the univariate analysis, deceased patients, compared to living patients, were more likely to be older and have a history of arterial thrombosis, catastrophic APS, concomitant systemic autoimmune diseases (SAIDs), and baseline cardiovascular disease (CVD) risk factors. Based on the Cox proportional hazards model adjusted for age and for each of the strongest predictors of death, arterial thrombosis (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.50-5.76), concomitant SAIDs (HR 2.97, 95% 1.56-5.63), and baseline any CVD risk factor (HR 2.43, 95% CI 1.05-5.71) were significantly associated with mortality. In our cohort of persistently aPL-positive patients, the mortality rate was 5% after a median follow-up of five years and was highest for patients ≥60 years old at registry entry. History of arterial thrombosis, concomitant SAIDs, and baseline any CVD risk factor independently predicted future death.

Background Growing evidence showing that systemic autoimmune diseases (SAD) are associated with a high risk of incident atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown. Purpose To assess the risk of all-cause death, thrombotic events, and bleeding in AF patients with SAD. Methods Retrospective cohort study within a global health care network (TriNetx). Using ICD codes, AF patients were categorized into two groups: 1) AF patients with SAD (M32: Systemic Lupus Erythematosus; M33: Dermato-polymyositis; M34: Systemic Sclerosis; M35: Sjogren syndrome), and 2) AF controls (without systemic autoimmune, autoinflammatory, or rheumatic diseases). The primary outcomes were the 5-year risks of 1) all-cause death, 2) thrombotic events (ischemic stroke, transient ischemic attack, peripheral arterial thromboembolism, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and 3) hemorrhagic outcome (intracranial hemorrhage and gastrointestinal bleeding). Secondary outcomes were each component of the composite primary outcomes. Cox regression analysis before and after propensity-score-matching (PSM) was used to estimate HR and 95% confidence interval (95%CI). Sensitivity analyses were done to investigate the risk of primary outcomes associated with each systemic autoimmune disease and with different types of oral anticoagulant (OAC). Results We identified 22,371 AF patients with SAD (67.7±13.7 years, 72.2% females), and 1,478,693 AF controls (69.7±14.0, 42.6% females). Before PSM, AF patients with SAD were younger, more often females, and with a higher prevalence of cardiovascular risk factors; no differences were found after PSM. After PSM, AF patients with SAD showed a higher risk of all-cause death (HR 1.21, 95% 1.17-1.25), thrombotic events (HR 1.55, 95%CI 1.49-1.61), and hemorrhagic events (HR 1.39, 95%CI 1.32-1.46) compared to AF controls (Table 1). On sensitivity analyses, we found that the risk of primary outcomes in AF patients with SAD was independent from the OAC type, but NOAC was more effective than warfarin in reducing the risk of thrombotic events. The highest risk of all-cause death was associated with Systemic Sclerosis, while the highest risk of composite thrombotic events was associated with Systemic Lupus Erythematosus, and Dermato-polymyositis. The highest risk of stroke was associated with Sjogren syndrome; and myocardial infarction and deep vein thrombosis with Dermato-polymyositis, Systemic Lupus Erythematosus was associated with the highest risk of Intracranial hemorrhage, while Systemic Sclerosis to the highest risk of gastrointestinal bleeding (Table 2). Conclusion In AF patients the coexistence of SAD is associated with a high risk of all-cause death, thrombotic events, and bleeding. A personalized approach aimed to minimize the impact of SAD on the clinical course of AF patients is needed.Figure 1Figure 2

The objective of this study was to analyze complement activation in antiphospholipid antibody (aPL)-positive patients without other systemic autoimmune rheumatic diseases, using C3/C4 and cell-bound complement activation products (CB-CAPs) (B-lymphocytes [BC4d], erythrocytes [EC4d], and platelets [PC4d]). Persistently aPL-positive patients with or without aPL-related clinical manifestations (thrombotic APS [TAPS], microvascular APS [MAPS], obstetric APS, thrombocytopenia [TP], and/or hemolytic anemia [HA]) were enrolled in a single center study. Blood and clinical data were collected at baseline; a subgroup of patients completed 6- or 12-month follow-up. At baseline, 4/31 (13%) patients had decreased C3/C4, while 7/29 (24%) had elevated BC4d, 11/33 (33%) EC4d, and 12/32 (38%) PC4d. Based on different aPL profiles, all patients with decreased C3/C4 or elevated BC4d, EC4d, and PC4d had triple aPL or isolated lupus anticoagulant positivity. Based on different aPL clinical phenotypes, the number of patients with strongly positive EC4d and PC4d were proportionally higher in those with MAPS/TP/HA, compared to TAPS or no APS. Compared to baseline, the frequencies of BC4d, EC4d, and PC4d positivity were not significantly different in the subgroup of patients during their 6- or 12-month follow-up. There was a weak correlation between C3/C4 and CB-CAPs, especially for PC4d. In summary, complement activation in aPL-positive patients varies based on aPL profiles and clinical phenotypes. Given the higher percentage of aPL-positive patients with abnormal CB-CAPs, compared to C3/C4, and the poor inverse correlation between CB-CAPs and C3/C4, our study generates the hypothesis that CB-CAPs have a role in assessing disease activity and thrombosis risk in aPL-positive patients.

Studies have demonstrated a familial aggregation of systemic and organ-specific autoimmune diseases. The aim of the present survey was to obtain, by patient interviews, a preliminary estimate of the prevalence of systemic and organ-specific autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases (CTD) or inflammatory arthritis followed at our unit. Between June 2007 and January 2008, 626 patients and 85 controls (patients with osteoarthritis, osteoporosis, or fibromyalgia) were interviewed. Three hundred ten patients (50%) versus 21 controls (25%) were found to have at least one relative affected with an autoimmune condition (p < 0.0001). The most common conditions were organ-specific autoimmune diseases: 160 (34%) autoimmune thyroid (AT) disease, 112 (24%) psoriasis, 21 vitiligo, and 19 insulin-dependent diabetes mellitus. Systemic autoimmune diseases were reported in 126 relatives: rheumatoid arthritis (66 cases, 14%), 16 sacroileitis, and CTD (43 cases). A significant difference was observed in the prevalence of AT disease between the relatives of the patients and controls (3% versus 0.5%). In conclusion, these data confirm the high prevalence of autoimmune conditions, particularly of AT disease, among the relatives of patients.

Persistently positive antiphospholipid antibodies (aPLs) with thrombosis and/or pregnancy morbidity are the hallmark of the antiphospholipid syndrome. However, aPL-positive patients with no prior history of thrombosis exist. On the basis of a limited number of studies that predominantly included systemic lupus erythematosus patients, aPL-positive patients without previous thrombosis have a 0% to 3.8% annual incident thrombosis risk. Given that every positive aPL test is not clinically significant and every aPL-positive patient does not have the same thrombosis risk, risk stratification (based on aPL profile, age, systemic autoimmune diseases, and traditional cardiovascular disease or venous thrombosis risk factors) is crucial to determine the first thrombosis risk in aPL-positive patients. The optimal primary thrombosis prevention strategy in patients with clinically significant aPL profiles should include 1) regular monitoring and elimination of non-aPL thrombosis risk factors, 2) aggressive management of clinical and subclinical systemic autoimmune disease activity, and 3) patient counseling and education. The protective effect of low-dose aspirin against incident thrombosis in patients with clinically significant aPL profiles is not supported by randomized controlled data; general population cardiovascular disease risk prediction tools and prevention guidelines formulated based on risk-benefit calculations should play a role in the decision whether to recommend low-dose aspirin. The effectiveness of hydroxychloroquine, statins, or their combination remains to be determined by well-designed randomized controlled trials.

Systemic Autoimmune Diseases

SAT0426 Antiphospholipid Syndrome Alliance for Clinical Trials & International Networking (APS Action) Clinical Database and Repository (“Registry”) Cluster Analysis for Identification of Different Clinical Phenotypes Among Antiphospholipid Antibody-Positive Patients

Using an animal model for insulin-dependent diabetes mellitus (IDDM), the NOD mouse, we have demonstrated that allogeneic bone marrow transplantation (BMT) has a preventative effect on IDDM, and that a combined transplantation of pancreas and bone marrow can be used to treat IDDM. We have also shown that BMT has a curative effect on systemic autoimmune disease in (NZB x NZW) F1, BXSB, and (NZW x BXSB) F1 mice but not in MRL/lpr mice. Since MRL/lpr mice possess abnormal radioresistant hemopoietic stem cells (HSCs), they suffer a relapse 5 months after BMT. Recently, we have found that major histocompatibility complex (MHC)-matched stromal cells in the bone marrow are essential to the support of HSCs in the Go phase. We therefore attempted to treat autoimmune diseases in MRL/lpr mice by the transplantation of stromal cells with HSCs. Transplantation of HSCs with bone to recruit stromal cells was indeed found to have a curative effect on autoimmune diseases in the mice. These results indicate that BMT with bone graft will become a valuable strategy for the treatment of patients with both systemic and organ-specific autoimmune diseases. To prove that autoimmune diseases originate from defects in HSCs, we transferred the HSCs of autoimmune-prone mice to normal mice. BMT or transplantation of stem-cell concentrates induced organ-specific and/or systemic autoimmune diseases in [NOD-->C3H/HeN] and [(NZW x BXSB)F1-->C3H/HeN or C57BL/6J] chimeric mice. These results provide direct evidence that the etiopathogenesis of autoimmune diseases, including both organ-specific and systemic autoimmune diseases, is attributable to defects in the HSCs themselves. We further provide that various intractable diseases such as non-insulin-dependent diabetes mellitus and chronic nephritis (focal glomerulosclerosis) are also organ-specific autoimmune diseases, and that BMT can be used to treat them.

Autoimmune diseases encompass a wide range of organspecific and systemic disorders with a complex etiology.

Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients

This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus. Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n=214), we profiled autoantibodies using an autoantigen microarray platform. We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens.

ObjectiveTo review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide.Materials and methodsThe search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators.ResultsEighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered.ConclusionThe current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.

Polycystic ovary syndrome (PCOS) causes anovulation and hyperandrogenism. Hormonal imbalance is known to contribute to systemic autoimmune diseases. To examine the frequency of certain rheumatic diseases in PCOS. This retrospective study utilized and analyzed electronic medical records from January 2004 through February 2020. A diagnosis of PCOS and specified rheumatic diseases was searched using ICD-9 and ICD-10 codes. A total of 754 adult patients with PCOS and 1,508 age- and body mass index-matched patients without PCOS were included. Frequencies of the rheumatic diseases were compared between PCOS and non-PCOS subjects or literature data. The prevalence of rheumatoid arthritis (RA) was found to be 2.25% (17/737) in the PCOS patients, numerically higher than 1.26% (19/1489) in the non-PCOS subjects. The difference was significant with a confidence level of 90% (1.04-3.15) but not at 95% with an odds ratio of 1.808 (95% CI = 0.934-3.4, p = 0.0747). When compared with the literature data from the US female population, the prevalence of RA in PCOS patients was significantly higher (2.25% vs. 1.40%, p < 0.0001). Among the autoimmune diseases examined, both systemic sclerosis (0.40% vs. 0.0%, p = 0.0369) and undifferentiated connective tissue disease (0.53% vs. 0.0%, p = 0.0123) were significantly more frequent in the PCOS patients than the non-PCOS. Additionally, PCOS patients had a significantly higher frequency of osteoarthritis than non-PCOS patients (5.44% vs. 2.92%, p = 0.0030) with an odds ratio of 1.913 (95% CI = 1.239-2.955). We have shown unprecedentedly that certain rheumatic diseases are more prevalent in PCOS. This study provides important insight into autoimmunity in association with PCOS. Key Points • Polycystic ovary syndrome is postulated to cause systemic autoimmune disease due to its hormonal imbalance. • We conducted the first epidemiologic assessment of the prevalence of systemic autoimmune diseases. • Certain autoimmune and rheumatic diseases are more prevalent in polycystic ovary syndrome.