This is the most extensive study of APS incidence to date, including 19,163 participants with APS and using national population-based registry data. To our knowledge, this is also the first study to investigate the distributions of APS by sex and age in a population. Most epidemiological studies have not reported age distributions due to small study populations or have only declared the age distribution for women and men combined. Our study found that the female population had a higher annual incidence rate of APS than the male population. Female-to-male ratios ranging from 5:1 to 2:1 were reported in one study [24]. Furthermore, an increasing trend in APS incidence among the Taiwanese population was observed in our study. Environmental factors influence the onset of autoimmune diseases. However, an earlier study indicated that infection and drug exposure were correlated with APS [25]. The venereal disease research laboratory test, which involves using purified cardiolipin–lecithin–cholesterol antigen to detect anticardiolipin antibodies, is a screening test for syphilis; it can also positively identify autoimmune diseases such as APS and SLE [26]. Exposure to various bacteria and viruses, including Mycoplasma pneumonia, Streptococcus pyogenes, Helicobacter pylori, Epstein–Barr virus, and cytomegalovirus, is associated with an increased prevalence of aPLs [25]. Several drugs are involved in autoimmunity, including those that produce drug-induced lupus and drug-induced autoimmune hepatitis. Specifically, certain medications, such as procainamide, chlorothiazide, phenothiazines, quinine, and oral contraceptives, are associated with increased levels of aPLs [27]. Future studies are necessary to determine correlations between APS and environmental factors.

APS is characterized by vascular thromboses and pregnancy-related morbidity associated with persistently elevated aPLs [1], which are autoantibodies that recognize a variety of phospholipid-binding plasma proteins beta2-glycoprotein I, prothrombin, and annexin A5. The main pathogenetic mechanisms of aPL-induced thrombosis involve stimulation of the extrinsic coagulation pathway, platelet aggregation, and complement activation and inhibition of tPA, protein C, and protein S [28]. Oxidative stress was reported to affect the structure and function of beta2-glycoprotein I, a complement control protein constructed of five domains [29]. There are two forms of beta2-glycoprotein I – free thiol form (contains broken disulfide bridge at cysteine (Cys) 32 and Cys 60 in domain I and Cys 288 and Cys 326 in domain V) and oxidized form (contains disulfide bonds at these sites) [30]. The level of oxidized form was significantly higher in patients with APS. Lower levels of free thiol form cause a lack of buffer against oxidative stress [31]. Oxidative stress from exogenous sources followed by vascular endothelial injury can stimulate platelet aggregation and von Willebrand factor expression [32]. Antibodies binding to a particular epitope in domain I of beta2-glycoprotein I have been indicated to increase the risk of thrombosis [33]. Furthermore, beta2-glycoprotein I immune complexes can induce up-regulated activation of toll-like receptor 7 (TLR7) in plasmacytoid dendritic cells and monocytes to release pro-inflammatory cytokine and create a positive-feedback loop for further autoantibody generation [34].. Understanding these pathophysiologies provide insight into APS management. Rituximab, a chimeric monoclonal antibody that targets CD20, inhibits B cells involved in aPL-induced clinical manifestations of APS [35]. Hydroxychloroquine has been reported to decrease the overexpression of GPIIbIIIa on the membrane of aPL-activated platelets and inhibit platelet aggregation [36]. In pregnancy-related morbidity, 20% of female patients with APS experience recurrent pregnancy losses, including miscarriage, fetal loss, and stillbirth at any stage of pregnancy [37]. aPL binding to monocytes, endothelial cells, platelets, and plasma components of the coagulation cascade in the induction of thrombosis causes fetal death in APS. Direct effects of anti-β2GPI autoantibodies on the placenta include an inflammatory response resulting in trophoblast damage, binding to cultured cytotrophoblast cells that causes trophoblast membrane perturbation, and a reduction in the secretion of human chorionic gonadotropin [38, 39].

Our study discovered that patients with APS suffered more comorbidities such as hypertension, hyperlipidemia, heart failure, atrial fibrillation, and chronic kidney disease. To the best of our knowledge, one study indicated that the patients with hypertension have higher IgG levels of antibodies to endothelial cells and β2GPI (Beta-2-Glycoprotein I) than control groups. Furthermore, elevated insulin levels, insulin-like growth factor binding protein-1, and greater insulin resistance were associated with Anti-β2GP1 levels. These findings were correlated to our result and provided evidence of linkage between APS and metabolic variables [40]. Adipocytokine, a product produced by adipose tissues, was believed to contribute to low-grade inflammation and several diseases such as metabolic syndrome, atherosclerosis, and type 2 diabetes mellitus [41]. The patients with primary APS and coexistence of metabolic syndrome were reported to have more risks of arterial events by the deterioration of existing endothelial cell dysfunction [42].

Since the initial descriptions of APS were developed, hypertension has been considered one of the frequent signs related to the disease. Hughes identified that an association between livedo reticularis and elevated blood pressure contributed to renovascular etiology; the study population included patients with APS with varying degrees of hypertension ranging from mildly elevated to malignant [11, 12]. Renal involvement was an etiology of the elevated blood pressure in APS [13]. One research demonstrated an extensive series of renal biopsies in APS patients with renal manifestation. Vascular nephropathies such as small vessel vaso-occlusive lesions, recanalizing thrombi in arteries and arterioles, and focal cortical atrophy were found. In addition, 93% of those participants had systemic hypertension; given the high prevalence of hypertension in APS nephropathy (APSN), elevated blood pressure is considered a key marker of renal status [43]. One study indicated that anti-prothrombin antibodies are related to hypertension through a comparison of a patient group with severe essential hypertension with a matched group of healthy controls; it revealed that 8% of the participants in a patient group had anti-prothrombin antibodies compared with none of the healthy controls [44]. Shajit Sadanand et al. mentioned the association between lipid profile and aPLs. The most general dyslipidemia case in the study population is TG level > 150 mg/dL(51.9%), while LDL > 150 mg/dL(40.2%) takes second place. Statistics show a significant correlation among anti-β2G IgG levels, HDL and LDL level, and aCL IgM level and LDL [14]. Antibodies to oxidized LDLs and cardiolipins were associated with thrombosis and atherosclerotic complications in patients with SLE as early as 1993 [45]. These antibodies interfere with the regulation between platelets, endothelial cells, and coagulation factors and disturb the balance of coagulation and Fibrinolysis [46, 47]. One study suggested the assay of anti-β2GP1 with lupus anticoagulant can be used for early detection to those with APS and e thromboembolic events [48].

Our study population was mainly composed of East Asians living in Taiwan. We confirmed that APS was strongly associated with other autoimmune diseases, a finding that is consistent with research undertaken in Western countries. In one such cohort study, up to 36% of patients with APS were observed to have a history of SLE [10]. Compared with patients diagnosed as having primary APS, patients with APS as well as an SLE history presented increased incidences of arthralgias and arthritis, leukopenia, autoimmune hemolytic anemia, livedo reticularis, epilepsy, and myocardial infarction [17]. Furthermore, those patients exhibited higher rates of hypertension, dyslipidemia, diabetes, and severe lupus profiles with major organ involvement and higher rates of mortality [10, 49]. Their conditions required long-term anticoagulant treatment and immunosuppressive therapy, including high-dose corticosteroids, cyclophosphamide, and azathioprine [50].

The strength of this study was its employment of a database containing nationwide population-based data of approximately 99% of the 23 million people living in Taiwan. The database’s reliability and validity for epidemiological investigations have been reported previously [51]. The use of the ICD-10 definition of APS is uncommon rather than the more standard ICD-9-CM one. However, we suggest that future studies seek access to the medical records and laboratory data to investigate the diagnostic criteria applied to individual medical examinations. The limitation of this study was the anonymity of the NHIRD. The patients’ personal information, family histories and laboratory data were not available.

Our current findings indicate a relationship between APS and nonautoimmune comorbidities, such as hypertension, hyperlipidemia, heart failure, atrial fibrillation, and chronic kidney disease.