The UK CPRD study reported a peak age for incidence in men of years, whereas for women the incidence peaked at years [ 10 ]. Interestingly, in the Korean nationwide population-based study, the incidence of APS tended to increase with age only in men, peaking at ages of In women, the incidence peaked at ages and [ 8 ].
The differences in age when APS incidence peaked could be attributed to different characteristics of the population of each study, including different proportion of primary versus secondary APS and perhaps differences in racial and ethnic backgrounds.
The prevalence of aPL and the incidence of thrombotic events increase with age, making it harder to attribute the latter to the presence of aPL. Because of the increased incidence in thrombotic events, aPL may be tested more frequently in the elderly population, thus creating bias in these findings [ 16 ]. Childhood APS remains largely uninvestigated.
When breaking down primary and secondary pediatric APS, the former occurs at a younger age while the latter is more common during adolescent years. There have been conflicting reports regarding the frequency of APS in males and females. In Argentina, Luissi et al. In pediatric APS, the female to male ratio is 1. The mortality of APS has been shown to be higher than that of the general population both in population-based studies and in referral cohorts.
Rodziewicz et al. The SMR has been slightly higher in the referral center cohorts. In the Euro-Phospholipid project, a prospective cohort based on multiple referral centers, the year survival rate was The available studies have great heterogeneity both in methodology and definitions for aPL positivity.
In a study of centenarians without evidence of autoimmune disease, None was positive for LAC [ 24 ]. Frequency of aPL in the general healthy population without APS diagnosis as reported in selected studies since 1. Included only studies that reported the frequency of the different aPL and were published in or later. The frequency of aPL in children is understudied. In a meta-analysis of studies reporting frequency of aPL following viral infections, patients with HIV and Epstein-Barr virus were 10 times more likely to develop elevated aCL antibodies compared to healthy controls, while those with hepatitis C virus HCV and hepatitis B had 6 and 4 times the risk, respectively.
Bacterial infections have been associated with positive aCL, in particular, syphilis and leprosy. A recent systemic review of observational studies reporting aPL frequency among patients with various solid tumors found that patients with gastrointestinal and lung cancers had 5 times the risk to develop aCL compared to healthy controls while those with genitourinary cancers had 7 times the risk [ 30 ].
Regarding hematologic malignancies, Pusterla et al. Another study reported that patients with lymphoma had a single, double, and triple aPL positivity of Obstetric morbidity is one of the hallmarks of APS. Recurrent pregnancy loss, fetal death, placental insufficiency, and other adverse pregnancy outcomes have been associated with APS; however, these obstetric manifestations are also common in the general population and are usually multifactorial.
Regarding overall pregnancy loss, Infante-Rivard et al. Higher frequencies of aPL have been reported in women with recurrent early miscarriage.
Included only studies that reported the frequency of the different aPL. Consistently with the results of Andreoli et al. In women with fetal loss at or after 20 weeks of gestation, Silver et al.
Excluding stillbirths associated with fetal anomalies, Additionally, in another case-control multicentric study, 3 out of 7 women with stillbirth were positive for at least one aPL [ 36 ]. In a recently published case-control study, women having preterm births due to preeclampsia or placental insufficiency were more likely to have positive aPL than controls When separating between different outcomes associated with placental insufficiency, Andreoli et al.
Similarly, Neagoe et al. Further epidemiological studies are still needed to clarify exactly how much pregnancy morbidity can be attributed to APS, especially for risk stratification, prevention, and treatment of patients with APS obstetric manifestations. In a recent cross-sectional population-based study performed in Canada, incident patients with unprovoked VTE between ages 18 and 50 met the revised Sapporo criteria for APS.
Of these, Only 10 patients Similarly, in a prospective cohort of patients with first unprovoked VTE, 8. A review observed that around 9. The cerebral arteries are the most frequently involved in APS. Although less frequently, APS patients are at increased risk of myocardial infarction MI , renal artery thrombosis, mesenteric ischemia, retinal artery thrombosis, and limb ischemia due to arterial thrombosis.
There are multiple studies evaluating the frequency of aPL and APS among patients with cerebrovascular disease, especially among young patients. A meta-analysis that pooled data from young patients with a cardiovascular event CVE and healthy controls from 43 studies found an overall aPL frequency of Less frequently, MI is seen in 1—5. Other forms of coronary artery disease, like unstable angina, have also been associated with APS [ 51 ].
Urbanus et. In patients younger than 75 years hospitalized for an MI, Grosso et al. Our understanding of the epidemiology of APS remains limited, and many challenges and gaps in knowledge remain. The estimated incidence and prevalence ranges between 1 and 2 cases per , and 40 and 50 cases per ,, respectively.
The data however remains limited and fraught with methodological issues. The clinical heterogeneity of APS is not fully captured by the current criteria, which can lead to underestimation of the true burden of the disease in the population. Moreover, it remains to be elucidated if the frequency of APS among different racial and ethnic groups is different as is in the case of SLE. Larger population-based studies with diverse racial and ethnic groups are needed. As the classification criteria continues to evolve, it is likely that patients currently undiagnosed or classified differently may be reclassified as APS patients in the future; therefore, our current estimation of APS incidence and prevalence will continue to evolve.
This article does not contain any studies with human or animal subjects performed by any of the authors. This article is part of the Topical Collection on Antiphospholipid Syndrome.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Jesse Y. Dabit and Maria O. Valenzuela-Almada contributed equally to this work. Dabit, Email: ude. Maria O. Valenzuela-Almada, Email: ude. Sebastian Vallejo-Ramos, Email: ude. National Center for Biotechnology Information , U. Curr Rheumatol Rep. Published online Jan 5. Dabit , 1 Maria O. Author information Article notes Copyright and License information Disclaimer.
Corresponding author. Accepted Jun This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source.
Recent Findings There have been few population-based studies that estimated the prevalence and incidence of APS. Summary The epidemiology of APS has been difficult to elucidate. Keywords: Antiphospholipid syndrome, Epidemiology. Epidemiology of Antiphospholipid Syndrome in the General Population Estimating the frequency of APS has been challenging given the changes in the definition of the APS classification criteria, the lack of standardization to detect aPL, differences in laboratory cutoffs, and other difficulties such as confirming aPL positivity 12 weeks after the initial measurement.
Table 1 Data on APS incidence and prevalence around the world. Open in a separate window. Impact of Age and Gender on the Frequency of Antiphospholipid Syndrome Systemic autoimmune diseases tend to be more frequent in women, and many of them affect patients during midlife or the reproductive years.
Mortality in Antiphospholipid Syndrome The mortality of APS has been shown to be higher than that of the general population both in population-based studies and in referral cohorts. Table 2 Frequency of aPL in the general healthy population without APS diagnosis as reported in selected studies since 1.
Conclusions Our understanding of the epidemiology of APS remains limited, and many challenges and gaps in knowledge remain. Declarations Conflict of Interest Jesse Dabit declares that he has no conflict of interest. Valenzuela- Almada declares that she has no conflict of interest. Sebastian Vallejo-Ramos declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Contributor Information Jesse Y. Antiphospholipid syndrome: role of vascular endothelial cells and implications for risk stratification and targeted therapeutics. J Am Coll Cardiol. A review of the sapporo and revised Sapporo criteria for the classification of antiphospholipid syndrome. Where do the revised sapporo criteria add value? J Rheumatol. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome APS J Thromb Haemost.
Diagnosing antiphospholipid syndrome: 'extra-criteria' manifestations and technical advances. Nat Rev Rheumatol. A systematic review. Thromb Haemost. Arthritis Rheum. First population-based epidemiologic study of APS. Burden of antiphospholipid syndrome in a Thromboembolic Disease Registry [abstract]. Epidemiology of Antiphospholipid syndrome in Korea: a nationwide population-based study. J Korean Med Sci.
The epidemiology of the antiphospholipid syndrome in the UK, — [abstract]. Sex differences in systemic lupus erythematosus: epidemiology, clinical considerations, and disease pathogenesis. Mayo Clin Proc. Ann Rheum Dis. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. Antibodies Basel. Pediatric antiphospholipid syndrome: clinical and immunologic features of patients in an international registry.
Clinical characteristics and thrombosis outcomes of paediatric antiphospholipid syndrome: analysis of 58 patients. Clin Rheumatol. Antiphospholipid syndrome in Mexican children. Isr Med Assoc J. Soybilgic A, Avcin T. Clinical and immunological features of antiphospholipid syndrome in the elderly: a retrospective national multicentre study.
Rheumatology Oxford ; 58 6 — High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol. Anti-beta 2 glycoprotein I antibodies in centenarians. Exp Gerontol. Pediatric antiphospholipid syndrome. Eur J Rheumatol. Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus anticoagulant is frequent in patients with Covid J Thromb Haemost.
Antiphospholipid antibodies, antiphospholipid syndrome and infections. Autoimmun Rev. Systematic review of observational studies reporting antiphospholipid antibodies in patients with solid tumors. Progestin pill is not always well tolerated by the patients. Therefore, intrauterine devices with or without progestin are actually recommended. Though not part of the clinical classification criteria, symptoms and signs such as livedo reticularis, skin ulcers, sterile endocarditis, migraine, chorea, epilepsy and nephropathy are often observed in patients with APS.
Treatment of these features is a matter of debate and based on expert opinion; no conclusive clinical studies on this subject have been performed; however, many experts suggest the use of old and new immunosuppressive treatments with or without low-dose aspirin and warfarin. However, these data are based on a retrospective case series, subjected to inclusion bias. Due to the severity and rarety of the disease, no prospective studies on treatment of CAPS have been undertaken.
Complement inhibition may be of added value in the treatment of CAPS, but its position is not well established yet. Proposed algorithm for treatment of CAPS. Modified from Cervera et al Non-immunologists should also understand APS and its symptoms: it is difficult to diagnose rapidly and the patient can suffer multiple traumatic events such as multiple miscarriages , which might otherwise be avoided.
It is also difficult for patients to identify suitable specialists, as the symptoms are not always easily interpretable.
Again, this could be addressed through more widespread knowledge of the disease. The treatment should be tailored to the person, after careful study of the clinical history. It can even be difficult to withstand the financial burden eg, for specialist consultancies, for INR home measurement systems , especially without structured support from a public health service. Lastly, doctors could be more encouraging towards patients with APS: discouraging people from having children or creating anxiety regarding possible complications helps neither the patient nor research.
With APS being a rare disease, not many well-designed clinical trials have been performed, resulting in a lack of reliable clinical data. The 17 papers evaluated allocated to the respective areas could be useful in providing background information for a future clinical guideline.
However, some limitations concerning these papers were noted. First, some papers had a primary focus on systemic lupus erythematosus, including only scarce data and recommendations on APS. Second, most of the included papers were rather outdated, with only six articles published in the last 3 years, while others were published 5—9 years and one 14 years ago. In conclusion, we were able to identify 17 papers that provide important and helpful data on APS that should be taken into account for the development of a future clinical guideline.
However, much more well-designed clinical research is needed to answer the still many open questions in this disease. Large international collaborations will be necessary to have enough statistical power in future studies. Contributors: LM, NCC, TA: substantial contributions to the analysis and interpretation of data; substantial contributions to the conception and design of the work, the acquisition, analysis and interpretation of data; revising the work critically for important intellectual content; drafting the work and revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Competing interests: None declared. Patient consent: Not required. Provenance and peer review: Commissioned; externally peer reviewed. Data sharing statement: No additional data are available.
National Center for Biotechnology Information , U. RMD Open. Published online Oct Author information Article notes Copyright and License information Disclaimer. Corresponding author.
Correspondence to Angela Tincani; ti. No commercial re-use. See rights and permissions. Published by BMJ. This article has been cited by other articles in PMC. Key messages What is already known about this subject? Thereare still unmet needs with regard to diagnosis and management of APS.
What does this study add? How might this impact on clinical practice or futuredevelopments? Diagnosisand treatment of APS is largely based on consensus and expert opinion.
Table 1 List of the references discussing unmet needs in APS. Open in a separate window. Laboratory tests Although standardised testing for lupus anticoagulant LA , anticardiolipin and anti-beta2GPI antibodies remains a concern, both influencing research and clinical diagnosis, clear recommendations on best practices for immunoassays for the measurement of aPL by the three tests and on the most important requirements for technical and performance characteristics have been published.
Thrombosis treatment The mainstay of treatment of thrombotic APS remains vitamin K antagonists, although with recognised limitations especially in the long-term follow-up, 27 failing to prevent recurrent events. Obstetric complications With the introduction of combined low-dose aspirin and low molecular weight heparin, most of the aPL-related pregnancy loss can be prevented.
Figure 1. Non-criteria manifestations Though not part of the clinical classification criteria, symptoms and signs such as livedo reticularis, skin ulcers, sterile endocarditis, migraine, chorea, epilepsy and nephropathy are often observed in patients with APS.
Figure 2. Conclusions With APS being a rare disease, not many well-designed clinical trials have been performed, resulting in a lack of reliable clinical data. Footnotes Contributors: LM, NCC, TA: substantial contributions to the analysis and interpretation of data; substantial contributions to the conception and design of the work, the acquisition, analysis and interpretation of data; revising the work critically for important intellectual content; drafting the work and revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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