Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin antibodies and ...anti-beta2glycoprotein I (anti-β2GPI) antibodies) and a plethora of macro- and micro-vascular manifestations, affecting predominantly young adults. Cardiovascular events are the leading causes of morbidity and mortality in APS. APL-mediated thrombo-inflammation and atherothrombosis are emerging pathogenetic mechanisms of cardiovascular disease (CVD) in APS, involving endothelial cell and monocyte activation, cytokines and adhesion molecules expression, complement and neutrophils activation, neutrophil extracellular traps formation, platelet cell activation and aggregation, and subsequent thrombin generation, in parallel with an oxidized low-density lipoprotein (oxLDL)-β2GPI complex induced macrophage differentiation to foam cells. High risk aPL profile, especially the presence of lupus anticoagulant and triple aPL positivity (all three aPL subtypes), co-existence with Systemic Lupus Erythematosus (SLE), as well as traditional risk factors such as smoking, hypertension, hyperlipemia and obesity are associated with both subclinical atherosclerosis and cardiovascular events in APS. Increased awareness of CVD risk by the physicians and patients, regular assessment and strict control of traditional risk factors, and lifestyle modifications are recommended. Use of low-dose aspirin should be considered for cardiovascular prevention in asymptomatic aPL carriers or SLE patients with high-risk aPL profile. The role of older agents such as hydroxychloroquine and statins or new potential targeted treatments against immuno- and athero-thrombosis has been demonstrated by experimental and some clinical studies and needs to be further evaluated by randomized controlled studies. This review summarizes the available evidence about the pathogenetic mechanisms and prevalence of cardiovascular events and subclinical atherosclerosis, the interrelationship between traditional and disease-related CVD risk factors, and the cardiovascular risk assessment and management in APS.
•Cardiovascular disease (CVD) is a leading cause of mortality in APS.•APL-mediated thrombo-inflammation and atherothrombosis are emerging pathogenetic mechanisms of CVD in APS.•Increased awareness of CVD risk and strict control of traditional risk factors is recommended.•Immunoregulatory treatments may be new therapeutic approaches in CVD management in APS.
SLE is a chronic autoimmune rheumatic disorder of high heterogeneity in clinical presentation, treatment response and prognosis. Long-term outcomes in SLE have been dramatically improved over the ...past decades, however, increased morbidity and mortality, especially among young individuals, still exists. Unmet needs include residual disease activity and frequent flares, glucocorticoid treatment dependency and toxicity, comorbidity burden, reduced health-related quality of life, health disparities and damage. The main determinants of long-term outcomes in SLE are age, sex, race/ethnicity, genetic profile, environmental factors including smoking, disease activity, major organ involvement such as lupus nephritis and CNS involvement, comorbidities including cardiovascular disease and serious infections, coexistence with APS, treatment adherence, socio-economic factors and access to care. In this review we discuss trends in long-term outcomes in SLE over the years and major contributors such as genetic, disease-related, treatment, comorbidity, socio-economic and other factors.
Objective
End‐stage renal disease (ESRD) is a major consequence of lupus nephritis, but how this risk has changed over time is unknown. We conducted this systematic review to examine changes in ESRD ...among adults with lupus nephritis from 1971 to 2015 and to estimate risks of ESRD among contemporary patients.
Methods
We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for cohort studies and clinical trials on ESRD in adults with lupus nephritis. We analyzed studies from developed and developing countries separately. The outcome was probability of ESRD at 5, 10, and 15 years of lupus nephritis.
Results
We included 187 articles that reported on 18,309 patients. In developed countries, the 5‐year risk of ESRD decreased from 16% (95% confidence interval 95% CI 14–17%) in 1970–1979 to 11% (95% CI 10–12%) in the mid‐1990s and then plateaued. ESRD risks at 10 years and 15 years showed steeper declines in the 1970s and 1980s but also plateaued in 1993–1997, with a notable increase in the late 2000s. The decrease in risk after 1980 coincided with increased use of cyclophosphamide. The 15‐year ESRD risk was higher in developing countries than in developed countries. Patients with class IV lupus nephritis had the greatest risk of ESRD, with a 15‐year risk of 44% during the 2000s.
Conclusion
Risks of ESRD in lupus nephritis improved between the 1970s and the mid‐1990s and then plateaued, with an increase in the late 2000s. This pattern suggests limitations in the effectiveness of, or access to, current treatments.
Kidney damage is a well-recognized complication of the antiphospholipid syndrome (APS), either primary or systemic lupus erythematosus (SLE)-associated APS. Kidney involvement in APS involves a ...variety of manifestations, such as renal artery thrombosis or stenosis, renal vein thrombosis, allograft loss due to thrombosis after kidney transplantation, and injury to the renal microvasculature, also known as APS nephropathy. Biopsy in patients with APS nephropathy includes acute thrombotic microangiopathy lesions and chronic intrarenal vascular lesions such as interlobular fibrous intimal hyperplasia, arterial and arteriolar recanalizing thrombosis, fibrous arterial occlusion, and focal cortical atrophy. The most frequent clinical features are hypertension, microscopic hematuria, proteinuria (ranging from mild to nephritic levels), and renal insufficiency. It is uncertain whether antiphospholipid antibodies or other factors are implicated in the development of APS nephropathy, and whether it is driven mainly by thrombotic or by inflammatory processes. Experimental models and clinical studies of thrombotic microangiopathy lesions implicate activation of the complement cascade, tissue factor, and the mTORC pathway. Currently, the management of APS nephropathy relies on expert opinion, and consensus is lacking. There is limited evidence about the effect of anticoagulants, and their use remains controversial. Treatment approaches in patients with APS nephropathy lesions may include the use of heparin based on its role on complement activation pathway inhibition or the use of intravenous immunoglobulin and/or plasma exchange. Targeted therapies may also be considered based on potential APS nephropathy pathogenetic mechanisms such as B-cell directed therapies, complement inhibition, tissue factor inhibition, mTOR pathway inhibition, or anti-interferon antibodies, but prospective multicenter studies are needed to address their role.
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic and non-thrombotic macro- and microvascular manifestations and pregnancy complications in the ...setting of persistent antiphospholipid antibodies (aPL), namely anticardiolipin antibodies, anti-β2 glycoprotein-I antibodies and lupus anticoagulant. Four decades after its first description, APS prevalence and incidence are still not completely understood due to the limited number of well-designed, population-based multi-ethnic studies. Furthermore, despite decades of efforts to standardise aPL immunoassays, considerable intraassay and interlaboratory variances in aPL measures still exist. Large multicentre APS cohorts have shown a 10-year survival of ∼91% and the presence of catastrophic APS occurs in about 1% of the entire population, associated with a 50% mortality rate. Clinically, any organ can be affected in the context of large, medium or small vessel (artery and/or vein) thrombosis. Macrovascular thrombosis is the hallmark of the disease and veins are more frequently affected than arteries. Deep vein thrombosis/pulmonary embolism thromboembolic disease is the most common APS manifestation, while stroke and transient ischaemic attack are the most frequent arterial thrombosis events. Myocardial infarction can also occur and contributes to increased mortality in APS. A minority of patients present with thrombosis affecting the intraabdominal organs, including the liver, spleen, small and large bowel, and the kidneys. Microvascular thrombosis, including APS nephropathy, chronic skin ulcers and livedoid vasculopathy represent a diagnostic challenge requiring histologic confirmation. In this narrative review we summarize the available evidence on APS epidemiology, focusing on the description of the prevalence of macro- and microvascular manifestations of the disease.
Background:Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE).1 Patients with SLE have a 2- to 10-fold higher risk of ischemic heart ...disease and stroke compared with the general population. An interrelationship between immunological, disease-related, and traditional cardiovascular risk factors contributes to CVD pathogenesis.CVD Risk Assessment:Early recognition and management of CVD risk factors is important for the prevention of CVD events. For the assessment of CVD risk, generic clinical prediction scores have been used. Evidence has shown that Framingham score underestimates CVD risk in SLE, while limited data are available about the performance of the Systematic COronary Risk Evaluation (SCORE). The modified Framingham,2 and the modified SCORE, multiplied by 2 and 1.5, respectively have been developed, and the most recent version of the QRISK prediction score (QRISK3) included weights for SLE. The SLE Cardiovascular Risk Equation3 was recently developed including both traditional and disease-related CVD risk factors (SLEDAI, lupus anticoagulant, C3) and was found to have higher estimated risks than the ACS/AHA risk equation.Several vascular imaging markers (e.g. intima-media thickness, carotid and femoral atherosclerotic plaques) and circulating biomarkers have been evaluated for CVD risk stratification. Vascular ultrasound studies showed a 2- to 3-fold increased risk for asymptomatic plaque presence in patients with SLE compared to healthy controls, and a comparable risk to other high-cardiovascular risk disorders such as rheumatoid arthritis and diabetes mellitus.4 Markers of arterial stiffness or endothelial dysfunction such as the pulse wave velocity and flow-mediated dilation, respectively, have been also more impaired in SLE than in the general population in some studies.CVD Risk Management:According to the recent ‘EULAR recommendations for cardiovascular risk management in Rheumatic and Musculoskeletal Diseases including Systemic Lupus Erythematosus and Antiphospholipid Syndrome’,5 a blood pressure target of <130/80 mm Hg should be considered in patients with SLE. Use of ACE inhibitors or angiotensin receptor blockers is recommended for patients with lupus nephritis with urine protein-to-creatinine ratio >500 mg/g or arterial hypertension. Patients with SLE may be candidates for preventative strategies as in the general population, including low-dose aspirin, based on their individual cardiovascular risk profile. Regarding lipid control, recommendations used in the general population should be followed.Evidence from several observational studies has shown a lower risk of CVD events in patients treated with hydroxychloroquine versus those not treated. EULAR recommendations stated that treatment with hydroxychloroquine (which is recommended for all SLE patients) should be considered to also reduce the risk of cardiovascular events.5 Accordingly, the lowest possible glucocorticoid dose is recommended to minimise any potential cardiovascular harm. No specific immunosuppressives can be recommended for lowering the risk of cardiovascular events.In conclusion, CVD burden in SLE is high. Increasing of awareness of CVD risk in patients with SLE, regular screening and control of modifiable CVD risk factors, as well as patient education and lifestyle modifications, are crucial for CVD prevention and management in these patients.ReferencesTektonidou MG, et al. Trends in hospitalizations due to acute coronary syndromes and stroke in patients with systemic lupus erythematosus, 1996 to 2012. Arthritis Rheumatol 2016;68:2680–2685.Urowitz MB, et al. Modified Framingham risk factor score for systemic lupus erythematosus. J Rheumatol 2016;43:875–879.Petri MA, et al. Development of a systemic lupus erythematosus cardiovascular risk equation. Lupus Sci Med 2019;6:e000346.Tektonidou MG, et al. Subclinical atherosclerosis in systemic lupus erythematosus: comparable risk with diabetes mellitus and rheumatoid arthritis. Autoimmun Rev 2017 Mar;16(3):308–312.Drosos GC, et al. EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis 2022 Feb 2:annrheumdis-2021-221733.Learning ObjectivesDescribe the need for regular screening and control of modifiable CVD risk factors in patients with SLEExplain the importance of increasing awareness of CVD risk in patients with SLE, for improving patient outcomesDiscuss the potential impact of paient education and lifestyle modification for the prevention of CVD in patients with SLE
Type I Interferon gene expression has been shown to play an important role in the pathogenesis of several systemic autoimmune disorders, paving the way for its potential use as a surrogate marker or ...a therapeutic tool. While the concept of type I interferon signature and its correlation with clinical phenotypes and disease activity, along with anti-interferon targeted therapy have been vastly investigated in patients with systemic lupus erythematosus, there is a paucity of data concerning antiphospholipid syndrome patients. In this review, we summarize the current knowledge on the pathogenetic and clinical implications of type I interferon expression in antiphospholipid syndrome and discuss the therapeutic possibility of targeting molecules along the interferon signaling pathway. A number of recent studies have shown a type I interferon gene expression induction in patients with primary antiphospholipid syndrome via the plasmacytoid dendritic cell pathway, toll like receptors (TLRs) such as TLR7 and TLR9, anti-beta2glycoprotein I antibody-mediated neutrophil activation and neutrophil extracellular traps (NETs) release in a TLR4-dependent fashion, and a subsequent B cell and plasmablast activation. An association between type I interferon expression and several demographic, clinical and laboratory characteristics including age, gender, pregnancy complications such as eclampsia, anti-beta2glycoprotein I antibodies, and a negative correlation with hydroxychloroquine and/or statin use, has been shown. Correlation of high interferon scores to worse outcomes in prospective studies could direct the initiation for a prompt treatment in high-risk populations. Potential therapeutic approaches targeting type I interferon production and signaling pathway components might include anti-interferon or interferon receptor monoclonal antibodies, or an interferon based therapeutic vaccine as was indicated from previous systemic lupus erythematosus studies, TLR inhibitors including hydroxychloroquine and anti-TLR antibodies, plasmacytoid dendritic cell inhibition, adenosine-receptor agonists, and plasmablast targeting treatments. Well-designed studies are needed to further assess the immunomodulatory potential of the above targets for therapeutic intervention in patients with primary antiphospholipid syndrome.
•IFN-I signature has been demonstrated in primary antiphospholipid syndrome (APS).•IFN-I signature is associated with several APS clinical and laboratory characteristics.•IFN-I production/signal pathway targeting can be a new therapeutic approach in APS.
The definition of acute and chronic antiphospholipid syndrome (APS) nephropathy was recently updated using a multiphase methodology in the context of the development of the new APS classification ...criteria. Currently, there is no consensus for the treatment of APS nephropathy, which mainly relies on the general recommendations for the management of APS. Based on evidence from experimental studies and a few clinical studies and case series, targeted treatments such as B-cell depletion, anti-B-cell activating factor antibody, complement inhibition, mammalian target of rapamycin inhibition, and neutrophil extracellular traps or interferon targeting may show promise for the treatment of microvascular manifestations in APS, including APS nephropathy. Validation of the new APS nephropathy definition and/or efforts for improvement in proposed terminology, along with the assessment of the safety and efficacy of potential targeted treatments in randomized controlled trials, are major future research directions. In this review, we summarize the current knowledge of APS nephropathy and discuss unanswered questions.
•In the context of improving Antiphospholipid syndrome (APS) classification, better APS nephropathy definition was attempted.•Accumulating evidence supports the association between antiphospholipid antibodies and renal microvascular lesions.•Identifying the impact of APS nephropathy on renal prognosis in SLE and APS improves risk stratification and management.•Increasing data advocates for inflammatory mechanisms targeting in management of APS microvascular manifestations,
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