Time to diagnosis in systemic lupus erythematosus: Associated factors and its impact on damage accrual and mortality. Data from a multi-ethnic, multinational Latin American lupus cohort.

BACKGROUND: Systemic lupus erythematosus (SLE) often mimics symptoms of other diseases, and the interval between symptom onset and diagnosis may be long in some of these patients. Aims: To describe the characteristics associated with the time to SLE diagnosis and its impact on damage accrual and mortality in patients with SLE from a Latin American inception cohort. METHODS: Patients were from a multi-ethnic, multi-national Latin-American SLE inception cohort. All participating centers had specialized lupus clinics. Socio-demographic, clinical/laboratory, disease activity, damage, and mortality between those with a longer and a shorter time to diagnosis were compared using descriptive statistical tests. Multivariable Cox regression models with damage accrual and mortality as the end points were performed, adjusting for age at SLE diagnosis, gender, ethnicity, level of education, and highest dose of prednisone for damage accrual, plus highest dose of prednisone, baseline SLEDAI, and baseline SDI for mortality. RESULTS: Of the 1437 included in these analyses, the median time to diagnosis was 6.0 months (Q1-Q3 2.4-16.2); in 721 (50.2%) the time to diagnosis was longer than 6 months. Patients whose diagnosis took longer than 6 months were more frequently female, older at diagnosis, of Mestizo ethnicity, not having medical insurance, and having "non-classic" SLE symptoms. Longer time to diagnosis had no impact on either damage accrual (HR 1.09, 95% CI 0.93-1.28, p = 0.300) or mortality (HR 1.37, 95% CI 0.88-2.12, p = 0.200). CONCLUSIONS: In this inception cohort, a maximum time of 24 months with a median of 6 months to SLE diagnosis had no apparent negative impact on disease outcomes (damage accrual and mortality).

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Predictors of severe hemolytic anemia and its impact on major outcomes in systemic lupus erythematosus: Data from a multiethnic Latin American cohort.

OBJECTIVE: To determine the predictors of the occurrence of severe autoimmune hemolytic anemia (AIHA) and its impact on damage accrual and mortality in SLE patients. METHODS: Factors associated with time to severe AIHA (hemoglobin level ≤7 g/dL) occurring from the onset of SLE symptoms were examined by Cox proportional hazards regressions. The association of severe AIHA with mortality was examined by logistic regression analyses while its impact on damage was by negative binomial regression. RESULTS: Of 1,349 patients, 49 (3.6%) developed severe AIHA over a mean (SD) follow-up time of 5.4 (3.8) years. The median time from the first clinical manifestation to severe AIHA was 111 days (IQR 43-450). By multivariable analysis, male sex (HR 2.26, 95% CI 1.02-4.75, p = 0.044), and higher disease activity at diagnosis (HR 1.04, 95% CI 1.01-1.08, p = 0.025) were associated with a shorter time to severe AIHA occurrence. Of the SLEDAI descriptors, only hematologic (leukopenia and/or thrombocytopenia) showed a certain trend toward significance in the multivariable analysis (HR 2.36, 95% CI 0.91-6.13, p = 0.0772). Severe AIHA contributed neither to damage nor to mortality. CONCLUSIONS: Severe AIHA occurs during the early course of SLE. Male sex and higher disease activity at diagnosis emerged as independent predictors of a shorter time to severe AIHA occurrence. Although not statistically significant, hematological abnormalities at SLE diagnosis could predict the occurrence of severe AIHA in a shorter time. Damage and mortality did not seem to be impacted by the occurrence of severe AIHA.

Damage index for antiphospholipid syndrome during long term follow-up: Correlation between organ damage accrual and quality of life.

BACKGROUND: Consequences of organ damage in primary antiphospholipid syndrome (PAPS) are diverse, our aim was to determine organ damage over time and the correlation of organ damage accrual with health-related quality of life (HRQoL) in PAPS. METHODS: First phase: retrospective cohort applying Damage Index for Antiphospholipid Syndrome (DIAPS) at 1, 5, 10, 20 years, or longer since diagnosis. Second phase: cross-sectional study, assessing HRQoL by the Medical Outcomes Study Short Form 36 (SF-36), and organ damage accrual. Descriptive statistics and Spearman correlation coefficient were used. RESULTS: Sixty-seven patients were included, mean follow-up:15 years. Deep vein thrombosis prevailed (71.6%), pulmonary embolism (35.8%) and stroke (32.8%). Organ damage was found in 98.5%, with a cumulative DIAPS value of 3, with greater involvement in the neuropsychiatric and peripheral vascular domains. Regarding HRQoL, deterioration in the physical component summary (PCS) was found in 89.6%. Organ damage accrual correlated inversely and significantly with all the SF-36 domains, mainly with the total score and PCS. Body pain and PCS correlated the most (rho = -0.503, rho = -0.475). CONCLUSIONS: Organ damage accrual impaired HRQoL in PAPS. Secondary thromboprophylxis through adequate systemic management and control of cardiovascular risk factors are necessary to prevent further impairment.

Factors associated with neuropsychiatric involvement in Latin American patients with systemic lupus erythematosus.

INTRODUCTION: Factors related to presentation of neuropsychiatric (NP) SLE manifestations, early in the course of the disease, and during follow up have not been clearly established. PURPOSE: To identify disease and non-disease related factors associated with NP manifestations in early SLE. METHODS: We included 1193 patients from the GLADEL inception cohort free of NP involvement at cohort entry. We evaluated the association of demographic, clinical and laboratory data with NP involvement during follow-up. STATISTICAL METHODS: Independent factors associated with NP involvement were identified using a multivariable Cox regression model. RESULTS: Factors independently associated with NP manifestations were: mestizo ethnicity (HR 1.701, 95% CI 1.282-2.258, p = 0.0002), myalgias/myositis (HR 1.832, 95% CI 1.335-2.515, p = 0.0002), pneumonitis (HR 2.476, 95% CI 1.085-5.648, p = 0.0312), shrinking lung (HR 2.428, 95% CI 1.074-5.493, p = 0.0331) and hemolytic anemia (HR 1.629, 95% CI 1.130-2.347, p = 0.0089). Longer disease duration at cohort entry (13 to 24 months) was associated with a lower risk of developing NP manifestations (HR 0.642, 95% CI 0.441-0.934, p = 0.0206). CONCLUSIONS: Patients with myalgias/myositis, pneumonitis, shrinking lung and hemolytic anemia are at higher risk of NP involvement, whereas longer disease duration at cohort entry is associated with a lower risk of developing NP involvement.

Clinical features, damage accrual, and survival in patients with familial systemic lupus erythematosus: data from a multi-ethnic, multinational Latin American lupus cohort.

OBJECTIVES: This study aimed to compare the clinical features, damage accrual, and survival of patients with familial and sporadic systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multinational Latin American SLE cohort was studied. Familial lupus was defined as patients with a first-degree SLE relative; these relatives were interviewed in person or by telephone. Clinical variables, disease activity, damage, and mortality were compared. Odds ratios (OR) and 95% confidence intervals (CI) were estimated. Hazard ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for time to damage and mortality. RESULTS: A total of 66 (5.6%) patients had familial lupus, and 1110 (94.4%) had sporadic lupus. Both groups were predominantly female, of comparable age, and of similar ethnic distribution. Discoid lupus (OR = 1.97; 95% CI 1.08-3.60) and neurologic disorder (OR = 1.65; 95% CI 1.00-2.73) were significantly associated with familial SLE; pericarditis was negatively associated (OR = 0.35; 95% CI 0.14-0.87). The SLE Disease Activity Index and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) were similar in both groups, although the neuropsychiatric (45.4% vs. 33.5%; p = 0.04) and musculoskeletal (6.1% vs. 1.9%; p = 0.02) domains of the SDI were more frequent in familial lupus. They were not retained in the Cox models (by domains). Familial lupus was not significantly associated with damage accrual (HR = 0.69; 95% CI 0.30-1.55) or mortality (HR = 1.23; 95% CI 0.26-4.81). CONCLUSION: Familial SLE is not characterized by a more severe form of disease than sporadic lupus. We also observed that familial SLE has a higher frequency of discoid lupus and neurologic manifestations and a lower frequency of pericarditis.

First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR).

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an 'overarching' treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.

The number of flares patients experience impacts on damage accrual in systemic lupus erythematosus: data from a multiethnic Latin American cohort.

PURPOSE: To determine the association between the number of flares systemic lupus erythematosus (SLE) patients experience and damage accrual, independently of other known risk factors. METHODS: SLE patients (34 centres, nine Latin American countries) with a recent diagnosis (≤2 years) and ≥3 evaluations were studied. Disease activity was ascertained with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage with the SLICC/ACR Damage Index (SDI). Flare was defined as an increase ≥4 points in the SLEDAI between two study visits. An ambidirectional case- crossover design was used to determine the association between the number of flares and damage accrual. RESULTS: 901 patients were eligible for the study; 500 of them (55.5%) experienced at least one flare, being the mean number of flares 0.9 (SD: 1.0). 574 intervals from 251 patients were included in the case-crossover design since they have case and control intervals, whereas, the remaining patients did not. Their mean age at diagnosis was 27.9 years (SD: 11.1), 213 (84.9%) were women. The mean baseline SDI and SLEDAI were 1.3 (1.3) and 13.6 (8.1), respectively. Other features were comparable to those of the entire sample. After adjusting for possible confounding variables, the number of flares, regardless of their severity, was associated with damage accrual (SDI) OR 2.05, 95% CI 1.43 to 2.94, p<0.001 (OR 2.62, 95% CI 1.31 to 5.24, p=0.006 for severe and OR 1.91, 95% CI 1.28 to 2.83, p=0.001 for mild-moderate). CONCLUSIONS: The number of flares patients experience, regardless of their severity, increases the risk of damage accrual, independently of other known risk factors.

Primary cardiac disease in systemic lupus erythematosus patients: protective and risk factors--data from a multi-ethnic Latin American cohort.

OBJECTIVES: The aim of this study was to assess the cumulative incidence, risk and protective factors and impact on mortality of primary cardiac disease in SLE patients (disease duration ≤2 years) from a multi-ethnic, international, longitudinal inception cohort (34 centres, 9 Latin American countries). METHODS: Risk and protective factors of primary cardiac disease (pericarditis, myocarditis, endocarditis, arrhythmias and/or valvular abnormalities) were evaluated. RESULTS: Of 1437 patients, 202 (14.1%) developed one or more manifestations: 164 pericarditis, 35 valvulopathy, 23 arrhythmias, 7 myocarditis and 1 endocarditis at follow-up; 77 of these patients also had an episode of primary cardiac disease at or before recruitment. In the multivariable parsimonious model, African/Latin American ethnicity [odds ratio (OR) 1.80, 95% CI 1.13, 2.86], primary cardiac disease at or before recruitment (OR 6.56, 95% CI 4.56, 9.43) and first SLICC/ACR Damage Index for SLE assessment (OR 1.31, 95% CI 1.14, 1.50) were risk factors for the subsequent occurrence of primary cardiac disease. CNS involvement (OR 0.44, 95% CI 0.25, 0.75) and antimalarial treatment (OR 0.62, 95% CI 0.44, 0.89) at or before recruitment were negatively associated with the occurrence of primary cardiac disease risk. Primary cardiac disease was not independently associated with mortality. CONCLUSION: Primary cardiac disease occurred in 14.1% of SLE patients of the Grupo Latino Americano de Estudio de Lupus cohort and pericarditis was its most frequent manifestation. African origin and lupus damage were found to be risk factors, while CNS involvement at or before recruitment and antimalarial treatment were protective. Primary cardiac disease had no impact on mortality.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort.

OBJECTIVE: To examine the role of ethnicity and the use of anti-malarials (protective) on lupus renal disease. METHODS: A nested case-control study (1:2 proportion, n = 265 and 530) within GLADEL's (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort was carried out. The end-point was ACR renal criterion development after diagnosis. Cases and controls were matched for follow-up time (end-point or a comparable time, respectively). Renal disease predictors were examined by univariable and multivariable analyses. Additional analyses were done to determine if the protective effect of anti-malarials persisted after adjusting for intake-associated confounders. RESULTS: Of the cases, 233 (87.9%) were women; their mean (s.d.) age at diagnosis was 28.0 (11.9) years and their median (Q3-Q1 interquartile range) follow-up time for cases and controls was 8.3 months (Q3-Q1: 23.5); 56.6% of the cases and 74.3% of the controls were anti-malarial users. Mestizo ethnicity [odds ratio (OR) 1.72, 95% CI 1.19, 2.48] and hypertension (OR 2.26, 95% CI 1.38, 3.70) were independently associated with a higher risk of renal disease, whereas anti-malarial use (OR 0.39, 95% CI 0.26, 0.58), older age at disease onset (OR 0.98, 95% CI 0.96, 0.99) and female gender (OR 0.56, 95% CI 0.32, 0.99) were negatively associated with such occurrence. After adjusting for variables associated with their intake, the protective effect of anti-malarials on renal disease occurrence persisted (OR 0.38, 95% CI 0.25, 0.58). CONCLUSION: Mestizo patients are at increased risk of developing renal disease, whereas anti-malarial use protects patients from such an occurrence.

Eculizumab use in catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis from the "CAPS Registry".

OBJECTIVES: To describe the real-world experience of eculizumab use in patients with catastrophic antiphospholipid syndrome (CAPS) according to the information provided by the "CAPS Registry". METHODS: We analyzed the demographic, clinical and immunological data from all the patients included in the "CAPS Registry" treated with eculizumab and described the indications for eculizumab administration, dose, outcome, use of prophylactic vaccines and adverse effects. RESULTS: The "CAPS Registry" currently includes 584 patients from whom 39 (6.7%) were treated with eculizumab (it was used as a rescue therapy in 30 cases while in 6 cases it was used as first line therapy). Mean age of eculizumab treated patients was 39 years (SD = 14.6), 72% were female, 77% had a primary APS and 79% had a precipitating factor before the CAPS event. Thrombocytopenia was present in 28 (72%) cases and features of microangiopathic hemolytic anemia were present in 15 (38.5%). Twenty-nine (74.4%) patients recovered from the episode of CAPS (four showed only partial remission). Symptoms worsened in 9 patients, from whom 5 finally died despite the treatment. There was only one relapse after a median follow up of 10.7 months. The most common treatment regimen was 900 mg weekly for four weeks and 1200 mg fortnightly. CONCLUSION: According to the real-world experience provided by the "CAPS Registry", eculizumab can be considered in some patients with CAPS refractory to previous therapies, especially if they present with features of complement-mediated thrombotic microangiopathy.

Development of a New International Antiphospholipid Syndrome Classification Criteria Phase I/II Report: Generation and Reduction of Candidate Criteria.

OBJECTIVE: An international multidisciplinary initiative, jointly supported by the American College of Rheumatology and European Alliance of Associations for Rheumatology, is underway to develop new rigorous classification criteria to identify patients with high likelihood of antiphospholipid syndrome (APS) for research purposes. The present study was undertaken to apply an evidence- and consensus-based approach to identify candidate criteria and develop a hierarchical organization of criteria within domains. METHODS: During phase I, the APS classification criteria steering committee used systematic literature reviews and surveys of international APS physician scientists to generate a comprehensive list of items related to APS. In phase II, we reviewed the literature, administered surveys, formed domain subcommittees, and used Delphi exercises and nominal group technique to reduce potential APS candidate criteria. Candidate criteria were hierarchically organized into clinical and laboratory domains. RESULTS: Phase I generated 152 candidate criteria, expanded to 261 items with the addition of subgroups and candidate criteria with potential negative weights. Using iterative item reduction techniques in phase II, we initially reduced these items to 64 potential candidate criteria organized into 10 clinical and laboratory domains. Subsequent item reduction methods resulted in 27 candidate criteria, hierarchically organized into 6 additive domains (laboratory, macrovascular, microvascular, obstetric, cardiac, and hematologic) for APS classification. CONCLUSION: Using data- and consensus-driven methodology, we identified 27 APS candidate criteria in 6 clinical or laboratory domains. In the next phase, the proposed candidate criteria will be used for real-world case collection and further refined, organized, and weighted to determine an aggregate score and threshold for APS classification.

Predictors of renal damage in systemic lupus erythematous patients: data from a multiethnic, multinational Latin American lupus cohort (GLADEL).

AIM: A decrease in proteinuria has been considered protective from renal damage in lupus nephritis (LN), but a cut-off point has yet to be established. The aim of this study was to identify the predictors of renal damage in patients with LN and to determine the best cut-off point for a decrease in proteinuria. METHODS: We included patients with LN defined clinically or histologically. Possible predictors of renal damage at the time of LN diagnosis were examined: proteinuria, low complement, anti-double-stranded DNA antibodies, red cell casts, creatinine level, hypertension, renal activity (assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), prednisone dose, immunosuppressive drugs and antimalarial use. Sociodemographic variables were included at baseline. Proteinuria was assessed at baseline and at 12 months, to determine if early response (proteinuria <0.8 g/day within 12 months since LN diagnosis) is protective of renal damage occurrence. Renal damage was defined as an increase of one or more points in the renal domain of The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). Cox regression models using a backward selection method were performed. RESULTS: Five hundred and two patients with systemic lupus erythematosus patients were included; 120 patients (23.9%) accrued renal damage during their follow-up. Early response to treatment (HR=0.58), antimalarial use (HR=0.54) and a high SES (HR=0.25) were protective of renal damage occurrence, whereas male gender (HR=1.83), hypertension (HR=1.86) and the renal component of the SLEDAI (HR=2.02) were risk factors for its occurrence. CONCLUSIONS: Early response, antimalarial use and high SES were protective of renal damage, while male gender, hypertension and higher renal activity were risk factors for its occurrence in patients with LN.

Predictors of Remission and Low Disease Activity State in Systemic Lupus Erythematosus: Data from a Multiethnic, Multinational Latin American Cohort.

OBJECTIVE: To determine the predictors of remission and low disease activity state (LDAS) in patients with systemic lupus erythematosus (SLE). METHODS: Three disease activity states were defined: Remission = SLE Disease Activity Index (SLEDAI) = 0 and prednisone ≤ 5 mg/day and/or immunosuppressants (maintenance dose); LDAS = SLEDAI ≤ 4, prednisone ≤ 7.5 mg/day and/or immunosuppressants (maintenance dose); and non-optimally controlled state = SLEDAI > 4 and/or prednisone > 7.5 mg/day and/or immunosuppressants (induction dose). Antimalarials were allowed in all groups. Patients with at least 2 SLEDAI reported and not optimally controlled at entry were included in these analyses. Outcomes were remission and LDAS. Multivariable Cox regression models (stepwise selection procedure) were performed for remission and for LDAS. RESULTS: Of 1480 patients, 902 were non-optimally controlled at entry; among them, 196 patients achieved remission (21.7%) and 314 achieved LDAS (34.8%). Variables predictive of a higher probability of remission were the absence of mucocutaneous manifestations (HR 1.571, 95% CI 1.064-2.320), absence of renal involvement (HR 1.487, 95% CI 1.067-2.073), and absence of hematologic involvement (HR 1.354, 95% CI 1.005-1.825); the use of immunosuppressive drugs before the baseline visit (HR 1.468, 95% CI 1.025-2.105); and a lower SLEDAI score at entry (HR 1.028, 95% CI 1.006-1.051 per 1-unit decrease). These variables were predictive of LDAS: older age at entry, per 5-year increase (HR 1.050, 95% CI 1.004-1.098); absence of mucocutaneous manifestations (HR 1.401, 95% CI 1.016-1.930) and renal involvement (HR 1.344, 95% CI 1.049-1.721); and lower SLEDAI score at entry (HR 1.025, 95% CI 1.009-1.042). CONCLUSION: Absence of mucocutaneous, renal, and hematologic involvement, use of immunosuppressive drugs, and lower disease activity early in the course of the disease were predictive of remission in patients with SLE; older age was predictive of LDAS.

Renal Involvement in Antiphospholipid Syndrome.

Antiphospholipid syndrome is a complex autoimmune disease, characterized by the presence of vascular thrombosis, obstetric, hematologic, cutaneous, and cardiac manifestations. Renal disease in patients with antiphospholipid syndrome was not recognized in the first descriptions of the disease, but later on, the renal manifestations of the syndrome have been investigated widely. Renal manifestations of antiphospholipid syndrome conform a wide spectrum of diverse renal syndromes. Hypertension is one of the most frequent, but less commonly recognized renal alteration. It can be difficult to control as its origin is renovascular. Renal vascular thrombosis can be arterial or venous. Other alterations are renal infarction and vascular thrombosis in arterial territories. Venous thrombosis can be present in primary and secondary antiphospholipid syndrome; it presents with worsening of previous proteinuria or de novo nephrotic syndrome, hypertension and renal failure. Antiphospholipid syndrome nephropathy is a vascular disease that affects glomerular tuft, interstitial vessels, and peritubular vessels; histopathology characterizes the renal lesions as acute or chronic, the classic finding is thrombotic microangiopathy, that leads to fibrosis, tubule thyroidization, focal cortical atrophy, and glomerular sclerosis. Antiphospholipid syndrome nephropathy can also complicate patients with systemic lupus erythematosus, and there is vast information supporting the worse renal prognosis in this group of patients with the classic histopathologic lesions. Treatment consists of anticoagulation, as for other thrombotic manifestations of antiphospholipid syndrome. There is some evidence of glomerulonephritis as an isolated lesion in patients with antiphospholipid syndrome. The most frequently reported glomerulonephritis is membranous; with some reports suggesting that immunosuppressive treatment may be effective. Patients with end stage renal disease commonly are positive for antiphospholipid antibodies, but it is not clear what is the role of aPL in this setting. Patients with vascular access may have complications in the presence of antibodies so that anticoagulation is recommended. Patients ongoing renal transplant with persistent antiphospholipid antibody positivity may have early and late graft failure.

The Heart and APS.

The heart is a target organ in antiphospholipid syndrome (APS). Endocardial disease, intracardiac thrombosis, myocardial involvement including coronary heart disease and microvascular thrombosis, as well as pulmonary hypertension have all been described in APS patients. Valvular involvement is the most common manifestation with a prevalence of 82% detected by transesophageal echocardiography. Symmetrical, nodular thickening of the mitral and/or aortic valves is characteristic. Anticoagulant/antiplatelet treatment is ineffective in terms of valvular lesion regression. Some patients require cardiac valve replacement. However, patients with APS have shown an increased perioperative morbidity and mortality. Intracardiac thrombosis, although a rare complication, can cause pulmonary and systemic emboli. Differential diagnosis with myxoma may be very difficult.

Endothelial dysfunction in patients with antiphospholipid syndrome assessed with positron emission tomography.

BACKGROUND: There is limited knowledge about endothelial dysfunction in patients with primary antiphospholipid syndrome (PAPS). The purpose of this study was to evaluate endothelial function in patients with PAPS assessed by positron emission tomography. METHODS AND RESULTS: A 3-phase protocol--rest, cold pressor test (CPT), and adenosine positron emission tomography with nitrogen 13 ammonia--was used in 18 patients with PAPS and 18 healthy volunteers (HVs). Myocardial blood flow (MBF) was measured in each phase, with calculation of the endothelial-dependent vasodilation index, the increase in the MBF in response to CPT, and the myocardial flow reserve. An important trend was found in the myocardial flow reserve (2.76 +/- 1.04 in PAPS group vs 3.27 +/- 0.72 in HV group, P > .05), in the endothelial-dependent vasodilation index (1.19 +/- 0.31 in PAPS group vs 1.55 +/- 0.37 in HV group, P < .05), and in the percent change in the MBF in response to CPT (from rest) (19% +/- 31% in PAPS group vs 55% +/- 37% in HV group, P < .05). CONCLUSION: The CPT results obtained in this study showed that the PAPS patients studied have endothelial dysfunction.

Diagnosing antiphospholipid syndrome: 'extra-criteria' manifestations and technical advances.

First described in the early 1980s, antiphospholipid syndrome (APS) is a unique form of acquired autoimmune thrombophilia in which patients present with clinical features of recurrent thrombosis and pregnancy morbidity and persistently test positive for the presence of antiphospholipid antibodies (aPL). At least one clinical (vascular thrombosis or pregnancy morbidity) and one lab-based (positive test result for lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein 1 antibodies) criterion have to be met for a patient to be classified as having APS. However, the clinical spectrum of APS encompasses additional manifestations that can affect many organs and cannot be explained exclusively by patients being in a prothrombotic state; clinical manifestations not listed in the classification criteria (known as extra-criteria manifestations) include neurologic manifestations (chorea, myelitis and migraine), haematologic manifestations (thrombocytopenia and haemolytic anaemia), livedo reticularis, nephropathy and valvular heart disease. Increasingly, research interest has focused on the development of novel assays that might be more specific for APS than the current aPL tests. This Review focuses on the current classification criteria for APS, presenting the role of extra-criteria manifestations and lab-based tests. Diagnostic approaches to difficult cases, including so-called seronegative APS, are also discussed.