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Objective We aimed to investigate the association between the different antiphospholipid antibodies (aPL) and both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) manifestations. Methods Patients from the RELESSER registry, a Spanish retrospective, cross-sectional, forty-five hospital registry of adult SLE patients, were included. Results Out of a total of 3,658 SLE patients, 1372 were aPL positive (555 of them fulfilled criteria for APS). All aPL types showed a negative association with cutaneous SLE manifestations. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) were both associated with haematological, ophthalmological and neuropsychiatric manifestations. IgG isotypes were associated with a higher risk of lupus manifestations compared with IgM. We found that the risk of neuropsychiatric and ophthalmological manifestations significantly increased with a higher number of positive aPL whereas the risk of cutaneous symptoms showed a negative correlation. All types of aPL, and more strongly LA, were associated with non-criteria antiphospholipid syndrome (APS) manifestations such as thrombocytopenia and haemolytic anaemia. Moreover, LA and aCL (particularly IgG isotype) were also associated with Libman-Sacks endocarditis and cognitive impairment. This association was stronger with more than one positive aPL. All types of aPL were also associated with classic APS manifestations, although LA, IgG isotypes, and patients with more than one aPL displayed a higher risk. Conclusion There is a hierarchy for aPL and the risk of APS and SLE manifestations. aCL, and especially LA, confer a higher risk for major organ involvement in SLE. IgG isotypes seem to have a more important role. The load of aPL confer a higher risk for APS and certain SLE manifestations.

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia 80% for all items, explaining the higher overall specificity of the criteria set. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.

OBJECTIVES: Patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have an increased premature prevalence of atherosclerosis. We aimed to determine whether there are differences in the prevalence of classic cardiovascular risk factors between SLE and RA. We also analysed the effect of traditional cardiovascular risk factors on the development of subclinical atherosclerosis in both conditions and if some disease-characteristic features are associated with these traditional cardiovascular risk factors. METHODS: This was a cross-sectional study encompassing 602 individuals, 276 SLE and 326 RA patients. Subclinical atherosclerosis (presence of carotid plaques and carotid intima-media thickness [cIMT]) was determined by carotid ultrasonography. A multivariable regression analysis was performed to evaluate whether classic cardiovascular-related risk factors differentially influence subclinical carotid atherosclerosis in SLE compared to RA patients. RESULTS: Age (interaction factor [if] p=0.000), hypertension (if p=0.034), and diabetes (if p=0.037) had a higher effect on cIMT in RA than in SLE subjects. However, these traditional cardiovascular factors did not yield different effects on the presence of carotid plaques in RA and SLE when the univariate interaction was analysed. In addition, no differences were found in the influence of hypertension, diabetes, dyslipidaemia or current smoking on cIMT or carotid plaque after adjusting for demographics, the presence of other traditional cardiovascular factors, and disease-related data. Moreover, the additive effect of several cardiovascular risk factors on the subclinical carotid atherosclerosis did not differ between the two diseases. CONCLUSIONS: The influence of traditional cardiovascular risk factors on cIMT and carotid plaque is similar in RA and SLE. Spanish Ministry of Health, Subdireccion General de Evaluacion y Fomento de la Investigacion, Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 Fondo Europeo de Desarrollo Regional - FEDER - (Fondo de Investigaciones Sanitarias) (FIS PI14/00394; PI17/00083) Fondo de Investigacion Sanitaria of the Instituto de Salud Carlos III (ISCIII, Health Ministry, Spain) (PI06/0024) 4.473 JCR (2020) Q2, Rheumatology 1.184 SJR (2020) Q2, 88/213 Immunology No data IDR 2020 UEC

Objectives: To identify patterns (clusters) of damage manifestation within a large cohort of juvenile SLE (jSLE) patients and evaluate their possible association with mortality. Methods: This is a multicentre, descriptive, cross-sectional study of a cohort of 345 jSLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestation were identified and compared. Results: Mean age (years) ± S.D. at diagnosis was 14.2 ± 2.89; 88.7% were female and 93.4% were Caucasian. Mean SLICC/ACR DI ± S.D. was 1.27 ± 1.63. A total of 12 (3.5%) patients died. Three damage clusters were identified: Cluster 1 (72.7% of patients) presented a lower number of individuals with damage (22.3% vs. 100% in Clusters 2 and 3, P < 0.001); Cluster 2 (14.5% of patients) was characterized by renal damage in 60% of patients, significantly more than Clusters 1 and 3 (P < 0.001), in addition to increased more ocular, cardiovascular and gonadal damage; Cluster 3 (12.7%) was the only group with musculoskeletal damage (100%), significantly higher than in Clusters 1 and 2 (P < 0.001). The overall mortality rate in Cluster 2 was 2.2 times higher than that in Cluster 3 and 5 times higher than that in Cluster 1 (P < 0.017 for both comparisons). Conclusions: In a large cohort of jSLE patients, renal and musculoskeletal damage manifestations were the two dominant forms of damage by which patients were sorted into clinically meaningful clusters. We found two clusters of jSLE with important clinical damage that were associated with higher rates of mortality, especially for the cluster of patients with predominant renal damage. Physicians should be particularly vigilant to the early prevention of damage in this subset of jSLE patients with kidney involvement.

Background/Purpose: Correct classification of patients with systemic lupus erythematosus (SLE) is critical for clinical trials and clinical and translational science. The ACR 1997 criteria were criticized for their suboptimal sensitivity. The Systemic Lupus International Cooperating Clinics (SLICC) 2012 criteria increased sensitivity, but at the price of reduced specificity. This and further advances in the field led to the current four phase SLE criteria project. Following an item generation phase and item reduction via a Delphi and a nominal group exercise (1), the provisional criteria were derived from a multicriteria decision analysis exercise (2). These criteria were hence simplified and validated in a large international cohort. Methods: A large international cohort of 2, 321 patients was collected from 23 SLE expert centers, contributing up to 100 patients with SLE and with non-SLE, each. Diagnoses were verified by 3 independent reviewers for 1, 193 SLE and 1, 059 non- SLE patients. 501 randomly selected SLE and 500 non-SLE patients formed the derivation cohort. All other patients with confirmed SLE or non-SLE diagnosis formed the validation cohort. Sensitivity and specificity were compared to the ACR 1997 and the SLICC 2012 criteria. Results: The criteria were fine-tuned and simplified, using ANA of ≥1:80 as entry criterion and a classification threshold of 10. Items can only be counted for classification if there is no more likely cause, and at least one clinical item must be present.

Background: The co-existence of autoimmunity and primary antibody deficiency in some individiuals is intriguing. The transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene (TNFRSF13B) has been implicated in both autoimmunity and primary antibody deficiency to varying extents in mice and humans. However, the phenotype described in mice with TNFRSF13B polymorphisms has not been entirely consistent with patients with similar orthologous polymorphisms.Objective: To further understand the relationship between TNFRSF13B variants and PAD and autoimmunity, we set out to determine the association of the two most common TNFRSF13B polymorphisms with autoimmunity and immunodeficiency, in patients with primary antibody deficiency and SLE.Method: We genotyped the C104R and A181E polymorphisms of TNFRSF13B in193 individuals and 144 controls from the Australian and New Zealand Antibody Deficiency Allele (ANZADA) Study, 107 patients from the Australian Point Mutation in Systemic Lupus Erythematosus (APOSLE) study, 169 patients with SLE from a European population, and 263 European controls. We were also able to determine TNFRSF13B genotypes for family members for nine of twelve pedigrees with primary antibody deficiency identified with TNFRSF13B variants.Results: The total number of TNFRSF13B variants in the primary antibody deficiency cohort was significantly higher than in the control group (p=0.0089; OR 9.481 [95% CI 1.218−73.81]). Similar results were obtained when patients with systemic lupus erythematosus were analysed. TNFRSF13B variants were strongly associated with SLE (p=0.0161, OR 3.316 [95% CI 1.245-8.836]). Familial analysis revealed incomplete penetrance of the TNFRSF13B variants.Conclusion: Taken together, the two most common TNFRSF13B variants are associated with primary antibody deficiency and systemic lupus erythematosus.