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Objective. SLE has a great clinical heterogeneity and low prevalence, thus making the development of recommendations or clinical practice guidelines (CPG) based on high-quality evidence difficult. In the last few years, several CPG appeared addressing the management of the disease. The aim of this review is to critically compare the recommendations made in the most recent CPG and to analyse and compare their methodological quality. Methods. The Appraisal of Guidelines for Research and Evaluation (AGREE) II tool was used to compare the methodological quality of each of the CPG. Results. Most CPG agreed in the general management and first-line treatment recommendations where there is higher quality evidence and disagreed in refractory disease treatment where there is lack of quality evidence. Also, the CPG are agreed in whether a patient should be treated regarding the most severe clinical manifestation or taking into account the treatment that best serves all clinical manifestations. The majority of the appraised CPG scored high-quality ratings, especially for scope and purpose and clarity of presentation, while they were of less quality when assessing applicability of each CPG. Conclusion. CPG should aid, but not replace, the health professional's clinical judgment in daily clinical patient management.

Objectives. To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS). Methods. This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome. Results. A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C). Conclusion. Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients.

Objective: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. Methods: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. Results: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. Conclusions: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches. © The Author(s) 2020.

Background To compare the patients’ and physician’s global assessment of disease activity in Behçet’s syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance. Methods A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6–55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet’s syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients’ (PtGA) and physician’s global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA Results Median PtGA and PGA scores were 2.0 (0.3–5.0) and 1.0 (0.0–3.0) cm, respectively. The discordance prevalence varied (from 29.6 to 55.3%) according to the cutoff applied, and the majority (> 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0–2) and 0 (0–1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93–0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93–0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48–23.30, p = 0.012). Conclusions PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient’s health that negatively affect his well-being and the treatment.

Objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. Methods Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. Results The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to

Background: EULAR/ACR 2019 SLE Classification Criteria were validated in an international cohort. Objectives: To evaluate performance characteristics of SLE classification systems in sex, race/ethnicity, and disease duration subsets. Methods: Sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated in the validation cohort. Results: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients ; and patients with an SLE duration of 1-3 years (n=196), 3-5 years (n=157), and ≥5 years (n=879). Among patients with 1-3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% (95%CI 92-99%) vs 81% (95%CI 72-88%). The new criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). The new criteria had better sensitivity than the ACR criteria in White (95% vs 83%), Hispanic (100% vs 86%) and Asian patients (97% vs 77%). Conclusion: The EULAR/ACR 2019 criteria perform well in patients with early disease, and across sexes and ethnicities.

Management for patients with antiphospholipid syndrome (APS) and arterial thrombosis is controversial. There are no prospective data demonstrating the superiority of high- or moderate-intensity anticoagulation with vitamin K antagonists over antiplatelet agents. Using 2 antiphospholipid antibody databases (single center [New York Presbyterian Hospital] and multicenter [Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking]), we retrospectively collected demographic and clinical data of patients with APS and arterial thrombosis. The primary outcome was recurrent thrombosis rate after initial arterial thrombosis in patients with APS treated with antiplatelet and/or anticoagulant therapy. We identified 139 patients with a median follow-up time of 4.24 years after initial thrombosis. Thirty-seven patients (27.3%) received anticoagulants, 43 (30.9%) antiplatelets, and 58 (41.7%) combined therapy. Sixteen patients (37.2%) in the antiplatelet group, 9 (23.7%) in the anticoagulant group, and 4 (6.9%) in the combined therapy group experienced recurrent thrombosis. We estimate that 20% of patients will experience a recurrence by 3.4, 7.3, and 16.3 years, respectively, depending on assignment to antiplatelet, anticoagulant, or combined therapy. These results suggest that combined therapy decreases the rate of and increases the time to thrombosis recurrence in patients with APS presenting with arterial thrombosis.

Objective: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. Design: Retrospective study. Setting: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. Population: Women with Ob-APS. Methods: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). Main outcome measures: Risk factors for thrombosis and aGAPSS. Results: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4–16) versus 9 (4–13); P = 0.0089]. Conclusion: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. Tweetable abstract: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity. © 2018 Royal College of Obstetricians and Gynaecologists

The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research. © © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Objective To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. Results The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. Conclusion These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments. © 2018

Aim: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). Methods: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. Results: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in IIa, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). Conclusion: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.

Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion. © 2019 Author(s).

Objective. Given the complexity and heterogeneity of systemic lupus erythematosus (SLE), high-performing classification criteria are critical to advancing research and clinical care. A collaborative effort by the European League Against Rheumatism and the American College of Rheumatology was undertaken to generate candidate criteria, and then to reduce them to a smaller set. The objective of the current study was to select a set of criteria that maximizes the likelihood of accurate classification of SLE, particularly early disease. Methods. An independent panel of international SLE experts and the SLE classification criteria steering committee (conducting SLE research in Canada, Mexico, United States, Austria, Germany, Greece, France, Italy, and Spain) ranked 43 candidate criteria. A consensus meeting using nominal group technique (NGT) was conducted to reduce the list of criteria for consideration. Results. The expert panel NGT exercise reduced the candidate criteria for SLE classification from 43 to 21. The panel distinguished potential "entry criteria," which would be required for classification, from potential "additive criteria." Potential entry criteria were antinuclear antibody (ANA) = 1:80 (HEp-2 immunofluorescence), and low C3 and/or low C4. The use of low complement as an entry criterion was considered potentially useful in cases with negative ANA. Potential additive criteria included lupus nephritis by renal biopsy, autoantibodies, cytopenias, acute and chronic cutaneous lupus, alopecia, arthritis, serositis, oral mucosal lesions, central nervous system manifestations, and fever. Conclusion. The NGT exercise resulted in 21 candidate SLE classification criteria. The next phases of SLE classification criteria development will require refinement of criteria definitions, evaluation of the ability to cluster criteria into domains, and evaluation of weighting of criteria. Copyright © 2019. All rights reserved.

Background: Immune-mediated inflammatory diseases (IMID) are chronic and highly disabling diseases that share inflammatory sequences and immtutological dysregulations. Considered as a disease in itself; the prevalence of IMID is virtually unknown. The aim of this study was to assess the prevalence of 10 selected UDI, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondvlitis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, hictiadenitis suppurative, sarcoidosis and uveitis in Spain. Methods: A cross-sectional epidemiological study of point prevalence was made. Thu study was carried out through a series of computerized interviews in households chosen at random in 17 autonomous commurities in Spain. A structured questionnaire was used to determine the frequency of diagnosis and the concurrence of 10 IMID in the respondents and other individuals belonging to the same family nucleus. The point prevalence estimates were used and compared with the objective of determining the frequency of IMID by age, sex and communities. The data were processed using Excel 2016 (Microsoft, Redmond, WA, USA) and the SPSS V.019 system (IBM Corp. Armonk, NY, USA) for statistical analysis using the usual statistical tests in this type of studies. Results: Of the 7,980 respondents, 510 were diagnosed with an IMID, representing a cross-sectional study of 6.39% (95% CI: 6.02-6.76). One, two, three or more members of the family were affected in 87.2%, 7.8% and 5% of positive relatives in IMID, respectively. The most recurrent diseases were psoriasis (2.69% [95% CI: 2.32-3.06]) and rheumatic arthritis (1.07% [95% CI: 0.70-1.44]). There were differences in prevalence due to sex (p = 0.004) and age (p = 0.000). No significant difference: were identified related to geo-graphic location (p = 0.819). Attendance of at least 2 IMID was reported in 8.9% of respondents. Conclusions: The overall prevalence was of the IMID studied was 634%, psoriasis being the most frequent with 2.69%. This study constitutes an initial step to consider IMID as an independent disease within the health system..

Aim: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). Methods: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. Results: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in Era, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). Conclusion: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.

Background: Variability remains a challenge in lupus anticoagulant (LA) testing. Objective: To validate LA test performance between Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Core laboratories and examine agreement in LA status between Core and local/hospital laboratories contributing patients to this prospective registry. Methods: Five Core laboratories used the same reagents, analyzer type, protocols, and characterized samples for LA validation. Non-anticoagulated registry samples were retested at the corresponding regional Core laboratories and anticoagulated samples at a single Core laboratory. Categorical agreement and discrepancies in LA status between Core and local/hospital laboratories were analyzed. Results: Clotting times for the reference/characterized plasmas used for normalized ratios were similar between Core laboratories (CV