Predictors of lack of response to methotrexate in juvenile idiopathic arthritis associated uveitis.

OBJECTIVES: To investigate clinical features associated with lack of response to MTX in juvenile idiopathic arthritis associated uveitis (JIA-U). METHODS: Clinical records of JIA-U patients were retrospectively reviewed. Differences among variables were assessed by Mann-Whitney and χ 2 or Fisher's exact tests as appropriate. Association between predictors and requirement of a biological disease modifying antirheumatic drug (bDMARD) was evaluated by univariate Cox regression analysis and Kaplan-Meier curves. A multivariable logistic model was applied to estimate strength of association, adjusting for potential confounders. RESULTS: Data from 99 JIA-U patients treated with MTX were analysed (82.8% female), with a mean follow up of 9.2 years and a mean age at uveitis onset of 5.7 years. In 65 patients (65.7%) at least one bDMARD to control uveitis was required. Children requiring a bDMARD for uveitis had lower age at JIA and uveitis onset, more frequent polyarticular course, higher frequency of bilateral uveitis at onset and higher prevalence of systemic steroids' use. Despite similar frequency of ocular damage at onset, MTX non responders showed a higher percentage of ocular damage at last visit. Younger age at JIA onset, polyarticular course and a history of systemic steroids' use resulted independent factors associated to lack of response to MTX at Cox regression analysis. Kaplan-Meier curves and the multivariate model confirms the independent role of both polyarticular course and systemic steroids' use. CONCLUSIONS: Younger age at JIA onset, polyarticular course and a history of systemic steroids' use are predictors of a worse response to MTX in JIA-U.

Belimumab-induced periungual pyogenic granulomas: A case report.

Pyogenic granuloma (PG) is a benign vascular neoformation, presenting as a painful red nodule on the skin, mucosa or nail apparatus. It is usually related to local complications such as bleedings and superinfections. The etiology of PG remains still unclear, and several triggers can lead to its formation. In case of multiple lesions, systemic conditions and drugs remain the main causes. Antineoplastic treatments, retinoids, antiretrovirals, hormones and anticonvulsants are frequently implicated in PG formation. In literature, PG has been rarely described in the course of biological treatment due to rheumatological disease. The present case report describes the development of polydactolous PGs in a 21-year-old woman with juvenile systemic lupus erythematosus (jSLE) during treatment with belimumab, a monoclonal antibody directed against BlyS. The clinical presentation, in particular the timing and the multiplicity of the lesions, and the improvement after belimumab discontinuation allowed us to consider PG as drug-induced. This case highlights the importance of considering PG as a potential complication of rheumatologic treatments.

JAK inhibitors in the treatment of adult patients with juvenile idiopathic arthritis: a retrospective monocentric experience.

OBJECTIVES: This study aims to evaluate the efficacy and safety of JAK inhibitors (JAKi) in a monocentric cohort of adult patients with juvenile idiopathic arthritis (JIA). METHODS: Patients attending a rheumatology transition clinic were retrospectively included in case of: i) JIA diagnosis according to current classification criteria (1); ii) age ≥18 years and iii) treatment with JAKi for at least 3 months. RESULTS: Seventeen adult patients with JIA were treated with JAKi (as first JAKi, 9 patients (52.9%) received tofacitinib and 8 (47.1%) baricitinib). At 3 months after JAKi initiation, 8 patients (47%) achieved a response and 4 patients (23.5%) achieved disease remission (3 patients with baricitinib and 1 with tofacitinib, 37.5% vs. 16.7%, p=0.294). None of those with systemic JIA and enthesitis-related arthritis obtained remission; the remission rate at 3 months was higher, although not significantly, in the oligoarticular subset compared to the polyarticular subset (37.5% vs. 20%). Patients with ≤1 active joint involvement at JAKi start had a higher remission rate (50% vs. 22.2%). Subjects who achieved remission on JAKi had a significantly lower pre-treatment DAS28-CRP compared to those with still active disease (p=0.010, Mann-Whitney U=4). A pre-treatment DAS28-CRP <3.76 predicted response to JAKi with 100% sensitivity and 84.6% specificity (p=0.023). The remission rate was lower among patients who had been treated with ≥2 biological drugs before JAKi start (9% vs. 66.7%; p=0.05). One patient in concomitant treatment with leflunomide developed severe arterial hypertension. CONCLUSIONS: JAKi may represent an effective and safe treatment option for adult JIA patients with low/moderate disease activity, particularly in case of oligoarticular involvement.

Fibroblasts and Endothelial Cells in Three-Dimensional Models: A New Tool for Addressing the Pathogenesis of Systemic Sclerosis as a Prototype of Fibrotic Vasculopathies.

Two-dimensional in vitro cultures have represented a milestone in biomedical and pharmacological research. However, they cannot replicate the architecture and interactions of in vivo tissues. Moreover, ethical issues regarding the use of animals have triggered strategies alternative to animal models. The development of three-dimensional (3D) models offers a relevant tool to investigate disease pathogenesis and treatment, modeling in vitro the in vivo environment. We aimed to develop a dynamic 3D in vitro model for culturing human endothelial cells (ECs) and skin fibroblasts, simulating the structure of the tissues mainly affected in systemic sclerosis (SSc), a prototypical autoimmune fibrotic vasculopathy. Dermal fibroblasts and umbilical vein ECs grown in scaffold or hydrogel, respectively, were housed in bioreactors under flow. Fibroblasts formed a tissue-like texture with the deposition of a new extracellular matrix (ECM) and ECs assembled tube-shaped structures with cell polarization. The fine-tuned dynamic modular system allowing 3D fibroblast/EC culture connection represents a valuable model of the in vivo interplay between the main players in fibrotic vasculopathy as SSc. This model can lead to a more accurate study of the disease's pathogenesis, avoiding the use of animals, and to the development of novel therapies, possibly resulting in improved patient management.

Anti-SARS-CoV-2 vaccination in adolescent and adult patients with juvenile-onset systemic lupus erythematosus: tolerability and impact on disease activity.

OBJECTIVES: JSLE has a severe presentation and a remitting course. Patients with JSLE carry an increased vulnerability to infections, which also act as triggers of disease flare. Thus, vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important tool in JSLE. The objective of this study is to evaluate the tolerability and the safety of anti-SARS-CoV-2 vaccination, including the booster, in a monocentric cohort of JSLE patients. METHODS: Clinical records of JSLE patients who received at least one dose of any anti-SARS-CoV-2 vaccine were retrospectively reviewed. Data about disease activity, treatment, anti-SARS-CoV-2 vaccination and COVID-19 infection were collected. RESULTS: Sixty-five JSLE patients received at least one dose of anti-SARS-CoV-2 vaccination, while 46 patients completed the schedule with the booster. The rate of mild-moderate adverse events was 66%, mainly comprising fever, fatigue, arthromyalgias and pain at injection site. The rate of adverse events after the booster was similar to that registered after the first two doses. No significant changes after SARS-CoV-2 vaccination in BILAG and SLEDAI were observed. Disease flare rate (mainly LN) after immunization was 10.8%. Flares occurred predominantly in patients with moderate disease activity before immunization; accordingly, SLEDAI ≥4 identified patients at risk of flare while Lupus Low Disease Activity State (LLDAS) plays a protective role against post-vaccination flare. CONCLUSIONS: This study confirms that anti-SARS-CoV-2 vaccination in JSLE is well tolerated; a strict clinical monitoring and a thoughtful choice of vaccination timing should be devoted to patients not in LLDAS due to the risk of post-vaccine flare.

16th International congress on antiphospholipid antibodies task force report on antiphospholipid syndrome laboratory diagnostics and trends.

Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-ß2 glycoprotein I (anti-ß2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of ß2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of ß2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16th International Congress on aPL, Manchester, UK, September 2019.

Insights into the clinical presentation of juvenile systemic lupus erythematosus: the PRAGMA monocentric cohort of 177 patients.

OBJECTIVES: The aim of this work is to describe the clinical manifestations at onset and during follow-up in a monocentric cohort of patients with juvenile systemic lupus erythematosus (jSLE) from the Paediatric Rheumatology group of the Milan area (PRAGMA). METHODS: Patients were retrospectively included in case of i) SLE diagnosis according to the 1997 American College of Rheumatology or the 2012 SLICC classification criteria and ii) disease onset before 18 years. RESULTS: Among the 177 recruited patients (155 females), haematologic involvement was the most common disease manifestation (75%), followed by joint and cutaneous involvements (70% and 57%, respectively). Renal disease was observed in 58 patients (32.8%), neurological complications in 26 cases (14.7%). Patients presented most commonly 3 clinical manifestations (32.8%), while 2 organ involvements were identified in 54 patients (30.5%) and 4 in 25 subjects (14.1%). The 49 patients with disease onset <10 years had less commonly articular involvement (p=0.02), while patients aged >14.8 years displayed less neurological manifestations (p=0.02). At a median follow-up of 118 month, the disease progressed in 93 patients, with a median of 2 new manifestations per patient. Low complement at diagnosis predicted new clinical manifestations (p=0.013 for C3 and p=0.0004 for C4). The median SLEDAI at diagnosis was 13; SLEDAI was substantially similar at 6 months, decreased at 12 months to remain stable at 18 months and further reduce at 24 months (p<0.0001). CONCLUSIONS: These data from a large jSLE monocentric cohort allow gaining further insights into a rare disease with a still high morbidity burden.

Anti-SSA/Ro positivity and congenital heart block: obstetric and foetal outcome in a cohort of anti-SSA/Ro positive pregnant patients with and without autoimmune diseases.

OBJECTIVES: Neonatal lupus (NL) is an acquired disease caused by the transplacental passage of anti-SSA/Ro antibodies. The rate of congenital heart block (CHB), its most serious manifestation, ranges from 1 to 5%. The aim of this study was to retrospectively assess the prevalence of CHB in anti-SSA/Ro positive pregnant women with or without systemic autoimmune diseases from 2010 to 2020. METHODS: Patients underwent monthly visit and a shared follow-up programme of weekly (16th-24th week) foetal heart rate assessment by obstetric ultrasound. RESULTS: 322 pregnancies in 258 anti-SSA/Ro patients were included; 314 were followed from the beginning of pregnancy because of the known presence of anti-SSA/Ro autoantibodies and 1 case of CHB occurred in an anti-SSA/Ro+ asymptomatic subject (0.3%). In the same period, 8 additional patients were referred to our clinics after in utero CHB diagnosis and subsequent discovery of anti-SSA/Ro without a disease diagnosis. Globally, 9 cases of congenital CHB (2.8%) occurred: 7 complete, 1 II-III degree and 1 rst degree CHB. Anti-SSB/La positivity was associated with a higher risk of CHB (7.8% vs. 1.2%; p=0.0071). No differences in maternal or foetal outcomes were found in comparison with a large cohort of unselected pregnancies except for caesarian section. Hydroxychloroquine (HCQ) was used in 58.3% pregnancies, with a different prevalence according with maternal diagnosis. CONCLUSIONS: Our data suggest that anti-SSA/Ro positive patents with a de ned systemic autoimmune disease undergoing a strict follow-up since positive pregnancy test display a low risk of pregnancy complications, including but not limited to NL.

Increased COVID-19 mortality in patients with rheumatic diseases: results from the CONTROL-19 study by the Italian Society for Rheumatology.

OBJECTIVES: To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy. METHODS: We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results. RESULTS: We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29-4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55-2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs. CONCLUSIONS: Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases.

EUREKA algorithm predicts obstetric risk and response to treatment in women with different subsets of anti-phospholipid antibodies.

OBJECTIVES: aPL, the serum biomarkers of APS, are the most common acquired causes of pregnancy morbidity (PM). This study investigates the impact of aPL positivity fulfilling classification criteria ('criteria aPL') and at titres lower than thresholds considered by classification criteria ('low-titre aPL') on PM and assesses the effectiveness of low-dose aspirin (LDASA), low molecular weight heparin (LMWH) and HCQ in reducing the probability of PM (PPM). METHODS: Longitudinal data on 847 pregnancies in 155 women with persistent aPL at any titre and 226 women with autoimmune diseases and negative aPL were retrospectively collected. A generalized estimating equations model for repeated measures was applied to quantify PPM under different clinical situations. RESULTS: EUREKA is a novel algorithm that accurately predicts the risk of aPL-associated PM by considering aPL titres and profiles. aPL significantly impact PPM when at low titres and when fulfilling classification criteria. PPM was further stratified upon the aPL tests: aCL IgG/IgM and anti-ß2-glycoprotein I (ß2GPI) IgM, alone or combined, do not affect the basal risks of PPM, an increase occurs in case of positive LA or anti-ß2GPI IgG. LDASA significantly affects PPM exclusively in women with low-titre aPL without anti-ß2GPI IgG. The LDASA + LMWH combination significantly reduces PPM in all women with low-titre aPL and women with criteria aPL, except those carrying LA and anti-ß2GPI IgG. In this group, the addition of HCQ further reduces PPM, although not significantly. CONCLUSION: EUREKA allows a tailored therapeutic approach, impacting everyday clinical management of aPL-positive pregnant women.

Psychosocial burden in young patients with primary anti-phospholipid syndrome: an Italian nationwide survey (The AQUEOUS study).

OBJECTIVES: The AQUEOUS (Anti-phospholipid syndrome: a QUEstionnaire for yOUng patientS) study aimed to assess how the diagnosis of primary anti-phospholipid syndrome (PAPS) affects the psychosocial status of young patients. METHODS: Subjects with PAPS aged 18-45 years were invited to compile an ad hoc designed questionnaire and the Short Form-12 to assess quality of life (QoL). RESULTS: Ninety-two patients (83.7% females) were recruited in 10 Italian centres. Vascular and obstetric manifestations were equally represented. Nearly half of the patients perceived the need for psychological support, 89.2% when considering women after pregnancy complications. Social activities and working efficiency were reduced in APS patients, also intimacy was threatened. In all cases, fatigue appeared to be the main determinant. PAPS affected family planning, due to fears of treatment side-effects, disease hereditariness, inability to care for the newborn child. Fertility appeared to be conserved: the median time to pregnancy was 2 months; assisted reproduction techniques were pursued by 5 women. Our survey documented significantly lower rates of hospitalisation and learning disabilities in 51 children born after APS diagnosis as compared to 48 children born before. PAPS patients displayed lower QoL in physical and, to a greater extent, mental scores compared to the general Italian population. Both components were significantly lower in women and in patients with fatigue. CONCLUSIONS: The AQUEOUS study assessed for the first time the unmet needs of young PAPS patients, enabling the development of a future "youth-focused" strategy to reduce disease burden.

Pediatric Antiphospholipid Syndrome: from Pathogenesis to Clinical Management.

PURPOSE OF REVIEW: Elucidating the pathogenic mechanisms mediated by antiphospholipid antibodies (aPL) might exert important clinical implications in pediatric antiphospholipid syndrome (APS). RECENT FINDINGS: aPL are traditionally regarded as the main pathogenic players in APS, inducing thrombosis via the interaction with fluid-phase and cellular components of coagulation. Recent APS research has focused on the role of ß2 glycoprotein I, which bridges innate immunity and coagulation. In pediatric populations, aPL should be screened in appropriate clinical settings, such as thrombosis, multiple-organ dysfunction, or concomitant systemic autoimmune diseases. Children positive for aPL tests often present non-thrombotic non-criteria manifestations or asymptomatic aPL positivity. In utero aPL exposure has been suggested to result in developmental disabilities, warranting long-term follow-up. The knowledge of the multifaceted nature of pediatric APS should be implemented to reduce the risk of underdiagnosing/undertreating this condition. Hopefully, recent pathogenic insights will open new windows of opportunity in the management of pediatric APS.

Bleeding and antithrombotic therapy during pregnancy in women with poor aPL-related obstetric outcomes: A survey of 1075 cases from EUROAPS registry∗.

BACKGROUND: The combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) until the end of gestation are the currently the accepted standard of care for the treatment of antiphospholipid-related obstetric disorders. In refractory cases, hydroxychloroquine (HCQ) can be added to this standard of care. OBJECTIVE: To evaluate the haemostatic safety of LDA and LMWH (medium to high prophylactic doses) during pregnancy and the puerperium in women with both full-blown obstetric antiphospholipid syndrome (OAPS) (Sydney criteria) and noncriteria - incomplete - OAPS. STUDY DESIGN: Retrospective/prospective multicentre observational study. Obstetric background, laboratory categories, delivery mode, antithrombotic regimens and bleeding complications were compared. SETTING: A total of 30 tertiary European hospitals. PATIENTS: Mainly, Caucasian/Arian pregnant women were included. Other ethnicities were minimally present. Women were controlled throughout pregnancy and puerperium. MAIN OUTCOME MEASURES: The primary end-point was to evaluate the number of major and minor haemorrhagic complications in this cohort of women. Neuraxial anaesthetic bleeding complications were particularly assessed. Secondly, we aimed to compare local/general bleeding events between groups. RESULTS: We studied 1650 women, of whom 1000 fulfilled the Sydney criteria of the OAPS and 650 did not (noncriteria OAPS). Data on antithrombotic-related complications were available in 1075 cases (65.15%). Overall, 53 (4.93%) women had bleeding complications, with 34 being considered minor (3.16%) and 19 major (1.76%). Neither obstetric complications nor laboratory categories were bleeding-related. Assisted vaginal delivery and caesarean section were related to local haemorrhage. Heparin doses and platelet count were not associated with major bleeding. CONCLUSIONS: LDA and medium to high prophylactic LMWH during pregnancy in women with full-blown OAPS/noncriteria OAPS are safe. A slight increase in bleeding risk was noted in instrumental deliveries. No women who underwent spinal or epidural anaesthesia suffered bleeding complications. No haemorrhage was observed in cases where HCQ was added to standard therapy.

Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry.

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.

16th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome.

Obstetric antiphospholipid syndrome (APS) remains a clinical challenge for practitioners, with several controversial points that have not been answered so far. This Obstetric APS Task Force met on the 16th International Congress on Antiphospholipid Antibodies in Manchester, England, to discuss about treatment, diagnostic and clinical aspects of the disease. This report will address evidence-based medicine related to obstetric APS, including limitations on our current management, the relationship between antibodies against domain 1 of ß2GPI and obstetric morbidity, hydroxychloroquine use in patients with obstetric APS and factors associated with thrombosis after obstetric APS. Finally, future directions for better understanding this complex condition are also reported by the Task Force coordinators.

COVID-19 in rheumatic diseases in Italy: first results from the Italian registry of the Italian Society for Rheumatology (CONTROL-19).

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments.

Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO. METHODS: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected. RESULTS: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries. CONCLUSIONS: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Lung Disease in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an acquired prothrombotic condition characterized by vascular thrombosis and/or obstetric complications, in the persistent positivity of circulating antiphospholipid antibodies (aPLs). The clinical spectrum of manifestations associated with aPL positivity is progressively expanding, including the description of several lung manifestations. The most common pulmonary involvement related to aPL positivity is pulmonary embolism (PE), which has been reported to occur in 14.1% of APS patients during disease course. PE acknowledges a purely thrombotic etiology and thus might be accounted as a criterion for APS, making imperative to test aPL in young subjects with unprovoked PE. Pulmonary hypertension (PH) can manifest in APS patients, being the second most common lung complication of the syndrome, with a prevalence ranging between 1.8 and 3.5%. aPL-positive patients might present PH following a PE, might develop pulmonary arterial hypertension associated with connective tissue disease, or might present pulmonary venous hypertension due to Libman-Sacks endocarditis. Additional lung manifestations, such as diffuse alveolar hemorrhage, acute respiratory distress syndrome, and pulmonary fibrosis, are rarely described in APS patients; it is still not clear whether in these settings aPLs exert a pathogenic role or is a mere epiphenomenon. Hereby we discuss impact, clinical presentation, histopathologic findings, etiology, and treatment of each aPL-associated lung manifestation.

Management of Thrombotic Antiphospholipid Syndrome.

Persistent serum positivity for antiphospholipid antibodies (aPL) is required to diagnose antiphospholipid syndrome (APS), an autoimmune disease characterized by recurrent vascular thrombosis and/or pregnancy morbidity. The current therapeutic management of patients with thrombotic APS aims at preventing recurrences and long-term complications by attenuating the procoagulant state. There is overall consensus to reserve moderate-intensity anticoagulation to aPL-positive patients with a previous venous thrombosis; the therapeutic options for those with a history of arterial event comprise antiplatelet agents and high-intensity anticoagulation. Unfortunately, thrombotic occurrences might occur despite adequate anticoagulation, carrying a significant burden of morbidity and mortality. The management of refractory thrombotic APS and catastrophic APS is still not clear, warranting the issue of recommendations. Vitamin-K antagonists are limited by significant side effects, and a careful weighting of risks and benefits should be performed to reserve the optimal treatment to each patient. To overcome these limitations, novel oral anticoagulants have been introduced in the market, but their efficacy in thrombotic APS has still to be unraveled. The poor safety profile and the scarce efficacy of drugs acting on the coagulation cascade explain why novel therapeutic approaches are currently under investigation, to identify pharmacological tools specifically counteracting aPL-mediated prothrombotic effects.

The treatment of anti-phospholipid syndrome: A comprehensive clinical approach.

Anti-phospholipid syndrome (APS) is an acquired pro-thrombotic autoimmune disease that predisposes to thrombotic events and/or obstetric complications, in the persistent presence of anti-phospholipid antibodies (aPL). Life long moderate-intensity anticoagulation is the option of choice for aPL-positive patients with a previous thrombosis; critical issues concern the management of those with a history of arterial event due to the high rate of recurrence. Alternatives comprise anti-platelet agents and high-intensity anticoagulation. Low dose aspirin (LDASA) and low molecular weight heparin provide the mainstay of the treatment of obstetric APS, allowing a birth rate in 70% of cases. The management of refractory APS, thrombotic as well as obstetric, is highly debated, but an increasing burden of evidence points towards the beneficial effects of multiple treatments. Similarly, a management envisaging multiple drugs (anticoagulation, steroids, plasma exchange and/or intravenous immunoglobulins) is the most effective approach in catastrophic APS. Asymptomatic aPL carriers are at higher risk of thrombotic and obstetric complications compared to the general population, thus potentially benefitting of a pharmacological intervention. LDASA and hydroxychloroquine can be considered as options, in particular in case of high risk aPL profile, concomitant cardiovascular risk factors or associated autoimmune disease. APS is apparently a simple condition, but its multifaceted nature requires a complex and tailored treatment.