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.

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.

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.

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.

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.

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.

Beyond thrombosis: Anti-ß2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome.

Antibodies against ß2 glycoprotein I (anti-ß2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and conformation-dependent structure on ß2GPI domain (D) 1. Anti-ß2GPI domain profiling has been investigated in thrombotic APS, leading to the identification of antibodies targeting D1 as the main subpopulation. In contrast, scarce attention has been paid to obstetric APS, hence this study aimed at characterizing the domain reactivity with regards to pregnancy morbidity (PM). To this end, 135 women with persistently positive, medium/high titre anti-ß2GPI IgG, without any associated systemic autoimmune diseases and at least one previous pregnancy were included: 27 asymptomatic carriers; 53 women with obstetric APS; 20 women with thrombotic APS; and 35 women with both thrombotic and obstetric complications. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash® ß2GPI Domain 1 IgG and QUANTA Lite® ß2GPI D4/5 IgG, Inova Diagnostics). Positivity for anti-D1 antibodies, but not anti-D4/5 antibodies, was differently distributed across the 4 subgroups of patients (p < 0.0001) and significantly correlated with thrombosis (χ2 = 17.28, p < 0.0001) and PM (χ2 = 4.28, p = 0.039). Patients with triple positivity for anti-phospholipid antibodies displayed higher anti-D1 titres and lower anti-D4/5 titres compared to women with one or two positive tests (p < 0.0001 and p = 0.005, respectively). Reactivity against D1 was identified as a predictor for PM (OR 2.4, 95% confidence interval [CI] 1.2-5.0, p = 0.017); in particular, anti-D1 antibodies were predictive of late PM, conveying an odds ratio of 7.3 (95% CI 2.1-25.5, p = 0.022). Positivity for anti-D1 antibodies was not associated with early pregnancy loss. Anti-D4/5 antibodies were not associated with clinical APS manifestations. As a whole, our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positive anti-D4/5 antibodies are not predictive of thrombosis or PM.

Thrombosis and Anti-phospholipid Syndrome: a 5-Year Update on Treatment.

PURPOSE OF REVIEW: The aim of this review is to provide an update of the therapeutic tools for thrombotic anti-phospholipid syndrome (APS), focusing on the last 5 years. RECENT FINDINGS: Early studies appointed anticoagulation at moderate intensity as the mainstay of treatment of thrombotic APS; in the last 5 years, the strategy has not much mutated. Some uncertainties regarding the role of direct oral anticoagulants and the optimal regimen for arterial thrombotic APS still persist: high-intensity anticoagulation, anticoagulation plus anti-platelet agent, and double anti-platelet agents being the possible alternatives. Several drugs have been proposed as effective additional tools for the management of thrombotic APS: hydroxychloroquine, statins, vitamin D, and sirolimus might be beneficial when added on the top of anticoagulation. Pregnant women with thrombotic APS should be switched to low-dose aspirin plus low molecular weight heparin at therapeutic dose. Despite adequate treatment, APS patients display a significant rate of recurrences; rituximab, eculizumab, and intravenous immunoglobulins are among the options to be considered for these patients. From 2013 to date, the kaleidoscope of therapeutic options in thrombotic APS has been enriched, but tangible improvements in the management of patients are still awaited.

Does APS Impact Women's Fertility?

PURPOSE OF REVIEW: This review focuses on the relationship between anti-phospholipid antibodies (aPL) and female infertility by addressing three key questions: (i) how can aPL induce women's infertility?; (ii) are aPL more prevalent among infertile than fertile women?; (iii) do aPL-positive women display reduced fertility? RECENT FINDINGS: According to experimental data, aPL impair female fertility interfering with endometrial decidualization thus with implantation. Some aPL tests are more frequently detected among infertile women compared to controls; the association between aPL and assisted reproduction techniques outcome is not supported by most studies. Two reports suggest a decreased ovarian reserve among aPL-positive patients, while fertility is preserved in women with systemic lupus erythematosus, commonly associated with aPL positivity. Pregnancy rates drop after diagnosis and lupus women have fewer children than wished, due to many disease-related factors. While awaiting definitive conclusions on the relationship between aPL and infertility, rheumatologists should properly counsel female patients to safeguard fertility.

N-terminal pro Brain Natriuretic Peptide as predictor of outcome in scleroderma renal crisis.

OBJECTIVES: Although in scleroderma renal crisis (SRC) outcome has improved to a great extent with the introduction of ACE inhibitors, there remains significant mortality and morbidity with frequent requirement for renal replacement therapy. Therefore, novel biomarkers to identify patients at high risk of poor outcome would be valuable. The aim of this study was to assess the role of the N terminal fragment of pro Brain Natriuretic Peptide (N-TproBNP) as predictor of outcome in SRC. METHODS: 20 subjects with confirmed SRC were retrospectively enrolled. Clinical data, full blood count, creatinine, eGFR and N-TproBNP at presentation were collected. RESULTS: Patients requiring renal replacement therapy presented significantly higher levels of N-TproBNP and creatinine (p>0.01), lower eGFR (p<0.01) and haemoglobin levels (p=0.01) and shorter disease duration (p<0.01) compared to those who did not require dialysis. Whereas all the candidate variables significantly predicted renal outcome in univariate models, N-TproBNP was the only variable to hold significance in predicting renal outcome in a Firth's multivariate logistic regression model (p=0.05, OR 7.6). ROC curve of N-TproBNP to identify patients requiring renal replacement therapy provided a sensitivity of 88.9%, with a specificity of 81.8% at a cut-off value of 360 pmol/L (95% CI 0.84-1.00, area under the curve 0.94). In our cohort, this provided a positive predictive value of 80% and a negative predictive value of 90%. CONCLUSIONS: N-TproBNP peptide may be a useful biomarker in risk-stratification of renal outcome in SRC, selectively identifying patients likely to require renal replacement therapy.

Update on the pathogenesis and treatment of the antiphospholipid syndrome.

PURPOSE OF REVIEW: Many advancements in our understanding of the pathogenic mechanisms of the antiphospholipid syndrome (APS) have been accomplished over the recent months. Such progresses are paralleled by the development of innovative pharmacological tools that could provide novel therapeutic windows in APS management. The most recent and innovative findings about the biologic effects of antiphospholipid antibodies (aPLs) and the treatment APS will be hereby critically appraised. RECENT FINDINGS: Antibodies against the domain I of ß2 glycoprotein I (ß2GPI) are increasingly recognized as the main pathogenic subset; pioneer therapeutic options exploiting the pathogenicity of anti-domain I antibodies have been developed. AnnexinA2 and toll-like receptor (TLR)4 have been identified as the main receptors for ß2GPI/anti-ß2GPI antibodies on target cells; additional co-receptors might include TLR1, TLR2 and TLR6. Upon binding, aPLs engage intracellular mediators as nuclear factor kappa B and mammalian target of rapamycin, which provide potential therapeutic targets. Current innovative treatment options include novel oral anticoagulants and the complement inhibitor eculizumab. The addition to standard treatment of pleiotropic agents such as hydroxychloroquine, statins and vitamin D could allow better disease control. SUMMARY: The lively and intense research in the APS field opens new frontiers in aPL pathogenic mechanisms, as well as diagnosis and treatment of the syndrome. VIDEO ABSTRACT: http://links.lww.com/COR/A26.