Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study.

OBJECTIVES: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. METHODS: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. RESULTS: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. CONCLUSIONS: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

A critical view on autoantibodies in lupus nephritis: Concrete knowledge based on evidence.

Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.

Pregnancy in antiphospholipid syndrome: what should a rheumatologist know?

This review focuses on the management of reproductive issues in women who have antiphospholipid syndrome (APS) or are carriers of antiphospholipid antibodies (aPL). The importance of aPL detection during preconception counselling relies on their pathogenic potential for placental insufficiency and related obstetric complications. The risk of adverse pregnancy outcomes can be minimized by individualized risk stratification and tailored treatment aimed at preventing placental insufficiency. Combination therapy of low-dose acetylsalicylic acid and heparin is the mainstay of prophylaxis during pregnancy; immunomodulation, especially with hydroxychloroquine, should be considered in refractory cases. Supplementary ultrasound surveillance is useful to detect fetal growth restriction and correctly tailor the time of delivery. The individual aPL profile must be considered in the stratification of thrombotic risk, such as during assisted reproduction techniques requiring hormonal ovarian stimulation or during the follow-up after pregnancy in order to prevent the first vascular event.

Therapeutic Strategies and Outcomes in Neuropsychiatric Systemic Lupus Erythematosus: An International Multicenter Retrospective Study.

OBJECTIVES: The management of neuropsychiatric systemic lupus erythematosus (NPSLE) poses considerable challenges due to limited clinical trials. Therapeutic decisions are customized based on suspected pathogenic mechanisms and symptom severity. This study aimed to investigate therapeutic strategies and disease outcome for patients with NPSLE experiencing their first neuropsychiatric (NP) manifestation. METHODS: This retrospective cohort study defined NP events according to the American College of Rheumatology case definition, categorizing them into three clusters: central/diffuse, central/focal and peripheral. Clinical judgment and a validated attribution algorithm were used for NP event attribution. Data included demographic variables, SLE disease activity index, cumulative organ damage, and NP manifestation treatments. The clinical outcome of all NP events was determined by a physician seven-point Likert scale. Predictors of clinical improvement/resolution were investigated in a multivariable logistic regression analysis. RESULTS: The analysis included 350 events. Immunosuppressants and corticosteroids were more frequently initiated/escalated for SLE-attributed central diffuse or focal NP manifestations. At 12 months of follow-up, 64% of patients showed a clinical improvement in NP manifestations. Focal central events and SLE-attributed manifestations correlated with higher rates of clinical improvement. Patients with NP manifestations attributed to SLE according to clinical judgment and treated with immunosuppressants had a significantly higher probability of achieving clinical response (OR 2.55, 95%CI 1.06-6.41, p= 0.04). Age at diagnosis and focal central events emerged as additional response predictors. CONCLUSION: NP manifestations attributed to SLE by clinical judgment and treated with immunosuppressants demonstrated improved 12-month outcomes. This underscores the importance of accurate attribution and timely diagnosis of NPSLE.

What is the best instrument to measure disease activity in SLE? - SLE-DAS vs Easy BILAG.

Systemic lupus erythematosus (SLE) is a heterogeneous condition making assessment of disease activity challenging. However, thorough assessment is essential to evaluate patients longitudinally, to guide therapeutic decisions, and for clinical trials. Currently, the most popular disease activity index in clinical practice and trials is SLEDAI-2K. Its main advantage is ease of use, but significant weaknesses of SLEDAI-2K are omission of several serious manifestations, inability to capture change within an organ system, and fixed severity weightings that are often inappropriate. Recently several groups have developing improved tools. We report here the debate held at CORA meeting on this issue. SLE-DAS includes 17 weighted clinical and laboratory parameters including continuous measures in 4 items with an online calculator. A higher sensitivity to change compared to SLEDAI-2K has been demonstrated in its validation studies. Easy BILAG is an improved format of the BILAG-2004 that retains its content but greatly simplified. Its scoring using a single-page form that incorporates concise definitions for key terms next to clinical items. Easy-BILAG demonstrates higher accuracy and less variability and increased and better user feedback compared to the standard BILAG-2004 format. Both the indices discussed at CORA showed an advantage in measuring disease activity compared to SLEDAI.

Frequency Evaluation of the Interleukin-6 -174G>C Polymorphism and Homeostatic Iron Regulator (HFE) Mutations as Disease Modifiers in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

Autoimmune polyglandular syndrome type 4: experience from a single reference center.

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure.

COVID-19 prognosis in systemic lupus erythematosus compared with rheumatoid arthritis and spondyloarthritis: results from the CONTROL-19 Study by the Italian Society for Rheumatology.

INTRODUCTION: Data concerning SARS-CoV-2 in patients affected by SLE are contradicting.The aim of this study was to investigate disease-related differences in COVID-19 prognosis of patients affected by rheumatic diseases before vaccination; we tested the hypothesis that patients with SLE may have a different outcome compared with those with rheumatoid arthritis (RA) or spondyloarthritis (SPA). METHODS: We analysed data from the national CONTROL-19 Database with a retrospective, observational design, including rheumatic patients affected by COVID-19. The principal outcome measure was hospitalisation with death or mechanical ventilation. Differences between SLE, RA and SPA were analysed by univariable and multivariable logistic regression models. RESULTS: We included 103 patients with SLE (88.2% female, mean age 48.9 years, 50.4% active disease), 524 patients with RA (74.4% female, mean age 60.6 years, 59.7% active disease) and 486 patients with SPA (58.1% female, mean age 53.2 years, 58% active disease).Outcome prevalence was not different between patients with SLE and those with RA (SLE 24.5%, RA 25.6%), while patients with SPA showed a more favourable outcome compared with those with SLE (SPA 15.9%); data from the multivariable analysis confirmed this result.In SLE, age >65 years (OR 17.3, CI 5.51 to 63.16, p<0.001), hypertension (OR 6.2, CI 2.37 to 17.04, p<0.001) and prednisone (PDN) use (OR 3.8, CI 1.43 to 11.39, p=0.01) were associated with severe outcomes, whereas hydroxychloroquine use was found to be protective (OR 0.3, CI 0.14 to 0.91, p=0.03). CONCLUSION: Our data suggest that patients with SLE and RA do not show a different COVID-19 outcome, while patients with SPA have a more favourable disease course compared with those with SLE. Risk of hospitalisation with ventilation or death was associated with age >65 years, hypertension and PDN use in patients with SLE.

Efficacy of COVID-19 mRNA vaccination in patients with autoimmune disorders: humoral and cellular immune response.

BACKGROUND: The impact of immunosuppressive therapies on the efficacy of vaccines to SARS-CoV-2 is not completely clarified. We analyzed humoral and T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID). PATIENTS: We enrolled 38 patients and 11 healthy sex- and age-matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab, and 10 with tocilizumab. METHODS: Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4 and CD4-CD8 T cell-mediated immune response was analyzed by interferon-γ (IFN-γ) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (MCP-1, CXCL8, and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ, and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. Cluster analysis identified cluster 1, namely the "high immunosuppression" cluster, and cluster 2, namely the "low immunosuppression" cluster. RESULTS: After the second dose of vaccine, only abatacept-treated patients, compared to HC, showed a reduced anti-spike antibody response (mean: 432 IU/ml ± 562 vs mean: 1479 IU/ml ± 1051: p = 0.0034), and an impaired T cell response, compared with HC. In particular, we found a significantly reduced release of IFN-γ from CD4 and CD4-CD8 stimulated T cells, compared with HC (p = 0.0016 and p = 0.0078, respectively), reduced production of CXCL10 and CXCL9 from stimulated CD4 (p = 0.0048 and p = 0.001) and CD4-CD8 T cells (p = 0.0079 and p = 0.0006). Multivariable General Linear Model analysis confirmed a relationship between abatacept exposure and impaired production of CXCL9, CXCL10, and IFN-γ from stimulated T cells. Cluster analysis confirms that cluster 1 (including abatacept and half of rituximab treated cases) showed a reduced IFN-γ response, as well as reduced monocyte-derived chemokines All groups of patients demonstrated the ability to generate specific CD4 T activated cells after spike proteins stimulation. After the third dose of vaccine, abatacept-treated patients acquired the ability to produce a strong antibody response, showing an anti-S titer significantly higher compared to that obtained after the second dose (p = 0.0047), and comparable with the anti-S titer of the other groups. CONCLUSIONS: Patients treated with abatacept showed an impaired humoral immune response to two doses of COVID-19 vaccine. The third vaccine dose has been demonstrated to be useful to induce a more robust antibody response to balance an impaired T cell-mediated one. All patients, exposed to different immunosuppressive drugs, were able to produce specific CD4-activated T cells, after spike proteins stimulation. TRIAL REGISTRATION: Local Ethical Committee NP4187.

Early and Late Response and Glucocorticoid-Sparing Effect of Belimumab in Patients with Systemic Lupus Erythematosus with Joint and Skin Manifestations: Results from the Belimumab in Real Life Setting Study-Joint and Skin (BeRLiSS-JS).

AIM: To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. METHODS: All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (<2.6) and LDA (≥2.6, ≤3.2), CLASI = 0, 1, and improvement in DAS28 and CLASI indices ≥20%, ≥50%, and ≥70% were evaluated at 6, 12, 24, and 36 months. RESULTS: DAS28 < 2.6 was achieved by 46%, 57%, and 71% of patients at 6, 12, and 24 months, respectively. CLASI = 0 was achieved by 36%, 48%, and 62% of patients at 6, 12, and 24 months, respectively. Belimumab showed a glucocorticoid-sparing effect, being glucocorticoid-free at 8.5%, 15.4%, 25.6%, and 31.6% of patients at 6, 12, 24, and 36 months, respectively. Patients achieving DAS-LDA and CLASI-50 at 6 months had a higher probability of remission at 12 months compared with those who did not (p = 0.034 and p = 0.028, respectively). CONCLUSIONS: Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

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.

Similarities and differences between younger and older disease onset patients with newly diagnosed systemic lupus erythematosus.

OBJECTIVES: Several studies show that age at onset has an impact on the clinical-serological presentation, comorbidities and disease course of patients with systemic lupus erythematosus (SLE). We evaluated whether, in patients with recent onset SLE, the age at onset correlates with clinical-serological manifestations and with comorbidities. METHODS: We analysed 171 patients with a SLE diagnosis obtained within 12 months of diagnosis enrolled in the Early Lupus project. Based on the age of onset of the first disease symptom, they were stratified into 2 groups: early onset (18-45 years) and late onset (>45 years). The analysis was replicated by stratifying patients based on age at diagnosis (fulfillment of ACR classification criteria). Each comparison was made at baseline and at 36 months of follow-up. RESULTS: Baseline: patients with late onset displayed comorbidities (hypertension, dyslipidemia and osteoporosis) more frequently than early onset group. 11.4% of late onset patients had a malignancy in medical history, not recorded in the early onset cohort. The two groups differed neither in organ involvement (domain BILAG) nor in disease activity (ECLAM). Patients with early onset showed a disease with signs of higher serologic activity (higher frequency of anti-dsDNA positivity and lower mean C3 and C4 levels) and had malar rash more frequently than the late onset group (36.2% vs. 18.2%, p=0.042). Similar results were obtained by stratifying patients by age of diagnosis (18-45 years and >45 years), except for the higher frequency of discoid rash in the group with age at diagnosis >45 years (18% vs. 6.6%, p=0.045). 36 months: the 2 groups of patients independently of the stratification applied did not differ in the accumulation of damage, but showed a different pattern of 8 organ involvement. Musculoskeletal involvement was more frequent both in the late onset group (18.6% vs. 7.3%, p=0.043) and in the group with age at diagnosis >45 years (20.4% vs. 5.9%, p=0.009) compared to their counterparts, while renal involvement was more frequent in the group with age at diagnosis 18-45 years (21.4% vs. 6.1%, p=0.03).A sub analysis at 36 months on patients without hypertension and osteoporosis at enrollment showed that patients with older age at onset had a higher frequency of these comorbidities, compared to their counterparts. CONCLUSIONS: In our cohort, younger disease SLE onset seems to correlate with a more active immunological profile, while late onset with a higher incidence of comorbidities.

Systemic Sclerosis-Specific Antibodies: Novel and Classical Biomarkers.

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad's phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of "seronegative" SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2-7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients' stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns' interpretation. The gold-standard technique for autoantibodies' identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.

Long-term outcomes of COVID-19 vaccination in patients with rare and complex connective tissue diseases: The ERN-ReCONNET VACCINATE study.

Background: Vaccination is one of the most important measures to contain the COVID-19 pandemic, especially for frail patients. VACCINATE is a multicentre prospective observational study promoted by the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET) aimed at assessing the long-term outcomes of COVID-19 vaccination in patients with rare and complex connective tissue diseases (rcCTDs) in terms of efficacy and safety. Methods: Adult rcCTDs patients were eligible for recruitment. Demographic, clinical and vaccination data were collected at enrolment. Follow-up visits were scheduled 4, 12, 24, 36 and 48 weeks after completion of the first vaccination cycle; data on adverse events, disease exacerbations and the occurrence of new SARS-CoV-2 infections were collected at these time-points. Findings: 365 rcCTDs patients (87 % female, mean age 51.8 ± 14.6 years) were recruited. Overall, 200 patients (54.8 %) experienced at least one adverse event, generally mild and in most cases occurring early after the vaccination. During follow-up, 55 disease exacerbations were recorded in 39 patients (10.7 %), distributed over the entire observation period, although most frequently within 4 weeks after completion of the vaccination cycle. The incidence of new SARS-CoV-2 infections was 8.9 per 1000 person-months, with no cases within 12 weeks from vaccine administration and an increasing trend of infections moving away from the primary vaccination cycle. Only one case of severe COVID-19 was reported during the study period. Interpretation: COVID-19 vaccination seems effective and safe in rcCTDs patients. The rate of new infections was rather low and serious infections were uncommon in our cohort. No increased risk of disease flares was observed compared to previous disease history; however, such exacerbations may be potentially severe, emphasising the need for close monitoring of our patients.

Glucocorticoid tapering and associated outcome in patients with newly diagnosed systemic lupus erythematosus: the real-world GULP prospective observational study.

OBJECTIVE: A subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP). METHODS: Patients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDN<5 mg/day at any time and outcomes associated with different patterns of GCs tapering. RESULTS: The GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN <5 mg/day, and 17 (13.4%) discontinued PDN within a 2-year follow-up. Renal involvement (HR: 0.41; p=0.009) and lower C3 serum levels (HR: 1.04; p=0.025) predicted a lack of PDN tapering below 5 mg/day. High ECLAM scores were associated with a greater probability of increasing PDN dose (OR: 1.6; p=0.004), independently of daily intake. Disease relapse rate did not statistically differ (p=0.706) between patients tapering PDN <5 mg/day (42/99, 42.4%) and those tapering PDN without dropping below 5 mg/day (13/28, 46.4%). Every month on PDN <5 mg/day associated with lower damage accrual (IRR: 0.96; p=0.007), whereas never tapering PDN <5 mg/day associated with a higher risk of developing GC-related damage (OR 5.9; p=0.014). CONCLUSION: Tapering PDN <5 mg/day was achieved and maintained in half of newly diagnosed patients with SLE and may represent a good balance between the need to prevent damage accrual and the risk of disease relapse.

Evidence for charge-based mimicry in anti dsDNA antibody generation.

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Urinary incontinence in systemic sclerosis: a prospective multicentre cohort study.

Investigate the natural history of urinary incontinence (UI) in systemic sclerosis (SSc) and assess its impact on quality of life (QoL). A longitudinal, international observational study followed 189 patients with SSc for a median duration of 5 years (IQR: 4.8-5.3). Presence, subtype and severity of UI, hospital admission and QoL were assessed using serial self-administered questionnaires. Mortality data came from national death registries. Multilevel mixed-effect logistic regressions explored factors associated with UI. Cox models adjusted the effects of UI on hospitalization and death for age, sex and subtype of SSc. Mean annual rates of new-onset UI and remission were 16.3% (95%CI 8.3%-24.2%) and 20.8% (95%CI 12.6-29.1), respectively. Among UI patients, 57.9% (95%CI 51.8-64.0) changed from one UI subtype to another. Between annual questionnaires, the severity of UI was the same in 51.1% (95%CI 40.8-61.4), milder or resolved in 35.2% (95%CI 25.3-44.9), and worse in 13.8% (95%CI 6.7-20.9). Anti-centromere antibodies, digestive symptoms, sex, age, neurological or urological comorbidities, diuretics and puffy fingers were all associated with UI. The two strongest predictors of UI and UI subtypes were a recent UI episode and the subtype of previous leakage episodes. UI at inclusion was not associated with hospital admission (adjusted HR: 1.86; 95%CI 0.88-3.93), time to death (aHR: 0.84; 95%CI 0.41-1.73) or change in QoL over time. Self-reported UI among SSc patients is highly dynamic: it waxes and wanes, changing from one subtype to another over time.

Stopping bDMARDs at the beginning of pregnancy is associated with disease flares and preterm delivery in women with rheumatoid arthritis.

Objectives: Women with Rheumatoid Arthritis (RA) can experience flares during pregnancy that might influence pregnancy outcomes. We aimed at assessing the disease course during pregnancy and identifying risk factors for flares. Methods: Data about prospectively-followed pregnancies in RA were retrospectively collected before conception, during each trimester and in the post-partum period. Clinical characteristics, disease activity (DAS28-CRP3), medication use, and pregnancy outcomes were analysed with regard to disease flares. Results: Among 73 women who had a live birth, 64 (88%) were in remission/low disease activity before conception. During pregnancy, a flare occurred in 27 (37%) patients, mainly during first and second trimester. Flares during pregnancy were associated with the discontinuation of bDMARDs at positive pregnancy test (55% of patients with flare vs. 30% of patients with no flare, p 0.034, OR 2.857, 95% CI 1.112-8.323) and a previous use of >1 bDMARDs (33% of patients with flare vs. 10% of patients with no flare, p 0.019, OR 4.1, 95%CI 1.204-13.966). Preterm pregnancies were characterised by higher values of CRP [10 mg/L (5-11) vs. 3 mg/L (2.5-5), p 0.01] and DAS28-CRP3 [4.2 (1.9-4.5) vs. 1.9 (1.7-2.6), p 0.01] during the first trimester as compared with pregnancies at term. Preterm delivery was associated with the occurrence of flare during pregnancy (flare 27% vs. no-flare 7%, p 0.034, OR 4.625, 95%CI 1.027-20.829). Conclusion: Preterm delivery in RA patients was associated with flares during pregnancy. Flares occurred more frequently after the discontinuation of bDMARDs at positive pregnancy test. Women with aggressive RA on treatment with bDMARDs should be considered as candidates for continuing bDMARDs during pregnancy in order to reduce the risk of flare and adverse pregnancy outcomes.