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Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

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.

Objective To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. Methods We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. Results Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. Conclusion The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Objectives Survival and death prognostic factors of SSc patients varied during the past decades. We aimed to update the 5- and 10-year survival rates and identify prognostic factors in a multicentre cohort of Italian SSc patients diagnosed after 2009. Material and methods Patients who received a diagnosis of SSc after 1 January 2009 and were longitudinally followed up in four Italian rheumatologic centres were retrospectively assessed up to 31 December 2020. Overall survival of SSc patients was described using the Kaplan–Meier method. Predictors of mortality at 10-year follow-up were assessed by the Cox regression model. A comparison of our cohort with the Italian general population was performed by determining the standardized mortality ratio (SMR). Results A total of 912 patients (91.6% females, 20% dcSSc) were included. Overall survival rates at 5 and 10 years were 94.4% and 89.4%, respectively. The SMR was 0.96 (95% CI 0.81, 1.13), like that expected in the Italian general population. Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) associated with pulmonary hypertension (PH) significantly reduced survival (P Conclusions In the past decade, SSc patients have reached similar mortality of that expected in the Italian general population. Male gender, diffuse cutaneous involvement, comorbidities and PAH with or without ILD represent the main poor prognostic factors.

Background: Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking. Aims: To describe the systemic sclerosis–primary biliary cholangitis phenotype, including baseline characteristics and outcomes. Methods: We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis–specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit. Results: A total of 261 patients were enrolled (115 primary biliary cholangitis–systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis–primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies ( p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis–systemic sclerosis patients ( p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension ( p Conclusion: Our data show that systemic sclerosis–primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.

Objective Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or ‘never’ DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud’s duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51–24.87), active digital ischaemia: 6.30 (5.34–7.42) and death: 1.86 (1.48–2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.

To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc).Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests.Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p0.03 and p0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p0.05) and on morning stiffness at 6 and 12 months (p0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p0.05). No changes in lung or gastrointestinal involvement were found.ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Systemic sclerosis (SSc) is a rare systemic autoimmune disease, characterized by the presence of three main actors: vasculopathy, immune activation, and fibrosis. This pathologic process is then translated in a clinical picture with great variability among different patients in terms of type of organ involvement, disease severity and prognosis. This heterogeneity is a main feature of SSc, which, in addition to the presence of early phases of the disease characterized by mild symptoms, can explain the high difficulty in establishing classification criteria, and in defining patients’ subsets and disease outcomes. The definition of disease outcomes is particularly relevant in the setting of clinical trials, where the aim is to provide reliable endpoints, able to measure the magnitude of the efficacy of a certain drug or intervention. For this reason, in the last years, increasing efforts have been done to design measures of disease activity, damage, severity, and response to treatment, often in the context of composite indexes. When considering disease outcomes, the experience of the patient represents a relevant and complementary aspect. The tools able to capture this experience, the patient-reported outcomes, have been increasingly used in the last years in clinical practice and in clinical trials, both as primary and secondary endpoints. This comprehensive narrative review on SSc will therefore cover pathogenetic and histopathologic aspects, epidemiology, classification systems, and disease outcome measures, in order to focus on issues that are relevant for clinical research and design of clinical trials.

Systemic sclerosis (SSc) is a rare systemic autoimmune disease that can influence reproductive health. SSc has a strong female predominance, and the disease onset can occur during fertility age in almost 50% of patients. Preconception counseling, adjustment of treatment, and close surveillance during pregnancy by a multidisciplinary team, are key points to minimize fetal and maternal risks and favor successful pregnancy outcomes. The rates of spontaneous pregnancy losses are comparable to those of the general obstetric population, except for patients with diffuse cutaneous SSc and severe internal organ involvement who may carry a higher risk of abortion. Preterm birth can frequently occur in women with SSc, as it happens in other rheumatic diseases. Overall disease activity generally remains stable during pregnancy, but particular attention should be paid to women with major organ disease, such as renal and cardiopulmonary involvement. Women with such severe involvement should be thoroughly informed about the risks during pregnancy and possibly discouraged from getting pregnant. A high frequency of sexual dysfunction has been described among SSc patients, both in females and in males, and pathogenic mechanisms of SSc may play a fundamental role in determining this impairment. Fertility is overall normal in SSc women, while no studies in the literature have investigated fertility in SSc male patients. Nevertheless, some considerations regarding the impact of some immunosuppressive drugs should be done with male patients, referring to the knowledge gained in other rheumatic diseases.

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

Schnitzler's syndrome is a rare autoinflammatory disease. Clinical response to IL-1 inhibitor drugs has been described, but limited information is available on the long-term efficacy and safety of these agents in Schnitzler's syndrome.A retrospective study was conducted of patients with Schnitzler's syndrome fulfilling Strasbourg diagnostic criteria followed in 9 Italian centres. The retention rate of IL-1 inhibitors was evaluated using Kaplan-Meier analysis.Fifteen of 20 patients with Schnitzler's syndrome were treated with IL-1 inhibitors: in total, they received 16 courses of anakinra (median duration 20.0 months [6.0-58.3]), and 8 courses of canakinumab (median duration 19.0 months [13.5-31.0]). The retention rate of IL-1 inhibitors was 73.4% [SE 9.4] at 1 year and 63.6% [SE 10.4] at 2 years. There was no significant difference between the retention rate of anakinra and canakinumab. The retention rate was higher in patients with a definite diagnosis according to the Strasbourg criteria as compared with those with a probable diagnosis (p=0.03). At the last follow-up visit, all patients who started therapy with IL-1 inhibitors were still on treatment, although in some cases with an increased dosage compared to the start of therapy. A sparing effect on the use of conventional synthetic disease-modifying anti-rheumatic drugs and a significant reduction of prednisone dosage (p=0.02) and of serum amyloid A (SAA) levels (p=0.03) were observed.The retention rate of IL-1 inhibitors in patients with Schnitzler's syndrome was high, particularly in patients with a definite diagnosis according to the Strasbourg criteria, reflecting their effectiveness in the treatment of this syndrome.

Objectives: The recent introduction of direct-acting antiviral agents (DAAs) which can eliminate Hepatitis C virus (HCV) had revolutionized the treatment of HCV infections also in a complex clinical setting such as the patients with rheumatoid arthritis (RA). HCV elimination is also opportune due to the availability of more efficient immunosuppressive drugs, whose effect on the course of HCV infection is largely unknown. Methods: Consensus process was endorsed by the Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) to review the available evidence and produce practical, hospital-wide recommendations. The consensus panel consisted of 18 infectious diseases consultants, 20 rheumatologists and one clinical epidemiologist, who used the criteria of the Oxford Centre for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. Results: A core-set of statements about management of patients with RA and infection by HCV have been developed to help clinicians in their clinical practice. Conclusions: A screening for HCV should be performed in all RA patients and it is mandatory before starting an immunosuppressive therapy. Finally, a DAA treatment should be considered in all HCV-infected patients.Significance and Innovations HCV antibodies should be investigated at the time of diagnosis of RA and, in any case, before starting immunosuppressive therapy with disease-modifying antirheumatic drugs (DMARDs). HCV eradication with DAA should be attempted as soon as possible, depending on patient conditions allowing a continuous oral treatment lasting 8–12 weeks Conventional and biological DMARDs are allowed in patients with HCV infection, but they should be used cautiously in presence of advanced liver disease.

We read with great interest the letter by Kawada in which the studies assessing colchicine as a treatment for COVID-19 were reviewed.1 Given its known inhibitory effect on NACHT-LRRPYD-containing protein 3 inflammasome2 and its possible antiviral properties,2 colchicine was hypothesised as a candidate therapy for COVID-19 since the very beginning of the pandemic.3 4 To the best of our knowledge, our observational retrospective study5 reported on the largest number of patients with COVID-19 treated with colchicine (122 consecutive patients), and they were compared with a control group treated with the Standard of Care (SoC, 140 consecutive patients).5 Kawada underlined the effectiveness of colchicine in reducing mortality and the need for non-invasive ventilation, as shown by different studies.5–7 After the hospital discharge, we observed additional deaths in patients treated with colchicine and in those treated with SoC (p=0.25). The long-term analysis of our cohort confirmed the original description of improved survival for patients treated with colchicine (mortality rate at 270 days: colchicine 20% vs SoC 44%; p=0.0001). We would like to point out the statement by Kawada reporting that ferritin and arterial oxygen tension (or pressure) (PaO2 …

Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular risk although they display a preserved number of circulating angiogenic CD3+CD31+CXCR4+ T cells (Tang), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a Tang subset with immunosenescent features, including the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between Tang subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients aged less than 40 years and 10 healthy controls (HCs) were recruited. Serum levels of interleukin (IL) -6, -8, matrix metalloproteinase (MMP) -9 and interferon (IFN) -γ were measured and flow cytometric analysis of endothelial progenitor cells (EPCs) and Tang subsets were performed. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects’ serum stimulation were also evaluated. Results showed that the percentage of Tang and EPCs subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28null cells among Tang subset. Furthermore, IL-8 serum levels were directly correlated with the percentage of Tang and inversely related to the CD28null Tang subsets, SLE disease activity index -2000 (SLEDAI-2K) was inversed related to Tang cells percentage. We indirectly evaluated the role of the Tang subset on the endothelium upon stimulation with serum from subjects with a low percentage of Tang CD3+ cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM) -1, endothelial leukocyte adhesion molecule (ELAM) -1; cell proliferation rate was directly related to IL-8 serum levels and EPCs percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of Tang compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28null subset exerts detrimental role over the Tang phenotype, where Tang could exert an anti-inflammatory effect on endothelial cells and might orchestrate via IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.

Background:Schnitzler’s syndrome is an autoinflammatory disease characterized by monoclonal gammopathy and recurrent episodes of urticaria accompanied by clinical and laboratory signs of acute inflammation. Interleukin (IL)-1 inhibitors proved to be useful in the treatment, but data on long-term safety and efficacy of these agents are sparse.Objectives:To evaluate the retention rate of IL-1 inhibitors in patients with Schnitzler’s Syndrome.Methods:Retrospective analysis of an Italian multicenter cohort (9 Centers). All patients fulfilled Strasbourg diagnostic criteria. Data are expressed as median [IQR].Results:We identified 15 patients (8 females, 7 males) who received a total of 24 treatment courses with IL-1 inhibitor treatment (16 anakinra and 8 canakinumab) between January 2001 and December 2019, with a median treatment duration of 19 months [8.5-51.3]. Median age at diagnosis was 64.0 years [56.0-72.5] and median follow up was 5.0 years [2.0-8.0]. Before the biological treatment, all patients were treated with corticosteroids and 11 with at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD): methotrexate (5), colchicine (5), cyclosporine (3), azathioprine (1), mycophenolate mofetil (1), cyclophosphamide (1).Fifteen patients received 16 courses of Anakinra, which was the 1st line biological treatment in 14 patients. Seven patients continued it with benefit, while 7 patients discontinued it: 3 for secondary inefficacy; 3 for adverse events (2 injection site reactions, 1 severe allergic reaction); 1 for secondary inefficacy and leukopenia. Anakinra was used as 2nd line treatment in 1 case (after tocilizumab failure); in 1 patient anakinra was resumed after temporary discontinuation and an attempt with infliximab. One patient died for multiple myeloma progression while on treatment with anakinra. The median duration of the courses with anakinra was 20.0 months [6.0-58.3].Seven patients received 8 courses of canakinumab (150 mg/8weeks in 5 cases and 150 mg/4weeks in 3). In 5 cases the drug was administered as 2nd line biological treatment (after anakinra failure) and in 2 cases as 3rd line treatment (1 after tocilizumab and anakinra failures and 1 after anakinra and adalimumab failure). In 1 patient, it was resumed after temporary discontinuation and an attempt with etanercept. One patient died while on treatment with canakinumab due to a presumably unrelated adverse event. The median duration of canakinumab treatment courses was 19.0 months [13.5-31.0].At last follow-up visit, all patients were on treatment with an IL-1 inhibitor: 8 with anakinra (7 at the dosage of 100 mg/day, 1 at the dosage of 200 mg/day) and 7 with canakinumab (2 at the dosage of 150 mg/8 weeks, 4 at the dosage of 150 mg/4 weeks and 1 at the dosage of 300 mg/4 weeks). Notably, in 3 patients the dosage of canakinumab was increased since the start of the treatment.Among 9 patients who were on treatment with prednisone at the start of the last IL-1 inhibitor, the prednisone median dose was 12.5 mg/day [10.0-18.8] while at the last follow-up visit it was 5.0 mg/day [0-7.5] (p= 0.02).The retention rate of IL-1 inhibitors was 73.4% [SE 9.4] at 1 year and 63.6% [SE 10.4] at 2 years (Figure 1a). There was no significant difference between the retention rate of anakinra (at 1 year: 67.0% [12.2]; at 2 years: 59.6% [12.9]) and canakinumab (at 1 year: 85.7% [13.2]; at 2 years 71.4% [17.1]) (log-rank test: p=0.41) (Figure 1b).Figure 1.a) Retention rate of IL-1 inhibitors (24 courses); b) Retention rate of canakinumab (8 courses) and anakinra (16 courses).Conclusion:In this multicentric cohort of patients affected by Schnitzler’s syndrome, the treatment with IL-1 inhibitors as 1st, 2nd or 3rd line biological treatment permitted a good disease control and corticosteroid reduction in patients who did not respond to csDMARDs and/or to prior other biological DMARDs. The optimal dosage of these drugs needs to be tailored for every patient.Acknowledgements:AIDA NetworkDisclosure of Interests:Francesca Crisafulli: None declared, Antonio Vitale: None declared, Carla Gaggiano: None declared, Lorenzo Dagna: None declared, Giulio Cavalli Speakers bureau: SOBI, Novartis, Paid instructor for: SOBI, Novartis, Consultant of: SOBI, Novartis, Rolando Cimaz: None declared, Ombretta Viapiana: None declared, Florenzo Iannone: None declared, Giuseppe Lopalco: None declared, Roberto Bortolotti: None declared, Masen Abdel Jaber: None declared, Carlomaurizio Montecucco: None declared, Sara Monti: None declared, Silvia Balduzzi: None declared, Giacomo Emmi: None declared, Paolo Airò: None declared, Franco Franceschini: None declared, Luca Cantarini Speakers bureau: SOBI, Novartis, Paid instructor for: SOBI, Grant/research support from: SOBI, Novartis, Micol Frassi: None declared

Background:Nintedanib has shown to slow FVC decline by 41ml over 52 weeks in systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the long-term effect of nintedanib treatment on ILD progression and mortality in SSc patients is so far unknown.Objectives:Here, the 52-week treatment efficacy of nintedanib was modeled and extrapolated on the long-term FVC course and survival in SSc-ILD patients from the European Scleroderma Trial and Research (EUSTAR) database.Methods:SSc patients from the EUSTAR database fulfilling the inclusion criteria of the SENSCIS trial (SSc classification criteria, ILD confirmed by imaging, disease duration of Results:Of the 236 included patients, 75% were females, 65% had diffuse cutaneous SSc. Mean age was 50.6 years, mean FVC 78.2%pred and DLCO 56.3%pred at time of inclusion. Mean FVC change after 12±3 months was -2.3 ±6.9%pred. These parameters were largely similar to the characteristics of the SENSCIS population.In the longitudinal follow up of this population, the natural course of FVC showed a total FVC decline of -16.3%pred over 5 years. With assumed SENSCIS effects (effects of nintedanib treatment reported in SENSCIS), the 5-year FVC decline was reduced to -10.3%pred (Figure 1).The reduced FVC progression translated into an improved survival. The natural 5-year survival of this SSc-ILD population was 88.2%. When extrapolating also a severe FVC decline early in the course, frequently terminated by early mortality of SSc patients excluding them from long-term outcome assessment, the estimated 5-year survival was reduced to 81.6%. When the SENSCIS effects on FVC were considered, the 5-year extrapolated survival was increased to 86.3% (Figure 2).Conclusion:Long-term experience of nintedanib treatment in SSc-ILD patients is lacking so far, therefore we modeled and extrapolated the 52-week treatment efficacy of nintedanib on the long-term FVC course and survival in SSc-ILD patients from the EUSTAR database. We could demonstrate a significant reduction of FVC decline by extrapolating the annual treatment effects of nintedanib from the SENSCIS trial from 1 to 5 years in EUSTAR. Translating these reductions of FVC decline into survival, the 5-year mortality rate was reduced from 18% to 13%.Disclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Dörte Huscher: None declared, Paolo Airò Speakers bureau: Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Novartis, Elisabetta Zanatta Speakers bureau: Boehringer Ingelheim, Actelion, GSK, Paid instructor for: GSK, Consultant of: Boehringer Ingelheim, GSK, Patricia Carreira Speakers bureau: Actelion, Boehringer Ingellheim, Janssen, GSK, Paid instructor for: Boehringer Ingelheim, Consultant of: AbbVie, Boehringer Ingelheim, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Sanofi Genzyme, Grant/research support from: Roche, GSK, Yannick Allanore Consultant of: Honorarium received from Boehringer, MedsenicSanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Ulf Müller-Ladner Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Alessandro Giollo: None declared, Maria Rosa Pozzi: None declared, CAROLINA SOUZA MULLER Speakers bureau: Boehinger Ingelheim, Janssen, Roche, LIBBS, Bristol-Myers-Squib, Radim Bečvář Consultant of: Actelion, Boehringer Ingelheim, Michele Iudici: None declared, Dominik Majewski Speakers bureau: Boehringer Ingelheim - 2 x paid as a speaker, Armando Gabrielli Grant/research support from: Pfizer, CSL Behring, Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Boehringer Ingelheim International GmbH, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, Kymera Therapeutics, Lilly, Medac, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB, Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

Background:Tocilizumab (TCZ) showed trends for improving skin fibrosis and prevented progression of lung fibrosis in patients with systemic sclerosis (SSc) in placebo-controlled randomised clinical trials (RCTs). However, safety and effectiveness of TCZ beyond these selected and enriched clinical trial populations in SSc is still unknown.Objectives:To assess safety and effectiveness of TCZ treatment compared to standard of care in SSc patients from the large, multicentre, observational, real-life EUSTAR network/database using propensity score matching.Methods:SSc patients from the EUSTAR network/database, who fulfilled the ACR/EULAR 2013 classification criteria, with a baseline and a follow-up visit at 12±3 months, receiving TCZ or standard of care (controls), were selected. The following variables were used for the propensity score matching (1:1): age at diagnosis, gender, disease subtype, baseline modified Rodnan skin score (mRSS), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), co-therapy with immunosuppressives, disease duration, and year of treatment. Primary endpoints were mRSS and FVC at 12±3 months follow-up compared between the groups, using paired t-tests. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months follow-up according to standard definitions (1,2). Sensitivity analyses assessed pre-processing decisions (selection of most recent vs. random observation for control patients with multiple suitable time intervals), as well as the matching method (optimal vs. exact matching). Missing values were addressed with 100-fold multiple imputation using chained equations. Safety data were analysed in all patients. The study including the statistical analysis plan was pre-registered at www.drks.de (DRKS-ID: DRKS00015537).Results:We identified 93 SSc patients treated with TCZ and 2370 SSc patients with standard of care who fulfilled the inclusion criteria. Forty nine (57.7%) of the TCZ treated patients were diffuse, eight patients were not classified, disease duration was (mean±SD) 6.35±5.40 years, their baseline mRSS was 15.05±10.85, and 76 (81.7%) received immunosuppressive therapy in addition to TCZ.Through multiple imputation and propensity score matching, 100 imputed sets of 93 pairs of TCZ/controls were generated. Comparison between groups showed consistent effects of TCZ across all pre-defined primary and secondary endpoints: mRSS was lower in the TCZ group (mean difference (95% confidence interval (CI)) -1.8 (-4.79 to 1.19), p=0.24, Figure 1A). Similarly, FVC % predicted was higher in the TCZ group mean difference (2.25, 95% CI -4.57 to 9.06), p=0.51, Figure 1B). Considering secondary endpoints, the percentage of skin progressors as well as lung progressors at follow up was lower in the TCZ group (odds ratio OR 0.67 (95% CI 0.07 to 6.41), p=0.74 and OR 0.53 (95% CI 0.16 to 1.7); p=0.2, respectively. Consistently, the percentage of regressors for skin (OR 1.6 (95% CI 0.56 to 4.54), p=0.38) and for lung (OR 1.74 (95% CI 0.66 to 4.58), p=0.26) was higher in TCZ. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion:In this large, observational, controlled, real-life EUSTAR study, effectiveness of TCZ did not reach statistical significance compared to standard of care treatment but showed consistent positive effects of TCZ on skin and lung fibrosis across all pre-defined primary and secondary endpoints confirming data from recent RCTs.References:[1]Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis 2016:1743-8.[2]Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021:219-227.Disclosure of Interests:Simon Kuster: None declared, Suzana Jordan: None declared, Muriel Daniele Elhai: None declared, Ulrike Held: None declared, Klaus Steigmiller: None declared, Cosimo Bruni: None declared, Florenzo Iannone: None declared, Serena Vettori: None declared, Elise Siegert: None declared, Simona Rednic: None declared, Veronica Codullo: None declared, Paolo Airò Consultant of: Dr. Airo’ reports personal fees (consultancies) from Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Yolanda Braun-Moscovici: None declared, Nicolas Hunzelmann: None declared, Maria Joao Salvador: None declared, Valeria Riccieri: None declared, Ana Maria Gheorghiu: None declared, Juan Jose Alegre Sancho: None declared, Katarzyna Romanowska-Prochnicka: None declared, Ivan Castellví: None declared, Ina Koetter: None declared, Marie-Elise Truchetet Consultant of: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Grant/research support from: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Francisco J López-Longo: None declared, Pavel Novikov: None declared, Alessandro Giollo: None declared, Yuichiro Shirai: None declared, Laura Belloli: None declared, Elisabetta Zanatta: None declared, Eric Hachulla: None declared, Vanessa Smith: None declared, Christopher Denton: None declared, Ruxandra Ionescu: None declared, Tim Schmeiser: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold Consultant of: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape. Masataka Kuwana: None declared, Yannick Allanore: None declared, Oliver Distler Speakers bureau: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: The study was partially supported by a grant from Roche. Roche was not involved in analysis or interpretation of the results.

Background:There is renewed interest in the role of autoantibodies to predict outcomes in systemic sclerosis (SSc). Among the newly identified subsets, patients with limited cutaneous form (lcSSc) but anti-topoisomerase I antibodies (Scl70) positivity draw particular attention, and namely, assessing the risk of developing interstitial lung disease (ILD) —the main cause of death in SSc—to improve the management of Scl70-lcSSc patients.Objectives:We aimed to characterize patients with Scl70-lcSSc in the large multicenter European Scleroderma Trial and Research (EUSTAR) cohort.Methods:The EUSTAR database was locked in July 2019. We included all patients fulfilling 1980 ACR and/or 2013 ACR/EULAR criteria for SSc, with disease duration at database entry ≤3 yrs and known and stable skin form during the first 3 yrs. Patients with lcSSc were compared: Scl70-lcSSc (target group) vs. ACA-lcSSc and ANA-lcSSc (Step 1); and Scl70-lcSSc vs. Scl70-dcSSc (Step 2). In the ANA subgroup we included ANA+ patients with negative SSc-specific antibodies (Scl70, ACA, RNA polymerase III). In each step, we performed 5 generalized mixed models (GMM) for the risk of the new onset of ILD (defined by imaging), primary myocardial involvement (PMI), pulmonary hypertension (PH), “any severe” (ILD+PMI+PH+scleroderma renal crisis) and all-cause-mortality. An additional GMM assessed the risk of forced vital capacity (FVC) decline ≥10% vs. FVC value at ILD onset. Each GMM was adjusted for age, sex and confounders.Results:Overall, 1285 SSc patients were included: 1068 (83%) females, 860 (67%) lcSSc and 425 (33%) dcSSc. Among patients with lcSSc, 537 (62%) had ACA+, 194 (23%) Scl70+ and 129 (15%) ANA+; 425 patients had dcSSc and Scl70+. Median follow-up was similar in all 4 groups: 7.2 to 8.1 yrs.Step 1: At baseline, Scl70-lcSSc patients had significantly shorter time from Raynaud’s phenomenon (RP) to SSc onset, higher mRSS (5.8±4.8 vs. 4.3±4, p=0.001), and higher rate of articular and muscular involvement vs. ACA-lcSSc patients (Figure 1). No differences were found between Scl70-lcSSc and ANA-lcSSc comparing the aforementioned variables. ILD was more frequent in Scl70-lcSSc (46%) than in ACA-lcSSc (10%) and ANA-lcSSc (25%), as well as restrictive lung disease. GMM showed that Scl70-lcSSc carries a higher risk of ILD than both ACA-lcSSc (HR 4.55, 95%CI 3.23-6.67) and ANA-lcSSc (HR 2.17, 95%CI 1.39-3.45), with a rate of FVC decline ≥10% over time similar to the other limited forms. In Scl70-lcSSc patients the risk of “any severe” organ involvement was similar to ANA-lcSSc and higher than ACA-lcSSc (HR 1.89, 95%CI 1.40-2.50). In particular, Scl70-lcSSc shows a risk of PMI similar to ANA-lcSSc and lower than ACA-lcSSc; no differences regarding PH risk. The mortality risk in patients with Scl70-lcSSc was similar to the other limited forms’.Step 2: At baseline, time from RP to SSc onset was longer in patients with Scl70-lcSSc, with less frequent joint synovitis and tendon friction rubs vs. patients with Scl70-dcSSc. Conversely, the frequency of muscular, cardiac and pulmonary involvement was similar. The risk of ILD in Scl70-lcSSc patients was similar to Scl70-dcSSc, with a lower risk of FVC decline ≥10% over time. The risk of “any severe” involvement (HR 0.66, 95%CI 0.49-0.83), PMI and PH was lower and the mortality risk tended to be lower (HR 0.57, 95%CI 0.33-1.01, p=0.053) vs. Scl70-dcSSc.Conclusion:In our large multicenter EUSTAR cohort one quarter of lcSSc patients were Scl70+. We show a ranking for major organ involvement within lcSSc: Scl70 the most severe, ANA+ intermediate and ACA the milder form. Scl70-dcSSc patients present the most severe phenotype, and Scl70 positivity, more than the cutaneous subset, is strongly predictive of ILD, whereas other variables may influence progression. These results may provide new insight to improve the management of Scl70-lcSSc patients.Disclosure of Interests:Elisabetta Zanatta: None declared, Dörte Huscher: None declared, Paolo Airò: None declared, Alexandra Balbir-Gurman: None declared, Elise Siegert: None declared, Augusta Ortolan: None declared, Marco Matucci-Cerinic: None declared, Franco Cozzi: None declared, Gabriela Riemekasten: None declared, Anna-Maria Hoffmann-Vold: None declared, Oliver Distler Speakers bureau: has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe, Armando Gabrielli: None declared, Stefan Heitmann: None declared, Nicolas Hunzelmann: None declared, Carlomaurizio Montecucco: None declared, Jadranka Morovic-Vergles: None declared, Camillo Ribi: None declared, Andrea Doria: None declared, Yannick Allanore: None declared

We thank Della-Torre et al for their interest on our report on the retrospective, case-control observational study with colchicine in patients hospitalised for severe COVID-19,1 and for rising the really crucial issue of the timing of the therapeutic intervention with anti-inflammatory therapies in this disease.2 Our observations should be interpreted in the scenario of the uncontrolled epidemic that, during March and April 2020, overwhelmed the health system in Lombardy, Italy, with rapid shortage of intensive care unit beds. As pointed out by the authors in other papers, after this period, the severity of the COVID-19 progressively decreased, in parallel with the exhaustion of the epidemic.3 4 The COVID-19 related mortality observed in our study (27.5% in the overall cohort of 262 consecutive cases; 36.4% in the standard of care group, and 15.8% in …

The case reported by Guilpain et al attracted our attention. This case of granulomatosis with polyangiitis on immunosuppressants, including recent maintenance therapy with rituximab (RTX), developed a severe and life-threatening coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19). The particularity of this observation was the occurrence of a more progressive worsening than observed in most series.1 Herein, we report the observation of three patients with systemic sclerosis (SSc) routinely treated with RTX who were affected by COVID-19 and who also experienced a late clinical worsening to severe pneumonia. RTX is often used off-label in patients with SSc mainly for refractory skin, musculoskeletal or interstitial lung disease. Observational studies reported a safety profile similar to that reported in rheumatoid arthritis.2 Their main disease characteristics are presented in table 1. Patient 1 had early diffuse cutaneous SSc, with positive RNA polymerase-3 antibodies, and severe cutaneous involvement (peak modified Rodnan Skin Score at 32/51) as the main clinical involvement. Patient 2 had long-lasting limited cutaneous SSc with recurrent digital ulcers and inflammatory arthritis as the main disease manifestations. Patient 3 had a limited cutaneous subset evolving from 2 years, with positive RNA polymerase-3 antibodies and persisting arthritis. None of these patients had interstitial lung disease and primary or secondary heart involvement. Regarding the main comorbidities, patient 1 was treated for high blood pressure by perindopril, furosemide and lercanidipine, and patient 2 had chronic renal insufficiency and history …

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.

Background Systemic Lupus Erythematosus (SLE) patients show high levels of BLyS (B-lymphocyte stimulator) and other cytokines belonging to the tumor necrosis factor (TNF) superfamily1. Belimumab, a monoclonal antibody against BLyS, mainly targets B-cells2, but a BLyS-dependent T-cell activation pathway has been demonstrated3. Clinical studies showed that anti-DNA antibodies and complement levels at baseline are predictors of response to Belimumab. Our study aims at identifying other biomarkers as response predictors. Methods Twenty-one SLE patients received Belimumab. Biomarkers belonging to the TNF superfamily (BLyS, APRIL, sBCMA, sCD40L, sTACI, TWEAK) were tested by ELISA in all patients and lymphocyte immunophenotyping was performed by flow cytometry in ten subjects at baseline and every six months. SLE-disease activity was assessed by SLEDAI-2K score. Results BLyS and APRIL baseline serum levels and the number of CD3+CD8+ effector memory T-cells were correlated positively with SLEDAI-2K improvement after 12 months of treatment (Pearson correlation=0.535 (p=0.015), 0.504 (p=0.023) and 0.654 (p=0.040)). After backwards exclusion from linear regression analysis including SLEDAI-2K, effector T-cell relative number and BLyS or APRIL at baseline, only APRIL remained as significant independent predictor of SLEDAI-2K improvement after 12 months (adjusted R square=0.649; p=0.025). After comparing TNF-family members levels and SLEDAI-2K at baseline, only BLyS showed the best predictive value (adjusted R 0.564, p Conclusions In our cohort of SLE patients, baseline level of APRIL together with percentage of CD3+CD8+ effector memory T-cells, or BLyS serum level alone resulted as best predictors of response to Belimumab. Considering that immunophenotyping is rarely done in clinical practice, BLyS baseline serum levels alone could be used routinely as a good predictor of response, as suggested by post-hoc analyses of the BLISS study. References Ng LG, et al. J Immunol, 2004. Ramskold D, et al. EBioMedicine, 2019. Samy E, et al. Int Rev Immunol, 2017.

BackgroundPatients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression.MethodsThis was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient’s lifetime.ResultsThe analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p p p ConclusionsHAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc.

ObjectivesThe outbreak of COVID-19 posed the issue of urgently identifying treatment strategies. Colchicine was considered for this purpose based on well-recognised anti-inflammatory effects and potential antiviral properties. In the present study, colchicine was proposed to patients with COVID-19, and its effects compared with ‘standard-of-care’ (SoC).MethodsIn the public hospital of Esine, northern Italy, 140 consecutive inpatients, with virologically and radiographically confirmed COVID-19 admitted in the period 5–19 March 2020, were treated with ‘SoC’ (hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir). They were compared with 122 consecutive inpatients, admitted between 19 March and 5 April 2020, treated with colchicine (1 mg/day) and SoC (antiviral drugs were stopped before colchicine, due to potential interaction).ResultsPatients treated with colchicine had a better survival rate as compared with SoC at 21 days of follow-up (84.2% (SE=3.3%)vs63.6% (SE=4.1%), p=0.001). Cox proportional hazards regression survival analysis showed that a lower risk of death was independently associated with colchicine treatment (HR=0.151 (95% CI 0.062 to 0.368), pConclusionThis proof-of-concept study may support the rationale of use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.

Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated.

Objectives Recent data have shown a significant efficacy of rituximab (RTX) in SSc. An RTX biosimilar (RTX-B) is a more affordable option. We assessed the safety and efficacy of an RTX-B (CT-P10) in SSc. Methods SSc patients treated with RTX-B with at least 6 months of follow-up were retrospectively identified from six Italian referral centres. SSc patients naïve to RTX-B (RTX-Bn) or already treated with RTX originator and switched to an RTX-B (RTX-Bs) were evaluated. A comprehensive assessment of disease characteristics and organ involvement at baseline and after 6 months was obtained. Results Thirty-three SSc patients were selected: 29 (87.9%) females, mean age 51.6 years (s.d. 14.2), mean disease duration 9.8 years (s.d. 8.1); 21 (64.5%) with dcSSc, 20 (60.1%) anti-topoisomerase I, 7 (21.2%) anti-RNA polymerase III and 6 (18.2%) anti-centromere positive. Seventeen (51.5%) were RTX-Bn and 16 were on RTX-Bs (48.5%). RTX was introduced because of skin progression in 18 patients (54.5%), interstitial lung disease (ILD) worsening in 11 (33.3%) and arthritis in 12 (36.4%). All patients were previously treated with immunosuppressants. At RTX-B introduction, 21 (63.6%) patients were on concomitant immunosuppressants: 15 (71.4%) on MMF and 6 (28.6%) on MTX. Twenty-three (69.7%) were on low-dose steroids. After 6 months, a significant reduction of the modified Rodnan skin score (mRSS), 28-joint DAS and CRP was observed (P = 0.002, 0.005 and 0.008, respectively); the mRSS significantly improved both in RTX-Bn (P Conclusion Our data suggest that RTX-B can represent a cheaper option in SSc patients, as it is effective in improving skin and joint involvement and in stabilizing lung function.

Anti-RNA Polymerase III antibodies are the most frequent anti-nuclear antibodies in systemic sclerosis, after anti-centromere and anti-Topoisomerase I. Considering their specificity for systemic sclerosis, they have been included in 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis. They were first identified in 1993 using an immunoprecipitation method; the subsequent diffusion of commercial assays, based on the enzyme-linked immunosorbent assay or multiplex line immunoblot techniques, has allowed an increasing number of systemic sclerosis patients to be tested for this autoantibody; nevertheless, the diffusion of this test in systemic sclerosis patients is probably still sub-optimal. Anti-RNA Polymerase III antibodies have been associated with important clinical manifestations: rapid and diffuse cutaneous involvement, joint contractures, scleroderma renal crisis, gastric antral vascular ectasia and malignancies synchronous to systemic sclerosis onset. Moreover, other possible clinical associations, including pulmonary hypertension, still need confirmation. Since the correct approach for screening for anti- RNA Polymerase III antibodies in patients with suspected or definite systemic sclerosis is still debated, possible strategies are proposed here. Moreover, issues that are still controversial are discussed, including the interpretation of multiple simultaneous positivity for anti-RNA Polymerase III antibodies and other autoantibodies in line immunoassay, and the possible relevance of anti-RNA Polymerase III antibodies titre.

Background:Systemic Sclerosis (SSc) is characterized by increased mortality and organ damage accrual. A composite SSc Damage Index was recently developed by the Scleroderma Clinical Trials Consortium (SCTC-DI) and was demonstrated as a predictor of mortality both in the Australian derivation cohort and in the Canadian validation cohort (1). Several independent predictors of mortality in SSc have been reported, but only limited data are available on the role of smoking.Objectives:To evaluate smoking history and SCTC-DI as independent predictors of mortality in SSc in a single centre Italian cohort.Methods:A retrospective analysis was performed on patients prospectively followed in our centre from 1989 to 2019, with at least 2 evaluations and/or cause of death available. Organ damage was evaluated through the SCTC-DI (0-55 scale; severe damage>12), while comorbidities through the Charlson Comorbidity Index (CCI). Survival analysis was performed with Kaplan-Meier curves and with Log-rank test to compare different subsets. Cox-regression analysis was performed to identify baseline independent predictors of mortality.Results:648 SSc patients were 99% Caucasian, 90% female and had a median age at diagnosis of 55.5 years (IQR: 45.0-65.6); 19% had diffuse cutaneous involvement. ACA was positive in 52%; anti-TopoI in 22% and anti-RNA Polymerase III in 5%.Median SCTC-DI at diagnosis was 2 (0-4) (n=560); ever smokers were 27%. During the follow-up 240 patients died after a median period of 10.2 years (4.9-16.8). The cause of death was related to SSc in 41% (n=65; most frequent causes pulmonary arterial hypertension (n=35) and interstitial lung disease (n=30)) and to other diseases in 40% (n=95; most frequent cause cancer (n=40)), while was indeterminate in 19%.Overall survival at 5, 10, 15, 20 years was 87.8% (SE 1.3%), 75.6% (1.9), 63.8% (2.3), 47.7% (2.8), respectively and was higher in females vs. males (pIn the Cox-regression analysis smoking history and severe organ damage at diagnosis (score>12) were identified as independent predictors of death, while age at diagnosis, female gender, diffuse cutaneous subsets, ACA positivity and CCI were not (Table 1).Conclusion:Smoking history and severe organ damage were independent predictors of death in a large Italian single centre SSc cohort. SCTC-DI was confirmed as a useful tool to predict mortality at every timepointReferences:[1]Ferdowsi N, et al. Ann Rheum Dis. 2019;78:807-16.Disclosure of Interests:None declared

Background:Hydroxychloroquine (HCQ) is a well-tolerated drug that contributes to downregulating the immune response against autoantigens and it has been used in several autoimmune diseases. In systemic sclerosis (SSc) it is used to treat inflammatory arthritis without proof of efficacy.Objectives:Our aim was to evaluate the use of HCQ and its impact on Health Assessment Questionnaire disability index (HAQ-DI) and the Cochin Hand Function Status (CHFS). in a large SSc cohort compared to a propensity matched group of SSc patients not using HCQ.Methods:SSc patients from the European Scleroderma Trials and Research (EUSTAR) data base treated with HCQ for at least 6 months were evaluated. Demographic and clinical data, concomitant drugs, duration of HCQ treatment and reasons for its discontinuation, HAQ-DI and CHFS (at least 2 evaluation) were recorded and were the outcome variables of interest. Statistical analysis was performed using propensity score matching for age, gender, disease duration, corticosteroids, immunosuppressives, vasoactive drugs, DMARDs in a 3:1 control:HCQ ratio. Standard descriptive statistics and Student’s t-test and Chi-square test were used to assess the propensity-matched groups.Results:1,636 of 17,805 SSc patients (9.2%) were treated with HCQ for at least 6 months; out of these 3% (50/1636). had at least a baseline and follow-up HAQ-DI evaluation, (and 44/1636 (2.7%) had at least a baseline and follow-up CHFS evaluation. Propensity matching assured that pts were matched for demographic variables such as gender (mean on HCQ vs no HCQ:femals:92.0 vs 85.3), age(49.8 vs 49.97yrs) disease duration(8.3 vs 9.1 yrs), limited disease(55.3 vs 62.6%) as well as background medications (P>0.1-0.9). We did not find any significant changes in HAQ or CHFS (difference in slope) over 365 days of treatment, comparing the HCQ-treated group to the non-HCQ treated patients (p=0.240 for both (Figure 1).Conclusion:Results from the EUSTAR registry showed that HCQ was used by 9.2% of SSc patients. HCQ use did not improve the HAQ or CHFS, comparing HCQ users to non-HCQ users.Disclosure of Interests:Silvia Bellando Randone: None declared, Holly Wilhalme: None declared, Cosimo Bruni: None declared, Elise Siegert: None declared, Paolo Airò: None declared, Rosaria Irace: None declared, Oliver Distler: None declared, Andrea Doria: None declared, Lidia P. Ananieva: None declared, László Czirják: None declared, Christopher Denton: None declared, Yannick Allanore: None declared, Valeria Riccieri: None declared, ALESSANDRA VACCA: None declared, Ivan Foeldvari Consultant of: Gilead, Novartis, Pfizer, Hexal, BMS, Sanofi, MEDAC, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Marco Matucci-Cerinic: None declared, Daniel Furst: None declared

Background:T-cells play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and in its cardiovascular (CV) comorbidities, acting at microvascular level [1]. Since small artery remodeling is the earliest form of target organ damage in hypertension, the evaluation of microvascular alterations might provide clinically useful information. The evaluation of retinal arterioles is a non-invasive technique to identify a precocious microvascular damage, which is related to an increase of the wall-to-lumen ratio (WLR) [2]. CD3+CD31+CXCR4+ T-cells may be involved in damaged endothelium repair and are increased in patients with morphological microvascular alterations [3]. In addition to its effect on disease activity, abatacept (ABA), a co-stimulator blocker which is approved for the treatment of RA, may have specific CV protective action, modulating the numbers of certain subtypes of lymphocytes [4].Objectives:To non-invasively investigate morphological characteristics of retinal arterioles and to evaluate CD3+CD31+CXCR4+T-cells in a cohort of RA patients treated with ABA.Methods:Eleven RA patients [median (25th-75thpercentile) age=58 (50-65) years, baseline C-reactive protein (CRP)-DAS28=4.4 (3.8-4.6), body mass index (BMI)=23.4 (21.6-25.6) kg/m2, rheumatoid factor (RF) positive:45%, anti-citrullinated peptide autoantibodies (ACPA) positive:73%] without known CV risk factors (arterial hypertension, diabetes, hypercholesterolemia, previous CV events, smoking) were evaluated by adaptive optics, a validated technique quantifying microvascular damage [5], before and every 6 months of therapy with ABA (T0, T6 and T12). Phenotypic analysis of peripheral blood T lymphocytes was made by flow-cytometry in 5 patients of the cohort at T0 and T6.Results:A progressive significant reduction of the WLR of retinal arterioles was observed [T0=0.28 (0.25-0.30), T6=0.27 (0.24-0.31), T12=0.23 (0.23-0.26); p T0 vs T6=0.4; p T6 vs T12=0.01; p T0 vs T12=0.01] (Figure 1), without significant variations in the other parameters [internal diameter: T0=94.4 (84.1-104.0), T6=94.8 (84.6-107.7), T12=99.2 (89.1-109.1) µm; external diameter: T0=125.8 (111.1-131.0), T6=122.4 (109.1-134.5), T12=125.6 (113.9-134.4) µm; wall thickness: T0=13.2 (12.2-14.4), T6=13.4 (11.7-14.4), T12=12.5 (11.6-13.0) µm; wall cross-sectional area: T0=4581.0 (3788.7-5263.7), T6=4563.3 (3788.5-5295.2), T12=4099.7 (3899.0-5145.7) µm2)]. In 5 patients evaluated also for T-cell immunophenotyping a negative correlation was observed between CD3+CD31+CXCR4+ T-cell number and the retinal wall thickness at baseline (R=0.871;p=0.05). After ABA therapy a trend for reduction of CD3+CD31+CXCR4+T-cells [19.0 (13.8-38.3) vs 12.4 (5.2-18.0) % of CD3+], was observed as well as of significant reduction of retinal wall cross-sectional area [5123.3 (4385.0-5470.3) vs 4852.3 (4118.3-5228.0) µm2;p=0.04].Conclusion:In a cohort of RA patients without known CV risk factors, a reduction in retinal microvascular alterations arterioles was demonstrated after treatment for 12 months with ABA. CD3+CD31+CXCR4+T-cell number was inversely related to the possible presence of subclinical CV involvement. These results may suggest the possibility of microvascular abnormalities regression induced by the immune system modulation.References:[1]Dessein PH, J Rheumatol 2005.[2]Rizzoni D, Am J Hypertens. 2018.[3]Hur J, Circulation 2007.[4]Kallikourdis M, Nat Commun 2017.[5]De Ciuceis C, J Hypertens 2018.Acknowledgements:Bristol-Myers-Squibb Italy provided an unrestricted research grant for the study conduct.Figure 1.Disclosure of Interests:None declared

Background:Systemic Sclerosis (SSc) is a chronic rheumatic disease characterized by an autoimmune disorder with vasculopathy that leads to an excess in collagen and other extracellular matrix proteins deposition. This process results in progressive fibrotic and vascular damage of skin and visceral organs. According to observational studies conducted in last decades, mean survival of SSc patients had improved with significant changes in causes of death.Objectives:To assess the 10-years survival in a large Italian multicentre cohort of SSc patients in the last decade compared to previous periods published since the 1980s, and to identify features that can justify any change.Methods:We retrospectively analysed all medical records of our longitudinal SSc cohorts, fulfilling 1980 ARA and/or 2013 EULAR/ACR Classification Criteria, with a median (IQR) follow-up of 91.5 (51-120) months from 4 Scleroderma Units since January 2009. All clinical, laboratory and instrumental findings have been recorded and analysed. Survival rate was calculated with Kaplan-Meier curves and log-rank tests, and Cox proportional hazards models were used to identify any predictor. Then, observed SSc survival was compared to those previously published and to that expected in the general population, calculated using official data published on the website United Nation World Population Prospects (www.macrotrends.net/countries/ITA/italy/death-rate).Results:Of 912 SSc patients (91.6% female; mean (SD) age at first non-Raynaud symptom (RS) 51 (15.4) years; median (IQR) disease duration from non-RS 24 (0-84.7) months) diffuse cutaneous involvement was defined in 182 (20%) patients. Anti-centromere and anti-topoisomerase-I were detected in 390 (42.8%) and 302 (33.1%) patients, respectively, while 220 (24.1%) presented antibodies for other extractible nuclear antigens. Prevalent non-Raynaud manifestations were interstitial lung disease detected in 459 (50.3%), digital ulcers in 395 (43.3%) and oesophagopathy in 371 (40.7%) patients, respectively, while other gastrointestinal manifestations were reported in 234 (25.7%) patients. Chronic renal failure was observed in 61 (6.7%) patients and pulmonary arterial hypertension (PAH) was confirmed at right heart catheterization in 38 (4.2%) patients. Three hundred twenty-two (35.3%) patients received immunosuppressant, 215 (23.5%) assumed an endothelin receptor antagonist and/or a 5-phosphodiesterase inhibitor, and 72 (7.9%) were treated with a biologic agent. The global 10-years survival was 89.4%; female gender (HR 0.33, CI95% 0.17-0.67), diffuse cutaneous involvement (HR 2.14, CI95% 1.17-3.91), presence of pulmonary hypertension (HR 2.61, CI95%1.31-5.16) and older age at non-RS (HR 1.1, CI95% 1.06-1.12) affected survival. Furthermore, as compared to previous Italian studies, our cohort showed a significant improvement in rate (see Figure 1).Conclusion:Survival in SSc patients has improved in last 5 decades but still reduced compared to that expected in general population above all 5 years after diagnosis. Early diagnosis, with reduced renal involvement, along with better screening and innovative therapeutic strategies may explain these achievements.Figure 1.Ten-years survival in SSc patients since 2009 (left); comparison of survival across different Italian SSc cohorts (box: current analysis) (right).References:[1]Giordano M, et al. The Journal of Rheumatology. 1986; 13:911-916.[2]Ferri C, et al. Medicine. 2002; 81:139-53.[3]Vettori S, et al. Reumatismo. 2010; 62(3):202-209.[4]Ferri C, et al. Autoimmun Rev. 2014; 13(10):1026-34.Disclosure of Interests:None declared

Background:Systemic Sclerosis (SSc) is characterized by increased mortality and organ damage accrual. A composite SSc Damage Index was recently developed by the Scleroderma Clinical Trials Consortium (SCTC-DI) and was demonstrated as a predictor of mortality both in the Australian derivation cohort and in the Canadian validation cohort.Objectives:To evaluate in a single centre cohort of SSc patients with 10-years follow-up: (1) the evolution of organ damage over time; (2) factors associated with the development and accrual of organ damage.Methods:A retrospective analysis was performed on patients prospectively followed in our centre from 1989 to 2019. Organ damage was evaluated with SCTC-DI (0-55 scale; moderate damage >5, severe damage>12) and comorbidities with Charlson Comorbidity Index (CCI, which includes the age of the patient). Patients were included when a follow-up of at least 10 years was available together with SCTC-DI at the diagnosis (baseline, T0), 1 year (T1), 5 years (T5) and 10 years (T10) after the diagnosis. Univariable and multivariable analysis (logistic regression) were performed when appropriated.Results:253 SSc patients were included (female 93%; Caucasians: 99%; median age at diagnosis: 52 years (IQR: 43-60); diffuse cutaneous subset: 15%; anti-centromere (ACA)+ 55%; anti-Topoisomerase 1 + 20%; anti-RNA polymerase III+: 4%; ever smokers: 28%). Median interval between the first SSc symptom other than Raynaud’s phenomenon and the diagnosis was 1 year. SCTC-DI progressively increased from diagnosis to T10 (pModerate damage (score:6-12) was observed in 22 patients at T0 (8.7%), in 30 at T1 (11.9%), in 45 at T5 (17.7%) and in 73 at T10 (28.9%). None of the patients had severe damage (score:13-55) at T0 and T1, while it was present in 6 at T5 (2.4%) and in 13 at T10 (5.1%).At T0 no difference in SCTC-DI scores was observed when comparing different subgroups according to gender (female vs. male), disease subsets (diffuse vs. limited) and autoantibodies (ACA- vs. ACA+). At T1, SCTC-DI score was higher in patients with diffuse vs. limited cutaneous subset, and ACA- vs ACA+ (pMultivariable analysis demonstrated that a moderate or severe organ damage (SCTC-DI score >5) at 5 years was positively associated with diffuse cutaneous involvement (p:0.009, OR 4.55, 1.46-14.1), SCTC-DI at T0 (p:0.015, OR 1.34, 1.06-1.70) and at T1 (p:5 was associated with diffuse cutaneous involvement (p:0.013, OR 4.30, 1.36-13.7), SCTC-DI at T5 (p:Among 253 patients, 90 (36%) died after >10 years of follow-up. In non-survivors, as compared to survivors, SCTC-DI score was significantly higher at the baseline (T0) and during the entire follow-up (pConclusion:At the end of 10-years follow-up (T10), 35% of patients in our cohort had moderate or severe organ damage (SCTC-DI score>5). Diffuse cutaneous involvement was associated with higher SCTC-DI scores at different time points (T5 and T10). Organ damage, quantified by SCTC-DI at different time points, was confirmed as a factor associated with mortality in patients who reached more than 10 years of follow-up.References:[1]Ferdowsi N, et al. Ann Rheum Dis. 2019;78:807-16.Disclosure of Interests:None declared

Background:Coronavirus disease-19 (COVID-19) has been a major clinical challenge worldwide. Sex, age and comorbidities have been associated with worse outcome in the general population. Systemic sclerosis (SSc) is a severe, autoimmune disease with frequent multi-organ involvement.Objectives:To assess the impact of COVID-19 and to determine factors associated with worse outcome in SSc patients from the European Scleroderma Trial and Research (EUSTAR) database.Methods:SSc patients from the EUSTAR database with COVID-19 were prospectively collected between 15.03.-31.12.2020. Two outcomes were chosen: (1) hospitalization; and (2) severe outcome defined as either non-invasive ventilation, mechanical ventilation/extracorporeal membrane oxygenation (ECMO) or death. General risk factors assessed were sex, age and number of comorbidities. SSc related risk factors were SSc subtype, autoantibodies, disease duration, SSc associated organ manifestations including interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), cardiac, gastrointestinal (GI), and musculoskeletal involvement; digital ulcers (DU), CRP at last visit, renal disease (scleroderma renal crisis and SSc associated renal insufficiency), modified Rodnan skin score (mRSS) and immunosuppressive treatment. Descriptive statistics and logistic regression models were applied.Results:In total, 178 European SSc patients with COVID-19 were registered with a median observation time of 5.5 weeks (Table 1). 95 patients (53%) could recall SAR-Cov-2 contact, while 47 (26%) had no contact. 156 (88%) were symptomatic at COVID-19 onset with fever, cough, malaise and dyspnea being most prevalent. Over the disease course, 63 (36%) developed pneumonia. In total, 67/176 (38%) were hospitalized which were in 84% due to COVID-19. 41/170 (24%) had a severe outcome including 21 (12%) deaths. 128 (72%) recovered completely, while 14 (8%) complained of sequela, with 7 (50%) stating respiratory complications. Age, non-SSc comorbidities, presence of ILD, PAH and SSc associated renal or cardiac disease were numerically associated with hospitalization and severe outcome (Table 1). Univariable logistic analyses for hospitalization and severe outcome are shown in Figure 1. In multivariable logistic regression, age (OR 1.03, 95%CI 1.01-1.07, p=0.019), presence of non-SSc comorbidities (OR 2.52, 95%CI 1.16-5.47, p=0.019) and SSc-related renal disease (predicting success perfectly) were associated with hospitalization and for severe outcome age (OR 1.05, 95%CI 1.01-1.08).Conclusion:SSc patients at older age, with non-SSc comorbidities, SSc related renal disease or ILD are at risk of a more severe outcome and should follow precautions to avoid COVID-19 infections and need careful monitoring in case of COVID-19.Table 1.SSc disease characteristics of COVID-19 patientsAll(n=172)Hospitalized(n=67)Severe outcome(n=41)Age at COVID-19, yrs (SD)57 (14.0)63 (13.8)65 (12.2)Male sex, n (%)38 (21)18 (27)12 (29)≥1 comorbidity, n (%)63/176 (36)37 (55)30 (58)SSc disease duration at COVID, yrs (SD)11.5 (8.8)13.3 (9.7)12.7 (10.2)Diffuse cutaneous SSc, n (%)74 (42)29 (43)19 (46)mRSS, median (IQR)5 (8)5 (9)5 (7)ILD, n (%)90/175 (51)36/65 (55)26/40 (65)PAH, n (%)21/175 (12)11/65 (17)8/40 (20)GI disease, n (%)112/176 (64)45 (67)30 (73)Cardiac disease, n (%)37/166 (22)19/59 (32)16/36 (44)Musculoskeletal disease, n (%)40/175 (23)15/65 (23)6/40 (15)Renal disease, n (%)8/175 (5)7/65 (11)5/40 (13)Ever DU, n (%)69/175 (39)27/65 (42)14/40 (35)CRP, ng/ml (SD)35/177 (20)14 (21)9 (22)Immunosuppressive treatment, n (%)104/177 (59)41/66 (62)26 (63)Figure 1.Univariable logistic analyses for hospitalization and severe outcomeDisclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Francesca Tirelli: None declared, Patricia Carreira: None declared, Nicoletta Del Papa: None declared, Arsene Mekinian: None declared, Madelon Vonk: None declared, Alessandro Giollo: None declared, Giacomo De Luca: None declared, Maria De Santis: None declared, Corrado Campochiaro: None declared, Carina Mihai: None declared, Paolo Airò Speakers bureau: Bristol Myers Squibb, Bohringer Ingelheim, Consultant of: Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Maria Grazia Lazzaroni: None declared, Elisabetta Zanatta: None declared, Rosario Foti: None declared, Yannick Allanore: None declared, Daniel Furst: None declared, Marco Matucci-Cerinic: None declared, Armando Gabrielli: None declared, Oliver Distler Speakers bureau: Actelion, Kymera Therapeutics, Mitsubishi Tanabe Pharma, Abbvie, Acceleron, Alexion, Amgen, AnaMar, Arxx Therapeutics, Baecon, Discovery, Blade Therapeutics, Corbus Pharmaceuticals, Drug Development International, Ltd, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Kymera Therapeutics, Lilly, Novartis, Pfizer, Topadur and UCB, Consultant of: Actelion, Kymera Therapeutics, Mitsubishi Tanabe Pharma, Abbvie, Acceleron, Alexion, Amgen, AnaMar, Arxx Therapeutics, Baecon, Discovery, Blade Therapeutics, Corbus Pharmaceuticals, Drug Development International, Ltd, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Kymera Therapeutics, Lilly, Novartis, Pfizer, Topadur and UCB, Grant/research support from: Boehringer Ingelheim.

Background and objectives T-cell activation may be one of the pathogenic mechanisms of systemic lupus erythematosus (SLE). After repeated antigenic stimulation, T-cells undergo different modifications, leading to the differentiation into effector memory T-cells (CCR7−CD45RA−) and terminally differentiated effector memory (TDEM) T-cells (CCR7−CD45RA+). Similarly, down-modulation of CD28 may lead to the expansion of the CD28− T-cells, a subpopulation with peculiar effector activities. The aim of this study was the characterization of T-cell phenotype in a cohort of patients with SLE according to disease activity and damage index. Materials and methods Phenotypic analysis of peripheral blood T lymphocytes of 51 SLE patients and 21 healthy controls was done by flow-cytometry. SLE disease activity was evaluated by SLE Disease Activity Index-2000 (SLEDAI-2K) and damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The variations between different groups were evaluated by Mann–Whitney test. Bonferroni correction was applied to adjust for multiple comparisons ( padj). Spearman rank test was used to evaluate the correlations between quantitative variables. Results CD4+ lymphopenia was found among SLE patients. Patients showed a trend for a higher percentage of TDEM among the CD4+ T-cell subpopulation in comparison with healthy controls ( p = .04). SLE patients were divided into two groups according to disease activity: patients with SLEDAI-2K ≥ 6 ( n = 13) had a higher percentage of circulating CD4+ T-cells with CD28− phenotype ( padj = .005) as well as those with an effector memory ( padj = .004) and TDEM ( padj = .002) phenotype and a trend of decrease of regulatory T-cells (TREGs) ( p = .02), in comparison with patients with low disease activity ( n = 38). Patients with damage (SDI ≥ 1) tended to show an expansion of TDEM among CD4+ T-cells as compared with patients with no damage ( p = .01). In SLE patients an inverse correlation was found between the percentages of TREGs and those of TDEM ( p Conclusions CD4+ T-cell subpopulations displaying phenotype characteristics of effector lymphocytes are proportionally expanded in patients with active SLE and a higher damage index. These findings may suggest a role of effector T-cells in the pathogenesis of the disease and in the mechanisms of damage in SLE.