Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Phenotype of limited cutaneous systemic sclerosis patients with positive anti-topoisomerase I antibodies: data from the EUSTAR cohort.

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.

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.

Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients' subgroups.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study.

OBJECTIVES: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. METHODS: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. RESULTS: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. CONCLUSION: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

Skin ulcers in systemic sclerosis: correlation with clinical phenotype in a monocentric cohort from the north-east of Italy.

OBJECTIVES: To evaluate the prevalence of skin ulcers (SUs) and their association with clinical phenotype in a monocentric cohort of patients affected with systemic sclerosis (SSc). METHODS: Patients affected with SSc (ACR/EULAR 2013 criteria) in regular follow-up at the Rheumatology Unit of Padova University Hospital, Italy, were considered and retrospectively evaluated. Demographic, clinical and laboratory data, organ involvement and therapy were recorded. We analysed the occurrence, timing (single episode, recurrent/chronic) and site of SUs. The association between SUs and demographic and clinical variables was assessed by logistic regression analysis. RESULTS: We evaluated 211 SSc patients, aged 60.8±12.4 years, 187 (89%) females, 147 (70%) affected with limited cutaneous SSc. During a median follow-up of 120 months (50-216), 105 (50%) patients experienced at least one episode of SU; among them, 66% had recurrent or persistent SUs. Patients with a history of SUs compared with those never affected were younger at SSc diagnosis (p=0.009), had more frequently a diffuse cutaneous form (p=0.001), chronic anaemia (p<0.001), systemic inflammation (p=0.001), lung (p=0.002) and cardiac (p=0.004) involvement, and calcinosis (p=0.001). At multivariate analysis a younger age at SSc diagnosis (p=0.031), articular involvement (p=0.005) and telangiectasia (p=0.003) were independently associated with SUs. Telangiectasia, articular involvement, chronic anaemia and inflammatory state were found to be associated with the recurrence/chronicisation of SUs. CONCLUSIONS: SUs represent a common complication in our cohort of patients with a long-term follow-up. The association of SUs with some clinical manifestations of SSc suggests a combined role of microcirculatory damage and inflammation in their origin.

Systemic sclerosis Progression INvestiGation (SPRING) Italian registry: demographic and clinico-serological features of the scleroderma spectrum.

OBJECTIVES: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). METHODS: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. RESULTS: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. CONCLUSIONS: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

Mud-bath treatment of seronegative spondyloarthritis: experience at the Euganean Thermal Area.

Mud-bath therapy (MBT) has been used as a treatment for rheumatic diseases and musculoskeletal complaints in the Euganean Thermal Area (near Padova, Italy) since ancient time. There is no consensus about the use of MBT in patients with inflammatory rheumatic diseases, although experimental studies have suggested a beneficial effect of MBT on chronic articular inflammation. To evaluate the effects of MBT in patients affected by seronegative spondyloarthritis, very common chronic inflammatory rheumatic diseases, randomized controlled trials (RCT) performed in the Euganean Thermal Area have been reviewed. A significant improvement of spondylitis parameters was observed in enteropathic spondylitis, without bowel symptom exacerbation. A long-term amelioration of clinical evaluation indices was found in ankylosing spondylitis. A significant improvement of cutaneous lesions, arthritis activity, and patient's functional ability was observed in psoriatic arthritis. MBT was usually well tolerated and adverse side effects were rarely reported. The review of the RCT suggests that MBT may exert additional beneficial effects in patients with seronegative spondyloarthritis treated with pharmacological therapy.

The role of plasma exchange in the management of autoimmune disorders.

Therapeutic plasma exchange (TPE) has been mainly used in the treatment of autoimmune diseases. The main mechanisms of action of TPE include the removal of circulating autoantibodies, immune complexes, complement components, cytokines and adhesion molecules, along with sensitization of antibody-producing cells to immunosuppressant agents. TPE is useful in autoimmune haematological, renal, rheumatic and neurological diseases, and is recommended for acute disorders, together with relapsed or worsened chronic diseases that are often unresponsive to conventional treatments. The American Society for Apheresis and the British Society of Haematology have published guidelines on the clinical use of apheresis procedures, indicating the different levels of efficacy of TPE. Based on the evidence from current literature and our personal experience, this review discusses the indications and the suggested regimens for TPE in autoimmune haematological and non-haematological disorders.

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: in Vitro Evidence.

In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further.

Functional disability and its predictors in systemic sclerosis: a study from the DeSScipher project within the EUSTAR group.

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.

Balneotherapy in chronic inflammatory rheumatic diseases-a narrative review.

Since ancient time, thermal baths and mudpacks have been used as treatments for rheumatic diseases and other musculoskeletal complaints. Despite basic researches suggest an anti-inflammatory effect of spa therapy, there is no consensus about the benefits of balneotherapy in patients with chronic inflammatory rheumatic diseases. The aim of this review is to summarize the currently available information on clinical effects of balneotherapy in these diseases. We did a literature search for articles considering the randomized controlled trials (RCTs) published until today. Although many selected studies do not have an elevated methodological quality, data from these RCTs support a beneficial effect of spa therapy. Balneotherapy highly improves the clinical course of the disease in patients with predominant axial involvement, such as with ankylosing and enteropathic spondylitis; the effects are less favorable in patients with predominant peripheral articular inflammation, such as rheumatoid arthritis. Good results have been observed in patients with psoriatic arthritis, but only few RCTs have been conducted on this disease. Spa therapy appears safe, and adverse events have been reported only in a few patients.

Mapping and predicting mortality from systemic sclerosis.

OBJECTIVES: To determine the causes of death and risk factors in systemic sclerosis (SSc). METHODS: Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. RESULTS: We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. CONCLUSION: Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.

The limited cutaneous form of systemic sclerosis is associated with urinary incontinence: an international multicentre study.

Objectives: The aim of this study was to explore the association between urinary incontinence (UI) and the main clinical and serological subsets of SSc, to assess risk factors for UI and its impact on quality of life (QoL). Methods: UI and QoL were assessed through self-administered questionnaires in 334 patients with SSc from five European tertiary centres. Logistic regressions were performed to test the association between clinical forms, serological status and UI and to adjust for confounders. Further independent predefined SSc risk factors for UI were tested through a multivariable logistic model. Results: The prevalence of UI was 63% (95% CI: 60, 68%). lcSSc and ACAs were both significantly associated with UI even after adjusting for age, sex, disability, diabetes, BMI, caffeine consumption, dyspnoea, faecal incontinence, abnormal bowel movement, presence of overlapping rheumatological disease and pulmonary hypertension [adjusted odds ratio (OR) = 2.4; 95% CI: 1.2, 4.7]. ACA and lcSSc doubled the risk of frequent and heavy urinary leaks. Factors independently associated with UI were as follows: lcSSc (OR = 2.2; 95% CI: 1.1, 3.2), ACA (OR = 2.8; 95% CI: 1.4, 5.8), female sex (OR = 10.8; 95% CI: 2.8, 41.3), worsening of dyspnoea (OR = 6.8; 95% CI: 1.2, 36.7), higher HAQ-DI (OR = 3.2; 95% CI: 1.5, 6.7), BMI (OR = 1.1; 95% CI: 1.0, 1.1) and active finger ulceration (OR = 0.3; 95% CI: 0.1, 0.7). Patients suffering from UI had decreased QoL. Conclusion: Self-reported UI is frequent in SSc and disproportionally affects the limited cutaneous form of the disease and patients positive for ACA. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01971294.

Digital ulcers predict a worse disease course in patients with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. METHODS: Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. RESULTS: 3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure): 3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). CONCLUSIONS: In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival.

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (±2.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths. CONCLUSIONS: Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decision-making process.

HSiCl3-Mediated Reduction of Nitro-Derivatives to Amines: Is Tertiary Amine-Stabilized SiCl2 the Actual Reducing Species?

The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro-derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, and spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.

Determinants of impairment in lung diffusing capacity in patients with systemic sclerosis.

OBJECTIVES: Lung diffusing capacity for carbon monoxide (DLCO) is impaired in interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) associated to systemic sclerosis (SSc), but the mechanism of DLCO reduction remains controversial. We hypothesised that the determinants of DLCO impairment differ in interstitial or vascular involvement of the lung of SSc patients. METHODS: DLCO was partitioned into alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) using combined single-breath DLNO and DLCO measurements. Seventeen SSc patients without pulmonary involvement (SSc), 20 SSc patients with ILD (SSc-ILD), with and without PAH, and 21 healthy controls were included. RESULTS: DLNO and Dm were reduced in SSc patients as compared with controls, whereas Vc was not significantly different. SSc-ILD patients showed a highly significant decrease in Dm and Vc as compared with SSc patients and controls. Vc tended to be more reduced than Dm in SSc-ILD patients with PAH. Dm and Vc were negatively correlated with PAPs and HCRT scores, but the relationship with the HRCT score was stronger. CONCLUSIONS: DLNO is more sensitive than DLCO in detecting functional impairment in SSc without radiologic or haemodynamic alterations. A disproportional reduction of Dm relative to Vc suggests a thickening of the blood-gas diffusion barrier in these patients. In SSc patients with detectable ILD, the gas exchange impairment is due to both components of lung diffusing capacity, and partitioning of DLCO in Dm and Vc is of little use in distinguishing the patients with only ILD from those with ILD complicated by PAH.

Lengthening the time intervals between doses of biological agents in psoriatic arthritis patients: A single-center retrospective study.

Anti-tumor necrosis factor (TNF) alpha therapy has changed the course of psoriatic arthritis (PsA), but clinical experience about lengthening of time intervals between drug administrations is still limited. The aims of the study were to evaluate: (1) the long-term efficacy (over a 4-year period) of etanercept/adalimumab in a subset of PsA patients who did not require switches; and (2) the progressive lengthening of time intervals between treatments in patients who achieved minimal disease activity (MDA). PsA outpatients attending the Rheumatology Clinic-University of Padova who took a single anti-TNF agent (etanercept/adalimumab) for a 4-year period were studied. Therapy efficacy was assessed using clinical, biochemical, and disease activity (DA) indexes. The intervals between treatments were empirically and progressively lengthened after MDA was reached and maintained. One hundred and forty-one patients (mean age, 51.22 ± 12.34 years; mean disease duration, 12.1 ± 8.42 years) treated with etanercept/adalimumab (47.5% and 52.5%, respectively) were studied. DA indexes showed a marked, persistent improvement in all the patients throughout 4 years. The interval between injections could be extended in 46.1% of the patients (35% for adalimumab, 58% for etanercept) without provoking relapses. The mean therapy interval at the end of the study period was 3.12 weeks for adalimumab 40 mg (with respect to 2 weeks) and 2.75 weeks for etanercept 25 mg (with respect to 0.5 weeks). The new therapy timetable also led to cost savings. In conclusion, lengthening the time intervals between injections of anti-TNF agents in PsA patients who reach MDA is safe, effective, cost-effective, and facilitates patient compliance.

Plasma-exchange as a "rescue therapy" for dermato/polymyositis in acute phase. Experience in three young patients.

There are few data in the literature supporting the efficacy of plasma-exchange in dermato/polymyositis. The authors report three cases of patients with acute disease phase showing severe pharyngo-esophageal muscle weakness unresponsive to conventional therapy (corticosteroids and immunosuppressant agents) who were treated with plasma-exchange. As the patients were at high risk of "aspiration pneumonia", tracheostomy and PEG tubes were placed. The patients underwent a series of plasma-exchange for a mean of 15 weeks, during which time they progressively recovered muscle strength, their serum muscle enzyme values returned to normal levels, and MRI showed resolution of muscle edema. The tracheostomy and PEG tubes could be removed. Our findings suggest that plasma-exchange in association with immunosuppressant agents could play a relevant role in the management of dermato/polymyositis in acute phase.