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ObjectivesTo evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) subpopulation.MethodsThis post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling.ResultsThe analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548).ConclusionsThe benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up.Trial registration number NCT01178073.

Objective The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). Methods Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5–10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. Results After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP − 1 ± 6.4 mmHg vs. placebo − 0.73 ± 3.59 mmHg at rest, p  = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m 2 vs. − 0.31 ± 0.71 l/min/m 2 , p  = 0.010; PVR − 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p  = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m 2 vs. − 0.45 ± 1.36 l/min/m 2 , p  = 0.015; PVR − 0.84 ± 0.48 WU vs. − 0.0032 ± 0.34 WU, p  < 0.0001). Conclusion This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. Trial registration www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14 th of November 2014.

Background Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT 4 ) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT 4 receptor affinity. Prucalopride is a high-affinity 5-HT 4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed. Methods Forty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods. Results There were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations ( p  < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p  < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p  < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p  = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p  = 0.035). Conclusions The safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating. Trial registration EU Clinical Trial Registry, EudraCT2012-005348-92 . Registered on 19 February 2013.

ObjectivesDespite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue.MethodsTreatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations.ResultsIn the French cohort, baseline cardiac output (CO) (R2=0.19, p=0.001) and New York Heart Association class (R2=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but weaker, correlation with CO was also found in the Food and Drug Administration sample (R2=0.04, p<0.001). During follow-up, there was no association between the changes in 6MWD and haemodynamic parameters in patients under PAH-specific treatments.ConclusionsIn SSc-PAH, CO independently correlates with 6MWD at baseline, but accounts for a small amount of the variance of 6MWD in both study samples. This suggests that other non-haemodynamic factors could have an impact on the walk distance. Moreover, variations of 6MWD do not reflect changes in haemodynamics among treated patients. Our results suggest that 6MWD is not an accurate surrogate marker for haemodynamic severity, nor an appropriate outcome measure to assess changes in haemodynamics during follow-up in treated SSc-PAH.

Background Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis. Methods A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors. Results A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68–6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03–3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival. Conclusions Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.

The prevalence of autoimmune conditions is two-fold higher in women than in men, especially during the reproductive years. Autoimmune conditions have been associated with a greater risk of adverse pregnancy outcomes, and some conditions have been studied more than others with inconsistent findings. The objective of this umbrella review was to identify, appraise, synthesise, and consolidate findings from published systematic reviews of autoimmune conditions and adverse pregnancy outcomes. In this umbrella review, we searched Medline, Embase, and Cochrane databases for systematic reviews from inception to Sept 30, 2022, without language restrictions. We used the Medical Subject Headings and free text search for autoimmune conditions and pregnancy outcomes. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data was extracted using a standardised form, which was piloted before use. Data were synthesised narratively and quantitatively. Odds ratios (ORs) with 95% CIs were reported. The protocol has been registered to PROSPERO (CRD42022334992). We selected 33 reviews, which included 709 primary studies. Pregnant women with autoimmune conditions were at high risk of both adverse maternal and fetal outcomes. The risk of miscarriage was increased in pregnant women with Sjögren's syndrome (relative risk [RR] 8·85, 95% CI 3·10–25·26), systemic lupus erythematosus (SLE; OR 4·90, 95% CI 3·10–7·69), thyroid autoimmunity (OR 2·77, 2·10–3·65), systemic sclerosis (OR 1·60, 1·29–2·22), and coeliac disease (OR 1·38, 1·12–1·69). The risk of pre-eclampsia was increased in pregnant women with type 1 diabetes (T1DM; OR 4·19, 3·08–5·71) and SLE (OR 3·20, 2·54 – 4·20). The risk of gestational diabetes was increased in pregnant women with inflammatory bowel disease (IBD; OR 2·96, 1·47–5·98) and thyroid autoimmunity (OR 1·49, 1·07–2·07). The risk of intrauterine growth restriction (IUGR) was increased in pregnant women with systemic sclerosis (OR 3·20, 2·21–4·53) and coeliac disease (OR 1·71, 1·36–2·14). The risk of delivering a small-for-gestational age baby was increased in pregnant women with SLE (OR 2·49, 1·88–3·31) and rheumatoid arthritis (OR 1·49, 1·22–1·82). The risks of other fetal outcomes such as stillbirth, preterm birth, and low birthweight were also increased in pregnant women with autoimmune disorders. T1DM in women was associated with lower odds of small-for-gestational-age outcome (OR 0·68, 0·56–0·83). Pregnant women with autoimmune conditions are at greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to post-natal care for women with autoimmune conditions. Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR).

IntroductionCovid-19 infection poses a serious challenge for immune-compromised patients with inflammatory autoimmune systemic diseases. We investigated the clinical-epidemiological findings of 1641 autoimmune systemic disease Italian patients during the Covid-19 pandemic.MethodThis observational multicenter study included 1641 unselected patients with autoimmune systemic diseases from three Italian geographical areas with different prevalence of Covid-19 [high in north (Emilia Romagna), medium in central (Tuscany), and low in south (Calabria)] by means of telephone 6-week survey. Covid-19 was classified as (1) definite diagnosis of Covid-19 disease: presence of symptomatic Covid-19 infection, confirmed by positive oral/nasopharyngeal swabs; (2) highly suspected Covid-19 disease: presence of highly suggestive symptoms, in absence of a swab test.ResultsA significantly higher prevalence of patients with definite diagnosis of Covid-19 disease, or with highly suspected Covid-19 disease, or both the conditions together, was observed in the whole autoimmune systemic disease series, compared to “Italian general population” (p = .030, p = .001, p = .000, respectively); and for definite + highly suspected diagnosis of Covid-19 disease, in patients with autoimmune systemic diseases of the three regions (p = .000, for all comparisons with the respective regional general population). Moreover, significantly higher prevalence of definite + highly suspected diagnosis of Covid-19 disease was found either in patients with various “connective tissue diseases” compared to “inflammatory arthritis group” (p < .000), or in patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs treatments (p = .011).ConclusionsThe finding of a higher prevalence of Covid-19 in patients with autoimmune systemic diseases is particularly important, suggesting the need to develop valuable prevention/management strategies, and stimulates in-depth investigations to verify the possible interactions between Covid-19 infection and impaired immune-system of autoimmune systemic diseases.Key Points• Significantly higher prevalence of Covid-19 is observed in a large series of patients with autoimmune systemic diseases compared to the Italian general population, mainly due to patients’ increased susceptibility to infections and favored by the high exposure to the virus at medical facilities before the restriction measures on individual movement.• The actual prevalence of Covid-19 in autoimmune systemic diseases may be underestimated, possibly due to the wide clinical overlapping between the two conditions, the generally mild Covid-19 disease manifestations, and the limited availability of virological testing.• Patients with “connective tissue diseases” show a significantly higher prevalence of Covid-19, possibly due to deeper immune-system impairment, with respect to “inflammatory arthritis group”.• Covid-19 is more frequent in the subgroup of autoimmune systemic diseases patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs, mainly hydroxyl-chloroquine and methotrexate, which might play some protective role against the most harmful manifestations of Covid-19.

BackgroundValidity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised.MethodsThree investigators assigned an activity score on a 0–10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate–multivariate linear regression analyses were used to define variables predicting the ‘gold standard’, their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0–10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS).ResultsA weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001).ConclusionsA preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.

Background Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. Main body All patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD. Conclusions Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the \"anti-synthetase syndrome.\"