Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.

Clinical presentation, course, and prognosis of patients with mixed connective tissue disease: A multicenter retrospective cohort.

OBJECTIVES: The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD). METHODS: We performed an observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included. RESULTS: Three hundred and thirty patients (88% females, median [interquartile range] age of 35 years [26-45]) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow-up of 8 (3-14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty-five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2-11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio [OR] = 2.44, 95% confidence interval [95%CI] [1.11-5.58]) and parotid swelling (OR = 3.86, 95%CI [1.31-11.4]) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow-up (51.8% vs. 25.9%). CONCLUSIONS: This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow-up.

Risk factors for hypogammaglobulinemia and association with relapse and severe infections in ANCA-associated vasculitis: A cohort study.

OBJECTIVES: B-cell depletion induced by rituximab (RTX) in ANCA-associated vasculitis (AAV) is a risk factor for hypogammaglobulinemia. Aggregating data on gammaglobulin levels kinetics during RTX and its association with the risk of relapse and severe infection is of interest. METHODS: Gammaglobulin levels were collected before induction therapy and during RTX maintenance therapy. We used different definitions of gammaglobulin decline: 1/gammaglobulin levels <6 g/L after induction; 2/>25 % decline in gammaglobulin levels between induction and maintenance, and 3/both. Our primary objective was the impact of gammaglobulin decline on the risk of relapse and severe infections. RESULTS: We included 98 patients. Patients with gammaglobulin level <6 g/L after induction and gammaglobulin decline >25 % were older (OR 3.9; 95%CI 1.1-16.1), had more frequently baseline gammaglobulin levels <10 g/L (OR 6.0; 95%CI 1.7-25.8) and received more frequent pulses of methylprednisolone at induction (OR 4.6; 95%CI 1.3-18.5). Severe infection-free survival was significantly poorer in patients with both gammaglobulin <6 g/L and gammaglobulin decline >25 % (adjusted HR 2.3; 95%CI 1.0-5.1) and in those who received pulses of methylprednisolone (HR 5.6; 95%CI 2.3-13.4). Gammaglobulin decline was in contrast not associated with the risk of relapse. CONCLUSION: Older age, low gammaglobulin levels and pulses of methylprednisolone at induction increase the likelihood of gammaglobulin decline after induction therapy. Such decline was associated with an increased risk of severe infections but not lower risk of vasculitis relapse. Pulses of methylprednisolone at induction had an independent negative impact on gammaglobulin levels and the risk of severe infections.

Anti-U1RNP antibodies are associated with a distinct clinical phenotype and a worse survival in patients with systemic sclerosis.

OBJECTIVES: To clarify the impact of anti-U1RNP antibodies on the clinical features and prognosis of patients with SSc. METHODS: We conducted a monocentric case-control, retrospective, longitudinal study. For each patient with SSc and anti-U1RNP antibodies (SSc-RNP+), one patient with mixed connective tissue disease (MCTD) and 2 SSc patients without anti-U1RNP antibodies (SSc-RNP-) were matched for age, sex, and date of inclusion. RESULTS: Sixty-four SSc-RNP+ patients were compared to 128 SSc-RNP- and 64 MCTD patients. Compared to SSc-RNP-, SSc-RNP+ patients were more often of Afro-Caribbean origin (31.3% vs. 11%, p < 0.01), and more often had an overlap syndrome than SSc-RNP- patients (53.1 % vs. 22.7%, p < 0.0001), overlapping with Sjögren's syndrome (n = 23, 35.9%) and/or systemic lupus erythematosus (n = 19, 29.7%). SSc-RNP+ patients were distinctly different from MCTD patients but less often had joint involvement (p < 0.01). SSc-RNP+ patients more frequently developed interstitial lung disease (ILD) (73.4% vs. 55.5% vs. 31.3%, p < 0.05), pulmonary fibrosis (PF) (60.9% vs. 37.5% vs. 10.9%, p < 0.0001), SSc associated myopathy (29.7% vs. 6.3% vs. 7.8%, p < 0.0001), and kidney involvement (10.9% vs. 2.3% vs. 1.6%, p < 0.05). Over a 200-month follow-up period, SSc-RNP+ patients had worse overall survival (p < 0.05), worse survival without PF occurrence (p < 0.01), ILD or PF progression (p < 0.01 and p < 0.0001). CONCLUSIONS: In SSc patients, anti-U1RNP antibodies are associated with a higher incidence of overlap syndrome, a distinct clinical phenotype, and poorer survival compared to SSc-RNP- and MCTD patients. Our study suggests that SSc-RNP+ patients should be separated from MCTD patients and may constitute an enriched population for progressive lung disease.

Prognostic value of automated assessment of interstitial lung disease on CT in systemic sclerosis.

OBJECTIVE: Stratifying the risk of death in SSc-related interstitial lung disease (SSc-ILD) is a challenging issue. The extent of lung fibrosis on high-resolution CT (HRCT) is often assessed by a visual semiquantitative method that lacks reliability. We aimed to assess the potential prognostic value of a deep-learning-based algorithm enabling automated quantification of ILD on HRCT in patients with SSc. METHODS: We correlated the extent of ILD with the occurrence of death during follow-up, and evaluated the additional value of ILD extent in predicting death based on a prognostic model including well-known risk factors in SSc. RESULTS: We included 318 patients with SSc, among whom 196 had ILD; the median follow-up was 94 months (interquartile range 73-111). The mortality rate was 1.6% at 2 years and 26.3% at 10 years. For each 1% increase in the baseline ILD extent (up to 30% of the lung), the risk of death at 10 years was increased by 4% (hazard ratio 1.04, 95% CI 1.01, 1.07, P = 0.004). We constructed a risk prediction model that showed good discrimination for 10-year mortality (c index 0.789). Adding the automated quantification of ILD significantly improved the model for 10-year survival prediction (P = 0.007). Its discrimination was only marginally improved, but it improved prediction of 2-year mortality (difference in time-dependent area under the curve 0.043, 95% CI 0.002, 0.084, P = 0.040). CONCLUSION: The deep-learning-based, computer-aided quantification of ILD extent on HRCT provides an effective tool for risk stratification in SSc. It might help identify patients at short-term risk of death.

Factors associated with physical function among people with systemic sclerosis: a SPIN cohort cross-sectional study.

OBJECTIVES: To compare physical function in systemic sclerosis (SSc, scleroderma) to general population normative data and identify associated factors. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the Physical Function domain of the Patient-Reported Outcomes Measurement Information System Version 2 upon enrolment. Multivariable linear regression was used to assess associations of sociodemographic, lifestyle, and disease-related variables. RESULTS: Among 2,385 participants, mean physical function T-score (43.7, SD = 8.9) was ∼2/3 of a standard deviation (SD) below the US general population (mean = 50, SD = 10). Factors associated in multivariable analysis included older age (-0.74 points per SD years, 95% CI -0.78 to -1.08), female sex (-1.35, -2.37 to -0.34), fewer years of education (-0.41 points per SD in years, -0.75 to -0.07), being single, divorced, or widowed (-0.76, -1.48 to -0.03), smoking (-3.14, -4.42 to -1.85), alcohol consumption (0.79 points per SD drinks per week, 0.45-1.14), BMI (-1.41 points per SD, -1.75 to -1.07), diffuse subtype (-1.43, -2.23 to -0.62), gastrointestinal involvement (-2.58, -3.53 to -1.62), digital ulcers (-1.96, -2.94 to -0.98), moderate (-1.94, -2.94 to -0.93) and severe (-1.76, -3.24 to -0.28) small joint contractures, moderate (-2.10, -3.44 to -0.76) and severe (-2.54, -4.64 to -0.44) large joint contractures, interstitial lung disease (-1.52, -2.27 to -0.77), pulmonary arterial hypertension (-3.72, -4.91 to -2.52), rheumatoid arthritis (-2.10, -3.64 to -0.56) and idiopathic inflammatory myositis (-2.10, -3.63 to -0.56). CONCLUSION: Physical function is impaired for many individuals with SSc and associated with multiple disease factors.

Hydroxychloroquine levels in pregnancy and materno-fetal outcomes in Systemic Lupus Erythematosus patients.

OBJECTIVES: Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). METHODS: We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). RESULTS: We included 174 patients (median age: 32.1 years, IQR 28.8-35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. CONCLUSION: In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02450396.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

Moderators of Loneliness Trajectories in People with Systemic Sclerosis During the COVID-19 Pandemic: A SPIN COVID-19 Cohort Longitudinal Study.

BACKGROUND: Many individuals with systemic sclerosis (SSc) are at heightened risk for COVID-19 related morbidity and isolation due to interstitial lung disease, frailty, and immunosuppressant use. Minimal research has explored loneliness predictors in individuals with chronic illnesses during COVID-19. This study evaluated moderators of loneliness trajectories in individuals with SSc during COVID-19. METHODS: Longitudinal data were analyzed across 30 timepoints from April 2020 to May 2022 from 775 adults in the Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort. Hierarchical linear modeling evaluated cross-level moderators of loneliness trajectories, including marital status, baseline number of household members, number of virtual or telephone one-on-one or virtual group conversations, number of hours spent enjoying in-person household conversations or activities, and satisfaction with quality of in-person household conversations (all in the past week). Level-1 moderation analyses assessed effects of conversation, activity, and satisfaction means and slopes over time. RESULTS: Baseline values were not statistically significant moderators of loneliness trajectories. Higher mean (averaged over time) virtual or telephone one-on-one and in-person household conversations, in-person household activity, and in-person household conversation satisfaction were associated with lower loneliness trajectories (ps < .05). The relationship between in-person household conversation satisfaction and loneliness trajectory was statistically significantly but minimally attenuated over time (p < .001). CONCLUSIONS: For people with SSc, higher mean conversation, activity, and satisfaction variables were associated with lower levels of loneliness during the pandemic, but changes in these social variables were generally not predictive of changes in loneliness.

Thrombopoietin-Dependent Myelo-Megakaryopoiesis Fuels Thromboinflammation and Worsens Antibody-Mediated Chronic Renal Microvascular Injury.

SIGNIFICANCE STATEMENT: Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGF ß -dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases.Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases. BACKGROUND: Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain emergency hematopoiesis and fuel the thromboinflammatory process. METHODS: Using a murine model of antibody-mediated chronic kidney disease (AMCKD) and pharmacological interventions, we comprehensively monitored the response to injury in the circulating blood, urine, bone marrow, and kidney. RESULTS: Experimental AMCKD was associated with chronic thromboinflammation and the production of HGFs, especially thrombopoietin (TPO), by the injured kidney, which stimulated and skewed hematopoiesis toward myelo-megakaryopoiesis. AMCKD was characterized by vascular and kidney dysfunction, TGF ß -dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGF ß -dependent glomerulosclerosis, and increased bioavailability of TPO. Analysis of albumin, HGF, and inflammatory cytokine levels in sera from patients with extracapillary glomerulonephritis allowed us to identify treatment responders. Strikingly, TPO neutralization in the experimental AMCKD model normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. CONCLUSION: TPO-skewed hematopoiesis exacerbates chronic thromboinflammation in microvessels and worsens AMCKD. TPO is both a relevant biomarker and a promising therapeutic target in humans with CKD and other chronic thromboinflammatory diseases.

Proteinuria and hematuria after remission induction are associated with outcome in ANCA-associated vasculitis.

In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined end point of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti-proteinase 3-ANCA and 35% had anti-myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (interquartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio [HR] 3.06, 95% confidence interval 1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, 1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV.

Mouth opening in systemic sclerosis: A longitudinal analysis from the French National Cohort Study.

BACKGROUND: Few studies have evaluated mouth opening (MO) in systemic sclerosis (SSc). None have studied MO trajectories. OBJECTIVE: To study MO trajectories in SSc. METHODS: This multicentre study included patients enrolled in the French national SSc cohort with at least one MO assessment, described patients based on MO baseline measure, modeled MO trajectories, and associated MO measures with SSc prognosis. RESULTS: We included 1101 patients. Baseline MO was associated with disease severity. On Kaplan-Meier analysis, MO < 30 mm was associated with worse 30-year-survival (p<0.01) and risk of pulmonary arterial hypertension (p<0.05). Individual MO trajectories were heterogenous among patients. The best model of MO trajectories according to latent-process mixed modeling showed that 88.8% patients had a stable MO trajectory and clustered patients into 3 groups that predicted SSc survival (p<0.05) and interstitial lung disease (ILD) occurrence (p<0.05). The model highlighted a cluster of 9.5% patients with diffuse cutaneous SSc (dcSSc) (p<0.05) and high but decreasing MO over 1 year (p<0.0001) who were at increased risk of poor survival and ILD. CONCLUSION: MO, which is a simple and reliable measure, could be used to predict disease severity and survival in SSc. Although MO remained stable in most SSc patients, dcSSc patients with high but decreasing MO were at risk of poor survival and ILD. This article is protected by copyright. All rights reserved.

Clinico-radiological correlation and prognostic value of baseline chest computed tomography in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES: While chest high-resolution CT (HRCT) is correlated to severity and prognosis in asthma, it has not been studied in eosinophilic granulomatosis with polyangiitis (EGPA). Our objective is to study the prognostic value of baseline HRCT in EGPA patients. METHODS: Retrospective, multicentre observational study in three French hospitals, including EGPA patients with available chest HRCT before any systemic treatment. Two experienced radiologists blinded to clinical data evaluated HRCT images using semi-quantitative scoring. HRCT characteristics were correlated with clinical features and outcome. RESULTS: Among 46 patients, 38 (82.6%) had abnormal parenchymal findings on HRCT, including bronchial wall thickening (69.6%), mosaic perfusion (63.0%), ground-glass opacities (32.6%), bronchiectasis (30.4%), mucous plugging (21.7%) and consolidations (17.4%). Patients were clustered into three groups depending on HRCT features: ground-glass pattern, i.e. with ground-glass opacities with or without bronchial abnormalities (group 1, 28.3%), bronchial pattern (group 2, 41.3%) and extra-pulmonary pattern with no significant abnormality (group 3, 30.4%). Group 2 showed less frequent cardiac involvement (31.6 vs 46.2 and 42.9% in groups 1 and 3), more frequent positive ANCA (52.6 vs 0.0 and 14.3%) and higher eosinophil count (median 7510 vs 4000 and 4250/mm3). Group 1 showed worse prognosis with more frequent steroid-dependency (58.3 vs 11.1 and 28.6%) and requirement for mepolizumab (25.0 vs 11.1 and 7.1%). Conversely, group 2 showed a better outcome with higher rates of remission (88.9 vs 41.6 and 71.4%). CONCLUSION: Chest HRCT at diagnosis of EGPA may have prognostic value and help clinicians better manage these patients.

Anti-PM-Scl antibodies-positive patients encompass three different groups with distinct prognoses.

OBJECTIVE: To help identify homogeneous subgroups among patients with anti-PM-scleroderma-antibodies (PM-Scl-Abs) positive auto-immune diseases regardless of diagnostic classifications. MATERIAL AND METHODS: This multicentric (four hospitals) retrospective study collected all consecutive patients (from 2011 to 2021) with positive testing for anti-PM-Scl-Abs in a context of CTD. Subgroups of patients with similar clinico-biological phenotypes were defined using unsupervised multiple correspondence analysis and hierarchical clustering analysis of the features recorded in the first year of follow-up. RESULTS: One hundred and forty-two patients with anti-PM-Scl-Abs were evaluated and 129 patients were included in the clustering analysis and divided into three clusters. Cluster 1 (n = 47) included patients with frequent skin thickening, digestive involvement and interstitial lung disease (ILD) with non-specific interstitial pneumonia (NSIP). They were more likely to develop progressive fibrosing ILD. Cluster 2 (n = 36) included patients who all featured NSIP with frequent organizing pneumonia-associated pattern and mechanic's hands. This subgroup had increased risk of relapse and ILD was characterized by a good functional outcome. Cluster 3 (n = 46) was characterized by predominant or isolated musculoskeletal involvement and frequently matched UCTD criteria. Although very frequent among anti-PM-Scl-Abs positive patients, muscle involvement was less discriminating compared with skin thickening and ILD pattern to classify patients into subgroups. CONCLUSION: Anti-PM-Scl-Abs associated auto-immune diseases are segregated into three subgroups with distinct clinical phenotype and outcomes. Skin thickening and NSIP are determinant predictors in segregation of theses populations.

Determination of four homogeneous subgroups of patients with antiphospholipid syndrome: a cluster analysis based on 509 cases.

OBJECTIVE: APS is a heterogeneous disease with different phenotypes. Using an unsupervised hierarchical cluster analysis, we aimed to determine distinct homogeneous phenotypes among APS patients. METHODS: We performed an observational, retrospective study of APS patients enrolled in the French multicentre 'APS and SLE' registry who met the Sydney classification criteria. The clustering process involved an unsupervised multiple correspondence analysis followed by a hierarchical ascendant clustering analysis; it used 27 variables selected to cover a broad range of APS clinical and laboratory manifestations. RESULTS: These analyses included 509 patients, mainly women (77.8%). Mean (s.d.) age at APS diagnosis was 36.2 (14.6) years, and mean follow-up since diagnosis 10.3 (8.5) years. This hierarchical classification cluster analysis yielded four homogeneous groups of patients: cluster 1, mostly with venous thromboembolism without any associated autoimmune disease; cluster 2, older, lowest proportion of women, history of arterial events, and/or with migraines, arterial hypertension, diabetes mellitus, or dyslipidaemia; cluster 3, younger, highest proportion of women, associated SLE or other autoimmune diseases, and a history of venous thromboembolism or pregnancy morbidity; and cluster 4, mainly with a history of catastrophic antiphospholipid syndrome, aPL-associated nephropathy, and pregnancy morbidity, with frequent triple positivity and more deaths (16.7%). CONCLUSIONS: Our study applied an unsupervised clustering method to distinguish four homogeneous APS patient subgroups that were predominantly venous; arterial; associated with SLE or another autoimmune disease; and arterial microthrombotic. Heterogeneous pathophysiological mechanisms may explain these findings.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. METHODS: MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS: Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION: PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

The association between air pollution and the severity at diagnosis and progression of systemic sclerosis-associated interstitial lung disease: results from the retrospective ScleroPol study.

OBJECTIVE: To investigate the association of air pollution exposure with the severity of interstitial lung disease (ILD) at diagnosis and ILD progression among patients with systemic sclerosis (SSc)-associated ILD. METHODS: We conducted a retrospective two-center study of patients with SSc-associated ILD diagnosed between 2006 and 2019. Exposure to the air pollutants particulate matter of up to 10 and 2.5 µm in diameter (PM10, PM2.5), nitrogen dioxide (NO2), and ozone (O3) was assessed at the geolocalization coordinates of the patients' residential address. Logistic regression models were used to evaluate the association between air pollution and severity at diagnosis according to the Goh staging algorithm, and progression at 12 and 24 months. RESULTS: We included 181 patients, 80% of whom were women; 44% had diffuse cutaneous scleroderma, and 56% had anti-topoisomerase I antibodies. ILD was extensive, according to the Goh staging algorithm, in 29% of patients. O3 exposure was associated with the presence of extensive ILD at diagnosis (adjusted OR: 1.12, 95% CI 1.05-1.21; p value = 0.002). At 12 and 24 months, progression was noted in 27/105 (26%) and 48/113 (43%) patients, respectively. O3 exposure was associated with progression at 24 months (adjusted OR: 1.10, 95% CI 1.02-1.19; p value = 0.02). We found no association between exposure to other air pollutants and severity at diagnosis and progression. CONCLUSION: Our findings suggest that high levels of O3 exposure are associated with more severe SSc-associated ILD at diagnosis, and progression at 24 months.

Mental health symptoms in scleroderma during COVID-19: a Scleroderma Patient-centred Intervention Network (SPIN) cohort longitudinal study.

OBJECTIVES: People with systemic sclerosis (SSc) are vulnerable in COVID-19 and face challenges related to shifting COVID-19 risk and protective restrictions. We evaluated mental health symptom trajectories in people with SSc through March 2022. METHODS: The longitudinal Scleroderma Patient-centred Intervention Network (SPIN) COVID-19 cohort was launched in April 2020 and included participants from the ongoing SPIN Cohort and external enrolees. Analyses included estimated means with 95% CIs for anxiety and depression symptoms pre-COVID-19 for ongoing SPIN Cohort participants and anxiety, depression, loneliness, and fear of COVID-19 for all participants across 28 COVID-19 assessments up to March 2022. We conducted sensitivity analyse including estimating trajectories using only responses from participants who completed >90% of items for ≥21 of 28 possible assessments ("completers") and stratified analyses for all outcomes by sex, age, country, and SSc subtype. RESULTS: Anxiety symptoms increased in early 2020 but returned to pre-COVID-19 levels by mid-2020 and remained stable through March 2022. Depression symptoms did not initially change but were slightly lower by mid-2020 compared to pre-COVID-19 and were stable through March 2022. COVID-19 fear started high and decreased. Loneliness did not change across the pandemic. Results were similar for completers and for all subgroups. CONCLUSIONS: People with SSc continue to face COVID-19 challenges related to ongoing risk, the opening of societies, and removal of protective restrictions. People with SSc, in aggregate, appear to be weathering the pandemic well, but health care providers should be mindful that some individuals may benefit from mental health support.