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.

ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

OBJECTIVES: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. METHODS: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. RESULTS: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. CONCLUSION: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

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 lupus erythematosus (15.8%) or systemic sclerosis (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.

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.

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.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Autoantibodies versus Skin Fibrosis Extent in Systemic Sclerosis: A Case-Control Study of Inverted Phenotypes.

Objective: to describe the prevalences, characteristics, and survivals of patients with anti-topoisomerase 1 antibodies (ATA) and limited cutaneous systemic sclerosis (lSSc) and anti-centromere antibodies (ACA) and diffuse cutaneous systemic sclerosis (dSSc). Methods: patients with ATA lSSc or with ACA dSSc were included in a case-control retrospective study. Results: In our cohort of scleroderma, the prevalence of ACA dSSc and ATA lSSc was 1.1% (12/1040) and 8.9% (93/1040), respectively. ACA dSSc patients had less interstitial lung disease (ILD) (5 (41.7) vs. 74 (79.6); p < 0.01), more cardiac involvement, and more muscle involvement (3 (25) vs. 4 (4.3); p = 0.03 and 4 (33.3) vs. 4 (7.5); p = 0.02,) than ATA dSSc patients. ATA lSSc patients had a higher modified Rodnan skin score than ACA lSSc patients (4 [2−7.5] vs. 2 [0−5]; p < 0.01) and less cardiac or muscle involvement than ATA dSSc patients (6 (6.5) vs. 19 (20.4%); p < 0.01 and 15 (16.1) vs. 54 (58.1); p < 0.0001, respectively). The cumulative 5-year survival rate was 71% in ACA dSSc patients, 95% in ATA lSSc patients, 84% in ACA lSSc patients, and 66% in ATA dSSc patients (p < 0.0001). Conclusion: ATA lSSc and ACA dSSc have specific characteristics when compared to ATA dSSc or ACA lSSc. ATA lSSc patients have more ILD than ACA lSSc patients, and ATA dSSc patients have the worst prognosis. Overall, inverted phenotypes show the value of a patient assessment combining antibody and skin subset and should be considered as a separate group.

Revisiting characteristics, treatment and outcome of cardiomyopathy in eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss).

OBJECTIVES: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing eosinophil-rich vasculitis. Specific cardiomyopathy (CM) was described in early studies as the most important predictor of mortality. We aimed to revisit EGPA-related CM and investigate its outcome in recent decades. METHODS: We reviewed all EGPA patients managed from 2000 to 2019 in our vasculitis clinic. Baseline characteristics and outcomes were analysed. EGPA-related CM was defined as clinical or extra-clinical manifestations of patent myocardial involvement, after exclusion of other causes. RESULTS: We included 176 patients. The median age was 47 years [interquartile range (IQR) 36-58 years]. Specific CM was observed in 70 patients (40%). Cardiac symptoms were observed in 81% of CM+ patients, including mainly typical or atypical chest pain and peripheral oedema. Abnormal ECG, transthoracic echocardiography and cardiac MRI (CMRI) were found in 72%, 72% and 99% of CM+ patients, respectively, contrasting with abnormalities in 32%, 38% and 60% of CM-negative patients, respectively. Late gadolinium enhancement (LGE) was the most frequent abnormality on CMRI (70%). CM+ patients were less frequently ANCA-positive, had less frequent peripheral neuropathy and had higher eosinophil count. Major adverse cardiovascular events (MACEs) occurred in 13% of patients, both in CM+ and CM- patients. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs. Four patients died, but none from cardiac causes. CONCLUSION: Specific cardiomyopathy is frequent in EGPA, especially in ANCA-negative patients with high eosinophil counts. Long-term outcome was better than previously reported. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs.

Characteristics of thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly syndrome: a retrospective study from a large Western cohort.

Idiopathic multicentric Castleman disease (iMCD) is a non-clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD-not otherwise specified (iMCD-NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD-NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD-NOS, respectively. The two-year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients.

Impact of Cardiovascular Risk Factors on the Occurrence of Cardiovascular Events in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitides.

Despite improvement in the prognosis of ANCA-associated vasculitides (AAVs), increased mortality, mainly from a cardiovascular origin, persists. We aimed to determine the role of cardiovascular risk factors (CVRFs) on the occurrence of major cardiovascular events (MACEs) in AAVs. Patients with AAVs were successively included in a prospective cohort study, which assessed CVRFs (defined by age >50 years in men and >60 years in women, personal history of cardiovascular disease, smoking status, obesity, diabetes, dyslipidemia, hypertension, and sedentary lifestyle), the use of glucocorticoids and immunosuppressive agents at baseline and during follow-up, and the occurrence of MACEs. One hundred and three patients were included, with a median follow-up time of 3.5 years. In the glucocorticoids and cyclophosphamide adjusted multivariate analysis, the occurrence of MACEs was associated with older age (p = 0.001, OR = 14.71, 95% CI (confidence interval) = 2.98-72.68), cardiovascular history (p = 0.007, OR (odds ratio) = 6.54, 95% CI = 1.66-25.71), sedentary lifestyle (p = 0.011, OR = 4.50, 95% CI = 1.42-14.29), hypertension (p = 0.017, OR = 5.04, 95% CI = 1.33-19.12), and dyslipidemia (p = 0.03, OR = 3.86, 95% CI = 1.14-13.09). The occurrence of MACEs was associated with the number of CVRFs (p < 0.001), but not with the use of glucocorticoids or cyclophosphamide (p = 0.733 and p = 0.339, respectively). The implementation of a screening and management program for modifiable CVRFs, particularly hypertension, sedentary lifestyle, and dyslipidemia, may be beneficial for AAV patients in order to reduce their cardiovascular risk.

Elastic Registration-driven Deep Learning for Longitudinal Assessment of Systemic Sclerosis Interstitial Lung Disease at CT.

Background Longitudinal follow-up of interstitial lung diseases (ILDs) at CT mainly relies on the evaluation of the extent of ILD, without accounting for lung shrinkage. Purpose To develop a deep learning-based method to depict worsening of ILD based on lung shrinkage detection from elastic registration of chest CT scans in patients with systemic sclerosis (SSc). Materials and Methods Patients with SSc evaluated between January 2009 and October 2017 who had undergone at least two unenhanced supine CT scans of the chest and pulmonary function tests (PFTs) performed within 3 months were retrospectively included. Morphologic changes on CT scans were visually assessed by two observers and categorized as showing improvement, stability, or worsening of ILD. Elastic registration between baseline and follow-up CT images was performed to obtain deformation maps of the whole lung. Jacobian determinants calculated from the deformation maps were given as input to a deep learning-based classifier to depict morphologic and functional worsening. For this purpose, the set was randomly split into training, validation, and test sets. Correlations between mean Jacobian values and changes in PFT measurements were evaluated with the Spearman correlation. Results A total of 212 patients (median age, 53 years; interquartile range, 45-62 years; 177 women) were included as follows: 138 for the training set (65%), 34 for the validation set (16%), and 40 for the test set (21%). Jacobian maps demonstrated lung parenchyma shrinkage of the posterior lung bases in patients found to have worsened ILD at visual assessment. The classifier detected morphologic and functional worsening with an accuracy of 80% (32 of 40 patients; 95% confidence interval [CI]: 64%, 91%) and 83% (33 of 40 patients; 95% CI: 67%, 93%), respectively. Jacobian values correlated with changes in forced vital capacity (R = -0.38; 95% CI: -0.25, -0.49; P < .001) and diffusing capacity for carbon monoxide (R = -0.42; 95% CI: -0.27, -0.54; P < .001). Conclusion Elastic registration of CT scans combined with a deep learning classifier aided in the diagnosis of morphologic and functional worsening of interstitial lung disease in patients with systemic sclerosis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

High D-dimer plasma concentration in systemic sclerosis patients: Prevalence and association with vascular complications.

Objective: To determine the frequency of elevated D-dimer plasma concentration (>500 ng/mL) in patients with systemic sclerosis and evaluate its association with systemic sclerosis-specific microvascular and macrovascular complications. Methods: Retrospective observational study of patients with systemic sclerosis followed in a tertiary referral center with at least one measurement of D-dimer between 2010 and 2018. Results: A total of 214 patients were analyzed. Mean age at inclusion was 55.1 ± 14.7 years; 180 (84.1%) were female; 74 (34.6%) had diffuse cutaneous systemic sclerosis. Anti-Scl70 and anti-centromere antibodies were positive in 74 (34.6%) and 75 (35.0%) patients, respectively. D-dimer level was elevated in 93 (43.5%) patients, independently of cutaneous subtype (44.6% in diffuse cutaneous systemic sclerosis vs 42.9% in limited cutaneous systemic sclerosis, p = 0.81). At least one microvascular complication was found in 108 (50.5%) patients: 105 (49.1%) with previous or current digital ulcers, 6 (2.8%) with renal crisis, and 4 (1.9%) with pulmonary arterial hypertension. Microvascular complications were more frequent in patients with elevated D-dimer (57.0% vs 45.5%, p = 0.09), significantly so after exclusion of patients with a history of cancer and/or venous thromboembolism (60.5% vs 44.8%, p = 0.04). Macrovascular complications were detected in 15 (7.0%) patients and were associated with a high D-dimer level (11.8% vs 3.3%, p = 0.03). Over a median follow-up of 2.3 years [1.1-3.3] after D-dimer measurement, new macrovascular complications occurred only in patients with high D-dimer (n = 8). Conclusion: High D-dimer levels are frequently found in systemic sclerosis patients and seem to be associated with the occurrence of macrovascular and microvascular complications after adjustment for confounding factors.

Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

Cardiac Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging With T1 Mapping to Assess Myocardial Perfusion and Fibrosis in Systemic Sclerosis: Association With Cardiac Events From a Prospective Cohort Study.

OBJECTIVE: Myocardial involvement may occur during systemic sclerosis (SSc) and can lead to impaired myocardial contraction and/or arrhythmia. Cardiac magnetic resonance imaging (MRI) is used for noninvasive characterization of the myocardium. The aim of this study was to evaluate the utility of cardiac MRI with intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and longitudinal relaxation time (T1) sequence mapping for assessment of myocardial microvascular and interstitium impairment in SSc. METHODS: In this single-center prospective cohort study, 40 consecutive patients with SSc and 20 healthy controls were assessed by cardiac MRI with IVIM DWI and T1 mapping sequences on a 3T scanning system. Images were analyzed independently by 2 assessors, and Bland-Altman plots were used to assess interreader concordance and reproducibility. Characteristics of the patients were compared according to quartiles of T1 and perfusion fraction (f-coefficient) values, using exact Cochran-Ermitage trend tests for qualitative variables and analysis of variance for quantitative variables. Kaplan-Meier cardiac events-free survival curves were plotted and compared with a log-rank test for trend. RESULTS: T1 values were higher in SSc patients than in healthy controls, and were higher in the diffuse cutaneous SSc (dcSSc) subset (P = 0.02). Higher T1 values were associated with the immunologic pattern seen in patients with the dcSSc form (P = 0.0001), a higher modified Rodnan skin thickness score (MRSS) (P = 0.003), and a higher frequency of interstitial lung disease (P = 0.03). Moreover, higher T1 values were correlated with higher MRSS scores (r = +0.32, P = 0.04) and reduced forced vital capacity (r = -0.34, P = 0.048), and tended to be correlated with reduced total lung capacity (r = -0.30, P = 0.07). Lower f-coefficient values, as a measure of decreased tissue perfusion, were associated with less frequent use of vasodilators (P = 0.02 for angiotensin-converting enzyme inhibitors and P = 0.06 for calcium-channel blockers) and more frequent use of glucocorticoids (P = 0.02). The f-coefficients were inversely correlated with the T1 values (r = -0.31, P = 0.02). Furthermore, higher T1 values were associated with higher incidence of cardiac events (log-rank test for trend P = 0.03). CONCLUSION: Increased T1 values, potentially suggesting microscopic fibrosis, were observed more frequently in patients with dcSSc, and higher T1 values were associated with interstitial lung disease and more frequent cardiac events during follow-up. The results of this study show that cardiac MRI with T1 mapping sequences and IVIM DWI may be useful in assessing myocardial involvement in patients with SSc.

Handgrip strength is a comorbidity marker in systemic necrotizing vasculitides and predicts the risk of fracture and serious adverse events.

OBJECTIVE: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV. METHODS: Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models. RESULTS: One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37-13.2), P =0.01] and serious adverse events [HR 2.80 (1.35-5.81), P =0.006]. CONCLUSION: Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain.

Abdominal adipose tissue predicts major cardiovascular events in systemic necrotising vasculitides.

OBJECTIVES: Cardiovascular (CV) events are highly prevalent in systemic necrotising vasculitides (SNV). Visceral/subcutaneous adipose tissue (VAT/SAT) ratio has been shown to be associated with CV events in various diseases. We aimed to assess the relevance of abdominal adipose tissue measurement to predict major CV events (MCVEs) in SNV. METHODS: Patients with SNV were successively included in a longitudinal study assessing MCVEs and other sequelae. Dual x-ray absorptiometry was performed to evaluate abdominal adipose tissue. Patients were prospectively followed for MCVEs, defined as myocardial infarction, unstable angina, stroke, arterial revascularisation and/or hospitalisation for or death from CV causes. RESULTS: One hundred and twenty consecutive SNV patients were included and analysed (54 males, mean age 53±18 years). High CV risk was found in 28 (23.3%) patients. In univariate analysis, age, male gender, VDI, VAT/SAT ratio and serum troponin level were significantly associated with high CV risk, whereas age and VAT/SAT ratio remained independently associated with high CV risk. Variables associated with high tertile of VAT/SAT ratio included age and metabolic risk factors. After median follow-up of 42 months, 19 (16%) patients experienced MCVEs. Hazard ratios for incident MCVEs compared with 1st tertile of VAT/SAT ratio were 7.22 (1.02-51.3; p=0.048) and 9.90 (3.15-31.2; p=0.0002) in the 2nd and 3rd tertile, respectively. CONCLUSIONS: Abdominal visceral adipose tissue is a reliable surrogate marker of CV risk and predicts incident MCVEs in SNV patients. Abdominal adipose tissue should be probably evaluated routinely in these patients to assess CV risk.

Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France.

Background: Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method: Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results: Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions: Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.

Relevance of diagnostic investigations in patients with uveitis: Retrospective cohort study on 300 patients.

OBJECTIVE: The diagnostic workup of uveitis is a challenge due to the wide range of diagnoses and the lack of a well-codified diagnostic procedure. We aimed to evaluate the relevance of diagnostic investigations for the etiological diagnosis of uveitis. METHODS: Retrospective cohort study of patients referred for etiological diagnosis of uveitis. Uveitis related to ophthalmological diseases or occurring during the course of previously diagnosed diseases were not included. RESULTS: Three hundred patients were included. Chest CT-scan was suggestive of sarcoidosis in 83 (29%). Features associated with abnormal CT-scan were: snowballs and/or peripheral multifocal choroiditis (PMC) upon ocular examination (P=0.004), blood lymphopenia (P<0.0001), angiotensin converting enzyme (ACE) level>1.5 ULN (P=0.0003). Bronchoscopy showed granuloma in 18 (11%) while alveolar lymphocytosis suggestive of sarcoidosis was reported in 45 (27%). Presence of granuloma on bronchial biopsies was always associated with chest CT-scan abnormalities, whereas 31% of patients with alveolar lymphocytosis had normal CT-scans. Features associated with contributive bronchoscopy were: snowballs and/or PMC (P=0.003), ACE>1.5 ULN (P=0.007), abnormal chest-CT scan (P<0.0001). Salivary gland biopsy revealed granuloma in 12 patients (5%). Cerebral MRI was abnormal in 15 patients (9%) who mostly presented with snowballs and/or retinal vasculitis. Finally, the main causes of uveitis were latent tuberculosis (25%) and sarcoidosis (22%), but 34% remained of undetermined origin. Uveitis relapses were observed in 31% and did not differ between patients with an identified diagnosis and those with idiopathic uveitis. CONCLUSION: Identification of factors associated with abnormal investigations might improve the optimal diagnostic workup adapted to each patient.