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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.

Background:Rituximab (RTX) administration in autoimmune diseases (AID) is associated with severe infectious events (SIE). Frequency of SIE and immune reconstitution (B cells, T cells, and immunoglobulins) after RTX have not yet been comprehensively assessed in a prospective study in patients with various AID.Objectives:To explore the impact of RTX on immune system in patients with AID including kinetic evolution of biological parameters, and to estimate the rates of hypogammaglobulinemia (HG), severe infectious events (SIE) and immunoglobulins replacement therapy (IgRT).Methods:Patients treated by RTX for AID were included in a prospective study (planned enrollment of 200 patients between May 2019 and May 2022, clinical trial number: NCT03778840). Clinical and biological parameters were recorded at baseline and then every 3 months for one year (M3, M6, M9 and M12). The influence of baseline characteristics on immune reconstitution was assessed using mixed models.Results:The anticipated number of inclusions was not met because of the SARS-CoV-2 pandemic, which limited RTX prescription and patients’ recruitment. Seventy-two patients were included. There were mostly women (45/72, 62%) presenting with autoimmune cytopenia, connective tissue diseases, organ-specific AID, systemic vasculitis, acquired hemophilia, and other AID. All patients experienced deep B cells depletion and decreased neutrophils count. Both were not influenced by baseline characteristics according to the mixed models. CD4+ and CD8+ T cells count varied over time, with a more profound depletion at M3 and M9 (Figure 1A and B). Mixed model revealed that the use of immunosuppressants (IS) prior to RTX was associated with a more pronounced decrease in CD8+ T cells (p-value: 0.022) and concomitant use of IS at baseline was associated with a more pronounced decrease in CD4+ T cells (p-value: 0.003). We observed a progressive depletion of IgG, IgM, and IgA over time between baseline and M9 (Figure 1C, D and E). HG occurred in 9 patients at M3, 6 at M6, 9 at M9, and 5 at M12. The mixed model revealed that concomitant use of glucocorticosteroids (GC) ≥ 10 mg/day was associated with a more pronounced decrease in IgG rate in the first 6 months (p-value: 0.036). Concomitant use of IS influenced IgM evolution over time (p-value: 0.013). A history of GC ≥ 10 mg/day was associated with a more pronounced decrease of IgA rate during follow-up (p-value: 0.023) and IS use prior to RTX injection influenced the evolution of IgA rate over time (p-value: 0.037). We observed 10 SIE in 9 patients. Three patients received IgIV for immunomodulatory indication (2g/kg), including 2 during the first 3 months of follow-up.Figure 1.Evolution of CD8+ T cells (A), CD4+ T cells (B), immunoglobulins G (IgG) (C), Immunoglobulins M (IgM) (D) and immunoglobulins A (IgA) (E). M: month. Cells count is/mm3 and immunoglobulins counts are expressed in gramme/liter (g/L). Kinetic of evolution are represented in mean and standard deviation (SD).Conclusion:Our study provides several insights into immune reconstitution in patients treated with RTX for AID. B cell depletion and decreased neutrophils count appeared to be directly linked to RTX administration. IgG levels trajectories were influenced by GC. CD4+ and CD8+ T cells count trajectories appeared to be influenced by IS use.REFERENCES:NIL.Acknowledgements:GrifolsDisclosure of Interests:None declared.

Background:Systemic sclerosis (SSc) is a heterogeneous connective tissue disease characterized by autoimmunity, vasculopathy and excessive fibrosis. Functional antibodies such as angiotensin II type 1 receptor and endothelin-1 type A receptor have been described in SSc and might be implicated in vasculopathy, in which endothelial cells (EC) are key players. Antinuclear antibodies (ANA) are strong diagnostic and prognosis biomarkers but their pathogenicity in vasculopathy remains unclear.Objectives:To explore the effect of purified IgG from SSc patients on the proteome of EC and analyse the influence of ANA.Methods:Human umbilical vein endothelial cells (HUVEC) were cultured in presence of purified IgG from: 10 diffuse cutaneous SSc (dcSSc) anti-topoisomerase-I positive patients (dcSSc ATA+), 10 limited cutaneous SSc anticentromere positive patients (lcSSc ACA+), 10 dcSSc anti-RNA polymerase III autoantibodies positive patients (dcSSc RNAP+), 10 healthy controls (HC) and 5 patients with systemic lupus erythematosus (SLE). After 24h, the proteome was analysed using Liquid Chromatography with tandem Mass Spectrometry. Proteomic data were visualized by principal component analysis (PCA). Differential analysis and enrichment analysis were performed to compare pattern of protein expression between groupsResults:Proteomics identified and quantified 2,141 proteins. PCA showed 3 distinct groups of subjects: a first including mostly dcSSc ATA+, a second including mostly lcSSc ACA+ and third groups more heterogeneous including dcSSc RNAP+ patients, SLE patients and HC (Figure 1). The comparison of HUVEC’s proteome in the presence of purified IgG from dcSSc ATA+ vs HC and lcSSc ACA+ vs HC revealed 614 and 288 differentially expressed proteins respectively. Proteins overexpressed in dSSc ATA+ group were enriched in macromolecule localization and protein binding and overexpressed proteins in lcSSc ACA+ groups were enriched in RNA and mRNA proteins binding. Eleven proteins were commonly overexpressed in dcSSc ATA+ or lcSSc ACA+.Figure 1.Protein expression profiles in LC-MS/MS analysis.Principal component analysis (PCA) represented HUVEC protein expression according to the patient ANA status. ATA: purified IgG from diffuse systemic sclerosis anti-topoisomerase-I positive patients; ACA: purified IgG from limited systemic sclerosis anti-centromere positive patients; RNAP: purified IgG from diffuse systemic sclerosis RNA-polymerase III positive patients; SLE: purified IgG from systemic lupus erythematosus patients; HC: purified IgG from healthy controls; HUVEC: Human umbilical vein endothelial cells (HUVEC).Conclusion:Using a proteomic approach, we identified that IgG from SSc modified EC proteome which appeared explained by ANA status. In particular, IgG from both ATA+ et ACA+ patients induced EC singular and distinct proteomic profiles.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Anti-Ro52-kDa/SSA (TRIM21) antibodies are increasingly reported in systemic sclerosis (SSc), with heterogenous results both in prevalence and clinical significance [1], thus preventing a clear understanding of their implication in patients care.Objectives:To estimate the global prevalence of anti-TRIM21 antibodies in SSc, and describe the associated clinical phenotype, through a systematic review and meta-analysis of published reports and new data from our French cohort.Methods:Anti-TRIM21 seropositivity and associated SSc characteristics were assessed in a cross-sectional study including 300 patients of Lille University Hospital. A systematic review of the literature was performed in Pubmed and Embase, followed by a meta-analysis, using data on prevalence, clinical/demographical/biological characteristics of SSc patients and the type of assay used for anti-TRIM21 antibodies detection.Results:In the cross-sectional study, anti-TRIM21 antibodies prevalence was 26.0% [95% CI: 21.1; 31.3]. Anti-centromere antibodies were the most frequent SSc specific autoantibodies coexisting with anti-TRIM21. Patients with anti-TRIM21 antibodies were more frequently women (91% vs 77%, p = 0.006), more likely to present an associated Sjögren’s syndrome (31% vs 11%, p<0.001), had a higher rate of pulmonary arterial hypertension (PAH) (21% vs 9%, p = 0.017) and a greater frequency of digestive complications such as dysphagia (20% vs 9%, p = 0.038) or nausea/vomiting (18% vs 5%, p = 0.009) than anti-TRIM21 negative patients. Thirty-five articles corresponding to a total of 11,751 SSc patients were included in the meta-analysis. In this population, the overall seroprevalence of anti-TRIM21 antibodies was 23% [95%CI: 21-27%] with a high degree of heterogeneity (I2: 93% Phet: <0.0001), partly explained by the methods of detection (Figure 1). Anti-TRIM21 seropositivity was positively associated with female sex (OR: 1.60 [1.25, 2.06]), limited cutaneous subset (OR: 1.29 [1.04, 1.61]), joint manifestations (OR: 1.33 [1.05, 1.68]), pulmonary hypertension (PH) (OR: 1.82 [1.42, 2.33]), and interstitial lung disease (ILD) (OR: 1.31 [1.07, 1.60]).Conclusion:Anti-TRIM21 antibodies frequently co-exist with usual SSc antibodies but are independently associated to a higher risk of cardio-pulmonary complications. The presence of these autoantibodies should therefore be considered when assessing the risk of developing PH and ILD, and deserves further studies on appropriate screening and follow-up of patients.REFERENCES:[1] Decker P, Moulinet T, Pontille F, et al. An updated review of anti-Ro52 (TRIM21) antibodies impact in connective tissue diseases clinical management. Autoimmun Rev. 2022;21:103013.Figure 1.Forest plot showing the prevalence of anti–TRIM21 antibodies in SSc patients, in all studies, according to the method of detection. Each square represents an individual prevalence, with the size of the square being proportional to the weight given to the study. Lines represent the 95% confidence interval for the prevalence estimated in each study. Diamonds represent the pooled prevalence for each detection method. ALBIA: addressable laser bead immunoassay, ELISA: enzyme-linked immunosorbent assay, ELiA: fluorescence enzyme immunoassay,WB: Western blot, NA: not available.Acknowledgements:NIL.Disclosure of Interests:Marie-Elise Martel: None declared, Amelie LEURS CSL Vifor and NOVARTIS, outside the submitted work, David Launay Takeda, Biocryst and CSL Behring, outside the submitted work, GSK, Octapharma, Pfizer, Takeda, Biocryst, CSL Behring, outside the submitted work, Hélène Béhal: None declared, Aurélien Chepy: None declared, Aurore Collet: None declared, Sebastien SANGES: None declared, Eric Hachulla: None declared, Sylvain Dubucquoi: None declared, Luc Dauchet Feder Ecrin and ADEM French environment agency outside the submitted work, Vincent Sobanski Boehringer-Ingelheim, Grifols, Ultragenyx, outside the submitted work, Grifols, outside the submitted work.

Objectives:To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc).Methods:Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities.Results:At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation.Conclusions:This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.

Background As lack of awareness of rare diseases (RDs) among healthcare professionals results in delayed diagnoses, there is a need for a more efficient approach to RD training during academic education. We designed an experimental workshop that used role-play simulation with patient educators and focused on teaching “red flags” that should raise the suspicion of an RD when faced with a patient with frequently encountered symptoms. Our objective was to report our experience, and to assess the improvement in learners’ knowledge and the satisfaction levels of the participants. Results The workshop consisted of 2 simulated consultations that both started with the same frequent symptom (Raynaud phenomenon, RP) but led to different diagnoses: a frequent condition (idiopathic RP) and an RD (systemic sclerosis, SSc). In the second simulated consultation, the role of the patient was played by a patient educator with SSc. By juxtaposing 2 seemingly similar situations, the training particularly highlighted the elements that help differentiate SSc from idiopathic RP. When answering a clinical case exam about RP and SSc, students that had participated in the workshop had a higher mean mark than those who had not (14 ± 3.7 vs 9.6 ± 5.5 points out of 20, p  = 0.001). Participants mostly felt “very satisfied” with this training (94%), and “more comfortable” about managing idiopathic RP and SSc (100%). They considered the workshop “not very stressful” and “very formative” (both 71%). When asked about the strengths of this training, they mentioned the benefits of being put in an immersive situation, allowing a better acquisition of practical skills and a more interactive exchange with teachers, as well as the confrontation with a real patient, leading to a better retention of semiological findings and associating a relational component with this experience. Conclusions Through the use of innovative educational methods, such as role-play simulation and patient educators, and by focusing on teaching “red flags”, our workshop successfully improved RP and SSc learning in a way that satisfied students. By modifying the workshop’s scenarios, its template can readily be applied to other clinical situations, making it an interesting tool to teach other RDs.

Objective To evaluate rituximab (RTX) in primary Sjögren's syndrome (pSS) with peripheral nervous system (PNS) involvement. Methods Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. Results 17 patients (age 60 years (44–78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1–5) to 2 (1–5), 2 (1–5) and 2 (1–6) after 3, 6 and 9 months (p=0.02). European Sjögren's Syndrome Disease Activity Index decreased from 18 (10–44) to 11 (5–20), 11 (5–29) and 12 (5–30) after 3, 6 and 9 months (p<0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1. Conclusion RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.

Systemic sclerosis (SSc) is an autoimmune disorder that is characterized by a interplay of vascular abnormalities, immune system activation and an uncontrolled fibrotic response associated with interstitial lung disease affecting about 40% of patients. Identification of ILD relies on high-resolution CT that identify features suggestive of the histologic patterns of SSc(1). CT is used to determine pattern and extent of ILD and participates in the prediction of ILD progression(2). All group of pulmonary hypertension (PH) may occur with an overall prevalence reported in up to one fifth of patient. Whereas extensive SSc-ILD can be responsible for PH, PH can also be seen as a consequence of myocardial abnormalities or as primarily affecting small pulmonary arteries and classified as pulmonary arterial hypertension. Dual-energy CT introduction offers perspectives in the evaluation of SSc-related pulmonary manifestations. While these are not strictly perfusion images, they have been reported as adequate surrogate markers of lung perfusion (3). In the field of PH, detection of perfusion defects highly concordant with V/Q scintigraphic findings has been reported in the diagnostic approach of CTEPH but also in the differential diagnosis between PAH and peripheral forms of CTEPH (4). To investigate lung perfusion abnormalities in patients with SSc. The study population included 101 patients who underwent dual-energy CT (DECT) angiography in the follow-up of SSc. CT examinations were obtained on a 3rd-generation dual-source CT system with reconstruction of morphologic and perfusion images. All patients underwent pulmonary function tests within two months of the follow-up CT scan. Fifteen patients had right heart catheterization-proven PH. Our population included patients without SSc lung involvement (Group 1; n=37), patients with SSc-related ILD (Group 2; n=56) of variable extent (Group 2a: ≤10%: n=17; Group 2b: between 11-50%: n=31; Group 2c: >50%: n=8) and patients with PVOD/PCH (Group 3; n=8). Lung perfusion was abnormal in 8 patients in G 1 (21.6%), 14 patients in G 2 (25%) and 7 patients in G 3 (87.5%). Perfusion changes were mainly composed of bilateral perfusion defects, including patchy, PE-type perfusion defects and areas of hypoperfusion of variable size. In G 1 and G 2a (n=54): (a) patients with abnormal lung perfusion (n=14) had a significantly higher proportion of NYHA III/IV scores of dyspnea (p=0.031), a shorter mean walking distance at the 6MWT (p=0.042) and a trend towards lower mean DLCO% (p=0.055) when compared to patients with normal lung perfusion (n=40); (b) a negative albeit weak correlation was found between the iodine concentration in both lungs and the DLCO% (r=-0.27; p=0.059) whereas no correlation was found with PAPs (r=0.16; p=0.29) and walking distance during the 6MWT (r=-0.029; p=0.84). DECT lung perfusion provides complementary information to HRCT scans, depicting perfusion changes in SSc patients with normal or minimally infiltrated lung parenchyma. [1]Kim EA, Lee KS, Johkoh T, Kim TS, Suh GY, Kwon OJ, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. Radiogr Rev Publ Radiol Soc N Am Inc. 2002 Oct;22 Spec No:S151-165. [2]Goh NSL, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1248–54. [3]Fuld MK, Halaweish AF, Haynes SE, Divekar AA, Guo J, Hoffman EA. Pulmonary perfused blood volume with dual-energy CT as surrogate for pulmonary perfusion assessed with dynamic multidetector CT. Radiology. 2013 Jun;267(3):747–56. [4]Giordano J, Khung S, Duhamel A, Hossein-Foucher C, Bellèvre D, Lamblin N, et al. Lung perfusion characteristics in pulmonary arterial hypertension and peripheral forms of chronic thromboembolic pulmonary hypertension: Dual-energy CT experience in 31 patients. Eur Radiol. 2017 Apr;27(4):1631–9. None declared

Objectives:To describe the clinical characteristics and muscle pathological features of patients with systemic sclerosis (SSc) and myopathy and analyse their impact on muscle outcome.Methods:Thirty-five patients with myopathy and available muscle biopsy were restrospectively investigated from the charts of four hospital centres.Results:Twenty-six (74%) cases had diffuse SSc. The median time from SSc diagnosis was 5 years (range 0–23) at myopathy onset. The main myopathological features were mononuclear inflammation (63%), muscle atrophy (60%), necrosis (59%), regeneration (44%), fibrosis (24%) or microangiopathy (27%). After a median follow-up of 4.4 years, 24 patients (69%) showed complete or partial muscle remission. Only histological muscle inflammation was associated with good muscle prognosis in multivariate analysis (odds ratio 44.7, 95% CI 2.8 to 704.7). Patients without muscle inflammation had a poor response to corticosteroids (38% favourable response vs 90% in patients with inflammation).Conclusion:Muscle histopathology is critical in the therapeutic management of SSc-associated myopathy.

BackgroundInterstitial lung disease (ILD) is a leading cause of morbidity and mortality in systemic sclerosis (SSc). While factors associated with the presence of ILD in SSc (SSc-ILD) are identified, those associated with ILD outcome are still debated and studies assessing the evolution of SSc-ILD on HRCT are scarce. Yet, it is important to identify patients at risk of SSc-ILD worsening because those patients are thought to benefit the most from immunosuppressants.ObjectivesThus, the aims of our study were: to describe the evolution of HRCT extension and patterns of SSc-ILD, to identify baseline prognosis factors of ILD outcome on serial HRCT and to investigate whether the evolution of pulmonary function tests (PFTs) parameters correlated with the evolution on HRCT.MethodsWe included 58 SSc patients with HRCT proven ILD, with at least two available HRCT, and collected clinical, biological data and PFT at baseline. We collected all HRCT and PFTs available during follow-up. We modelized PFTs and HRCT evolution using linear mixed model with random coefficients.ResultsMean ILD extension at baseline was 32.3%±28.7%. During a mean follow-up of 5.3±4.9 years, we found a significant mean progression of ILD extension of 0.92%±0.36% per year (p=0.018). Male sex, anti-topoisomerase 1 antibodies, diffuse cutaneous SSc were associated with faster progression of ILD extension. Limited ILD according to Goh et al. staging system, and a coarseness score at zero (meaning 100% of ground glass opacification) were associated with a faster progression of ILD extension. We also found a significant decline of DLCO, FVC and TLC during follow-up. There was a significant correlation between the progression of ILD extension on HRCT and the decline of DLCO, but not with the evolution of FVC.ConclusionsMale patients, patients with diffuse SSc/antitopoisomerase 1, patients with less severe and less extensive ILD at baseline were more likely to experiment a faster progression of ILD extension on serial HRCT. To our knowledge, this is the first study that clearly highlighted the diffuse form of SSc/presence of antitopoisomerase 1 as a worsening factor of SSc-ILD on HRCT. FVC might not be the best mirror of ILD progression while DLCO significantly correlated with change in ILD extension. Our study helps to define the profile of patients who are going to experience a progression of ILD on HRCT during follow up.Disclosure of InterestNone declared