Connective Tissue Disease Patients Research Articles

P156 Type I interferon is raised across connective tissue diseases and is associated with haematological abnormalities and specific autoantibody profiles

Abstract Background/Aims The overlapping clinical and serological features among connective tissue diseases (CTDs) suggest a shared molecular aetiology. A molecular taxonomy of CTDs offers new opportunities in clinical trial design, which can potentially be translated into targeted treatment. In a previous study of 164 patients, we identified a type I interferon (IFN) positive subgroup within an unselected CTD cohort associated with specific clinical and serological features. Here, we aim to investigate the relationship between type I IFN and the clinical and immunological phenotype in a larger CTD cohort and determine whether a distinct subpopulation of patients can be identified. Methods Adult patients with at least 1 CTD clinical feature and CTD-related autoantibody were recruited from five rheumatology centres in North West England into the Lupus Extended Autoimmune Phenotype (LEAP) cohort. A 24-gene interferon-stimulated gene (ISG) score was calculated using NanoString as described by Neasens et al. 2022. Results Most patients had lupus (36%). 160 of 344 (46.5%) patients had a positive ISG score across all CTDs with 64/125 (51%) of lupus patients (Fig.1). Patients with positive ISG score were younger and had longer disease duration (p < 0.005 for both). There were no differences in mucocutaneous or internal organ involvement between the ISG subgroups. The ISG-positive group had significantly increased frequency of specific autoantibodies (anti-Smith, anti-Chromatin, anti-RNP, anti-Ro) and Rheumatoid Factor, and haematological abnormalities (lower haemoglobin, and lower total white cell and neutrophil counts) in an adjusted model including the CTD subtype. Conclusion In CTD patients, IFN type I positivity was identified across a subset of patients of all CTDs and is associated with specific autoantibodies and haematological parameters; these results support the findings of our previous smaller study. The identification of an IFN I-positive subgroup within an unselected CTD regardless of clinical diagnosis supports a molecular-based approach to treatment. Disclosure A. Madenidou: Grants/research support; Janssen and UCB. G.I. Rice: None. S. Dyball: Grants/research support; UCB, Novartis,Eli Lilly. B. Parker: Honoraria; Fresenius-Kabi and AbbVie. Member of speakers’ bureau; Eli Lilly and Roche. Grants/research support; Genzyme/Sanofi and GlaxoSmithKline. T.A. Briggs: Grants/research support; Janssen. I.N. Bruce: Consultancies; AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Serono and UCB. Member of speakers’ bureau; AstraZeneca, GlaxoSmithKline and UCB. Grants/research support; Genzyme/Sanofi, GlaxoSmithKline, Roche, Novartis, Janssen and UCB.

Patient characteristics, diagnostic testing, and initial treatment profiles of patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) using a Japanese claims database.

To investigate the diagnostic and therapeutic landscape for patients with connective tissue disease (CTD) and CTD-associated pulmonary arterial hypertension (CTD-PAH) in acute-care general hospitals in Japan. We conducted a retrospective cohort study by analysing the Medical Data Vision (MDV) database from April 2008 and September 2020. CTD patients who prescribed immunosuppressants were included in cohort 1, and CTD-PAH patients extracted from cohort 1 were included in cohort 2. Patient characteristics, diagnostic screening frequencies for PAH, and initial PAH-specific treatment patterns were assessed. Overall, 16648 patients with CTD and 81 patients with CTD-PAH were included in cohorts 1 and 2, respectively. The frequencies of screening tests for PAH, including brain natriuretic peptide (BNP), transthoracic echocardiogram (TTE), and diffusing capacity of the lungs for carbon monoxide (DLCO), among CTD patients were 0.7, 0.3, and 0.1 tests/person-year, respectively. The most common initial PAH-specific treatment therapy was monotherapy (87.7%), followed by dual therapy (7.4%), and triple therapy (2.5%). This is the first study to describe the patient flow from PAH diagnosis to initial PAH-specific treatment for real-world patients who were followed regularly due to CTD in Japanese clinical practice.

Association of serum uric acid with right cardiac chamber remodeling assessed by cardiovascular magnetic resonance feature tracking in patients with connective tissue disease.

Right cardiac chamber remodeling is widespread in patients with connective tissue disease (CTD). Serum uric acid (SUA) is considered a potential independent risk factor for cardiovascular disease, and elevated SUA levels are often observed in patients with CTD. The correlation between SUA levels and right cardiac chamber remodeling remains unclear. This study investigated the association of SUA with right cardiac chamber remodeling as assessed by cardiac magnetic resonance feature-tracking (CMR-FT) in CTD patients. In this cross-sectional study, a total of 104 CTD patients and 52 age- and sex-matched controls were consecutively recruited. All individuals underwent CMR imaging, and their SUA levels were recorded. The patients were divided into three subgroups based on the tertiles of SUA level in the present study. CMR-FT was used to evaluate the right atrial (RA) longitudinal strain and strain rate parameters as well as right ventricular (RV) global systolic peak strain and strain rate in longitudinal and circumferential directions for each subject. Univariable and multivariable linear regression analyses were used to explore the association of SUA with RV and RA strain parameters. Compared with the controls, the CTD patients showed significantly higher SUA levels but a lower RV global circumferential strain (GCS) and RA phasic strain parameters (all p < 0.05), except the RA booster strain rate. RV GCS remained impaired even in CTD patients with preserved RV ejection fraction. Among subgroups, the patients in the third tertile had significantly impaired RV longitudinal strain (GLS), RV GCS, and RA reservoir and conduit strain compared with those in the first tertile (all p < 0.05). The SUA levels were negatively correlated with RV GLS and RV GCS as well as with RA reservoir and conduit strain and strain rates (the absolute values of β were 0.250 to 0.293, all P < 0.05). In the multivariable linear regression analysis, the SUA level was still an independent determinant of RA conduit strain (β = -0.212, P = 0.035) and RV GCS (β = 0.207, P = 0.019). SUA may be a potential risk factor of right cardiac chamber remodeling and is independently associated with impaired RA conduit strain and RV GCS in CTD patients.

Naifold capillaroscopy in mixed connective tissue disease patients.

Mixed connective tissue disease (MCTD) is a rare systemic disease characterized by overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermato-/polymyositis (DM/PM), and rheumatoid arthritis (RA). Naifold capillaroscopy (NFC) is a non-invasive test for evaluating the capillaries of the nail shaft used in the diagnosis of rheumatic diseases. To determine whether there are characteristic abnormalities in NFC in MCTD patients, and whether the type of NFC lesions correlates with organ involvement in these patients. Clinical picture and NFC patterns were analyzed in 43 patients with MCTD. Capillaroscopic images were divided into scleroderma-like pattern (SD-like pattern) according to the Cutolo classification, non-specific lesions, and normal images. Relationships between the clinical aspects considered in the MCTD classification criteria and the changes in the capillaroscopic images were evaluated. SD-like pattern was present in 20 MCTD patients (46.51%) with a predominance of the "early" pattern. Giant, branched, dilated capillaries and reduced capillary density were found more frequently in MCTD patients compared to the control group (p-values 0.0005, 0.005, 0.02, < 0.0001 respectively). There were associations found between the presence of a reduced number of vessels, avascular areas, and SD-like pattern with the presence of sclerodactyly in MCTD patients (p = 0.002, p = 0.006, p = 0.02, respectively), alongside an association between the presence of branched vessels and the subpapillary plexus with pulmonary arterial hypertension (PAH) (p = 0.04 and p = 0.005, respectively). MCTD patients are significantly more likely to have abnormalities upon NFC. It is worthwhile to perform capillaroscopic examination in MCTD patients. Key Points • Scleroderma-like pattern was found in more than half of the MCTD patients. • Reduced capillary density was found to be a significant predictor of the diagnosis of MCTD. • There were relationships between the presence of reduced capillary density, avascular areas, and SD-like with the presence of sclerodactyly in the MCTD patients. • There was an association between the presence of branched vessels and the visibility of the subpapillary plexus and pulmonary arterial hypertension (PAH).

Effectiveness and safety of eltrombopag in connective tissue disease patients with refractory immune thrombocytopenia: a retrospective study.

We aimed to investigate the safety and effectiveness of eltrombopag for adult patients with refractory immune thrombocytopenia (ITP) secondary to connective tissue disease (CTD). This is a single-centre, retrospective cohort and propensity score-matched study. Data from CTD-ITP patients treated with eltrombopag between January 2019 and January 2023 were retrospectively analysed. Baseline characteristics and follow-up information were recorded. CTD patients without ITP were matched to identify the risk factors associated with CTD-ITP performed by Logistic regression analysis. Twenty patients were enrolled, including 5 systemic lupus erythematosus (SLE), 9 Sjögren's syndrome (SS) and 6 undifferentiated connective tissue disease (UCTD). Nineteen (95%) patients were female, and the median age was 59 years. Logistic regression analysis showed that anaemia (OR = 8.832, P = 0.007) was associated with increased risk of ITP, while non-erosive arthritis (OR = 0.045, P = 0.001) and interstitial lung disease (OR = 0.075, P = 0.031) were associated with reduced risk. Fourteen patients (70%) achieved a complete response (CR) and one (5%) achieved a partial response (PR). The median response time was 14 days. The median platelet count was 8.5 × 109/l at baseline of eltrombopag and increased to 122 × 109/l after 4 weeks. No adverse events were observed. Eltrombopag appears to be effective, safe and well-tolerated in refractory ITP patients with CTD; larger studies are needed to confirm the generalizability of these findings.

Systemic Connective Tissue Disease and Neuromyelitis Optica Spectrum Disorder Coexistence: A Systematic Review and Meta-Analysis.

Several results support the hypothesis that a group of pathologies falling within the Neuromyelitis Optica Spectrum Disorders (NMOSD) diagnostic criteria may coexist with Connective Tissue Diseases (CTD) in patients with a high susceptibility to autoimmune conditions. However, the relationship between NMOSD and rheumatologic diseases deserves further investigations to clarify all clinical aspects of this coexistence. We designed a systematic review and a proportional meta-analysis to estimate the association between CTD and MNOSD, with the aim of helping to plan the best strategy to achieve the most significant public health benefit for these conditions. We conducted a systematic review of the literature published until February 2023, searching in four databases: PubMed, Web of Science, EmBase, and OVID. Then, we conducted a random-effects proportional meta-analysis and assessed the risk of bias of the included studies using the Joanna Briggs Institute checklist. The literature search yielded an overall result of 3176 publications (272 from PubMed, 880 from Web of Science, 634 from EmBase and 1390 from OVID). Of these, 29 were included in this systematic review. Analyzing studies that recruited unselected patients with Systemic Lupus Erythematosus (SLE) and Sjogren Syndrome (SjS), the pooled percentages of NMOSD overlapping were 0.6% (95% Confidence Interval [95% CI]: 0.1%-1.4%,) and 6.5% (95% CI: 4.7-8.6), respectively. Studies enrolling rheumatologic patients with nervous system symptoms involvement reported higher percentage of NMOSD (i.e., among SjS patients, a pooled percentage of 26.5%, 95% CI: 5.5-54.6%, was found). Similarly, recruiting patients with NMOSD, we found pooled percentages of SjS or SLE respectively of 7.0% and 3.5%. Our research found that the coexistence of these two disorders was more frequent in female rheumatologic patients with a SjS diagnosis with neurological manifestations and in neurologic patients for whom a SjS diagnosis was suspected. Similarly, NMOSD are less frequently found in SLE and very rarely incident in Mixed Connective Tissue Disease (MCTD) patients. These considerations should be taken into account in clinical experience of rheumatologists and neurologists, since early diagnosis of both conditions may influence the timing of immunosuppressive therapy and the prevention of systemic disabilities.

Genetic link between primary biliary cholangitis and connective tissue diseases in European populations: A two-sample Mendelian randomization study.

An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30-1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04-1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12-1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC.

Nailfold capillaroscopy abnormalities and pulmonary hypertension in mixed connective tissue disease and systemic sclerosis patients.

Pulmonary arterial hypertension (PAH) represents an important vascular complication of mixed connective tissue disease (MCTD) and systemic sclerosis (SSc). Microvascular involvement in these diseases can be investigated by means of nailfold capillaroscopy (NFC). Microvascular involvement detected in the nailfold bed is the mirror of the microvascular damage occurring in the entire body, further indicating the involvement of the target organs. The aim of this study was to evaluate the microvascular involvement in MCTD patients with or without PAH, compared to that found in SSc patients with or without PAH. This cross-sectional study was performed in the Department of Internal Medicine and Department of Rheumatology, Timișoara, Romania, during the time period between January 2017 and December 2022, on a group of 26 patients with MCTD and 26 SSc patients. Antinuclear antibodies, anti-U1-RNP, anti-Scl 70, anti-centromere, anti-cardiolipin antibodies (aCL) (IgM, IgG), anti-β2-glycoprotein I (aβ2GPI) (IgM, IgG) antibodies, and lupus anticoagulant (LAC) were determined in both the groups. PAH was evaluated through cardiac ultrasonography, determining the sPAP (systolic pulmonary artery pressure). Nailfold capillaroscopy was performed using a USB Digital Microscope and 2.0-megapixel digital camera recording capillaries density, giant capillaries, enlarged capillaries, capillaries hemorrhages, avascular areas, ramified/bushy capillaries scores. Data were recorded and presented as mean ± standard deviation. Statistical analyses were performed using the Student's t-test, ANOVA test, and Pearson's correlation. Differences were considered statistically significant if p-value < 0.05. Among the MCTD patients, PAH was identified in 12 patients (46.15%), while among the SSc patients PAH was identified in 14 patients (53.84%). Development of PAH in MCTD patients was associated with lower capillaries density (p-value < 0.00001), higher scores of giant capillaries, ramified/bushy capillaries, and capillary hemorrhages (p-value < 0.00001, for each of them). Anti-U1-RNP, aCL, aβ2GPI antibodies and LAC were also found to be involved in PAH-associated MCTD development. Unlike MCTD patients, SSc patients with PAH presented with lower capillaries density and ramified/bushy capillaries scores (p-value < 0.05). The MCTD patients who presented significant NFC abnormalities (especially active and late scleroderma-like capillaroscopic pattern) are prone to PAH development. Capillary density reduction is the most important factor associated with the occurrence of PAH. Differences in NFC findings (especially capillary density and ramified/bushy capillaries) were detected among patients with MCTD and SSc having PAH.

Fatigue and sleep quality in Chinese adults with connective tissue disease: A cross-sectional study.

This study aims to evaluate fatigue and sleep quality among adults with connective tissue disease (CTD), and the interrelationship. From April 2020 to February 2021, adult CTD patients hospitalized were invited to complete sociodemographic and disease-related data, Fatigue Severity Scale (FSS), and Pittsburgh Sleep Quality Index (PSQI), as well as laboratorydetection through computer query. Statistical analysis was performed using SPSS 22.0. A total of 363 patients with CTD were included in the study. Of which, 313 patients were accompaniedby single CTD (systemic lupus erythematosus (SLE) = 109, Sjogren's syndrome (SS) = 51, rheumatoidarthritis (RA) = 44, idiopathic inflammatory myopathies (IIM) = 36, Vasculitis = 17, systemic sclerosis (SSc) = 14, other = 42, respectively), and 50 patients had CTD ≥ 2. Compared with CTD = 1, patients with CTD ≥ 2 had longer disease duration, higher erythrocyte sedimentation rate, and higher IgG level (all P < 0.05). The prevalence of poor sleep quality in 363 CTD patients was 61.2%, among which, 59.1% for CTD = 1 and 74.0% for CTD ≥ 2, with significant difference (P = 0.045). Additionally, 75.5% experienced fatigue, and 75.4% for CTD = 1, 76.0% for CTD ≥ 2 (P = 0.927). Fatigue and sleep quality interacted in CTD patients (r = 0.236, P < 0.01; χ2 = 11.302, P = 0.001). Interestingly, no significant differences were found in the prevalence of fatigue and poor sleep quality among CTD subgroups, as well as the FSS score, the seven components of sleep quality and total PSQI score (P > 0.05). More than 3/5 CTD patients experience fatigue and poor sleep quality, and not different among CTD subgroups. Targeted interventions are needed to reduce fatigue, improve sleep quality, and ultimately improve the prognosis of patients with CTD.

Evaluation of early retinal changes in patients on long-term hydroxychloroquine using optical coherence tomography angiography.

Connective tissue diseases (CTD), including systemic lupus erythematosus and rheumatoid arthritis (RA), have long been treated with hydroxychloroquine (HCQ). However, prolonged HCQ use poses a risk of adverse effects, particularly retinopathy. To detect early retinal changes assessed by optical coherence tomography angiography (OCTA) in CTD patients with long-term HCQ treatment and to explore the relationship between OCTA parameters and the concentrations of HCQ and its metabolites. A cross-sectional study conducted from March 2020 to October 2021 at the First Affiliated Hospital of Anhui Medical University. The area and perimeter of the foveal avascular zone (FAZ), the thickness of the fovea and parafovea, and the vascular density of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in each area of the macula were measured by OCTA in 43 CTD patients treated with HCQ for over 6 months. Meantime, blood concentrations of HCQ and its metabolites were determined by high-performance liquid chromatography-tandem mass spectrometry, and the clinical documents of all 43 involved patients were collected. There is no significant correlation between OCTA outcomes and the patient's age, disease duration, and weight-dependent dose. HCQ cumulative duration positively correlated with FAZ area and perimeter (r = 0.419, p = 0.005 and r = 0.407, p = 0.007, respectively) and negatively correlated with the foveal vessel density in DCP (r = -0.378, p = 0.012). HCQ cumulative dose had a positive correlation with FAZ area and perimeter (r = 0.445, p = 0.003 and r = 0.434, p = 0.004, respectively) and had a negative correlation with foveal vessel density in SCP and DCP (r = -0.383, p = 0.011 and r = -0.424, p = 0.005, respectively). OCTA outcomes did not correlate with HCQ and its metabolite concentrations. OCTA could be used to detect microvascular changes in the macula of CTD patients with long-term HCQ therapy. It was not found the concentrations of HCQ and its metabolites were associated with retinal vascular changes.

Clinicoepidemiological Spectrum of Connective Tissue Diseases in the Pediatric Population in a Tertiary Care Center in North India: A Cross-sectional Observational Study

Abstract Background: Connective tissue diseases (CTDs) are chronic in nature and carry a high risk of morbidity, disability, and mortality if not recognized and treated promptly. Data on clinical spectrum of CTDs in the pediatric age group are sparse from developing countries such as India. Objective: To study the clinicoepidemiological spectrum of CTDs in the pediatric age group. Methodology: A hospital-based, cross-sectional, observational study was undertaken over a period of 16 months from January 2021 to June 2022 in the dermatology outpatient department and pediatric rheumatology clinic in a tertiary care hospital in North India. Clinical and laboratory findings were recorded. Results: A total of 100 children diagnosed with a CTD were included in the study. The mean age was 11.11 ± 4.20 years. Out of 100 children, 55% were female and 45% were male with a male-to-female ratio of 1:1.2. Our study included 63% juvenile idiopathic arthritis, 17% systemic lupus erythematosus, 7% juvenile dermatomyositis, 6% Kawasaki disease, 3% systemic sclerosis, and 2% Henoch–Schonlein purpura and mixed CTD patients each. Mucocutaneous features commonly seen were rash (40%), oral ulcers (22%), and photosensitivity (18%). Commonly seen systemic features were joint pain (77%), followed by fever (63%). Conclusion: Mucocutaneous manifestations are frequently seen in CTDs and constitute a frequent and an early manifestation of CTD. Early recognition of CTD in the pediatric age group will help in timely initiation of treatment to prevent disabilities and mortality.

Clinical significance of interleukin-6, total bilirubin, CD3 + CD4 + T cells counts in the acute exacerbation of connective tissue disease-associated interstitial lung disease: a cross-sectional study

ObjectiveInterstitial lung disease (ILD) is a severe complication of connective tissue disease (CTD) that can significantly impact patients' prognosis and quality of life. However, the current diagnostic arena lacks reliable biomarkers for detecting and monitoring the progression and exacerbation of CTD-ILD. This study aimed to investigate the clinical value of 12 serum cytokines in the diagnosis of CTD-ILD and prediction of the risk of acute exacerbation (AE) in this disease.MethodsThis study was a cross-sectional investigation. Ninety-one hospitalized CTD patients were allocated into two groups: CTD-ILD group (n = 61) and CTD-non-ILD group (n = 30), and 30 sex-age matched healthy volunteers were enrolled as controls. The serum concentrations of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, and IL-1β were measured by Luminex suspension arrays. Logistic regression was employed to determine the significance of variables in the occurrence of AE-CTD-ILD. A nomogram was constructed to visualize the independent variables.ResultsElevated levels of IL-6, IL-8, and TNF-α were observed and compared in the CTD-ILD group with CTD-non-ILD (all P < 0.05). Similarly, the levels of IL-6, IL-8 and TNF-α were higher in the acute exacerbation (AE-CTD-ILD) group compared with stable CTD-ILD (S-CTD-ILD) (P < 0.001, P < 0.001, and P = 0.022). Significant correlations between serum IL-6 and PaO2/FiO2 ratio (r = − 0.463, P < 0.001), percent predicted forced vital capacity (FVC%; r = − 0.362, P < 0.05), and total ground-glass opacity (GGO) score (r = 0.439, P < 0.001) were observed in CTD-ILD patients. Multivariate logistic regression analysis revealed that elevated IL-6 levels, total bilirubin (TBil), and decreased CD3 + CD4 + T cells counts were independent risk factors for the occurrence of AE-CTD-ILD (OR = 1.121, P = 0.024; OR = 1.865, P = 0.047; OR = 0.983, P = 0.037, respectively). Furthermore, by employing these three variables in combination for the prediction of AE status, their collective impact surpasses the independent effects of any single biomarker.ConclusionsElevated levels of serum IL-6, IL-8, and TNF-α were associated with the complication of ILD in CTD patients and the occurrence of AE in CTD-ILD patients. IL-6 could be a promising serum biomarker of severity and the occurrence of AE in CTD-ILD patients. The combination of the three variables (IL-6 level, TBil and CD3 + CD4 + T cells) predicted the AE-CTD-ILD better.

Autoantibody status according to multiparametric assay accurately estimates connective tissue disease classification and identifies clinically relevant disease clusters

ObjectiveAssessment of circulating autoantibodies represents one of the earliest diagnostic procedures in patients with suspected connective tissue disease (CTD), providing important information for disease diagnosis, identification and prediction of potential...

The phenotype of mixed connective tissue disease patients having associated interstitial lung disease

ObjectiveWe aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity. MethodsThis international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements. Results300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001). ConclusionIn this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease.

Association of anti-Ro52 antibody with depression and anxiety in patients with connective tissue diseases: an observational, single-centre, cross-sectional study.

To explore the risk factors of anxiety and depression, especially their association with serum autoantibodies, in patients with connective tissue diseases (CTDs). Three hundred and fifty-two inpatients with CTDs were recruited and their demographic, serological and imaging data were collected through the medical record system. Depression and anxiety were assessed by the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 Scale (GAD-7) respectively. Analysis of variance (ANOVA), rank sum test, chi-square test and logistic regression were performed to investigate risk factors for depression and anxiety. The prevalence of depression (PHQ-9 ≥ 5) and anxiety (GAD-7 ≥5) in CTD patients was significantly higher than that in the Chinese general population (depression: 44.3% vs. 32.2%, anxiety: 39.5% vs. 22.2%). Sleep time was a protective factor for both depression and anxiety (OR=0.734, 95% CI: 0.616~0.874, p<0.001 and OR=0.684, 95% CI: 0.559~0.835, P<0.001, respectively) while anti-Ro52 antibody was a risk factor for them (OR=5.466, 95% CI: 2.978~10.032, p<0.001 and OR=4.075, 95% CI: 2.073~8.010, p<0.001, respectively). Further analysis showed that anti-Ro52 antibody was a risk factor for depression and anxiety in all four subgroups, namely SLE, SS, RA, and other CTDs. Anti-Ro52 antibody is probably a risk factor for depression and anxiety in patients with connective tissue diseases. CTD patients with the presence of anti-Ro52 antibody are more prone to depression and anxiety than those without it.

No evidence of increased anti-M3 muscarinic acetylcholine receptor autoantibodies in SSA-positive connective tissue disease patients.

Anti-muscarinic type 3 receptor autoantibodies (M3R) and anti-SSA antibodies are both related to salivary secretion. The presence of M3R antibodies in Sjögren's syndrome is previously demonstrated; nevertheless, the relationship between the anti-SSA antibodies and M3R fragment antibodies, namely the N terminal, first, second, and third extracellular loops, remains to be elucidated. In this study, we analyzed the antibodies against the M3R epitopes in healthy controls and anti-SSA antibody-positive connective tissue disease patients through ELISA method. Antibodies against the first, second, and third extracellular loop (M3R211-230 ) were not increased in anti-SSA positive patients compared to healthy controls. Indeed, antibodies against the N terminal (M3R1-33 ) were found to be high in healthy controls. High levels of M3R1-33 in healthy controls are a novel original finding; further research is needed for the clinical significance. There is no significant difference between SSA-positive patients and healthy controls in terms of autoantibodies against the remainder of the linear M3R fragments.

Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta.

Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in col1a2 serve as a murine model of OI (oim/oim), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of oim/oim mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention.

The Possible Relation of Demodex and Facial Erythema in Connective Tissue Diseases.

We aimed to investigate the frequency of Demodex infestation and clinical implications in connective tissue disease patients with facial erythema. Patients diagnosed with a connective tissue disease and had facial erythema were consecutively enrolled in the study from 2019-2020. An age and gender matched control group was formed from healthy volunteers. Presence of Demodex was investigated by standardized skin surface biopsy. Number of Demodex mites over 5 per centimeter square was considered meaningful for infestation. Topical or systemic metronidazole treatment was given to the connective tissue disease patients with Demodex infestation. Facial erythema visual analog scale was questioned in patients at treatment onset and one month after. A total of 31 connective tissue disease patients with facial erythema were enrolled. Control group included 31 healthy volunteers. Demographics and comorbidities were similar between groups. Demodex infestation was present in 58.1% of the disease group and in 25.8% of the control group (P=0.01). Pruritus was the most common symptom in patients with infestation. Median (IQR) facial erythema visual analog scale score was 6 (3) at treatment onset and was 2 (2.5) one month later (P<0.001). When evaluating facial cutaneous lesions, Demodex infestation should not be overlooked in a patient group like connective tissue diseases with dysfunctional immune system.

Retrospective cohort study of pulmonary arterial hypertension associated with connective tissue disease effect on patients' prognosis.

The objectives of this study are to clarify clinical characteristics and recognize prognostic factors of CTD-PAH patients. A retrospective cohort study of consecutive patients with documented CTD-PAH diagnosis from Jan 2014 to Dec 2019 was conducted, the ones who have other comorbid conditions that cause PH were excluded. Survival functions were plotted using the Kaplan-Meier method. Univariable and multivariable Cox regression analysis was applied to determine the survival-related factors. In 144 patients with CTD-PAH analyzed, the median sPAP value was 52.5 (44.0, 71.0) mmHg, the overall targeted drug usage rate was 55.6%, and only 27.5% patients were given combination. Twenty-four non-PAH-CTD patients with sPAP value were included as the control group. Compared with non-PAH-CTD groups, CTD-PAH patients had worse cardiac function, higher NT-pro BNP and γ-globulin level, and lower PaCO2 level. Compared with the mild PAH group, the moderate-severe PAH group had worse cardiac function; increased Hb, HCT, and NP-pro BNP level; and decreased PaO2. Kaplan-Meier analysis showed significant difference for survival among non-PAH-CTD, mild CTD-PAH, and moderate-severe CTD-PAH groups. The univariate analyses showed that Hb, pH, and Ln (NT-pro BNP) were identified as factors significantly associated with survival, and Hb and pH showed significant association with risk of death in the multivariate model. Kaplan-Meier analysis also showed that Hb > 109.0 g/L and pH > 7.457 affected CTD-PAH patients' survival significantly. PAH is not rare in CTDs patients; PAH affects CTD patients' prognosis significantly. Higher Hb and pH were associated with an increased risk of death. Key Points • Pulmonary arterial hypertension affects connective tissue disease patients' prognosis significantly. • The significantly factors associated with survival is hemoglobin, pH, and Ln (NT-pro BNP).

KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study.

Krebs von den Lungen 6 (KL-6) is a potential biomarker for determining the severity of interstitial lung disease (ILD) in patients with connective tissue disease (CTD). Whether KL-6 levels can be affected by potential confounders such as underlying CTD patterns, patient-associated demographics, and comorbidities needs further investigation. From the database created by Xiangya Hospital, 524 patients with CTD, with or without ILD, were recruited for this retrospective analysis. Recorded data included demographic information, comorbidities, inflammatory biomarkers, autoimmune antibodies, and the KL-6 level at admission. Results of CT and pulmonary function tests were collected one week before or after KL-6 measurements. The percent of predicted diffusing capacity of the lung for carbon monoxide (DLCO%) and computed tomography (CT) scans were used to determine the severity of ILD. Univariate linear regression analysis showed that BMI, lung cancer, TB, lung infections, underlying CTD type, white blood cell (WBC) counts, neutrophil (Neu) counts, and hemoglobin (Hb) were related to KL-6 levels. Multiple linear regression confirmed that Hb and lung infections could affect KL-6 levels independently; the β were 9.64 and 315.93, and the P values were 0.015 and 0.039, respectively. CTD-ILD patients had higher levels of KL-6 (864.9 vs 463.9, P < 0.001) than those without ILD. KL-6 levels were closely correlated to the severity of ILD assessed both by CT and DLCO%. Additionally, we found that KL-6 level was an independent predictive factor for the presence of ILD and further constructed a decision tree model to rapidly determine the risk of developing ILD among CTD patients. KL-6 is a potential biomarker for gauging the incidence and severity of ILD in CTD patients. To use this typical value of KL-6, however, doctors should take Hb and the presence of lung infections into account.