MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Machine Learning of Plasma Proteomics Classifies Diagnosis of Interstitial Lung Disease.

RATIONALE: Distinguishing connective tissue disease associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging. OBJECTIVES: Identify proteins that separate and classify CTD-ILD from IPF patients. METHODS: Four registries with 1247 IPF and 352 CTD-ILD patients were included in analyses. Plasma samples were subjected to high-throughput proteomics assays. Protein features were prioritized using Recursive Feature Elimination (RFE) to construct a proteomic classifier. Multiple machine learning models, including Support Vector Machine, LASSO regression, Random Forest (RF), and imbalanced-RF, were trained and tested in independent cohorts. The validated models were used to classify each case iteratively in external datasets. MEASUREMENT AND MAIN RESULTS: A classifier with 37 proteins (PC37) was enriched in biological process of bronchiole development and smooth muscle proliferation, and immune responses. Four machine learning models used PC37 with sex and age score to generate continuous classification values. Receiver-operating-characteristic curve analyses of these scores demonstrated consistent Area-Under-Curve 0.85-0.90 in test cohort, and 0.94-0.96 in the single-sample dataset. Binary classification demonstrated 78.6%-80.4% sensitivity and 76%-84.4% specificity in test cohort, 93.5%-96.1% sensitivity and 69.5%-77.6% specificity in single-sample classification dataset. Composite analysis of all machine learning models confirmed 78.2% (194/248) accuracy in test cohort and 82.9% (208/251) in single-sample classification dataset. CONCLUSIONS: Multiple machine learning models trained with large cohort proteomic datasets consistently distinguished CTD-ILD from IPF. Identified proteins involved in immune pathways. We further developed a novel approach for single sample classification, which could facilitate honing the differential diagnosis of ILD in challenging cases and improve clinical decision-making.

Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation.

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.

Exercise entrainment of musculoskeletal connective tissue clocks.

The musculoskeletal system, crucial for movement and support, relies on the delicate balance of connective tissue homeostasis. Maintaining this equilibrium is essential for tissue health and function. There has been increasing evidence in the last decade that shows the circadian clock as a master regulator of extracellular matrix (ECM) homeostasis in several connective tissue clocks. Very recently, exercise has emerged as a significant entrainment factor for cartilage and intervertebral disc circadian rhythms. Understanding the implications of exercise on connective tissue peripheral clocks holds promise for enhancing tissue health and disease prevention. Exercise-induced factors such as heat, glucocorticoid release, mechanical loading, and inter-tissue crosstalk may play pivotal roles in entraining the circadian rhythm of connective tissues. This mini review underscores the importance of elucidating the mechanisms through which exercise influences circadian rhythms in connective tissues to optimize ECM homeostasis. Leveraging exercise as a modulator of circadian rhythms in connective tissues may offer novel therapeutic approaches to physical training for preventing musculoskeletal disorders and enhancing recovery.

Clinical-Genomic Analysis of 1261 Patients with Ehlers-Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome).

Systematic evaluation of 80 history and 40 history findings diagnosed 1261 patients with Ehlers-Danlos syndrome (EDS) by direct or online interaction, and 60 key findings were selected for their relation to clinical mechanisms and/or management. Genomic testing results in 566 of these patients supported EDS relevance by their differences from those in 82 developmental disability patients and by their association with general rather than type-specific EDS findings. The 437 nuclear and 79 mitochondrial DNA changes included 71 impacting joint matrix (49 COL5), 39 bone (30 COL1/2/9/11), 22 vessel (12 COL3/8VWF), 43 vessel-heart (17FBN1/11TGFB/BR), 59 muscle (28 COL6/12), 56 neural (16 SCN9A/10A/11A), and 74 autonomic (13 POLG/25porphyria related). These genes were distributed over all chromosomes but the Y, a network analogized to an 'entome' where DNA change disrupts truncal mechanisms (skin constraint, neuromuscular support, joint vessel flexibility) and produces a mirroring cascade of articular and autonomic symptoms. The implied sequences of genes from nodal proteins to hypermobility to branching tissue laxity or dysautonomia symptoms would be ideal for large language/artificial intelligence analyses.

People with a connective tissue disorder may be especially vulnerable to the endothelial damage that characterizes long COVID due to the fragility of their vasculature and slow wound healing.

A growing body of evidence documents the central role that endothelial damage plays in the pathophysiology of long COVID. But it remains unclear why only certain people get Long COVID and why recovery times are so long for many affected individuals. One potential explanation is that some forms of long COVID are experienced disproportionately by people with a connective tissue disorder who are more vulnerable than others to incurring serious damage to the endothelium and the vascular extracellular matrix from the inflammatory processes triggered by COVID-19 and much slower to heal. Further research is needed to explore this hypothesis.

Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with "idiopathic" interstitial lung disease.

BACKGROUND: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD. METHODS: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation. RESULTS: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11. CONCLUSION: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11.

Mechanical Stress-induced Connective Tissue Growth Factor Plays a Critical Role in Intestinal Fibrosis in Crohn's-like Colitis.

Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation and intestinal fibrosis. Mechanisms of fibrosis in CD are not well understood. Transmural inflammation is associated with inflammatory cell infiltration, stenosis, and distention, which present mechanical stress (MS) to the bowel wall. We hypothesize that MS induces gene expression of pro-fibrotic mediators such as connective tissue growth factor (CTGF), which may contribute to fibrosis in CD. A rodent model of CD was induced by intracolonic instillation of TNBS to the distal colon. TNBS instillation induced a localized transmural inflammation (site I), with a distended colon segment (site P) proximal to site I. We detected significant fibrosis and collagen content not only in site I, but also in site P in CD rats by day 7. CTGF expression increased significantly in sites P and I, but not in the segment distal to the inflammation site. Increased CTGF expression was detected mainly in the smooth muscle cells (SMC). When rats were fed exclusively with clear liquid diet to prevent mechanical distention in colitis, expression of CTGF in sites P and I was blocked. Direct stretch led to robust expression of CTGF in colonic SMC. Treatment of CD rats with anti-CTGF antibody FG-3149 reduced fibrosis and collagen content in both sites P and I and exhibited consistent trends towards normalizing expression of collagen mRNAs. In conclusion, our studies suggest that mechanical stress, by up-regulating pro-fibrotic mediators i.e. CTGF, may play a critical role in fibrosis in CD.

Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases.

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

FcγR-dependent apoptosis regulates tissue persistence of mucosal and connective tissue mast cells.

Rodent mast cells can be divided into two major subtypes: the mucosal mast cell (MMC) and the connective tissue mast cell (CTMC). A decade-old observation revealed a longer lifespan for CTMC compared with MMC. The precise mechanisms underlying such differential tissue persistence of mast cell subsets have not been described. In this study, we have discovered that mast cells expressing only one receptor, either FcγRIIB or FcγRIIIA, underwent caspase-independent apoptosis in response to IgG immune complex treatment. Lower frequencies of CTMC in mice that lacked either FcγRIIB or FcγRIIIA compared with WT mice were recorded, especially in aged mice. We proposed that this paradigm of FcγR-mediated mast cell apoptosis could account for the more robust persistence of CTMC, which express both FcγRIIB and FcγRIIIA, than MMC, which express only FcγRIIB. Importantly, we reproduced these results using a mast cell engraftment model, which ruled out possible confounding effects of mast cell recruitment or FcγR expression by other cells on mast cell number regulation. In conclusion, our work has uncovered an FcγR-dependent mast cell number regulation paradigm that might provide a mechanistic explanation for the long-observed differential mast cell subset persistence in tissues.

Development and maintenance of tendons and ligaments.

Tendons and ligaments are fibrous connective tissues vital to the transmission of force and stabilization of the musculoskeletal system. Arising in precise regions of the embryo, tendons and ligaments share many properties and little is known about the molecular differences that differentiate them. Recent studies have revealed heterogeneity and plasticity within tendon and ligament cells, raising questions regarding the developmental mechanisms regulating tendon and ligament identity. Here, we discuss recent findings that contribute to our understanding of the mechanisms that establish and maintain tendon progenitors and their differentiated progeny in the head, trunk and limb. We also review the extent to which these findings are specific to certain anatomical regions and model organisms, and indicate which findings similarly apply to ligaments. Finally, we address current research regarding the cellular lineages that contribute to tendon and ligament repair, and to what extent their regulation is conserved within tendon and ligament development.

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

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

Annals of the Rheumatic Diseases collection on pregnancy 2018-2023: observational data-driven knowledge.

Pregnancy can be an exciting time but for those living with rheumatic musculoskeletal diseases (RMDs), it can also be a time fraught with concern, including what effect pregnancy will have on the underlying RMD and what effect the RMD may have on the pregnancy and the baby, including the effects of medications. Generating an evidence base in pregnancy is challenging. Few interventional trials of medications in RMD pregnancies have ever been conducted, often for concerns of safety for both the mother and the child. Therefore, observational research remains important for informing clinical practice and helping women with RMDs make decisions regarding their health preconception and during pregnancy. The Annals of the Rheumatic Diseases (ARD) continues to publish important research on pregnancy in RMDs to increase the evidence base on this subject. Here we present an overview of papers published on this topic between January 2018 and December 2023. Our focus includes papers on pregnancy and RMD outcome, the effects of drug exposure, fetal outcomes as well as fertility.

Validation of a new glucocorticoid-specific Patient-Reported Outcome Questionnaire (the Steroid PRO).

OBJECTIVES: Glucocorticoids used in the treatment of inflammatory rheumatic conditions can impact on health-related quality of life. An underpinning qualitative study developed a long-list of candidate items for a treatment-specific patient-reported outcome (PRO) measure. The objective of this paper is to determine scale structure and psychometric properties of the Steroid PRO. METHODS: A cross-sectional survey of adults from the UK, USA, Australia and New Zealand, taking glucocorticoids for a rheumatic disease. Initial survey collected demographics, clinical information, 40 Steroid PRO candidate items and EuroQol-5 Dimensions- 5 levels (EQ-5D-5L). Follow-up, 3-5 days later, collected Steroid PRO candidate items and a condition-change ('transition') question. Analysis included Rasch measurement model, exploratory factor analysis (EFA), and hypothesis testing for discriminative validity, convergence validity and test-retest reliability. RESULTS: Total responses 946: UK n=743 (79%); USA n=139 (15%); Australia/New Zealand n=64 (7%); mean age 57.6 (SD=13.6); 833 (88%) women. Participants with inflammatory arthritis n=197 (21%), connective tissue disease and/or vasculitis n=402 (42%), giant cell arteritis and/or polymyalgia rheumatica n=347 (37%). Twenty-five items were removed due to lack of fit to Rasch model. Of the remaining items, EFA suggested four subscales: Social impact (4 items); Impact on appearance (3 items); Psychological impact (5 items); Treatment concerns (3 items). Rasch modelling supported a four-subscale structure and total score, confirming construct validity and reliability. Hypothesis testing confirmed discriminant and convergence validity. Intraclass correlation coefficient (total score) was 0.809 demonstrating excellent (test-retest) reliability. CONCLUSIONS: The Steroid PRO is a 15-item, valid and reliable scale for measuring the impact of glucocorticoid therapy in people with rheumatic diseases.

CD7 activation regulates cytotoxicity-driven pathology in systemic sclerosis, yielding a target for selective cell depletion.

OBJECTIVES: Cytotoxic T cells and natural killer (NK) cells are central effector cells in cancer and infections. Their effector response is regulated by activating and inhibitory receptors. The regulation of these cells in systemic autoimmune diseases such as systemic sclerosis (SSc) is less defined. METHODS: We conducted ex vivo analysis of affected skin and blood samples from 4 SSc patient cohorts (a total of 165 SSc vs 80 healthy individuals) using single-cell transcriptomics, flow cytometry and multiplex immunofluorescence staining. We further analysed the effects of costimulatory modulation in functional assays, and in a severely affected SSc patient who was treated on compassionate use with a novel anti-CD3/CD7 immunotoxin treatment. RESULTS: Here, we show that SSc-affected skin contains elevated numbers of proliferating T cells, cytotoxic T cells and NK cells. These cells selectively express the costimulatory molecule CD7 in association with cytotoxic, proinflammatory and profibrotic genes, especially in recent-onset and severe disease. We demonstrate that CD7 regulates the cytolytic activity of T cells and NK cells and that selective depletion of CD7+ cells prevents cytotoxic cell-induced fibroblast contraction and inhibits their profibrotic phenotype. Finally, anti-CD3/CD7 directed depletive treatment eliminated CD7+ skin cells and stabilised disease manifestations in a severely affected SSc patient. CONCLUSION: Together, the findings imply costimulatory molecules as key regulators of cytotoxicity-driven pathology in systemic autoimmune disease, yielding CD7 as a novel target for selective depletion of pathogenic cells.

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.

Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

Anti-survival motor neuron complex antibodies as a novel biomarker for pulmonary arterial hypertension and interstitial lung disease in mixed connective tissue disease.

OBJECTIVE: The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing MCTD. The aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. METHODS: A total of 158 newly diagnosed consecutive cases of SLE, SSc or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analysed. RESULTS: Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc and idiopathic inflammatory myopathies, anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs-positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. CONCLUSIONS: Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD.

Prospective Assessment of Glucocorticoid Toxicity in Rheumatology Practice: A Focus on the Glucocorticoid Toxicity Index.

OBJECTIVE: The glucocorticoid toxicity index (GTI) is developed to measure glucocorticoid (GC)-related morbidity over time. This study aimed to assess GC-toxicity in patients at a rheumatology outpatient clinic by using the GTI and to identify the factors that interfere with the GTI. METHODS: This prospective study included patients with inflammatory arthritis (IA), connective tissue disease, and vasculitis who were newly prescribed GC-treatment (GC-naive) or have been still on GC-treatment for ≤2 years (GC-experienced). Patient demographics and disease characteristics, aggregate improvement score (GTI-AIS), cumulative worsening score (GTI-CWS), and cumulative GC-doses were recorded at baseline, 3rd month, and 6th month. Generalized estimating equations (GEE) were used to evaluate the GTI scores and associated factors including cumulative GC-doses. RESULTS: The study included 156 (48.7% GC-naive) patients with a mean age of 49.1 ± 17.1 years. More than half of the patients in both groups had a diagnosis of vasculitis. A higher cumulative GC-dose was found to be associated with higher GTI-scores in both groups (p< 0.001). In the GC-naive group, patients with vasculitis showed higher GTI-scores than IA patients (p< 0.001); there was also a significant increase in the GTI-CWS at the 6th month compared with the 3rd month. In the GC-experienced group, GTI-AIS and GTI-CWS were significantly different at 3rd and 6th month (p< 0.05). CONCLUSION: It was shown that GTI scores were associated with cumulative GC-doses and vasculitis patients in the GC-naive patients had higher GTI scores than inflammatory arthritis. The GTI allows individualized assessment and management of adverse effects experienced by patients as a result of GC treatment.