Lung transplantation represents a potential life-extending therapy for patients with advanced CTD-ILD. This study aims to characterize lung transplant listing outcomes among CTD-ILD patients over a 20-year period using the Organ Procurement and Transplantation Network (OPTN) national database. Data analyzed from the OPTN between 2003-2023 included adults ≥18 years of age with CTD-ILD listed for lung transplantation. Patients were categorized into six diagnoses: scleroderma, lupus, rheumatoid arthritis (RA), myositis, Sjögren’s, and "Other" (including mixed connective tissue disease, CTD, etc.). Disease and patient specific data were obtained. Trends in listing and outcomes were analyzed in four time periods across the 20 years and among various diagnoses. We used descriptive summary statistics to characterize the sample, and univariate and multivariable logistic regression models to identify factors associated with undergoing lung transplantation. A total of 1,977 CTD-ILD patients were listed. Scleroderma constituted the majority (47%). Listings increased fourfold (185 to 744) from the first to last time periods. Listings for all diagnoses increased with time, with rising representation of non-White patients. Trend noted towards listing patients with more advanced lung disease with time. Transplant rates rose, while wait times, and waitlist mortality declined overtime. All diseases received transplants at comparable rates. Older age, lower lung allocation scores, and male sex were associated with higher odds of transplantation, female sex with lower odds. Over two decades, CTD-ILD transplant listings have increased in volume, matched with substantially improved outcomes. This reflects the evolution of listing practices and a growing confidence in lung transplantation as a viable option for CTD-ILD.
Objective This study aims to characterize pathogenic somatic mutations in patients with autoinflammatory or autoimmune diseases lacking disease‐causing germline mutations, explore their contribution to disease pathogenesis and progression, and evaluate their implications for diagnosis and targeted therapy. Methods We performed a systematic analysis of somatic mutations in a selected panel of 185 immune‐related genes in 2,912 patients with autoinflammatory or autoimmune diseases, recruited from 41 medical centers across China, who were previously negative for germline mutations based on whole‐exome sequencing. Results We identified both previously reported and novel somatic mutations in genes such as UBA1 , KRAS , and NLRP3 . Pathogenic somatic mutations in TNFAIP3 were discovered first in patients with autoinflammatory diseases. The pathogenic somatic mutation detection rate was 1.35% in adults and 0.97% in children, emphasizing the importance of genetic diagnosis and novel gene discovery for somatic mutations. In addition, somatic mutations in Ras‐related genes were identified in seven patients, and 39 clonal hematopoiesis–associated mutations were identified in 36 adult patients. Moreover, myeloid cells harboring somatic mutations expanded during disease flare and reduced during remission. Disregarding the dynamic elevation of the variant allele fraction during disease progression led to therapeutic failure. Conclusion This study delineated the genetic landscape of pathogenic somatic mutations underlying autoinflammatory and autoimmune diseases, offering valuable insights for genetic diagnosis and targeted therapies.
The overall malignancy risk in ASyS appears low. Age and length of follow-up were associated with higher malignancy risk, whereas clinical manifestations were not. Although the malignancy rates differed between antibody subtypes, with the numerically highest prevalence in anti-OJ antibodies, these findings were not statistically significant. Since the risk of malignancy in the ASyS population appears to be low in general, cancer screening should be tailored according to the patients age and sex.
In a large IIM cohort, Fitbit® PAM variables demonstrate favourable compliance and psychometric properties with strong test-retest reliability and validity. PAMs can complement current measurements to remotely track patient performance, quality of life, and disease activity.
In our tertiary referral centre, approximately one quarter of adult IIM patients who had a cancer diagnosis in the three years before IIM onset went on to develop an additional malignancy, either a recurrence or a new primary.
Cardiac involvement as detected by cardiac magnetic resonance imaging is common at time of diagnosis in patients with IIM and is closely linked to the severity of skeletal muscle involvement.
Objective Myositis‐specific autoantibodies guide the diagnosis and classification of idiopathic inflammatory myopathies, but current immunoassays vary in accuracy, particularly for autoantibodies associated with interstitial lung disease. To compare the performance of the luciferase immunoprecipitation systems (LIPS) assay with line blot and immunoprecipitation (IP) and to evaluate whether antibody‐specific thresholds modify line blot concordance. Methods We analyzed 279 sera with line blot results from the Johns Hopkins Myositis Center. LIPS was performed for anti–Jo‐1, anti–PL‐7, anti–PL‐12, anti–MDA‐5, anti‐EJ, and anti‐Ro52 autoantibodies. Line blot results were evaluated using standard thresholds (≥36 and ≥71 arbitrary units [AU]). Assay performance was evaluated against IP (n = 141). In patients without IP (n = 138), clinical diagnoses were examined. Results LIPS showed excellent agreement with IP (κ = 0.90, area under the receiver operating characteristic curve 0.935), outperforming line blot. Line blot cutoffs influenced performance: ≥36 AU increased sensitivity (92.9%) but reduced specificity (73.8%), whereas ≥71 AU improved specificity (92.9%) but lowered sensitivity (82.8%). Antibody‐specific thresholds modified concordance but remained quantitatively inferior to LIPS. In patients without IP, concordance between LIPS and line blot was 89% at ≥36 AU and 83% at ≥71 AU. LIPS‐positive cases were enriched for antisynthetase syndrome and dermatomyositis. Among discordant cases (line blot positive and LIPS negative), most were clinically classified as inclusion body myositis (5 of 11). For anti‐Ro52, discrepancies were most frequent at titers <36 AU. Conclusion LIPS provides quantitative discrimination, strong concordance with IP, and improved performance compared with line blot, particularly at low to intermediate titers. By reducing misclassification and complementing antibody‐specific thresholds, LIPS has the potential to enhance clinical stratification in patients with myositis. image
Idiopathic inflammatory myopathy (IIM) is commonly treated with glucocorticoids and other immunosuppressants, which substantially increase the risk of opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP). Therefore, trimethoprim-sulfamethoxazole (TMP/SMX) is frequently used as prophylaxis against PJP in patients with IIM. In addition to its role in PJP prevention, TMP/SMX has been reported to reduce the risk of severe infections in other immunosuppressed populations. We evaluated the association between TMP/SMX use and the risk of severe infections other than PJP in IIM. This retrospective, single-center study included 89 patients diagnosed with IIM who underwent remission induction therapy. After excluding 2 patients who developed PJP, the final study population consisted of 87 patients. We evaluated the incidence of severe infections during the follow-up period. Cox regression analysis was used to identify risk factors for severe infection. Sixteen patients developed severe infections other than PJP, with respiratory infections being the most common. Patients who received TMP/SMX had a significantly lower incidence of severe infections than those who did not. Respiratory tract infections were also significantly less common in patients using TMP/SMX. Multivariate analysis showed that older age increased the risk of severe infection (hazard ratio [HR] 1.063; 95% CI, 1.019-1.109; p=0.005), while TMP/SMX use significantly reduced the risk (HR 0.178; 95% CI, 0.056-0.57; p=0.004). TMP/SMX use was associated with a lower risk of severe infections in patients with IIM who underwent remission induction therapy, especially respiratory tract infections.
Objective Juvenile dermatomyositis (JDM) is a rare autoimmune condition. The treat‐to‐target strategy has garnered interest in pediatric rheumatology. It is based on defining clear therapeutic targets, with frequent disease activity monitoring, and adjustment of the treatments if targets are not met within a defined time frame. Recently, an international task force of experts launched an initiative aimed at the development of recommendations for the adoption of treat‐to‐target strategy in JDM. This study was done to support those recommendations. We aimed to determine the time‐to‐treatment response in patients with JDM, to better inform the development of a treat‐to‐target strategy in JDM. Methods This is a retrospective review of patients with a physician‐confirmed diagnosis of JDM, observed at two tertiary care centers—the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini (Gaslini), and The Hospital for Sick Children (SickKids). Demographic and clinical data were obtained on all patients with JDM during the first two years following diagnosis. Kaplan‐Meier survival curves were used to determine time to outcome definitions. Results A total of 187 patients were identified across two sites; the mean age of diagnosis was 8 years. On average, patients with JDM achieved normalization of muscle enzymes and muscle remission three months and six months after treatment initiation, respectively. Skin remission occurred within 12 months after starting treatment. Time to reach inactive disease varied between the sites, with median time being 10.3 months (Gaslini) and 8.8 months (SickKids). Conclusion This study provides real‐world data for potential timelines to target with a treat‐to‐target strategy for JDM.
Background Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with overlapping features with systemic lupus erythematosus, systemic sclerosis, and inflammatory idiopathic myopathies, characterized by anti-U1-RNP antibodies. Although subclinical retinal microvascular changes have been described in other connective tissue diseases, such data are lacking in patients with MCTD. Methods We performed a cross-sectional exploratory pilot study including patients with a defined diagnosis of MCTD according to one of the sets of classification criteria and age- and sex-matched healthy controls (HC), with elderly individuals equally distributed. Data on disease duration, renal function (creatinine and eGFR), and complement levels (C3 and C4) were recorded. All participants underwent optical coherence tomography angiography (OCT-A) to evaluate retinal vessel density (VD) using parafoveal, perifoveal, and foveal scans, whole images, and foveal avascular zones (FAZs). Nailfold videocapillaroscopy (NVC) was performed in patients with MCTD on four fingers of both hands to assess microangiopathy patterns. Results Patients with MCTD (n = 20, mean age 60.6 ± 11.4 years, 85% females) showed a significant reduction in both superficial and deep retinal VD across all evaluated regions compared with 20 HC. In patients with MCTD, deep retinal VD was inversely correlated with disease duration (r = −0.6, P = 0.0003) and directly correlated with eGFR (r = 0.4, P = 0.05). In patients with MCTD, C3 levels were positively correlated with age (r = 0.4, P = 0.03) and superficial parafoveal VD (r = 0.5, P = 0.008). In MCTD, NVC abnormalities, including non-specific microangiopathy and scleroderma patterns, occurred in 60% (n = 12) of cases and did not correlated with OCT-A findings. Conclusion Patients with MCTD present subclinical retinal microvascular abnormalities detectable by OCT-A. Our hypothesis-generating study
Antisynthetase syndrome (ASyS) is an idiopathic inflammatory myopathy characterized by interstitial lung disease (ILD), mechanic’s hands, fever, arthritis, and Raynaud’s phenomenon. Although several domestic and international reports have described the clinical manifestations of ASyS, regional differences in clinical characteristics, including skin involvement, remain poorly understood. This study aimed to compare the regional differences in clinical features of ASyS by comparing data of Japanese patients with ASyS with those of previously published cohorts. We conducted a retrospective chart review of 48 patients with ASyS at Yokohama City University Hospital between 2010 and 2024 and compared their data with those of previously published cohorts using univariate analysis. A literature review was performed using the PubMed database, with the search results limited to articles published between January 2010 and December 2024. The mean age at onset was 56.5 ± 14.0 years, with a male-to-female ratio of 13:35. The prevalence of anti-Jo1 antibody was 35%. ILD and muscle weakness were observed in 97% and 52% of the patients, respectively. The most frequent skin involvement was Gottron’s sign (73%), followed by mechanic’s hands (65%) and periungual erythema (40%). A literature review using the same ASyS diagnostic criteria revealed that Asian cohorts, including ours, tend to have higher rates of ILD complications and a lower prevalence of anti-Jo1 antibodies than European cohorts. Furthermore, in the comparison of clinical manifestations with other Japanese and Asian cohorts, the rates of Raynaud’s phenomenon, muscle weakness, and malignant complications were nearly identical, although slight differences were observed in skin manifestations. By contrast, the European cohort was characterized by a high frequency of Raynaud’s phenomenon (39%), muscle weakness (85%), and anti-Jo1 antibody positivity (83%); meanwhile, ILD and mechanic’s hands were observed
Objective Dysregulated type I interferon (IFN) signaling contributes to autoimmune myositis pathogenesis. We investigated the therapeutic effects of JAK inhibitors in two mouse models. We also examined how type I IFNs affect muscle vasculature. Methods Myositis was induced in MHC class I transgenic (HT) female mice at day 21. Mice were randomized into four groups (n=10‐11/group): baricitinib (10 mg/kg), tofacitinib (20 mg/kg), vehicle, and healthy controls. Outcomes included survival, weight, muscle strength, histopathology, and IFN stimulated gene expression. To model IFNβ overexpression, C57BL/6 mice received AAV9‐tMCK‐IFNβ and were treated with vehicle or tofacitinib (40 mg/kg/day) for 10 weeks (n=8‐13/group). Results Tofacitinib—but not baricitinib—significantly reduced IFN scores in severe myositis mice (p<0.05). Survival differed across groups (overall log‐rank p<0.01), with untreated‐ and baricitinib‐treated HT mice showing shorter survival than BL/6 controls, while tofacitinib‐treated mice did not differ from controls. IFNβ overexpression induced muscle inflammation (p<0.01), reduced grip strength (p<0.0001), and increased the IFN score (p<0.0001) and H2Kb (p<0.0001) expression. Conclusion Tofacitinib reduced the IFN signature, and survival in this group did not differ significantly from healthy controls, whereas untreated‐ and baricitinib‐treated HT mice showed shorter survival; functional improvement was not observed. Our results also show that type I IFN signaling contributes to muscle inflammation and weakness, making it a key driver of muscle damage and thereby reinforcing its potential as a therapeutic target. image
To explore how appropriate different intervals between monitoring blood tests are considered in relation to the risk of clinically significant adverse drug reactions in adults prescribed conventional synthetic DMARDs (csDMARDs) for ≥1 year for systemic autoimmune rheumatic diseases (SARD). A RAND/UCLA Appropriateness Method consensus study was undertaken. Members of the BSR csDMARD guideline working group who manage adults with SARD participated. Experts rated the extent to which intervals between blood tests were appropriate using Likert-type scales with responses from 1 (totally inappropriate) to 9 (totally appropriate) for nine scenarios with 5-year predicted risk of discontinuing treatment due to abnormal monitoring blood tests from 5% to 25%. Median score and the number that voted 1-3 (inappropriate), 4-6 (unsure) and 7-9 (appropriate) were calculated for every interval in each scenario. Scenarios for which agreement could not be reached in the first round were recirculated, enclosing individual round 1 response and the panel median score. Consensus that an interval was appropriate for a scenario was reached where the median panel score was ≥7 and up to six experts rated 10% over 5 years, respectively. A threshold to aid risk-stratified monitoring during established csDMARD treatment was agreed for adults with SARD.
Abstract Objectives To develop and validate enzyme-linked immunosorbent assay (ELISA) systems for the detection of autoantibodies against signal recognition particle (SRP), nuclear matrix protein 2 (NXP2), and small ubiquitin-like modifier activating enzyme (SAE). Methods Serum samples from 288 individuals were analysed, including 183 patients with idiopathic inflammatory myopathies (IIM), 20 with other neuromuscular diseases, 35 with non-IIM systemic autoimmune rheumatic diseases, and 50 healthy controls. ELISA systems were established using recombinant SRP, NXP2, and SAE proteins expressed in insect cells or Escherichia coli. The diagnostic performance of the ELISAs was assessed in comparison with the ‘gold-standard’ immunoprecipitation (IP) assays. Results The ELISAs demonstrated high concordance with IP assays, with positive and negative percent agreements of 97.4% and 100% for anti-SRP, 100% and 99.6% for anti-NXP2, and 100% and 99.6% for anti-SAE antibodies, respectively. Conclusions The newly developed ELISA systems showed excellent agreement with IP assays, supporting their applicability for routine clinical use in detecting anti-SRP, anti-NXP2, and anti-SAE autoantibodies.
International guidelines recommend having a positive anti-nuclear antibody (ANA) and clinical suspicion of systemic autoimmune rheumatic diseases (SARD) when requesting ANA subserologies. Compliance with these guidelines by physicians has been questioned in different parts of the world. To analyse the requesting pattern of ANA and anti-extractable nuclear antigens (ENA) simultaneously in the University of Malaya Medical Centre (UMMC). This is a retrospective descriptive study involving 1529 adult patients who had their ANA and ANA subserologies requested simultaneously by clinicians. The ANA, anti-ENA screening (ENASc) and anti-ENA specific (ENASp) results were retrieved. Their case records on their relevant diagnosis and follow-up tests were reviewed. Among the 1,529 samples, 536 (35%) patients were positive, and 993 (65%) patients were negative for ANA by indirect immunofluorescence assay (IIF). In the ANA positive group, 109 (20%) were positive and 46 (9%) were borderline for ENASc. Of those ENASc positive patients, only 47 patients were requested for ENASp. Forty-one (87.2%) were positive for ENASp, In the ANA negative group, 111 (11%) were positive and 66 (7%) were borderline for ENASc. The majority of the ENASc positive (86, 77%) or borderline (63, 95%) had not been requested for ENASp in this group. Of those who had ENASp tests done (28), 19 (76%) were positive and 3 were borderline positive for ENASp. A total of 223 patients were diagnosed with SARD, out of which 147 had SARD in the ANA positive group (66%), with systemic lupus erythematosus being identified as the commonest SARD. A total of 76 patients were diagnosed with SARD in the ANA negative group (34%), with rheumatoid arthritis being identified as the commonest SARD. A large number of ENASc negative results are obtained concurrently
jMCTD share the same clinical characteristics as aMCTD patients, but less frequently have puffy fingers. Outcomes appear more favorable in jMCTD than aMCTD, with higher remission rates, albeit at the cost of more intensive treatment.