Clinical Characteristics of Anti-Synthetase Syndrome: Analysis from the CLASS project.

OBJECTIVE: Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD. METHODS: We utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort. RESULTS: Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD. CONCLUSION: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD.

High frequency of defecation under metformin use may be a potential glucose-lowering factor independent of the dose-dependent effect of metformin in patients with type 2 diabetes mellitus.

Objective Our previous study indicated that the efficacy of metformin in lowering glycated hemoglobin (HbA1c) levels may be influenced by the pretreatment frequency of defecation (FD) in patients with type 2 diabetes mellitus (T2DM). This study aimed to further examine how FD and the metformin dose may affect HbA1c changes (ΔHbA1c) in T2DM patients. Methods A retrospective analysis was conducted on inpatients who received antidiabetic treatment without altering dosages for six months post-discharge, except for minor insulin adjustments. For new patients, FD was assessed before (pretreatment FD) and after the initiation of antidiabetic therapy (posttreatment FD). For patients already on treatment, FD was evaluated during hospitalization (posttreatment FD). Patients were categorized based on their metformin use, and the relationship between FD and ΔHbA1c was assessed 1.5-6 months post-discharge. The impact of the metformin dose and posttreatment FD on the ΔHbA1c level was analyzed, along with other factors affecting posttreatment FD. Results The analysis included 89 patients (41 on metformin, 21 newly treated; 48 not on metformin, 17 newly treated). Both pre- and posttreatment FD were linked to ΔHbA1c levels in the metformin group. The metformin dose correlated with posttreatment FD but not with pretreatment FD. A significant relationship was observed between ΔHbA1c and the metformin dose. A multiple regression analysis identified posttreatment FD and metformin dose as significant independent factors influencing ΔHbA1c levels. Additionally, diabetic peripheral neuropathy and diabetes duration were found to diminish the effectiveness of metformin, likely due to decreased posttreatment FD. Conclusion FD may independently contribute to the dose-dependent HbA1c-lowering effects of metformin.

Calculated estimation of the metabolic clearance rate of insulin measured by glucose clamp examination in out-patient clinical practice.

Purpose: A subpopulation of Japanese patients with type 2 diabetes mellitus (T2DM) who have elevated insulin clearance (IC) exists. We tested our hypothesis that it is possible to estimate IC using common and simple test results collected in routine clinical practice. Methods: We recruited patients with newly diagnosed, treatment-naïve T2DM and measured the metabolic clearance rate of insulin (MCRI) determined by a hyperinsulinemic-euglycemic clamp examination. Multivariable regression analysis was performed with body mass index (BMI), serum uric acid (UA), and fasting plasma insulin (F-IRI) which were independently associated with IC increase in our previous reports as explanatory variables to calculate a prediction equation for MCRI. Results: We enrolled 101 patients in this study. Because MCRI is not normally distributed, we calculated the logarithmically transformed estimated Log10MCRI as a prediction formula for IC. Multivariable regression analysis showed that Log10BMI (ß = - 0.3257, P < 0.001), UA (ß = - 0.1834, P = 0.0081), and Log10F-IRI (ß = - 0.4367, P < 0.001) were significant independent factors for Log10MCRI. The regression equation was as follows: estimated Log10MCRI = - 0.5421 × Log10BMI - 0.0167 × UA - 0.1792 × Log10F-IRI + 3.8251 (r = 0.7677, R 2 = 0.5894, P < 0.001). Conclusion: IC can easily be predicted using BMI, UA, and F-IRI which are common and simple test results collected in routine clinical practice.

Nonocclusive mesenteric ischemia in a toddler during hypothermia after cardiac arrest: a case report.

While nonocclusive mesenteric ischemia (NOMI) has been reported in a significant percentage of adults who were resuscitated after cardiac arrest, it is rare in children. This report presents the first known Japanese case of pediatric NOMI after return of spontaneous circulation following cardiac arrest. A 16-month-old boy experienced cardiac arrest due to asphyxiation from foreign bodies in the airway. After receiving 10 doses of adrenaline, with a maximum arrest time of 95 minutes, the patient achieved return of spontaneous circulation. However, 40 hours after onset, the patient developed NOMI, resulting in refractory hypotensive shock with decreased blood pressure, distended abdomen, and increased intravesical pressure. The patient was successfully rescued with two laparotomies and was discharged. Although NOMI is uncommon in children, appropriate treatment can be lifesaving.

Heat-Induced Liquid Hovering in Liquid-Gas Coexistence under Gravity.

We study a liquid-gas coexistence system in a container under gravity with heat flow in the direction opposite to gravity. By molecular dynamics simulation, we find that the liquid buoys up and continues to float steadily. The height at which the liquid floats is determined by a dimensionless parameter related to the ratio of the temperature gradient to gravity. We confirm that supercooled gas remains stable above the liquid. We provide a phenomenological argument for explaining the phenomenon from a simple thermodynamic assumption.

Pacing cycle length-dependent electrophysiologic changes in left atrium: Poor validity of using low-voltage area and slow conduction area under specific pacing cycle length as absolute substrates of atrial fibrillation.

BACKGROUND: Pacing cycle length (PCL)-dependent changes in left atrial (LA) electrophysiologic properties have not been fully elucidated. OBJECTIVE: We aimed to elucidate these changes using a high-resolution mapping system. METHODS: Forty-eight patients underwent atrial fibrillation ablation with RHYTHMIA HDx. Paired LA maps under a baseline PCL (600 ms) and rapid PCL (300 ms) were acquired after pulmonary vein isolation under right atrial appendage pacing. The PCL-dependent change in the low-voltage area (LVA; area with <0.5 mV bipolar voltage), LA activation time (interval from first LA activation to wavefront collision at lateral wall), regional mean voltage, regional mean wave propagation velocity, and slow conduction area (area with <0.3 m/s wave propagation velocity) were quantitatively analyzed. RESULTS: Under the rapid PCL, the total LVA was significantly increased (7.6 ± 9.5 cm2 vs 6.7 ± 7.6 cm2; P = .031), especially in patients with a 10 cm2 LVA on the baseline PCL map (21.5 ± 9.1 cm2 vs 18.1 ± 6.5 cm2; P = .013). The LA activation time was also prolonged (87.9 ± 16.2 ms vs 84.0 ± 14.0 ms; P < .0001). Although the rapid PCL did not decrease the regional mean voltage, it significantly decreased the regional mean wave propagation velocity and increased the slow conduction area in all measured regions. CONCLUSION: LVA and slow conduction area can be emphasized by rapid PCL LA mapping. There may be poor validity in using these areas as absolute atrial fibrillation substrates without considering the PCL-dependent changes.

Severe periodontal disease in Japanese patients with high HbA1c levels: a cross-sectional study.

Objective: This study aimed to investigate the relationship between plasma glucose profiles and periodontal disease (PD) severity in men and women. Methods: We conducted a cross-sectional cohort study, enrolling all eligible patients with type 2 diabetes mellitus (T2DM) who regularly visited the outpatient department. Results: Patients were divided into severe and non-severe PD groups. The severe PD group showed a male predominance and significantly higher hemoglobin A1c (HbA1c) levels than the non-severe PD group. The optimal HbA1c cutoff value on the receiver operating characteristic curve for predicting severe PD was 7.3% [56 mmol/mol] (sensitivity, 52%; specificity, 73%; P = 0.01). Multivariate logistic regression revealed that male sex (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19-6.34; P = 0.01) and higher HbA1c levels (OR, 3.09; 95% CI, 1.42-6.70; P < 0 .01) were independently and significantly associated with the presence of severe PD. The prevalence rates of severe PD in patients with HbA1c levels < 7.3% [56 mmol/mol] and HbA1c levels ≥ 7.3% [56 mmol/mol] were 17.4% and 53.3% in women, and 50.0% and 66.7% in men, respectively. Conclusions: Men with T2DM had a high risk of severe PD independent of HbA1c levels. Plasma glucose management may be crucial for maintaining periodontal health in T2DM patients, particularly in women.

Paradoxical generator impedance behavior during catheter ablation in a patient with severe polycythemia.

An extremely high generator impedance in the blood pool can be observed in a patient with severe polycythemia. However, ablation can be performed safely as long as the generator impedance during contact with the myocardial tissue is within acceptable limits.

Age-independent benefits of postoperative rehabilitation during chemoradiotherapy on functional outcomes and survival in patients with glioblastoma.

PURPOSE: To investigate the impact of early and continuous postoperative inpatient rehabilitation during chemoradiotherapy on functional outcomes and overall survival (OS) in patients with glioblastoma (GBM), particularly in different age groups. METHODS: This retrospective cohort study at a university hospital (2011-2016) included 75 of 119 consecutive patients newly diagnosed with GBM who underwent standardized treatment and postoperative rehabilitation. Patients were divided into older (≥ 65 years, n = 45) and younger (< 65 years, n = 30) groups, engaging in a 50-day rehabilitation program. We assessed rehabilitation progress, Barthel Index (BI), Brunnstrom Recovery Stage (BRS), adverse events, and OS. BI at discharge and survival were analyzed using multivariate and Cox regression models, respectively. RESULTS: The mean age was 72.5 ± 6.3 and 52.4 ± 7.8 years in the older and younger groups, respectively. Both groups demonstrated significant improvements in BI and BRS. Despite more adverse events in the older group, no significant difference existed in median OS (older group: 18.7 months vs. younger group: 18.3 months, p = 0.87). Early walking training, reduced fatigue during chemoradiotherapy, and high Karnofsky Performance Status at admission significantly impacted the BI at discharge. Cox regression analysis identified the BI at discharge as a significant predictor of survival (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.97-0.99, p = 0.008). CONCLUSION: Integrated rehabilitation improves functional outcomes, and enhanced ADL at discharge is associated with improved survival outcomes in patients with GBM, regardless of age. This highlights the need for personalized rehabilitation in treatment protocols. Further prospective studies are warranted to confirm these findings.

A 37-Year-Old Man With Intellectual Disability Discovered to Have Aspartylglucosaminuria: Implications for the Diagnosis of Genetic Causes.

Objectives: The causes of intellectual disability (ID) are varied, with as many as 1,400 causative genes. We attempted to identify the causative gene in a patient with long-standing undiagnosed ID. Methods: Although this was an isolated case with no family history, we searched for the causative gene using trio-based whole-exome sequencing (trio-WES), because severe ID is often caused by genetic variations, and inherited metabolic disorders (IMDs) are assumed to be the cause when regression and epilepsy occur. Results: We identified homozygous donor splice-site variants in the AGA gene (aspartylglucosaminidase; NM_000027.4) Chr4(GRCh38):g. 177436275C>A, c.698+1G>T. This gene is implicated in aspartylglucosaminuria (AGU; OMIM #208400) and originated from both of the patient's parents. We confirmed the pathogenicity of the variant by detecting the splicing defect in cDNA from the patient's blood and accumulation of aberrant metabolites in the patient's urine. Discussion: We discuss how to more readily achieve an accurate diagnosis for patients with undiagnosed intellectual disabilities. Medical practitioners' awareness of the characteristics of the disease leading to clinical suspicion in patients with matching presentations, and the performance of newborn screening when possible, is important for the diagnosis of ID. In addition, the characteristic symptoms and course of the disease give rise to suspicion of IMDs. Given our results, we consider trio-WES to be a powerful method for identifying the causative genes in cases of ID with genetic causes.

Docking Proteins Upregulate IL-1ß Expression in Lower Esophageal Sphincter Muscle in Esophageal Achalasia.

Background/Objectives: Esophageal achalasia is an archetypal esophageal motility disorder characterized by abnormal peristalsis of the esophageal body and impaired lower esophageal sphincter (LES) relaxation. Methods: In this study, the mRNA expression of docking proteins 1 and 2 (DOK1 and DOK2, respectively) were analyzed and the mechanisms underlying achalasia onset were investigated. Results:DOK1 and DOK2 mRNA levels significantly increased in the LES of patients with achalasia. Moreover, significant correlations were observed between IL-1ß and DOK1, IL-1ß and DOK2, ATG16L1 and DOK1, and HSV1-miR-H1-3p and DOK2 expression levels. However, a correlation between ATG16L1 and DOK2 or between HSV-miR-H1-3p and DOK1 expression was not observed. In addition, a positive correlation was observed between patient age and DOK1 expression. Microarray analysis revealed a significant decrease in the expression of hsa-miR-377-3p and miR-376a-3p in the LES muscle of patients with achalasia. Conclusions: These miRNAs possessed sequences targeting DOK. The upregulation of DOK1 and DOK2 expression induces IL-1ß expression in the LES of achalasia patients, which may contribute to the development of esophageal motility disorder.

Efficacy of Self-Review of Lifestyle Behaviors with Once-Weekly Glycated Albumin Measurement in People with Type 2 Diabetes: A Randomized Pilot Study.

INTRODUCTION: Lifestyle management, including appropriate modifications of nutrition, exercise, and medication behaviors, is essential for optimal glycemic control. The absence of appropriate monitoring methods to validate the lifestyle change may hinder the modification and continuation of behaviors. In this study, we evaluated whether once-weekly glycated albumin (GA) measurement received via a smartphone application could improve glycemia management in patients with type 2 diabetes mellitus by supporting self-review and modification of lifestyle behaviors. METHODS: This open-label, randomized controlled, single-center study in Japan with an 8-week intervention period was conducted in individuals with type 2 diabetes mellitus and HbA1c levels between 7.0 and 9.0% (53‒75 mmol/mol). The intervention was once-weekly home monitoring of GA with a daily self-review of lifestyle behaviors using a smartphone application, in addition to conventional treatment. RESULTS: A total of 98 participants (72.0% males; age 63.2 ± 11.4 years; HbA1c 7.39 ± 0.39% [57.3 ± 4.3 mmol/mol]) were randomly assigned to the intervention or control group. Significant decreases of the GA and HbA1c levels from the baseline to the last observation day were observed in the intervention group (- 1.71 ± 1.37% [- 39.1 ± 31.3 mmol/mol] and - 0.32 ± 0.32% [- 3.5 ± 3.5 mmol/mol], respectively). Significant decreases of the body weight, waist circumference, and caloric expenditure (p < 0.0001 and p = 0.0003, p = 0.0346, respectively), but not of the caloric intake (p = 0.678), were also observed in the intervention group as compared with the control group. CONCLUSIONS: Self-review of lifestyle behaviors in combination with once-weekly GA home testing received via a smartphone application might potentially benefit glycemic management in people with type 2 diabetes mellitus. TRIAL REGISTRATION: jRCTs042220048.

Clinical phenotyping in patients with anti-synthetase antibodies using cluster analysis.

Objectives: To characterize clinically distinct subgroups among unselected patients with anti-synthetase antibodies using cluster analysis. Methods: This study evaluated patients with anti-synthetase antibodies registered to two independent cohorts; 106 consecutive patients from a prospective, single-centre cohort of the Scleroderma/Myositis Centre of Excellence (SMCE) were used as a derivation cohort and 125 patients from the Multicentre Retrospective Cohort of Japanese Patients with Myositis-Associated Interstitial Lung Disease (JAMI) were used as a validation cohort. Anti-synthetase antibodies were identified by RNA immunoprecipitation. A multiple correspondence analysis followed by hierarchical clustering was performed to aggregate the patients into homogeneous subgroups. Subsequently, a simple-to-use classification tree was generated using classification and regression tree analysis. Results: Three clusters were identified in the SMCE cohort: cluster 1 (n = 48), the interstitial pneumonia with autoimmune features/amyopathic dermatomyositis cluster, associated with older age at diagnosis and a higher frequency of malignancy; cluster 2 (n = 46), the DM cluster, corresponded to a younger age at diagnosis with a higher prevalence of myositis, arthritis, DM pathognomonic rashes, mechanic's hands and fever; and cluster 3 (n = 12), the SSc cluster, characterized by chronic interstitial lung disease. There was no significant difference in overall survival or progression-free survival between the clusters. A simple classification tree using myositis and RP was created in the SMCE cohort. Clusters 1 and 2 were successfully reproduced and the classification tree demonstrated favourable performance in the JAMI cohort. Conclusion: Patients with anti-synthetase antibodies were classified into three distinct phenotypes, indicating substantial heterogeneity within this patient group.

Impaired health-related quality of life in idiopathic inflammatory myopathies: a cross-sectional analysis from the COVAD-2 e-survey.

Objectives: To investigate health-related quality of life in patients with idiopathic inflammatory myopathies (IIMs) compared with those with non-IIM autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs) and without autoimmune diseases (controls) using Patient-Reported Outcome Measurement Information System (PROMIS) instrument data obtained from the second COVID-19 vaccination in autoimmune disease (COVAD-2) e-survey database. Methods: Demographics, diagnosis, comorbidities, disease activity, treatments and PROMIS instrument data were analysed. Primary outcomes were PROMIS Global Physical Health (GPH) and Global Mental Health (GMH) scores. Factors affecting GPH and GMH scores in IIMs were identified using multivariable regression analysis. Results: We analysed responses from 1582 IIM, 4700 non-IIM AIRD and 545 nrAID patients and 3675 controls gathered through 23 May 2022. The median GPH scores were the lowest in IIM and non-IIM AIRD patients {13 [interquartile range (IQR) 10-15] IIMs vs 13 [11-15] non-IIM AIRDs vs 15 [13-17] nrAIDs vs 17 [15-18] controls, P < 0.001}. The median GMH scores in IIM patients were also significantly lower compared with those without autoimmune diseases [13 (IQR 10-15) IIMs vs 15 (13-17) controls, P < 0.001]. Inclusion body myositis, comorbidities, active disease and glucocorticoid use were the determinants of lower GPH scores, whereas overlap myositis, interstitial lung disease, depression, active disease, lower PROMIS Physical Function 10a and higher PROMIS Fatigue 4a scores were associated with lower GMH scores in IIM patients. Conclusion: Both physical and mental health are significantly impaired in IIM patients, particularly in those with comorbidities and increased fatigue, emphasizing the importance of patient-reported experiences and optimized multidisciplinary care to enhance well-being in people with IIMs.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Evaluation of a creatinine clearance correction equation based on body fat mass in older Japanese patients with diabetes.

Background: The estimation of creatinine clearance (CCr) in older adult patients with diabetes is subject to deviations from the results of actual measurements because of changes in body composition. In the present study, we aimed to create a correction for the equation used for the estimation of CCr in older adult Asian patients with diabetes using body composition parameters. Methods: We enrolled 50 older Japanese patients with diabetes in whom the measured values of CCr were compared with values estimated using the Cockcroft-Gault equation. The relationships between the error in the estimated CCr and body composition parameters were investigated, and the Cockcroft-Gault equation was corrected using the appropriate parameters. To evaluate the generalizability of the corrected equation, the utility of the Cockcroft-Gault equation, which was corrected on the basis of body composition measured using a household body composition meter, was also investigated. Results: Body fat mass (BFM) was closely correlated with the error in the estimated CCr. The BFM-corrected Cockcroft-Gault equation was more accurate than the original equation. Similarly, the error became smaller using BFM measured with a household body composition meter. Conclusion: The BFM-corrected Cockcroft-Gault equation may provide an accurate method of estimating CCr that can be used in general practice.

Prevalence of Drug Fever among Cases of Nosocomial Fever: A Systematic Review and Meta-analysis.

Objective Drug fever is defined as a fever that temporally coincides with the start of a culprit drug and disappears after discontinuation of the drug. It is a common cause of nosocomial fever, which refers to a fever that develops beyond the first 48 h after hospital admission. However, the exact prevalence of drug fever among cases of nosocomial fever is unclear, as is the variation in prevalence depending on the clinical setting and most common causative drugs. Methods PubMed MEDLINE, Dialog EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were systematically searched. Studies that reported the prevalence of drug fever in patients with nosocomial fever were included. Two of the four reviewers conducted independent assessments of the inclusion, data extraction, and quality. Pooled adjusted odds ratios were generated using a random-effects model and presented with 95% confidence intervals (CIs). Results Fifteen meta-analysis from 15 studies were included. Ten studies did not report the definition of drug fever or excluded febrile patients who were admitted to the hospital within 24-48 h. The pooled prevalence of drug fever among cases of nosocomial fever was 3.0% (95% CI, 0.6-6.8%), which was largely consistent across the settings, except for at oriental medicine hospital. Only four studies reported the causative agents, and antibiotics were the most frequently reported. Conclusions The prevalence of drug fever is low in patients with nosocomial fever. Clinicians should recognize that drug fever is a diagnosis of exclusion, even in cases of nosocomial fever.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Dissociating Autoantibody Responses against Ro52 Antigen in Patients with Anti-Synthetase or Anti-MDA5 Antibodies.

We aimed to dissociate the autoantibody response against the Ro52 protein in patients with anti-synthetase or anti-melanoma differentiation-associated gene 5 (MDA5) antibodies to explore the potential roles of different anti-Ro52 autoantibody responses in disease subclassification. This study used a single-center, prospective myositis cohort involving 122 consecutive patients with anti-synthetase antibodies identified by RNA immunoprecipitation (RNA-IP) and 34 patients with anti-MDA5 antibodies detected using enzyme immunoassay (EIA). Anti-Ro52 antibodies were measured using commercial EIA kits, while anti-Ro/SSA antibodies were identified using RNA-IP. Clinical features and outcomes were stratified according to two different patterns of autoantibody responses against Ro52, including "isolated anti-Ro52", defined by positive anti-Ro52 and negative anti-Ro/SSA antibodies, and "anti-SSA-Ro52", defined by positive anti-Ro52 and anti-Ro/SSA antibodies. Isolated anti-Ro52 positivity was the most prevalent autoantibody response in patients with both anti-synthetase (40/122; 32.8%) and anti-MDA5 antibodies (8/34; 23.5%). Isolated anti-Ro52 or anti-SSA-Ro52 positivity was associated with Gottron's sign in patients with anti-synthetase antibodies, while in patients with anti-MDA5 antibodies, isolated anti-Ro52 positivity was associated with respiratory insufficiency at initial presentation and poor overall survival. Isolated anti-Ro52 positivity could be a potential biomarker for patient stratification; however, the clinical significance of dissociating isolated anti-Ro52 positivity from overall anti-Ro52 positivity was not evident.