Serum 25-hydroxyvitamin D levels and dermatomyositis: A 2-sample mendelian randomization study.

BACKGROUND: Previous studies have reported low serum 25-hydroxyvitamin D [25(OH)D] levels in dermatomyositis (DM) patients, but the exact causal relationship between them remains elusive. Our aim is to confirm the causal relationship between 25(OH)D and DM risk through a Mendelian randomization study. METHODS: Retrieve genome-wide association study (GWAS) data on 25(OH)D (n = 441 291) and DM (n cases = 201, n controls = 172 834) from the GWAS database (https://gwas.mrcieu.ac.uk/). Select single-nucleotide polymorphisms (SNPs) strongly correlated with 25(OH)D as instrumental variables (IVs). The primary analytical approach involves the use of the inverse-variance weighted method (IVW), supplemented by MR-Egger regression and weighted median methods to enhance the reliability of the results. Heterogeneity and sensitivity analyses were conducted using Cochran's Q and leave-one-out approaches, respectively. RESULTS: The IVW analysis confirmed a positive causal relationship between genetic variation in 25(OH)D levels and DM (OR = 2.36, 95% CI = 1.01-5.52, p = .048). Although not statistically significant (all p > .05), the other methods also suggested a protective effect of 25(OH)D on DM. Based on MR-Egger intercepts and Cochran's Q analysis, the selected SNPs showed no horizontal pleiotropy and heterogeneity. Sensitivity analysis demonstrated the robustness of the results against individual SNPs. CONCLUSION: We provide the first evidence of a causal relationship between 25(OH)D levels and DM. Our findings support the importance of measuring serum 25(OH)D levels and considering vitamin D supplementation in clinical practice for patients with DM.

Imatinib-induced dermatomyositis sine dermatitis - a rare case report.

Idiopathic Inflammatory Myopathies are rare conditions with several heterogeneous disease subtypes. They can range from limited muscle or skin involvement to severe, systemic, life-threatening disease. Although the etiology is unknown, some evidence suggests a role for external agents, particularly drugs. Herein, we present a case of a 71-year-old woman with chronic myeloid leukemia who developed imatinib-induced dermatomyositis sine dermatitis. The presentation was predominantly muscular, characterized by proximal muscle weakness and myalgia of the lower limbs, with positive anti-Mi2a antibodies. Spontaneous recovery was observed after drug discontinuation, without the need for immunosuppressive therapy. This is the first confirmed description of an imatinib-induced dermatomyositis sine dermatitis. It reflects the importance of a high awareness from rheumatologists and hematologists to accurately anticipate and identify similar situations.

Juvenile dermatomyositis with Anti-SAE antibodies in a Moroccan child associated with pseudo-angioedema: a case report.

BACKGROUND: Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized by a variable combination of muscular, dermatological, and visceral involvement. Myositis-specific autoantibodies help define homogeneous subgroups with common clinical characteristics and prognoses. Anti-SAE (small ubiquitin-like modifier 1 (SUMO-1) activating enzyme) antibodies are among the most recently discovered specific autoantibodies. The presence of these antibodies is very rare, making it challenging to define clinical features and prognosis in the juvenile form. We report the first case of an African patient with juvenile dermatomyositis and positive anti-SAE antibodies. CASE REPORT: A 5-year-3-month-old Moroccan boy presented to the pediatric emergency department with dysphagia that had been evolving for two days, preceded two months earlier by facial erythema associated with fatigue, lower limb pain, difficulty walking, and progressive inflammatory polyarthralgia. On admission, the child had a heliotrope rash with predominant pseudo-angioedema on the lips, periungual telangiectasia, and Gottron's papules over the bilateral interphalangeal and metatarsophalangeal joints. The patient had a more pronounced proximal muscle weakness in the lower limbs. He had no urticaria, fever, arthritis, calcinosis, cutaneous ulcers, or lipodystrophy. The Joint examination was normal, as was the pleuropulmonary examination. The electroneuromyography showed myogenic changes in all four limbs. Laboratory findings showed elevated levels of creatine phosphokinase and lactate dehydrogenase and a mild inflammatory syndrome. The electrocardiogram was normal. The anti-SAE antibodies were positive. The boy was diagnosed with juvenile dermatomyositis. He received methylprednisolone bolus therapy followed by oral prednisone. The latter was gradually tapered in combination with weekly intramuscular methotrexate. As a result, dysphagia disappeared within 48 h. After two weeks, there was an improvement in the muscular score and a significant regression of facial pseudo-angioedema. CONCLUSION: We report the first African patient with anti-SAE autoantibody-positive JDM. He had a typical dermatological manifestation of JDM associated with pseudo-angioedema predominant on the lips; a rarely reported sign in DM and JDM patients. The patient responded well to corticosteroid therapy and methotrexate.

Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis.

BACKGROUND: Dermatomyositis (DM) is prone to nasopharyngeal carcinoma (NPC), but the mechanism is unclear. This study aimed to explore the potential pathogenesis of DM and NPC. METHODS: The datasets GSE46239, GSE142807, GSE12452, and GSE53819 were downloaded from the GEO dataset. The disease co-expression module was obtained by R-package WGCNA. We built PPI networks for the key modules. ClueGO was used to analyze functional enrichment for the key modules. DEG analysis was performed with the R-package "limma". R-package "pROC" was applied to assess the diagnostic performance of hub genes. MiRNA-mRNA networks were constructed using MiRTarBase and miRWalk databases. RESULTS: The key modules that positively correlated with NPC and DM were found. Its intersecting genes were enriched in the negative regulation of viral gene replication pathway. Similarly, overlapping down-regulated DEGs in DM and NPC were also enriched in negatively regulated viral gene replication. Finally, we identified 10 hub genes that primarily regulate viral biological processes and type I interferon responses. Four key genes (GBP1, IFIH1, IFIT3, BST2) showed strong diagnostic performance, with AUC>0.8. In both DM and NPC, the expression of key genes was correlated with macrophage infiltration level. Based on hub genes' miRNA-mRNA network, hsa-miR-146a plays a vital role in DM-associated NPC. CONCLUSIONS: Our research discovered pivot genes between DM and NPC. Viral gene replication and response to type I interferon may be the crucial bridge between DM and NPC. By regulating hub genes, MiR-146a will provide new strategies for diagnosis and treatment in DM complicated by NPC patients. For individuals with persistent viral replication in DM, screening for nasopharyngeal cancer is necessary.

[Dermatomyositis].

Dermatomyositis (DM) is distinguished from other idiopathic inflammatory myopathies by the characteristic skin rashes, muscle pathology, and muscle symptoms. Five myositis-specific autoantibodies have been identified in DM, and the correlation between each antibody and the clinical picture is clear. Pathological analysis has also identified DM as a type I interferonopathy of the skeletal muscle. Consideration of treatment strategies requires careful evaluation of muscle strength, systemic inflammatory findings, muscle pathology, muscle imaging, and complications such as malignancy and interstitial lung disease. Corticosteroids are administered as first-line treatment, and immunosuppressive agents and intravenous immunoglobulins are employed as important second-line treatments. Some patients exhibit resistance to these therapies. Currently, treatment strategies for refractory cases are not well established, necessitating further development of treatment methods.

Elevated type I IFN signalling directly affects CD8+ T-cell distribution and autoantigen recognition of the skeletal muscles in active JDM patients.

The link between type I IFN and adaptive immunity, especially T-cell immunity, in JDM still remained largely unclear. This study aimed to understand the effect of elevated type I IFN signaling on CD8+ T cell-associated muscle damage in juvenile dermatomyositis (JDM). This study used flow cytometry (FC) and RT‒PCR were used to examine the circulating cell ratio and type I IFN response. And scRNA-seq was used to examine peripheral immunity in 6 active JDM patients, 3 stable JDM patients, 3 juvenile IMNM patients and 3 age-matched healthy children. In vivo validation experiments were conducted using a mouse model induced by STING agonists and an experimental autoimmune myositis model (EAM). In vitro experiments were conducted using isolated CD8+ T-cells from JDM patients and mice. We found that active JDM patients showed an extensive type I IFN response and a decreased CD8+ T-cell ratio in the periphery (P < 0.05), which was correlated with muscle involvement (P < 0.05). Both new active JDM patients and all active JDM patients showed decreased CD8+ TCM cell ratios compared with age and gender matched stable JDM patients (P < 0.05). Compared with new pediatirc systemic lupus erythematosus (SLE) patients, new active JDM patients displayed decreased CD8+ T-cell and CD8+ TCM cell ratios (P < 0.05). Active JDM patient skeletal muscle biopsies displayed an elevated type I IFN response, upregulated MHC-I expression and CD8+ T-cell infiltration, which was validated in EAM mice. sc-RNAseq demonstrated that type I IFN signalling is the kinetic factor of abnormal differentiation and enhances the cytotoxicity of peripheral CD8+ T cells in active JDM patients, which was confirmed by in vivo and in vitro validation experiments. In summary, the elevated type I IFN signalling affected the differentiation and function of CD8+ T cells in active JDM patients. Skeletal muscle-infiltrating CD8+ T cells might migrate from the periphery under the drive of type I IFN and increased MHC I signals. Therapies targeting autoantigen-specific CD8+ T cells may represent a potential new treatment direction.

Successful Treatment of Ultrasound-confirmed Synovitis in Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Corticosteroid Therapy.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.

[Magnetic resonance imaging T2 mapping could reflect disease status in patients with dermatomyositis or polymyositis].

This study aimed to explore the value of magnetic resonance imaging (MRI) T2 mapping in the assessment of dermatomyositis (DM) and polymyositis (PM). Thirty-three confirmed cases (myosin group) and eight healthy volunteers (healthy control group) at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Kunming Medical University, from October 2016 to December 2017, were collected and analyzed. Multiple parameters of the myosin group were quantified, including creatine kinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3, and complement C4. Disease status was evaluated using a panel of tools: myositis disease activity assessment tool-muscle (MDAAT-muscle), myositis disease activity assessment tool-whole (MDAAT-all), health assessment questionnaire (HAQ), medical outcomes study health survey short form-36 item (SF-36), hand muscle strength test (MMT-8) score, and MRI T2 mapping of muscle (22 muscles in the pelvis and thighs) T2 values. The results showed that in the myositis group, the measurements for CK, ESR, CRP, complement C3, and complement C4 were 457.2 (165.6, 1 229.2) IU/L, 20 (10, 42) mm/1h, 3.25 (2.38, 10.07) mg/L, 0.90 (0.83, 1.06) g/L, and 0.18 (0.14, 0.23) g/L, respectively. The scores for MMT-8, MDAAT-muscle, MDAAT-all, HAQ, and SF-36 were 57.12±16.23, 5.34 (4.00, 6.00), 34.63±12.62, 1.55 (0.66, 2.59), and 44.66±7.98, respectively. T2 values were significantly higher in all 22 muscles of the pelvis and thighs of patients with DM or PM compared with the healthy controls [(54.99±11.60)ms vs. (36.62±1.66)ms, P<0.001], with the most severe lesions in the satrorius, iliopsoas, piriformis, gluteus minimus, and gluteus medius muscles. The total muscle T2 value in the myositis group was positively correlated with CK, MDAAT-muscle, MDAAT-all, and HAQ (r=0.461, 0.506, 0.347, and 0.510, respectively, all P<0.05). There was a negative correlation between complement C4, SF-36, and MMT-8 scores (r=-0.424, -0.549, and -0.686, respectively, all P<0.05). Collectively, the findings from this study suggest that MRI T2 mapping can objectively reflect the disease status of DM and PM.

Elevated serum B-cell activator factor levels predict rapid progressive interstitial lung disease in anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis.

BACKGROUND: Rapid progressive interstitial lung disease (RP-ILD) is the leading cause of anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) related death. Elevated serum B-cell activating factor (BAFF) levels have been implicated in connective tissue diseases associated ILD. Here, we evaluate whether BAFF could be a prognostic biomarker for predicting RP-ILD in anti-MDA5+DM patients. METHODS: Serums were collected from 39 patients with anti-MDA5+DM (20 with RP-ILD and 19 with non-RP-ILD), 20 antisynthase syndrome (ASS) patients and 20 healthy controls (HC). BAFF concentration was measured by an enzyme-linked immunosorbent assay. RESULTS: Serum BAFF level was higher in anti-MDA5+DM patients than those in ASS patients and HC (3882.32 ± 1880.09 vs. 2540.89 ± 1403.04 and 2486.28 ± 767.97 pg/mL, p = 0.0056 and 0.0038, respectively). Within anti-MDA5+DM groups, RP-ILD patients exhibited higher BAFF concentration than non-RP-ILD group (4549.78 ± 1839.97 vs. 3297.28 ± 1794.69 pg/mL, p = 0.04). The BAFF concentration was positively correlated with levels of C-reactive protein (CRP), dehydrogenase (LDH) and cytokeratin (CK) in anti-MDA5+DM patients (r = 0.350, p = 0.035; r = 0.393, p = 0.016; r = 0.518, p = 0.001; respectively). The best cut-off value of BAFF concentration was 2971.5 pg/mL by ROC curve (AUC area = 0.690, p = 0.045) and BAFF > 2971.5 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR = 9.389, 95% CI = 1.609-54.769; p = 0.013). CONCLUSIONS: Serum BAFF could be a useful prognostic biomarker for early detecting RP-ILD risk in anti-MDA5+DM patients.

Reduced expressions of apoptosis-related proteins TRAIL, Bcl-2, and TNFR1 in NK cells of juvenile-onset systemic lupus erythematosus patients: relations with disease activity, nephritis, and neuropsychiatric involvement.

Background: Lupus pathogenesis is mainly ascribed to increased production and/or impaired clearance of dead cell debris. Although self-reactive T and B lymphocytes are critically linked to lupus development, neutrophils, monocytes, and natural killer (NK) cells have also been implicated. This study assessed apoptosis-related protein expressions in NK cells of patients with juvenile-onset systemic lupus erythematosus (jSLE) and relations to disease activity parameters, nephritis, and neuropsychiatric involvement. Methods: Thirty-six patients with jSLE, 13 juvenile dermatomyositis (JDM) inflammatory controls, and nine healthy controls had Fas, FasL, TRAIL, TNFR1, Bcl-2, Bax, Bim, and caspase-3 expressions in NK cells (CD3-CD16+CD56+) simultaneously determined by flow cytometry. Disease activity parameters included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, erythrocyte sedimentation rate, C-reactive protein level, anti-double strain DNA antibody level, complement fractions C3 and C4 levels. Results: Patients with jSLE had a profile of significantly reduced expression of TRAIL, Bcl-2, and TNFR1 proteins in NK cells when compared to healthy controls. Similar profile was observed in patients with jSLE with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. Patients with jSLE with positive anti-dsDNA also had reduced expression of Bax in NK cells when compared healthy controls and to those with negative anti-dsDNA. Yet, patients with jSLE with negative anti-dsDNA had reduced mean fluorescence intensity (MFI) of Bim in NK cells compared to healthy controls. Patients with jSLE with nephritis also had reduced MFI of Fas in NK cells when compared to those without nephritis. In addition, in patients with jSLE, the proportion of FasL-expressing NK cells directly correlated with the SLEDAI-2K score (rs = 0.6, p = 0.002) and inversely correlated with the C3 levels (rs = -0.5, p = 0.007). Moreover, patients with jSLE had increased NK cell percentage and caspase-3 protein expression in NK cells when compared to JDM controls. Conclusion: This study extends to NK cells an altered profile of TRAIL, Bcl-2, TNFR1, Fas, FasL, Bax, Bim, and caspase-3 proteins in patients with jSLE, particularly in those with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. This change in apoptosis-related protein expressions may contribute to the defective functions of NK cells and, consequently, to lupus development. The full clarification of the role of NK cells in jSLE pathogenesis may pave the way for new therapies like those of NK cell-based.

A case of autoimmune pulmonary alveolar proteinosis during the course of treatment of rapidly progressive interstitial pneumonia associated with anti-MDA5 antibody-positive dermatomyositis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Dynamic change in red cell distribution width as a predictor for short-time mortality in dermatomyositis-associated rapid progressive interstitial lung disease.

AIM: We aimed to explore a new and readily available practical marker for rapidly progressive interstitial lung disease (RP-ILD) and poor short-term outcomes in patients with idiopathic inflammatory myopathies (IIM). METHODS: A total of 1822 consecutive patients with IIM between 2009 and 2021 were evaluated retrospectively. All proven cases of naïve ILD with complete medical records were included. Red cell distribution width (RDW) values at the initial stage, 3 months and last follow-up were collected. The clinical characteristics and outcomes of the patients were recorded. RESULTS: We identified 532 patients with IIM with an average follow-up of 4 years. ILD prevalence was higher in patients of elevated RDW (p<0.001). The patients with ILD and elevated RDW had lower levels of PaO2/FiO2, FVC% and DLco% and a higher prevalence of RP-ILD than those with normal RDW (p<0.001). Prognostic analysis revealed that RDW was an independent risk factor for prognosis in patients with IIM-ILD (HR=2.9, p=0.03). Patients with dermatomyositis (DM) with RP-ILD with a change in RDW within 3 months (∆RDW-3) greater than 0 were more likely to die within 3 months. Moreover, the prevalence of ∆RDW-3>0 was higher in patients with RP-ILD and positive for anti-melanoma differentiation-associated gene 5 antibody who died within 3 months (87.5%) compared with those alive at 3 months (24.6%) (p<0.001). CONCLUSION: These findings suggest that repeated RDW assays could assist physicians in identifying patients with DM-ILD who were at a high risk of RP-ILD and death.

Pembrolizumab-associated anti-MDA5 dermatomyositis in a patient with lung cancer: a first case report.

We report the first case of anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis as a systemic immune-related adverse event in a 64-year-old man receiving pembrolizumab to treat advanced lung cancer. The patient experienced hypothyroidism, myalgia, skin involvement, dyspnoea and diarrhoea. Laboratory tests revealed raised inflammatory markers, hypercreatinekinasemia and anti-MDA5 autoantibodies. Electroneuromyography and pathognomonic signs on physical examination confirmed the diagnosis of pauci-myopathic dermatomyositis. Pembrolizumab was discontinued and immunosuppressive therapy led to rapid and progressive improvement, with complete remission of dermatomyositis. This case report widens the spectrum of systemic immune-related adverse events associated with pembrolizumab.

Therapeutic efficacy and safety of JAK inhibitors in treating polymyositis/dermatomyositis: a single-arm systemic meta-analysis.

Introduction: We performed a single-arm meta-analysis to evaluate the efficacy and safety of JAK inhibitors in the treatment of dermatomyositis (DM)/ polymyositis (PM). Methods: Relevant studies from four databases were systematically searched until April 25, 2023. The primary endpoint was Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and other outcomes were Manual Muscle Testing (MMT) and Creatine Kinase (CK). According to the type of JAK and medication regimen, we conducted subgroup analyses. The registration number in PROSPERO was CRD42023416493. Results: According to the selection criteria, we identified 7 publications with a total of 91 patients. Regarding skin lesions, the CDASI decreased by 17.67 (95% CI: -20.94 ~ -14.41). The CK increased by 8.64 U (95% CI: -28.25 ~ 45.53). About muscle lesions, MMT increased by 10.31 (95% CI: -2.83 ~ 23.46). Subgroup analysis revealed that different types of JAK inhibitors had various degrees of reduction. CDASI in patients treated with RUX had the lowest one [-20.00 (95% CI: -34.9 ~ -5.1)], followed by TOF [-18.29 (95% CI: -21.8 ~ -14.78)] and BAR [-11.2 (95% CI: -21.51 ~ -0.89)]. Additionally, the mean reduction in CDASI in patients treated with TOF alone was 16.16 (95% CI: -21.21 ~ -11.11), in combination with other immunosuppressants was 18.59 (95% CI: -22.74 ~ -14.45). For safety evaluation, one patient developed Orolabial HSV, and two patients developed thromboembolism events. Discussion: In summary, this meta-analysis demonstrated that JAK inhibitors can potentially treat DM/PM without severe adverse reactions. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42023416493, identifier CRD42023416493.