Autoimmunity against melanoma differentiation-associated gene 5 induces interstitial lung disease mimicking dermatomyositis in mice.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model.

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.

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.

Anti-SAE dermatomyositis: clinical and histologic characteristics from a monocentric Italian cohort.

OBJECTIVES: Multiple myositis-specific antibodies have been identified, each associated with different clinical subsets of dermatomyositis (DM). Anti-SAE associated DM is considered the least studied subset. Our study aimed to evaluate the clinical and histological characteristics of DM patients with anti-SAE antibodies. As reference, patients with anti-Mi2 antibodies associated DM, representing a well-characterised subset, were analysed. METHODS: We recorded data from our DM cohort in the INflammatory MYositis REgistry (INMYRE). Patients were divided into two groups: those positive for anti-SAE and those positive for anti-Mi2 antibodies. Clinical characteristics, including skin, muscle, and extra-muscular involvements, were recorded. Available muscle biopsies were compared between the two groups. RESULTS: Of 92 DM patients, 10 (10.9%) were positive for anti-SAE and 17 (18.5%) for anti-Mi2. Anti-SAE positive DM patients showed classic DM findings but were characterised by a higher prevalence of skin itching (60% vs. 11.8%, p<0.01), shawl sign (40% vs. 5.9%, p<0.05) and lung involvement (30% vs. 0%, p<0.05) compared to anti-Mi2 positive patients. Furthermore, anti-SAE positive DM patients showed lower creatine kinase levels than those with anti-Mi2 (median [IQR]: 101 [58-647] vs. 1984 [974-3717], p<0.05) and a lower percentage of muscle fibre degeneration and necrosis (1.5%±1.7 vs. 5.9%±3.2, p<0.05) in muscle biopsies. No other differences were observed. CONCLUSIONS: Anti-SAE DM represents a disease subset characterised by classic cutaneous involvement often associated with itching, less severe muscle involvement, but potential pulmonary involvement that should always be investigated in these patients.

Prevalence of hearing loss, tinnitus, vertigo and sudden deafness among patients with polymyositis and dermatomyositis.

Little is known about a possible association of autoimmune inner ear disease among patients diagnosed with polymyositis (PM)/dermatomyositis (DM). This study aimed to explore differences in the prevalence of inner ear symptoms among patients with and without PM/DM using a nationwide population-based dataset. Data for this study were retrieved from the Taiwan National Health Insurance Research Database. The study sample included 1622 patients diagnosed with PM/DM and 8109 propensity-score matched comparison patients without PM/DM. We performed multivariate logistic regressions to calculate odds ratios (ORs) and 95% confidence interval (CI) for tinnitus, hearing loss, sudden deafness, and vertigo among patients with PM/DM versus comparison patients. Chi-square tests showed statistically significant differences between patients with PM/DM and comparison patients in the prevalence of tinnitus (16.1% vs. 12.7%, p < 0.001), non-conductive hearing loss (9.2% vs. 6.8%, p < 0.001), and vertigo (14.4% vs. 11.1%, p < 0.001). The adjusted ORs for tinnitus, non-conductive hearing loss, and vertigo, respectively, were 1.332 (95% CI = 1.147-1.547), 1.399 (95% CI = 1.154-1.696), and 1.374 (95% CI = 1.173-1.611) for patients with PM/DM when compared to comparison patients. Our study finds that patients with PM/DM have higher prevalence rates of tinnitus, non-conductive hearing loss, and vertigo than comparison patients.

Diagnosis of multiple tuberculous muscle abscesses in a patient with systemic lupus erythematosus by metagenomic next-generation sequencing- a case report and literature review.

BACKGROUND: Early diagnosis of muscular tuberculosis (TB) without coexistent active skeletal involvement is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of muscular TB, we present a case of multiple tuberculous muscle abscesses in a systemic lupus erythematosus (SLE) female, but without pulmonary tuberculosis (PTB), in order to increase awareness of and stress the need of early detection of muscular TB. CASE PRESENTATION: A 44-year-old woman with a 6-year history of SLE who had been treated with methylprednisolone for a long time complained of erythema on her trunk and extremities for five months, along with edema and myalgia for two months, and fever for one month. The patient was first misdiagnosed as SLE overlap dermatomyositis. However, an ultrasound-guided drainage of muscle abscesses revealed positive acid-fast staining combined with positive deoxyribonucleic acid fragment of Mycobacterium tuberculosis using metagenomic next-generation sequencing (mNGS). The patient was cured and released following standard anti-tuberculosis medication, local puncture drainage, and an intravitreal injection of streptomycin. Literature search found only 19 cases of tuberculous muscle abscesses occurring in the extremities reported from 1999 to 2023. CONCLUSIONS: Extrapulmonary TB with predominantly muscle involvement is rare and with no specific clinical presentation. Muscular tuberculosis may be disdiagnosed for dermatomyositis due to the high muscle enzyme levels, delaying diagnosis and treatment. mNGS technology is helpful in the early and rapid diagnosis of muscular TB. On the basis of traditional anti-tuberculosis treatment, an ultrasound-guided percutaneous puncture drainage and intracavitary injection of streptomycin for the treatment of tuberculous muscle abscess is easy to operate, safe and effective, which is worthy of clinical popularization and application.

Concurrence of dermatomyositis and psoriasis: a case report and literature review.

Dermatomyositis (DM) is a type of inflammatory myopathy with unknown causes. It is characterized by distinct skin lesions, weakness in the muscles close to the body, and the potential to affect multiple organs. Additionally, it may be associated with the presence of malignancies. The development of DM is influenced by genetic susceptibility, autoimmune response, and various external factors like cancer, drugs, and infectious agents. Psoriasis is a chronic, recurring, inflammatory, and systemic condition. Scaly erythema or plaque is the typical skin manifestation. The etiology of psoriasis involves genetic, immune, environmental and other factors. It is uncommon for a patient to have both of these diseases simultaneously, although individuals with DM may occasionally exhibit symptoms similar to those of psoriasis. Our patient was diagnosed with psoriasis in his 50s because of scalp squamous plaques, but he did not receive standard treatment. Ten years later, he developed symptoms of muscle pain and limb weakness. He was diagnosed with psoriasis complicated with dermatomyositis in our department and received corresponding treatment. Moreover, we reviewed the relevant literature to evaluate similarities and differences in clinical manifestation and treatment to other cases.

Successful Treatment of Rapidly Progressive Interstitial Lung Disease in Juvenile Dermatomyositis.

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease characterized by cutaneous findings, muscle inflammation, and vasculopathy. Patients with antimelanoma differentiation associated gene 5 (anti-MDA5) JDM may have subtle muscle weakness, absence of pathognomonic rashes, and more polyarthritis and ulcerative skin lesions when compared with other JDM subtypes. Although there is a known association of rapidly progressive interstitial lung disease (RP-ILD) in patients with anti-MDA5 dermatomyositis, few case reports describe this association in the pediatric literature. Even fewer reports describe successful treatment. We report an unusual case of RP-ILD in a pediatric patient with a hypomyopathic presentation complicated by prolonged intubation and pulmonary hemorrhage. A 4-year-old underweight female presented in respiratory distress and quickly progressed to severe hypoxic and hypercarbic respiratory failure requiring intubation. She experienced fatigue, intermittent fever, and transaminitis. The diagnosis was delayed because of recent travel history and a lack of typical cutaneous features of JDM, except a small erythematous papule on her antihelix. Her pulmonary hemorrhage and ear lesion prompted additional rheumatic workup. The myositis-specific antibody panel revealed high positive anti-MDA5 antibodies that prompted aggressive combination therapy with plasmapheresis, systemic steroids, inhibitors of Janus kinase, agents to deplete B-cells, and intravenous immunoglobulin. The patient responded well to treatment and was ultimately extubated and discharged. To our knowledge, this is the first thoroughly documented case of anti-MDA5 JDM with RP-ILD presenting with pulmonary hemorrhage and lacking typical cutaneous features. Early recognition of this highly fatal condition is important for improved prognosis.

[A CASE OF CLINICALLY AMYOPATHIC DERMAMYOSITIS WITH INTERSTITIAL LUNG DISEASE SHOWING TWO DETERIORATIONS IN 4 YEARS].

We report the case of a 45-year-old man who was diagnosed with clinically amyopathic dermamyositis (CADM) and interstitial lung disease (ILD) after presenting with skin lesions typical of CADM and testing positive for anti-Melanoma Diferentiation-Associated gene 5 (anti-MDA5) anti-bodies. He was treated with a regimen including steroid pulse therapy, intravenous cyclophosphamide (IVCY), and calcineurin Inhibitor drug, which initially improved his ILD. However, three months post-treatment, the first deterioration of his conditions occurred, necessitating further administration of steroid pulse therapy and IVCY. After eight cycles of IVCY therapy, the serum levels of KL-6 and anti-MDA5 antibodies decreased, and reaching their lowest values. Nevertheless, two years and six months after the first observed deterioration, the second deterioration of his conditions occurred, leading to acute respiratory failure, treated again with steroid pulse therapy and IVCY. This treatment did not result in improvement of respiratory failure, therefore plasma exchange was attempted, which demonstrated a beneficial effect on the ILD for a short time. This case suggests that IVCY and plasma exchange might be effective therapeutic options for CADM with ILD.

Defining criteria for disease activity states in juvenile dermatomyositis based on the Juvenile Dermatomyositis Activity Index.

OBJECTIVES: To develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in children with juvenile dermatomyositis (JDM). METHODS: For cut-off definition, data from 139 patients included in a randomised clinical trial were used. Among the six versions of the JDMAI, JDMA1 (score range 0-40) and JDMAI2 (score range 0-39) were selected. Optimal cut-offs were determined against external criteria by calculating different percentiles of score distribution and through receiver operating characteristic curve analysis. External criteria included the modified Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically ID in JDM (for ID) and PRINTO levels of improvement in the clinical trial (for LDA and HDA). MDA cut-offs were set at the score interval between LDA and HDA cut-offs. Cut-off validation was conducted by assessing construct and discriminative ability in two cohorts including a total of 488 JDM patients. RESULTS: The calculated JDMAI1 cut-offs were ≤2.4 for ID, ≤6.6 for LDA, 6.7-11 for MDA and >11 for HDA. The calculated JDMAI2 cut-offs were ≤5.2 for ID, ≤8.5 for LDA, 8.6-11.3 for MDA and >11.3 for HDA. The cut-offs discriminated strongly among disease activity states defined subjectively by caring physicians and parents, parents' satisfaction or non-satisfaction with illness outcome, levels of pain, fatigue, physical functional impairment and physical well-being. CONCLUSIONS: Both JDMAI1 and JDMAI2 cut-offs revealed good metrologic properties in validation analyses and are, therefore, suited for application in clinical practice and research.

Cancer Risk and Mortality in Hospitalized Patients With Idiopathic Inflammatory Myopathies in Western Australia.

OBJECTIVE: To compare cancer incidence, type, and survival between patients with idiopathic inflammatory myopathies (IIMs) in Western Australia (WA) and the general population. METHODS: Administrative health data for hospitalized patients with incident IIM (n = 803, 56.5% female, median age 62.0 yrs), classified by a validated algorithm as polymyositis (PM; 36.2%), dermatomyositis (DM; 27.4%), inclusion body myositis (IBM; 17.1%), overlap myositis (OM; 10.7%), and other IIM (8.6%), were linked to WA cancer and death registries for the period of 1980 to 2014. Cancer incidence rates (CIRs) before and after IIM diagnosis as well as cancer mortality were compared with age-, sex-, and calendar year-matched controls (n = 3225, 54.9% female, median age 64 yrs) by rate ratios (RRs) and Kaplan-Meier survival estimates. RESULTS: The prediagnosis CIR was similar for patients with IIM and controls (6.57 vs 5.95; RR 1.11, 95% CI 0.88-1.39) and for patients evolving to DM (n = 220) or other IIM subtypes (6.59 vs 6.56; RR 1.01, 95% CI 0.38-3.69). During follow-up, CIR was higher for all DM (4.05, 95% CI 3.04-5.29), with increased CIR for lung cancer vs controls (1.05 vs 0.33; RR 3.18, 95% CI 1.71-5.47). Cancer post diagnosis shortened life span by 59 months for patients with IIM (103 vs 162 months, P < 0.01), but reduced survival rates were observed only in patients with DM and IBM. CONCLUSION: Cancer risk was not increased prior to IIM, but CIR for lung cancer was increased following DM diagnosis. As cancer reduced survival only in patients with DM and IBM, these data support a strategy of limited cancer screening in IIM.

Extracellular Vesicles in the Pathogenesis, Clinical Characterization, and Management of Dermatomyositis: A Narrative Review.

Extracellular vesicles (EVs) are lipid-bilayer particles secreted from cells that primarily assist in cell-to-cell communication through the content of their cargo, such as proteins and RNA. EVs have been implicated in the pathogenesis of various autoimmune diseases, including dermatomyositis (DM), an inflammatory autoimmune disease characterized by distinct cutaneous manifestations, myopathy, and lung disease. We sought to review the role of EVs in DM and understand how they contribute to the pathogenesis and clinical characterization of the disease. We summarized the research progress on EVs in dermatomyositis based on recent publications. EV cargoes, such as double-stranded DNA, microRNA, and proteins, contribute to DM pathogenesis and mediate the proinflammatory response and cytokine release through signaling pathways such as the stimulator of interferon genes (STING) pathway. These nucleic acids and proteins have been proposed as disease-specific, stable biomarkers to monitor disease activity and responses to therapy. They also correlate with clinical parameters, inflammatory markers, and disease severity scores. Furthermore, some markers show an association with morbidities of DM, such as muscle weakness and interstitial lung disease. The continued study of EVs will help us to further elucidate our understanding of dermatomyositis.

Local injection of infliximab into calcinosis lesions in patients with juvenile dermatomyositis (JDM): a clinical trial.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare autoimmune disorder that primarily affects muscles and skin. One of the severe complications associated with JDM is calcinosis, and treating this condition presents significant challenges. This study aimed to evaluate the efficacy and safety of local injection of infliximab into calcinosis lesions in patients with JDM. METHODS: In this clinical trial, five patients diagnosed with JDM and calcinosis lesions were enrolled. The primary treatment consisted of weekly infliximab injections for 16 weeks, targeting all four sides of each lesion. Lesion dimensions, including length and width, were documented and monitored weekly. Before the intervention, patients underwent radiographic imaging. After the final injection in week 16, a follow-up radiographic assessment was performed. Data were analyzed using the Generalized Estimating Equation (GEE) method. RESULTS: The lesions' size significantly decreased in both length and width during each visit. On average, the lesion length reduced by 2.66%, and the width shrank by 3.32% per visit. Based on radiographic findings, the average length and width of lesions at the initial visit were 12.09 ± 5.05 mm (range: 6.00-25.50 mm) and 6.35 ± 3.00 mm (range: 2.00-16.00 mm), respectively. The average length and width at the last visit were 5.59 ± 7.05 mm (range: 0-23.00 mm) and 3.41 ± 4.05 mm (range: 0-13.00 mm), respectively. No specific side effects related to the treatment were reported. CONCLUSIONS: The results suggest that the direct administration of infliximab into the calcinosis lesions of patients with JDM could be a safe and effective treatment approach. TRIAL REGISTRATION: Name of the registry: The effect of infliximab injection into calcinosis lesions on patients with juvenile dermatomyositis (JDM), Trial registration number: IRCT20210808052107N1, Registration date: 2022-07-22, URL of trial registry record: https://en.irct.ir/trial/58329 .

Clinical features of macrophage activation syndrome in adult dermatomyositis: A single-center retrospective case-control study.

BACKGROUND: Little is known about the features of macrophage activation syndrome (MAS) in dermatomyositis, especially the association between rapidly progressive interstitial lung disease (RP-ILD) and MAS. OBJECTIVE: To determine the characteristics of MAS in patients with dermatomyositis and their association with RP-ILD. METHODS: This was a retrospective cohort study of 201 dermatomyositis patients at the First Affiliated Hospital of Zhejiang University over a 10-year period. RESULTS: A total of 22 (10.9%) patients were diagnosed with MAS. The rate of RP-ILD was significantly higher in patients with MAS than in those without MAS (81.8% vs. 17.4%, respectively, p < .001). Multivariate analysis indicated that RP-ILD (p = .019), ferritin level > 1685 ng/mL (p = .007) and hemoglobin < 100 g/L (p = .001) were independent risk factors for MAS. Furthermore, RP-ILD patients with MAS presented more cardiac injury (50.0% vs. 13.3%, respectively, p < .009), central nervous system dysfunction (42.8% vs. 3.4%, respectively, p < .001) and hemorrhage (38.9% vs. 3.3%, respectively, p = .003) than RP-ILD patients without MAS. The 90-day cumulative survival rate for patients with MAS was significantly lower than for those without MAS (18.2% vs. 82.1%, respectively, p < .001). CONCLUSION: MAS was a common and fatal complication of dermatomyositis in our cohort. MAS is closely related to RP-ILD in patients with dermatomyositis. When RP-ILD is present in dermatomyositis patients with abnormal laboratory findings, such as cytopenia and hyperferritinemia, the presence of MAS should be considered.

[Current update on dermatomyositis]. / Aktuelle Aspekte zur Dermatomyositis.

Dermatomyositis (DM) is a rare autoimmune disease with involvement of skin and muscle that is classified as an idiopathic inflammatory myopathy. In addition to cutaneous lesions as well as weakness and atrophy of muscles, the heart and lungs are the major affected organs. DM occurs in association with malignant tumors in 20% of affected adults. The pathogenesis of the disease is not completely understood. DM is a multifactorial disease influenced by genetic, environmental and immunological factors. The immune response is characterized by activation of innate and adaptive immune mechanisms and a strong activation of the type I interferon pathway. Myositis-specific antibodies are characteristic of DM and allow differential diagnosis. Therapies include corticosteroids, antimalarials, immunoglobulins, biologics such as rituximab or JAK inhibitors. Early diagnosis and treatment are essential for the prognosis.

Anti-MDA5 antibody-associated clinically amyopathic dermatomyositis diagnosed after the onset of pulmonary hypertension.

Idiopathic inflammatory myopathies (IIM) are a group of highly heterogeneous systemic autoimmune diseases, of which clinically amyopathic dermatomyositis (CADM) is a distinct sub-type. Pulmonary hypertension (PH) is a life-threatening medical condition that can occur as a complication of connective tissue diseases. Herein, our report first suggests that PH can develop in CADM. A 48-year-old woman came to our hospital due to a 3 months history of facial edema and shortness of breath. Relevant examinations revealed Gottron's sign, normal creatinine kinase levels, elevated levels of mean pulmonary artery pressure, double-positive anti-MDA5 and anti-Ro52 antibodies, and typical pathological changes associated with myositis. The diagnosis of CADM combined with PH was considered. The patient responded well to the immunosuppression therapy and PH-related drug therapy. We provide further insights that patients with IIM need to undergo regular assessment of PH.

Severe gastrointestinal involvements in patients with adult dermatomyositis with anti-NXP2 antibody.

OBJECTIVE: Gastrointestinal (GI) involvements were scarcely reported in adult anti-nuclear matrix protein 2 (NXP2) dermatomyositis (NXP2+DM). In this study, we investigated the clinical, pathological and molecular features as well as treatment options of this rare yet life-threatening disease. METHODS: We retrospectively collected the data of the cohort of NXP2+ DM from 2012 to 2022 in our hospital. RNA sequencing was performed in intestinal samples of perforated patients compared with healthy controls data set. RESULTS: A total of 56 patients with adult NXP2+DM were collected including 10 cases with GI involvements. Abdominal pain and melena were the initial manifestations for GI involvements with a median 10-month time lag after the diagnosis of NXP2+DM when myositis largely subsided. Within weeks, GI perforation occurred in 8 of 10 patients, while five patients underwent eight surgical interventions subsequently. The short-term mortality was observed in four patients. NXP2+DM with GI involvements presented with more extramuscular systemic manifestations such as interstitial lung disease and subcutaneous calcinosis. The GI pathological features encompassed vasculitis/vasculopathy with high MxA expression, intestinal smooth muscle necrosis and serosal calcinosis. Gene expression profile validated the type-I interferon activation and revealed that epithelial mesenchymal transition and focal adhesion pathway may also contribute. Finally, vedolizumab, an anti-α4ß7-integrin monoclonal antibody, exhibited promising therapeutic signals which should be further investigated. CONCLUSIONS: GI involvement is a unique complication in patients with adult NXP2+DM. Timely recognition and targeted therapy may turn out to be lifesaving.