Dermatomyositis associated with thymoma: A case report and literature review.

Abstract: Thymoma can present with paraneoplastic-autoimmune neuro-muscular disorders, including polymyositis, dermatomyositis, and granulomatous myositis. Rarely, concomitant subclinical myasthenia gravis (MG) can be a diagnostic dilemma and cause deleterious outcomes regarding missed or delayed diagnosis. We report a Turkish patient presented with thymoma associated dermatomyositis and positive acetylcholine receptor antibody without evident MG clinic.

Enhanced immune complex formation in the lungs of patients with dermatomyositis.

BACKGROUND: Interstitial lung disease is frequently comorbid with dermatomyositis and has a poor prognosis, especially in patients with the anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody. However, the pathogenesis of dermatomyositis-related interstitial lung disease remains unclear. METHODS: We examined 18 and 19 patients with dermatomyositis-related interstitial lung disease and idiopathic pulmonary fibrosis (control), respectively. Lung tissues obtained from these patients were semi-quantitatively evaluated by immunohistochemical staining with in-house anti-human MDA5 monoclonal antibodies, as well as anti-human immunoglobulin (Ig) G, IgM, IgA, and complement component 3(C3) antibodies. We established human MDA5 transgenic mice and treated them with rabbit anti-human MDA5 polyclonal antibodies, and evaluated lung injury and Ig and C3 expression. RESULTS: MDA5 was moderately or strongly expressed in the lungs of patients in both groups, with no significant differences between the groups. However, patients with dermatomyositis-related interstitial lung disease showed significantly stronger expression of C3 (p < 0.001), IgG (p < 0.001), and IgM (p = 0.001) in the lungs than control. Moreover, lung C3, but IgG, IgA, nor IgM expression was significantly stronger in MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease (n = 9) than in MDA5 autoantibody-negative dermatomyositis-related interstitial lung disease (n = 9; p = 0.022). Treatment with anti-MDA5 antibodies induced lung injury in MDA5 transgenic mice, and strong immunoglobulin and C3 expression was observed in the lungs of the mice. CONCLUSION: Strong immunoglobulin and C3 expression in the lungs involve lung injury related to dermatomyositis-related interstitial lung disease. Enhanced immune complex formation in the lungs may contribute to the poor prognosis of MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease.

Inflammatory myopathies and beyond: The dual role of neutrophils in muscle damage and regeneration.

Skeletal muscle is one of the most abundant tissues of the human body and is responsible for the generation of movement. Muscle injuries can lead to severe disability. Skeletal muscle is characterized by an important regeneration capacity, which is possible due to the interaction between the myoblasts and immune cells. Neutrophils are fundamental as inducers of muscle damage and as promoters of the initial inflammatory response which eventually allows the muscle repair. The main functions of the neutrophils are phagocytosis, respiratory burst, degranulation, and the production of neutrophil extracellular traps (NETs). An overactivation of neutrophils after muscle injuries may lead to an expansion of the initial damage and can hamper the successful muscle repair. The importance of neutrophils as inducers of muscle damage extends beyond acute muscle injury and recently, neutrophils have become more relevant as part of the immunopathogenesis of chronic muscle diseases like idiopathic inflammatory myopathies (IIM). This heterogeneous group of systemic autoimmune diseases is characterized by the presence of muscle inflammation with a variable amount of extramuscular features. In IIM, neutrophils have been found to have a role as biomarkers of disease activity, and their expansion in peripheral blood is related to certain clinical features like interstitial lung disease (ILD) and cancer. On the other hand, low density granulocytes (LDG) are a distinctive subtype of neutrophils characterized by an enhanced production of NETs. These cells along with the NETs have also been related to disease activity and certain clinical features like ILD, vasculopathy, calcinosis, dermatosis, and cutaneous ulcers. The role of NETs in the immunopathogenesis of IIM is supported by an enhanced production and deficient degradation of NETs that have been observed in patients with dermatomyositis and anti-synthetase syndrome. Finally, new interest has arisen in the study of other phenotypes of LDG with a phenotype corresponding to myeloid-derived suppressor cells, which were also found to be expanded in patients with IIM and were related to disease activity. In this review, we discuss the role of neutrophils as both orchestrators of muscle repair and inducers of muscle damage, focusing on the immunopathogenesis of IIM.

[Risk Factors of Rapidly Progressive Interstitial Lung Disease in Patients With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis].

Objective: To investigate the conditions of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis combined with rapidly progressive interstitial lung disease (RPILD), and to analyze the risk factors. Methods: A total of 145 patients diagnosed with anti-MDA5 antibody-positive dermatomyositis at West China Hospital, Sichuan University between January 2018 and September 2021 were selected, and their general and clinical data were collected. The patients were divided into two groups, a RPILD group of patients with comorbid RPILD and a non-RPILD group of those who did not have comorbid RPILD. Factors that might affect whether patients with anti-MDA5 antibody-positive dermatomyositis also had comorbid RPILD were screened out and binary logistic regression analysis was performed. Results: Among the 145 patients with anti-MDA5 antibody-positive dermatomyositis, 32 (22.07%) patients had comorbid RPILD, while the remaining 113 (77.93%) did not have comorbid RPILD. Binary logistic regression analysis showed that lactate dehydrogenase≥370 IU/L (compared with <370 IU/L, OR=4.066, 95% CI: 1.616-10.230) and carcinoembryo antigen≥5 ng/mL (compared with <5 ng/mL, OR=6.070, 95% CI: 2.013-18.303) were risk factors for comorbid RPILD in patients with anti-MDA5 antibody-positive dermatomyositis ( ß>0, OR>1, P<0.05). Conclusion: It is recommended that close attention be given to changes in high-resolution chest CT and pulmonary functions in patients with lactate dehydrogenase≥370 IU/L and carcinoembryo antigen≥5 ng/mL. If rapid progression of lung disease is detected, it is necessary to strengthen the treatment of the lung disease, thereby improving the prognosis of patients.

Long-term survival of patients with idiopathic inflammatory myopathies: anatomy of a single-centre cohort.

OBJECTIVES: We aimed to characterise clinical manifestations, disease course, treatment, and mortality of IIM patients. We have also attempted to identify predictors of mortality in IIM. METHODS: This was a retrospective single-centre study including IIM patients fulfilling the Bohan and Peter criteria. Patients were divided in 6 groups: adult-onset polymyositis (APM), adult-onset dermatomyositis (ADM), juvenile-onset dermatomyositis, 'overlap' myositis (OM), cancer-associated myositis, and antisynthetase syndrome. Sociodemographic, clinical and immunological features, treatment, and causes of death were recorded. Survival analysis and predictors of mortality was performed using Kaplan-Meier and Cox proportional hazards regression. RESULTS: A total of 158 patients were included with a mean age at diagnosis of 40.8±15.6 years. Most patients were female (77.2%) and Caucasian (63.9%). The most frequent diagnoses were ADM (35.4%), OM (20.9%) and APM (24.7%), respectively. Most patients (74.1%) were treated with a combination of steroids and one-to-three immunosuppressive drugs. Interstitial lung disease, gastrointestinal and cardiac involvement affected 38.5%, 36.5% and 23.4% of the patients, respectively. The survival rates at 5, 10, 15, 20 and 25 years of follow-up were 89%, 74%, 67%, 62% and 43%, respectively. During a median follow-up of 13.6±10.2 years, 29.1% have died, infection being the most common cause (28.3%). Older age at diagnosis (HR1.053, 95% CI 1.027-1.080), cardiac involvement (HR 2.381, 95% CI 1.237-4.584), and infections (HR 2.360, 95% CI 1.194-4.661) were independent predictors of mortality. CONCLUSIONS: IIM is a rare disease with important systemic complications. Early diagnosis and aggressive treatment of cardiac involvement and infections could improve survival of these patients.

Subcutaneous tissue involvement in idiopathic inflammatory myopathies: Systematic literature review including three new cases and hypothetical mechanisms.

INTRODUCTION: Involvement of subcutaneous tissue in idiopathic inflammatory myopathies (IIM) is poorly known. METHODS: We conducted a systematic review of the literature regarding panniculitis and lipodystrophy/lipoatrophy in juvenile and adult IIM via PubMed/Medline, Embase and Scopus databases. Three local observations are included in this review. Epidemiological, clinical, paraclinical and therapeutic data were collected. RESULTS: Panniculitis appears to be more common in adults than in juveniles. It was mainly localised in the upper and lower limbs. Panniculitis improved in most cases with steroids and panniculitis and myositis had a similar course in 83.3% and 72.2% of cases in juveniles and adults, respectively. Lipodystrophy appeared to be more frequent in juveniles and was only observed in dermatomyositis in both juveniles and adults. Lipodystrophy was mainly partial in juveniles and adults. The median time from myositis to the diagnosis of lipodystrophy was 6 years [0-35] and 2.5 years [0-10] in juveniles and adults, respectively. Lipodystrophy was associated with anti-TIF1 gamma auto-antibody positivity, a polycyclic/chronic course of myositis and the occurrence of calcinosis and might be an indicator of poor disease control. CONCLUSION: Adipose tissue involvement, particularly lipodystrophy, occurs almost exclusively in dermatomyositis. The insidious onset and lack of awareness of the diagnosis may underestimate its prevalence. Larger studies are needed to identify possible risk factors in these patients, to better potential underlying pathophysiological process, in order to discuss potential therapeutic targets.

Effect of Therapeutic Plasma Exchange on Itraconazole Pharmacokinetics: A Case Study.

ABSTRACT: The authors present the case of a 34-year-old male patient who underwent therapeutic plasma exchange (TPE) for amyopathic dermatomyositis. Immunosuppression resulted in Aspergillus lentulus pulmonary infection , requiring treatment with super bioavailable-itraconazole. Therapeutic itraconazole concentrations were attained after 2 weeks of treatment after dose adjustments. Interestingly, a substantial reduction in plasma itraconazole concentration was observed during TPE, which was attributed to an insufficient delay between the dosing of itraconazole and TPE initiation. Furthermore, there was an increase in plasma concentration post-TPE, which presumably reflects the redistribution of itraconazole from peripheral compartments back into plasma. This was confirmed by sampling of the TPE plasmapheresate, which revealed that changes in plasma concentration overestimated itraconazole clearance. These findings highlight that the pharmacokinetics of itraconazole are altered during TPE, which should be considered when timing drug administration and obtaining plasma concentrations.

Immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in dermatomyositis by upregulating RIG-I.

BACKGROUND: Perifascicular atrophy is a unique pathological hallmark in dermatomyositis (DM)-affected muscles; however, the mechanism underlying this process remains unclear. In this study, we aimed to investigate the potential role of the immunoproteasome subunit ß5i and retinoic acid-inducible gene-I (RIG-I) in DM-associated muscle atrophy. METHODS: The expression of ß5i and RIG-I in the muscles of 16 patients with DM was examined by PCR, western blotting and immunohistochemistry. The associations between ß5i and RIG-I expression levels and muscle disease severity were evaluated. Lentivirus transduction was used to overexpress ß5i in human skeletal muscle myoblasts (HSMMs) and consequent cell functional changes were studied in vitro. RESULTS: ß5i and RIG-I expression in the muscle of patients with DM was significantly increased and closely associated with muscle disease severity. Immunohistochemistry and immunofluorescence analyses showed the marked colocalised expression of ß5i and RIG-I in perifascicular myofibres. ß5i overexpression in HSMMs significantly upregulated RIG-I, the muscle atrophy marker MuRF1, type I IFN-related proteins (MxA and IFNß) and NF-κB pathway-related proteins (pIκBα, pIRF3 and pNF-κBp65). In addition, the viability of HSMMs decreased significantly after ß5i overexpression and was partly recovered by treatment with a ß5i inhibitor (PR957). Moreover, activation of RIG-I by pppRNA upregulated IFNß and MuRF1 and reduced the cell viability of HSMMs. CONCLUSION: The immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in DM via RIG-I upregulation; our findings suggest a pathomechanistic role of ß5i and RIG-I in DM-associated muscle damage, highlighting these components as potential therapeutic targets for the treatment of DM.

Anti-MDA5-positive dermatomyositis and remission in a single referral centre population.

OBJECTIVES: To describe a single-centre North American adult cohort of anti-MDA5-positive dermatomyositis patients, with emphasis on drug-free long-term remission. METHODS: We conducted an observational retrospective cohort study of anti-MDA5-positive DM patients. All consented patients seen in the Johns Hopkins Myositis Centre from 2003-2020 with suspected muscle disease were routinely screened for myositis-specific autoantibodies. All sera were screened for anti-MDA5 autoantibodies by line blot; positives were verified by enzyme-linked immunoassay. Patients whose sera were anti-MDA5 positive by both assays (n=52) were followed longitudinally. If clinical status was unavailable, structured telephone interviews were conducted. Clinical remission was defined as being off all immunosuppression >1 year while remaining asymptomatic. RESULTS: 38/52 (73%) of the patients were women with a median age at disease-onset of 47 (IQR 40-54). Twenty-five of the patients (48%) were White, 16 (30%) were Black and 3 (6%) were Asian. Most patients (42/52, 80%) had interstitial lung disease, defined by inflammatory or fibrotic changes on high resolution computed tomography (HRCT). 18/52 (35%) of patients required pulse-dose methylprednisolone, 4/52 (8%) experienced spontaneous pneumothorax/pneumomediastinum, 6/52 (12%) required intubation, and 5/52 (10%) died. Over longitudinal follow-up (median 3.5 years), 9 (18%) patients achieved clinical remission. The median time from symptom onset to clinical remission was 4 years, and the median duration of sustained remission was 3.5 years (range 1.4-7.8). No demographic or disease characteristics were significantly associated with remission. CONCLUSIONS: In this single centre, tertiary referral population of anti-MDA5-positive dermatomyositis, ~20% of patients experienced long-term drug-free remission after a median disease duration of 4 years. No clinical or biologic factors were associated with clinical remission.

Long-term secular trends in dermatomyositis and polymyositis mortality in the USA from 1981 to 2020 according to underlying and multiple cause of death mortality data.

BACKGROUND: People with dermatomyositis (DM) or polymyositis (PM) often die from cancer, pulmonary, cardiac complications, or infections. In such cases, DM or PM might not be designated as the underlying cause of death (UCD) for mortality tabulation. In this study, we investigated DM/PM mortality trends in the USA from 1981 to 2020 with respect to UCD and multiple causes of death (MCD) data. METHODS: We used the MCD data to identify all deaths with DM or PM mentioned anywhere on the death certificate and as the UCD in the USA from 1981-1982 to 2019-2020. We calculated age-adjusted mortality rates (AAMRs) and annual percentage changes (APCs) based on joinpoint regression analysis. RESULTS: We identified 12,249 (3985 with DM and 7097 with PM) and 23,608 (8264 with DM and 15,344 with PM) people who died between 1981 and 2020 according to the UCD and MCD data, respectively. For DM, the APC was - 6.7% (from 1981-1982 to 1985-1986), - 0.1% (from 1985-1986 to 2003-2004), and - 1.9% (from 2003-2004 to 2019-2020) according UCD and was - 1.2% (from 1981-1982 to 2003-2004), - 2.5% (from 2003-2004 to 2015-2016), and 2.8% (from 2015-2016 to 2019-2020) according MCD. For PM, the APC was 1.9% (from 1981-1982 to 1989-1990), - 2.3% (from 1989-1990 to 2005-2006), and - 5.2% (from 2005-2006 to 2019-2020) according UCD and was 1.3% (from 1981-1982 to 1991-1992) and - 4.1% (from 1991-1992 to 2019-2020) according MCD. CONCLUSION: We identified two times as many DM/PM deaths using the MCD as those identified using the UCD. Similar downward DM/PM mortality trends were noted according to UCD and MCD. However, the year of significant decline in PM mortality was about 10 years earlier according to MCD than those according to UCD.

Five genes as diagnostic biomarkers of dermatomyositis and their correlation with immune cell infiltration.

Background: Dermatomyositis (DM) is a rare autoimmune disease characterized by severe muscle dysfunction, and the immune response of the muscles plays an important role in the development of DM. Currently, the diagnosis of DM relies on symptoms, physical examination, and biopsy techniques. Therefore, we used machine learning algorithm to screen key genes, and constructed and verified a diagnostic model composed of 5 key genes. In terms of immunity, The relationship between 5 genes and immune cell infiltration in muscle samples was analyzed. These diagnostic and immune-cell-related genes may contribute to the diagnosis and treatment of DM. Methods: GSE5370 and GSE128470 datasets were utilised from the Gene Expression Omnibus database as DM test sets. And we also used R software to merge two datasets and to analyze the results of differentially expressed genes (DEGs) and functional correlation analysis. Then, we could detect diagnostic genes adopting least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) analyses. The validity of putative biomarkers was assessed using the GSE1551 dataset, and we confirmed the area under the receiver operating characteristic curve (AUC) values. Finally, CIBERSORT was used to evaluate immune cell infiltration in DM muscles and the correlations between disease-related biomarkers and immune cells. Results: In this study, a total of 414 DEGs were screened. ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA were identified as potential DM diagnostic biomarkers(AUC > 0.85),and the expressions of 5 genes in DM group were higher than that in healthy group (p < 0.05). Immune cell infiltration analyses indicated that identified DM diagnostic biomarkers may be associated with M1 macrophages, activated NK cells, Tfh cells, resting NK cells and Treg cells. Conclusion: The study identified that ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA as potential diagnostic biomarkers of DM and these genes were closely correlated with immune cell infiltration.This will contribute to future studies in diagnosis and treatment of DM.

Prognosis of spontaneous pneumomediastinum occurring in dermatomyositis or polymyositis patients with interstitial lung disease according to antimelanoma differentiation-associated gene 5 antibody status: a retrospective cohort study.

OBJECTIVES: Spontaneous pneumomediastinum (SPNM) historically has been considered a poor prognostic factor in dermatomyositis/polymyositis patients complicated with interstitial lung disease (ILD). However, there is a lack of actual data regarding the association between SPNM occurrence and mortality in dermatomyositis/polymyositis patients. This study aimed to assess the association between SPNM occurrence and mortality in myositis patients with ILD according to antimelanoma differentiation-associated gene 5 (MDA5) antibody status. METHODS: Dermatomyositis/polymyositis patients with ILD who were hospitalised at five Japanese hospitals from 2016 to 2020 were included in this retrospective observational study. We collected data about baseline characteristics including myositis-specific autoantibodies, treatments, SPNM and death within 1 year from therapy initiation or strengthening. Baseline characteristics and outcomes were compared between patients with and without SPNM (the SPNM group and the non-SPNM group, respectively). RESULTS: A total of 119 patients were analysed. SPNM occurred in 23 patients, and 15 patients died. Fifteen patients with SPNM were anti-MDA5 antibody positive. The mortality rate was significantly higher in the SPNM group (34.8%) than in the non-SPNM group (7.3%) (p=0.001). All deaths in the SPNM group occurred in anti-MDA5 antibody-positive patients (8/15), whereas none of the anti-MDA5 antibody-negative patients in the SPNM group died (0/8). In anti-MDA5 antibody-positive patients, the mortality rate was significantly higher in patients with SPNM occurrence (53.3%) than in those without SPNM occurrence (4.0%) (p=0.001). CONCLUSION: SPNM occurred more frequently in anti-MDA5 antibody-positive than in anti-MDA5 antibody-negative myositis patients. SPNM occurrence was associated with higher mortality risk, especially in anti-MDA5 antibody-positive patients.