Pharmacological Strategies in Dermatomyositis: Current Treatments and Future Directions.

Dermatomyositis (DM) is a complex and rare autoimmune disease characterized by muscle weakness and distinctive skin rashes. Its pathogenesis involves a combination of genetic susceptibility, environmental triggers, and immunological factors, with interferon pathways and specific gene upregulations playing crucial roles. Diagnosis is based on clinical presentation, laboratory findings, and imaging, with particular emphasis on myositis-specific antibodies and characteristic muscle and skin changes. The clinical heterogeneity of DM, including variants such as clinically amyopathic DM and DM-associated interstitial lung disease, necessitates a personalized diagnostic and therapeutic approach. Current pharmacological treatments for DM include glucocorticoids, which remain the first-line therapy despite their long-term adverse effects. Immunosuppressants, such as azathioprine, methotrexate, and mycophenolate mofetil, are commonly used in combination with glucocorticoids to enhance efficacy and reduce steroid dependence. Biologics, such as rituximab and intravenous immunoglobulin, have shown effectiveness in refractory cases. Emerging therapies, particularly Janus kinase inhibitors, offer promise for treatment-resistant DM, although they present significant safety concerns, including increased risks of infections and cardiovascular events. Despite significant advancements, managing DM remains challenging due to its rarity and variability. Future research should prioritize the development of precision medicine approaches tailored to individual genetic and pathological features. Additionally, integrated treatment strategies combining pharmacological and non-pharmacological interventions are crucial to improving patient outcomes and quality of life. Understanding the etiology and pathogenesis of DM more deeply will be vital for developing more effective and targeted treatments, ultimately leading to better disease management and prognosis.

14-month-old female with anti-MDA5 juvenile dermatomyositis complicated by liver disease: a case report.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare disorder with subtypes associated with different myositis-specific antibodies (MSAs) including anti-MDA5. Hepatic involvement in JDM is rare and has not previously been documented in anti-MDA5 JDM. There is a lack of formal research on treatment protocols for anti-MDA5 JDM, though tofacitinib is a highly regarded emerging therapy. CASE PRESENTATION: A previously healthy 14-month-old Hispanic female presented to a pediatric rheumatology clinic with eight months of worsening rash, weakness, periorbital edema, intermittent fevers, and weight loss. Her physical exam was notable for fever, thinning of hair, heliotrope rash, periorbital edema, violaceous macules on her bilateral elbows, forearms, arms, and knees, arthritis, Gottron's sign, and hepatomegaly. The patient was admitted, and symptoms progressed to include hypoxemia. Subsequent workup was notable for ground glass opacities of bilateral lung fields on chest CT, myositis visualized on MRI and confirmed with muscle biopsy, and liver biopsy showing nonspecific signs of liver injury. After a thorough infectious disease workup to rule out concomitant infection, the patient was started on high-dose steroids and induction with cyclophosphamide. She responded well with disease remission maintained with tofacitinib in the outpatient setting. DISCUSSION AND CONCLUSIONS: Our patient is notable due to her young age at presentation, histopathologically confirmed liver injury, and response to treatment. The case adds to the growing body of literature supporting tofacitinib for anti-MDA5 JDM in the pediatric population. Future research can better standardize effective treatment protocols and define the mechanism of liver involvement. For patients with nonspecific liver injury, muscular, and cutaneous disease, anti-MDA5 JDM should be considered in the differential diagnosis with treatment options including tofacitinib for confirmed cases.

Juvenile Dermatomyositis: Diagnosis and Management.

Juvenile dermatomyositis (JDM) is the leading cause of chronic idiopathic inflammatory myopathy of auto-immune origin in children.1 Seven patients with JDM found in the records from 1998-2019 of the Department of Dermatology Farhat Hached Hospital, Sousse, Tunisia. Our study concerned a total of six girls and one boy with a median age at disease onset of 8,16 years.2 The average time before diagnosis was 8,8 months. The onset of the disease was acute in 2 patients. All patients displayed skin manifestations at diagnosis, with proximal muscular weakness in 4 cases. Four patients had elevated muscle enzymes and all of them showed myopathic findings on electromyography. Oral corticosteroids were prescribed in 6 patients, in association with other systemic therapies. Three patients achieved a good outcome while two others relapsed. The two other patients showed corticosteroids resistance with a fatal outcome in one case. This study highlights the diagnostic features and management of juvenile dermatomyositis.

Postpartum onset anti-MDA5 antibody-positive clinically amyopathic dermatomyositis; case-based review of perinatal onset anti-MDA5 antibody-positive dermatomyositis.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive clinically amyopathic dermatomyositis (CADM) is a subtype of inflammatory myopathy associated with a distinct clinical phenotype, characterized by rapidly progressing interstitial lung disease and limited muscle involvement. Although cases with onset of anti-MDA5 antibody positive CADM during pregnancy or the postpartum period are rare, they present unique challenges due to a potential pregnancy complications and the possible severity of the disease course. We present a case of anti-MDA5 antibody positive CADM that developed during the postpartum period following childbirth without any pregnancy complication. Additionally, we conducted a comprehensive review of case reports and series of similar cases to elucidate the clinical characteristics and outcomes. Our analysis revealed considerable variability in disease presentation, ranging from severe cases requiring multi-targeted therapy to well-controlled cases with less demanding treatments. The scarcity of evidence in this population underscores the importance of accumulating evidence from case series to inform treatment strategies. More precise prediction tools are needed to effectively manage this rare subset of patients.

Current evidence for janus kinase inhibitors in adult and juvenile dermatomyositis and key comparisons.

INTRODUCTION: Adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) are rare autoimmune diseases with characteristic skin rashes, weakness, and other systemic features. Upregulated interferon signaling has been consistently described in both adult and juvenile DM which makes janus kinase inhibitors (jakinibs) an attractive therapeutic agent that has a targeted mechanism of action. AREAS COVERED: Herein is a review of the growing literature of jakinib use in adult and juvenile DM, including reports on specific disease features and safety of jakinibs in this population and a comparison between adult and juvenile DM. We performed a literature review using PubMed including all English-language publications before 1 February 2024 and abstracts from key recent rheumatology conferences. EXPERT OPINION: Jakinibs are an exciting and promising treatment in both adult and juvenile DM. Current Phase 2 and 3 randomized placebo-controlled trials of jakinibs in both adult and JDM will provide significant insights into the efficacy of this class of medication as a potentially more mechanistically targeted treatment of both skin and muscle disease. In fact, these results will likely inform the treatment paradigm of dermatomyositis in that it may even be considered as first or second line. The next five years in the therapeutic landscape of both juvenile and adult DM is an exciting time for both patients and medical providers.

Personalised medicine in juvenile dermatomyositis: From novel insights in disease mechanisms to changes in clinical practice.

Juvenile dermatomyositis is characterized by childhood-onset chronic inflammation of the muscles and skin, with potential involvement of other organs. Patients are at risk for long-term morbidity due to insufficient disease control and steroid-related toxicity. Personalised treatment is challenged by a lack of validated tools that can reliably predict treatment response and monitor ongoing (subclinical) inflammation, and by a lack of evidence regarding the best choice of medication for individual patients. A better understanding of the involved disease mechanisms could reveal potential biomarkers and novel therapeutic targets. In this review, we highlight the most relevant immune and non-immune mechanisms, elucidating the effects of interferon overexpression on tissue alongside the interplay between the interferon signature, mitochondrial function, and immune cells. We review mechanism-based biomarkers that are promising for clinical implementation, and the latest advances in targeted therapy development. Finally, we discuss key steps needed for translating these discoveries into clinical practice.

A case of refractory anti-MDA5-positive amyopathic dermatomyositis successfully treated with upadacitinib.

Purpose: Amyopathic dermatomyositis (ADM) is a rare, idiopathic, connective tissue disease and melanoma differentiation-associated protein 5 (MDA5) antibody-positive ADM is more treatment-resistant, especially in patients with interstitial lung disease (ILD). The purpose of this article is to report a case of anti-MDA5-positive ADM successfully treated with JAK inhibitor Upadacitinib.Materials and methods: A 35-year-old Chinese woman presented with recurrent itchy erythema on her face and scalp for 4 years. Upon examination, there were heliotrope erythema and eyelid edema, reddish rash on neck and scalp. Biopsy of the lesions was consistent with DM and a line blot assay confirmed the presence of anti-MDA5 antibodies. This patient was treated with oral Upadacitinib at a dosage of 30 mg daily.Results: After 6 weeks of treatment, she achieved complete clinical remission with no reported side effects or instances of relapse. The antibody titer of anti-MDA5 was also decreased.Conclusions: Upadacitinib may be a potential drug candidate in patients with treatment-resistant ADM, especially in cases with refractory cutaneous conditions.

ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets.

BACKGROUND: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. METHODS: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. RESULTS: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. CONCLUSION: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.

A Rare Case of Anti-TIF-1γ Antibody Positive Dermatomyositis in Adulthood.

Dermatomyositis (DM) presents with inflammatory myopathy and distinct skin manifestations, often linked to specific autoantibodies. Anti-transcriptional intermediary factor-1 gamma (TIF-1γ) antibodies (Abs) are typically linked to DM in older patients and malignancy in 15% to 40% of cases. We highlight a case of a 24-year-old female who presented with weakness of proximal muscles, periorbital edema, heliotrope rash, erosions on oral mucosa, and painful scaly rash on the lower extremities. Transcriptional intermediary factor-1 gamma Abs were positive, confirming inflammatory myopathy. Treatment with steroid pulse therapy and immunoglobulin led to improvement. Evaluation for malignancy yielded unremarkable results. This case underscores the importance of recognizing and managing DM with TIF-1γ Ab positive, even in atypical demographics, and highlights the need for comprehensive malignancy evaluation.

Amyopathic Dermatomyositis Presenting with Digital Ulcerations: Case Report and Literature Review.

ABSTRACT: Clinically amyopathic dermatomyositis (CADM) is a rare subtype of dermatomyositis that presents with cutaneous features and no muscle involvement. This case report describes a 26-year-old woman with recurrent and multiple digital ulcerations coinciding with the start of winter each year. There was no evidence of myopathy, and antibody testing yielded negative results. A diagnosis of CADM was ultimately made based on clinicopathologic correlation. The patient's ulcers demonstrated excellent response to a combination therapy of hydroxychloroquine and potent topical and systemic steroids. Herein, the authors discuss the pathologic and immunologic characteristics of CADM.

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.

Methotrexate Use and Risk of Interstitial Lung Disease in Dermatomyositis.

This cohort study examines the association between methotrexate use and interstitial lung disease in patients with dermatomyositis.

[Juvenile-onset anti-nuclear matrix protein 2 (NXP-2) antibody-positive dermatomyositis with joint contractures before manifestation of myositis: a case report].

A 23-year-old man was admitted to our hospital with a one-year history of muscle weakness and atrophy. He had noticed contractures of the fingers of both hands from the age of 18. Examination revealed a skin rash including heliotrope rash and Gottron's sign, joint contractures in the extremities, dysphagia, extensive muscle weakness and marked muscle atrophy. The serum creatine kinase level was 272 |IU/l and muscle biopsy showed typical perifascicular atrophy but little lymphocyte invasion. There was no interstitial pneumonia or malignancy, but muscle tendons showed elevated CT values suggesting calcification or fibrosis. Anti-nuclear matrix protein 2 (NXP-2) antibody-positive dermatomyositis was diagnosed on the basis of the serum antibody level. Methylprednisolone pulse therapy ameliorated the skin rash and bulbar palsy, but muscle weakness, atrophy and joint contractures were resistant to the treatment. There have been no previous reports of young adults with anti-NXP-2 antibody-positive dermatomyositis in whom joint contracture became evident as early as 4 years beforehand, which is a important feature for differential diagnosis of dermatomyositis.

Factors Associated With Complete Clinical Response and Remission in a Cohort of Romanian Children With Juvenile Dermatomyositis.

OBJECTIVES: To describe a Romanian cohort of patients with juvenile dermatomyositis (JDM) and to identify factors associated with disease severity, complete clinical response, and sustained remission. METHODS: We retrospectively reviewed data from 30 JDM patients from 2013 to 2022. The inactive disease state was defined as no active skin rash, muscle weakness, or elevated muscle enzymes. A complete clinical response implied a status of inactive disease maintained for six consecutive months while on medication and remission of inactive disease for at least six consecutive months after treatment. Association factors and predictors of time to complete clinical response and time to remission emerged from bivariate correlation (Pearson's coefficient) and univariate survival analysis (Kaplan-Meier analysis). RESULTS: The median times to complete clinical response and time to remission for the entire cohort were 30.5 months (2.5 years) and 48.5 months (4.04 years), respectively. Nine patients (30%) had a severe disease course, while twenty-one patients (70%) had a mild/moderate course. The presence of calcinosis, time to corticosteroid discontinuation, history of treatment escalation in the first 18 months, and treatment with azathioprine or biologic DMARDs were strongly associated with a longer time to clinical remission (Pearson's > 0.5, p < 0.05). Seven patients (23%) achieved remission, and none of them relapsed during the subsequent median follow-up of 19 months.