Unraveling the Complexities of Dermatomyositis Treatment: A Comprehensive Review and Future Perspectives

Dermatomyositis, characterized by muscle weakness and skin symptoms, is a condition linked to increased morbidity and mortality. It markedly affects the quality of life for individuals afflicted, as well as the well-being of their families. According to DelveInsight estimates in the latest Dermatomyositis Epidemiology Report, it has affected around 65K adults and 6.5K juveniles in the seven major geographies (the US, Germany, France, Italy, Spain, the UK, and Japan) in 2022.

Understanding the disease

Dermatomyositis is a rare autoimmune disorder associated with muscle inflammation (myositis) and skin inflammation (dermatitis). It falls under the classification of idiopathic inflammatory myopathies (IIM), a group comprising various connective tissue disorders characterized by the progressive weakening of muscles. The signs and symptoms of dermatomyositis may manifest suddenly or evolve gradually over time. The most common dermatomyositis symptoms include skin rash, muscle pain and weakness, fatigue, and ulcers. The precise cause of dermatomyositis remains unknown, although it is believed to stem from a combination of genetic predisposition and environmental stimuli.

Dermatomyositis affects people of all ages and genders but is more common among women. The disease can occur in childhood and is usually referred to as juvenile dermatomyositis (JDM). While both adult and juvenile dermatomyositis conditions exhibit characteristic signs like distinctive skin rashes and muscle inflammation, they are heterogeneous with various additional features and complications. For example, vasculopathy is more prevalent in juvenile cases than adult dermatomyositis. Similarly, although children face an elevated risk of calcinosis and ulceration, their long-term outlook is generally more favorable.

Current diagnostic and dermatomyositis treatment landscape 

Identifying the disease poses a challenge because of its resemblance in presentation to other forms of myositis. Accurate diagnosis involves a blend of clinical assessment, identification of distinctive physical indicators, specific laboratory tests, imaging examinations, and, in certain instances, muscle biopsies. Diagnostic criteria have been formulated, taking into account classification, pathological features, and symptoms of the disease.

In 1975, Bohan and Peter first suggested a set of five criteria to aid in the diagnosis and classification of dermatomyositis, which was accepted worldwide. Later on, other diagnostic criteria turned up, including the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) guideline for adults and juvenile IIM, published in 2017.

There is no cure for dermatomyositis, but medicines can minimize symptoms, reduce inflammation and vasculitis, and enhance the patient’s quality of life. The goals of managing dermatomyositis are focused on treating muscle weakness and skin disease and addressing any other underlying complications, including cardiac, pulmonary, gastrointestinal, joints, and malignancies. The recent approval of OCTAGAM as well as the presence of several management guidelines, including the British Society for Rheumatology guideline, the Japanese Society of Rheumatology guideline, and others, have simplified the treatment landscape for dermatomyositis. The first-line treatment for dermatomyositis includes the use of systemic glucocorticoids with or without immunosuppressants. Other dermatomyositis medications, including antimalarial drugs, antibiotics, and topical ointments, are given individually or in combination to eliminate symptoms. Further, rituximab, mycophenolate mofetil, calcineurin inhibitors, IVIG, and cyclophosphamide are preferred for resistant cases, patient’s unresponsive to initial treatment. 

Medical therapy for skin disease includes topical and systemic medications. Topical agents include corticosteroids and calcineurin inhibitors. Most patients require systemic drugs to control skin disease, including hydroxychloroquine and methotrexate. Besides, nonpharmacological management options such as diet and physiotherapy, plasmapheresis, sun-protective measures, extracorporal photochemotherapy, and total body irradiation, are employed as adjunctive treatment methods in cases of therapy-resistant dermatomyositis. While surgery is not a common approach for dermatomyositis, gastrotomy may be considered beneficial for patients experiencing severe esophageal dysfunction, and surgical removal of calcinotic nodules, if present, may also be performed.

According to DelveInsight, the market size for immunoglobulins was approximately USD 145 million in 2022, leading among other categories such as biologics, immunosuppressants, and corticosteroids. Changes in the dermatomyositis market are anticipated due to the global increase in diagnosed cases of dermatomyositis and the introduction of new drugs.

Ongoing challenges and unresolved obstacles in dermatomyositis treatment

To ensure proper care and enhance the well-being of individuals diagnosed with dermatomyositis, it is essential to acknowledge and attend to various deficiencies to fill the gaps. Some hurdles and challenges in the development and appropriate management of dermatomyositis include: Ensuring optimal care and improving the well-being of individuals diagnosed with dermatomyositis requires addressing various gaps and overcoming dermatomyositis treatment challenges. Some hurdles include:

Heterogeneity in the pathophysiology 

Although adults and JDM share the hallmark features of dermatomyositis, they are heterogeneous disorders with various additional disease features and complications. The occurrence of significant clinical aspects like calcinosis, interstitial lung disease, and malignancy significantly differs between adult and juvenile cases. Consequently, comparing disease outcomes between juvenile and adult myositis is challenging due to the absence of standardized outcome measures.

Complexity in epidemiological data 

Dermatomyositis is rare, and its epidemiology studies on prevalence or occurrence are scarce. The complex pathophysiology of dermatomyositis, coupled with overlapping symptoms with other idiopathic inflammatory myopathies (IIMs), adds intricacy to its epidemiological study. There is a need for new studies to acquire a more comprehensive understanding of the disease epidemiology, encompassing its various types, degrees of severity, and variations across different geographical regions.

Early detection and diagnostic gaps 

Early detection of dermatomyositis is crucial for initiating appropriate patient management. Myositis mimics are prevalent, and their shared features with idiopathic inflammatory myopathies (IIMs) present a diagnostic challenge, often leading to misdiagnosis and delays in dermatomyositis treatment. Such delays can result in complications such as lipodystrophy, loss of function and muscle mass, calcinosis, joint contractures, and involvement of extra muscular tissues.

Scarcity of effective therapies 

OCTAGAM 10% is the only approved drug for dermatomyositis treatment. The use of OCTAGAM is restricted due to potential side effects such as flushing, headache, dizziness, chills, etc. Despite standard off-label therapies, patients frequently endure flares, leading to disability and reduced productivity. Additionally, these off-label medications, including corticosteroids, are linked to various side effects and adverse events, such as osteoporosis, heightened susceptibility to infections, cushingoid features, and more. There is a pressing need for safer and more effective treatment options to enhance patient outcomes.

Challenges in the animal model  

Animal models serve as crucial tools for exploring new agents and understanding the mechanisms of various diseases. Despite various animal models providing insights into the underlying mechanisms of idiopathic inflammatory myopathies (IIM), none of these models fully replicate the clinical and pathological characteristics of human IIM, specifically dermatomyositis, resulting in limited resemblance.

Promising triumphs on the horizon for dermatomyositis treatment

In the last two decades, a substantial advancement in research has yielded new insights into the genetic risk factors and mechanisms underlying dermatomyositis, paving the way for promising therapeutic approaches to address the urgent need for effective dermatomyositis treatments. Priovant Therapeutics and Pfizer’s brepocitinib, CSL Behring’s HIZENTRA, AstraZeneca’s ULTOMIRIS (ravulizumab), Argenx’s efgartigimod, and Pfizer’s PF-06823859 (anti-beta interferon), are being actively developed, with these dermatomyositis therapies currently in Phase III and II/III. Many of these dermatomyositis treatments, already approved for other indications, demonstrate a favorable safety profile, and their exploration for dermatomyositis is grounded in evidence from off-label studies or their effectiveness in similar indications.

Brepocitinib: Tyrosine kinase (TYK2) and Janus kinases1 (JAK1) inhibitor

• Numerous case reports on tofacitinib in dermatomyositis provide compelling evidence supporting the potential efficacy of brepocitinib
• The pathobiology of dermatomyositis is influenced by dysregulation in cytokines, with signaling mediated by TYK2 and JAK1, particularly Type I interferon. This suggests that brepocitinib may exhibit greater efficacy than tofacitinib
• Comparative analyses between brepocitinib (30 mg daily) and tofacitinib in various autoimmune conditions indicate that dosing brepocitinib at 30 mg daily could yield clinically meaningful efficacy in dermatomyositis
• Delveinsight analysts anticipate that the drug will enter the US market by 2026 and reach its peak in the seventh year

PF-06823859: Interferon beta one fibroblast (IFNβ1) blocker

• In the Phase I trial, PF-06823859 demonstrated an acceptable safety, tolerability, and PK profile that supports clinical development for treating disorders associated with increased interferon β levels, such as dermatomyositis or systemic lupus erythematosus.
• In the Phase II trial, the drug improved clinical parameters like Manual Muscle Testing-8, Physician Global Assessment, patient-reported outcomes, and Health Assessment Questionnaire Disability Index in patients with muscle-predominant refractory moderate-to-severe dermatomyositis.
• As per Delveinsight, the drug is anticipated to enter EU4 (Germany, France, Italy, and Spain) and the UK market by 2027 and will attain its peak in the seventh year. 

In summary, dermatomyositis is a rare and complex condition marked by limited public awareness. Diagnosis poses challenges, often resulting in significant delays in obtaining a definitive diagnosis for dermatomyositis patients. Additionally, existing biotherapies do not provide a cure. The visible skin manifestations, coupled with the complexities of the disease, may contribute to psychosocial and emotional stress in individuals with dermatomyositis. As a result, there is an urgent call for extensive research and development to tackle the existing challenges in managing dermatomyositis.