Pharmacological Strategies in Dermatomyositis: Current Treatments and Future Directions

Introduction

Idiopathic inflammatory myopathies comprise a diverse set of autoimmune conditions. Within this group, polymyositis (PM) and dermatomyositis (DM) are prevalent subtypes [1]. DM predominantly affects women, with a global annual incidence ranging from 1 to 2 per 100 000, and this incidence is rising annually [2].

DM is caused by a combination of genetic, environmental, and immunological factors. Certain HLA subtypes increase genetic susceptibility. Environmental triggers, such as ultraviolet radiation, infections, and certain medications, can initiate DM in predisposed individuals. Immunologically, DM involves aberrant activation of the innate and adaptive immune systems, with interferon pathways playing a crucial role in disease development [3]. Furthermore, transcriptomic studies have demonstrated the significance of upregulated interferon-related genes in the pathogenesis of DM [4]. These form the foundation for using immunosuppressants and immunomodulators in treating patients with DM.

Clinically, diagnosing DM requires a blend of clinical, laboratory, and imaging assessments. DM is marked by symmetrical proximal muscle weakness and distinct rashes, such as heliotrope rash and Gottron papules. Laboratory tests typically show elevated muscle enzymes, such as creatine kinase and aldolase, along with myositis-specific antibodies, including anti-Mi2, anti-NXP2, anti-TIF1-γ, anti-MDA5, and anti-SAE. Magnetic resonance imaging is crucial for detecting muscle edema, while muscle biopsy confirming perifascicular atrophy and inflammatory infiltrates solidifies the diagnosis [5]. However, the disease heterogeneity of DM is significant, with some patients presenting only with typical skin rash without obvious muscle weakness symptoms, known as clinically amyopathic DM, some experiencing severe muscle involvement, such as difficulty swallowing and myocarditis, and others showing predominant lung involvement. The clinical manifestations and response to treatment vary among different subtypes of DM, based on antibody positivity. The rarity and heterogeneity of the disease pose significant challenges in the diagnosis and treatment of DM. Therefore, each patient with DM requires a personalized diagnostic and therapeutic approach, considering disease severity, systemic involvement, and the presence of malignancy.

The introduction of the 2017 EULAR/ACR criteria marks a significant advancement in the field of rheumatology. The consensus derived from 2 comparative studies underscores the importance of the 2017 EULAR/ACR classification criteria in the diagnosis and treatment of DM. The new criteria demonstrate superior sensitivity and specificity, compared with that of the Bohan and Peter criteria, allowing for more precise differentiation of idiopathic inflammatory myopathy subtypes. This precision facilitates early intervention and the implementation of individualized treatment strategies, thereby improving patient prognosis [6,7]. Overall, managing DM involves pharmacological and non-pharmacological approaches. Pharmacologically, treatments include glucocorticoids, immunosuppressants, like azathioprine, methotrexate, mycophenolate mofetil (MMF), biologics, such as rituximab, and intravenous immunoglobulin (IVIg). Non-pharmacological strategies focus on physical therapy to maintain muscle strength and preventive measures against ultraviolet exposure to protect the skin. These comprehensive strategies aim to control disease activity and improve patient outcomes.

In this article, we aim to review current approaches to the management of DM (Table 1).

Glucocorticoids

Although there are no current controlled trials assessing the efficacy of glucocorticoids in treating DM, it remains the first-line medication for DM treatment. Prednisone or prednisolone 1 mg/kg is commonly employed for remission induction in DM. In a study involving 11 adult DM patients receiving glucocorticoids at a dosage of 0.75 mg/kg/day, muscle function significantly improved in 8 patients, and muscle biopsies after treatment showed a near-complete disappearance of infiltrating inflammatory cells [8]. In severe cases of DM, intravenous pulse methylprednisolone (IVMP) is often used as an initial treatment. However, research on the efficacy of IVMP mainly focuses on juvenile DM, with limited evidence in adult patients with DM [9,10]. In a study assessing IVMP in adult DM patients with severe symptoms, such as speech/swallowing difficulties, respiratory distress, cardiac involvement, and complete loss of mobility, 7 patients received IVMP 0.5 g/day for 3 consecutive days per month over a total of 3 months. After the treatment, all patients exhibited improvements in muscle strength, levels of muscle enzymes, and C-reactive protein levels. Following the first month of pulse therapy, all patients experienced the disappearance of mechanic’s hands, vasculitis, and Gottron papules. However, heliotrope rash and skin discoloration persisted after 3 months of treatment, suggesting a poorer response of DM skin disease to glucocorticoids, and also suggesting that the presence of persistent skin damage does not necessarily indicate disease activity [11]. The main disadvantages of glucocorticoids are the severe long-term adverse effects associated with their prolonged use; glucocorticoid-related adverse effects were found to be the main cause of patient disability [12]. Therefore, in the treatment of DM, glucocorticoids are usually combined with other drugs such as immunosuppressants to enhance efficacy, reduce relapse, and effectively taper steroids.

Azathioprine

Azathioprine is a thymidine analog derived from 6-mercaptopurine, disrupting purine metabolism to obstruct DNA and RNA biosynthesis through multiple pathways. Consequently, immune cell proliferation, particularly in T lymphocytes, is suppressed, enabling its immunosuppressive effects. Based on these mechanisms, azathioprine typically takes 6 to 8 weeks of medication to gradually manifest its effects. Although the evidence supporting azathioprine as a treatment for DM primarily comes from retrospective studies and case reports, it has remained a commonly used initial combination therapy for patients with DM for decades [13]. In a 1981 long-term follow-up study of myositis patients over 3 years, no benefit was observed from adding azathioprine to prednisolone at 3 months. However, during long-term follow-up, a significant decrease in functional disability was noted in the azathioprine group, compared with the prednisolone-only group [14]. To prevent relapse, azathioprine combination therapy often needs to be maintained for more than 1 year, or even longer [15]. Multiple studies have indicated that taking azathioprine during pregnancy and lactation is safe [16,17].

Methotrexate

Methotrexate is an antimetabolite and anti-inflammatory drug. Its anti-inflammatory action is achieved by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide, consequently elevating intracellular adenosine levels [18]. While prospective randomized controlled trials on methotrexate for treating DM are currently lacking, there is still evidence supporting its effectiveness in this regard. Retrospective studies have shown satisfactory therapeutic effects when methotrexate is added to patients with inadequate response to prednisolone monotherapy [19,20]. A longitudinal cohort study on patients with PM/DM indicated that the early survival rate in the methotrexate treatment group was comparable to that in the azathioprine treatment group. However, the methotrexate group exhibited a higher 10-year survival rate [21]. The initial dosage of methotrexate for DM treatment is 15 mg/week, with a potential escalation to a maximum of 25 mg/week if the response is inadequate [22]. Administering methotrexate to DM patients with concurrent interstitial lung disease (ILD) should be done cautiously, as it is difficult to distinguish methotrexate-related lung diseases from DM-associated ILD.

Mycophenolate Mofetil

MMF is a selective immunosuppressant primarily recognized for its inhibitory effects on lymphocytes, as well as for its suppression of antibody production and leukocyte chemotaxis. Several case reports have shown that MMF has good efficacy in patients who are non-responsive to glucocorticoids monotherapy [23,24]. In a retrospective efficacy evaluation study, 12 patients with DM who were non-responsive or intolerant to conventional treatments received MMF at doses of 500 mg to 1 g per day. Skin lesions and muscle strength were assessed monthly after treatment. The study demonstrated improvements in cutaneous and muscular conditions for 10 patients undergoing MMF treatment, with most showing good tolerability within 4 to 8 weeks [25]. When patients with DM have concurrent interstitial ILD, MMF is considered a first-line therapy due to its proven efficacy in enhancing lung function and enabling successful glucocorticoid tapering [26,27]. Like other immunosuppressants, MMF carries the risk of exacerbating infections and increasing the incidence of malignancies. However, previous reports of MMF-related malignancies have mostly occurred in post-transplant populations [28,29].

Calcineurin Inhibitors

Calcineurin inhibitors mainly include cyclosporin A and tacrolimus, which primarily work by inhibiting T-cell function and were originally used to prevent organ transplant rejection. In the treatment of DM, calcineurin inhibitors are mainly used for DM patients with concurrent ILD or refractory DM unresponsive to first-line treatments [30,31]. In a prospective controlled study, rapid disease remission was achieved in 10 patients with DM treated with cyclosporin A, with only a 10% treatment failure rate [32]. Additionally, in a randomized controlled trial comparing cyclosporin A and methotrexate in 36 DM/PM patients, the patients in both groups showed significant improvements in clinical and serologic aspects after 1, 3, and 6 months of treatment. However, due to cost increases and drug risks, methotrexate should be prioritized over cyclosporin A [33]. In a systematic review evaluating the effectiveness and safety of tacrolimus in DM/PM, oral tacrolimus combined with glucocorticoids resulted in physical function and muscular strength recovery in 64.7% and 93.3% of patients, respectively, enzyme reduction in 100% of patients, lung function improvement in 89.3% of patients, and a decrease in the average glucocorticoid dose from 33.8 mg/day to 11.5 mg/day [34]. The primary adverse effect of calcineurin inhibitors is renal toxicity, with other adverse reactions generally being mild. Therefore, calcineurin inhibitors should be considered safe and efficacious for managing DM, but their specific efficacy and safety require validation through prospective, large-sample, randomized controlled trials.

Cyclophosphamide

Cyclophosphamide is currently the preferred adjunctive therapy for severe or progressive ILD in DM. In a clinical trial evaluating the effectiveness and safety of cyclophosphamide pulse therapy for DM/PM complicated by progressive interstitial pneumonia, over half of the patients experienced significant improvements in dyspnea symptoms, oxygen dependency, pulmonary function parameters, and high-resolution computed tomography scores after receiving cyclophosphamide at doses of 300 to 800 mg/m2 every 4 weeks for at least 6 months. No treatment-related deaths or severe toxic reactions were observed during the study [35]. Additionally, cyclophosphamide is suggested as the initial combined therapy for patients with MDA5+ DM complicated by rapidly progressive ILD [36]. A DM patient with rapidly progressive ILD failed to show improvement in dyspnea symptoms after 3 months of glucocorticoid and cyclosporin A treatment, with high-resolution computed tomography confirming ILD progression. However, after switching from cyclosporin A at 4.25 mg/kg/day to cyclophosphamide at 1000 mg/m2 every 4 weeks, the patient’s dyspnea symptoms improved within 2 months, ILD progression halted on imaging, and successful steroid tapering was achieved [37]. Multiple studies indicate that serious adverse reactions are generally uncommon with short-term intravenous cyclophosphamide pulse therapy [35,38,39]. Nevertheless, a randomized controlled trail comparing the efficacy of rituximab and cyclophosphamide for connective tissue disease-associated ILD showed that while rituximab was not superior to cyclophosphamide in treating patients with connective tissue disease-associated ILD, it had fewer adverse events, making it a potential alternative to cyclophosphamide [40].

Intravenous Immunoglobulin

Initially used as a replacement therapy for patients with immunodeficiency, intravenous IVIg has gained recognition for its anti-inflammatory and immunomodulatory effects in clinical practice. Since IVIg was first reported for treating idiopathic inflammatory myopathy in 1987, several randomized controlled studies have demonstrated its efficacy in treating DM over the years [41–43]. IVIg was also the first drug proven effective in double-blind, placebo-controlled studies for treating DM. In this study, 8 patients treated by IVIg at 2g/kg every 4 weeks showed evident muscular strength and neurological symptom improvement, with post-therapeutic muscle biopsy revealing increased muscle fiber diameter, increased capillary numbers, decreased capillary diameter, and disappearance of complement deposits in vessel walls. In contrast, among the 11 control patients receiving prednisone at 25 mg/day as monotherapy, 6 showed no significant improvement, while the remaining 5 experienced disease worsening [44]. Another randomized controlled study showed that following 3 months of IVIg treatment at 0.4 g/kg/day plus prednisone at 1 mg/kg/day, patients with DM experienced earlier onset of perceived muscle strength recovery, greater improvement in muscle weakness, decreased muscle pain assessed by visual analog scale scores, greater creatine phosphokinase decline rate, and lower steroid dosage, compared with prednisone monotherapy [45]. Two other studies also demonstrated rapid symptom relief with IVIg, along with significant reductions in enzyme levels and maintenance steroid doses [46,47]. Furthermore, IVIg was proven effective in severe DM cases involving lung and esophageal complications [46,48]. Two studies evaluating the long-term efficacy of IVIg showed that IVIg at 1 g/kg/day combined with glucocorticoids effectively treated refractory DM [49,50]. Adverse effects of IVIg are typically tolerable, and most adverse reactions can subside with measures such as slowing infusion rates and providing symptomatic treatment [51]. Thus, IVIg stands out as an effective, well-tolerated, and safe therapeutic choice for DM.

Biologics

Compared with other subtypes of idiopathic inflammatory myopathies, biologics are more widely used in DM, primarily for patients with DM complicated by ILD or refractory DM. In a randomized controlled study assessing the effectiveness and safety of rituximab in adult and pediatric patients with myositis, 195 patients with refractory DM who received 2 doses of 1g rituximab achieved remission criteria at around 20 weeks, approximately 83% of the patients [52]. Tocilizumab can be used as salvage therapy for patients with refractory rapidly progressive ILD [53], but a recent randomized controlled study showed that after 24 weeks of treatment with tocilizumab at 8 mg/kg every 4 weeks, 18 patients with refractory DM/PM did not meet the efficacy criteria [54]. Abatacept has also been proven effective in treating refractory DM [55].

The utilization of TNF-α inhibitors in managing DM is controversial, including agents such as adalimumab, infliximab, and etanercept. Etanercept was first reported to be successfully used in patients with glucocorticoid-resistant DM/PM in 2001 [56], and several case reports and retrospective studies have confirmed the effectiveness of etanercept in DM [57–59]. In a randomized controlled trail evaluating the safety of etanercept and the feasibility of steroid tapering in DM, more than half of the patients with DM receiving etanercept 50 mg/week successfully tapered steroids, with no notable difference in adverse events between the etanercept and control groups during the treatment period [60]. Infliximab is primarily targeted toward DM patients with specific complications such as hemophagocytic syndrome and ulcerative colitis. [61,62]. Adalimumab has been previously reported as effective in treating a case of DM-associated calcinosis [63]. However, studies have indicated that the efficacy of etanercept or infliximab in treating patients with refractory DM/PM is not ideal [58,64,65]. Therefore, the efficacy of TNF-α inhibitors in patients with DM still requires prospective, large sample size, randomized controlled studies for validation.

Janus Kinase Inhibitors

Janus kinase (JAK) is a family of intracellular non-receptor tyrosine protein kinases. Activation of pro-inflammatory cytokines mediated by the JAK-signal transducer and activator of transcription (STAT) signaling pathway is a contributing factor in the pathogenesis of DM [66]. JAK inhibitors work by competitively and reversibly inhibiting the adenosine triphosphate binding site of JAK, thereby suppressing JAK-STAT signal transduction in inflammatory responses and immune regulation processes [67].

To date, a substantial amount of evidence, mostly from case studies, suggests that JAK inhibitors can effectively treat patients with refractory DM who have not responded to glucocorticoids and immunosuppressive therapy, and they have also shown unique efficacy in treating concomitant ILD [68–70]. In a 12-week open-label study, all 10 patients with refractory DM showed improved disease activity according to the 2016 ACR/EULAR myositis response criteria after taking tofacitinib 11 mg daily, with minimal observable adverse effects, which demonstrated the effectiveness and safety of tofacitinib monotherapy [71]. In a single-center, open-label clinical study, 18 patients with amyopathic DM who were positive for anti-MDA5 antibodies and had concomitant ILD were prospectively enrolled. Compared with the control group, the treatment group with a combination of glucocorticoids with tofacitinib 5 mg twice daily had a significantly improved 6-month survival rate, ferritin levels, pulmonary function index, and findings on high-resolution computed tomography [72].

JAK inhibitors have shown promise in treating refractory DM, but their use comes with significant safety concerns and risks. While second-generation JAK inhibitors, like upadacitinib, are designed to be more selective in inhibiting JAK proteins, potentially reducing adverse effects, these medications still pose serious risks, such as the increased risk of infections, malignancies, thrombosis, and gastrointestinal perforations [73]. Most of all, the Food and Drug Administration has raised significant concerns regarding the use of JAK inhibitors, specifically upadacitinib, tofacitinib, and baricitinib, due to their association with major adverse cardiovascular events [74].

In summary, while JAK inhibitors have demonstrated efficacy in certain clinical scenarios, their safety concerns remain significant. Therefore, careful risk assessment and ongoing monitoring are essential when using these drugs.

Future Directions for DM Treatments

While corticosteroids and immunosuppressants remain the primary treatments for DM, their adverse effects and limited efficacy in refractory cases necessitate the development of new therapeutic options. Emerging treatments such as biologics and JAK inhibitors show promise due to their targeted action, which results in fewer adverse effects and enhanced effectiveness. However, the lack of sufficient clinical evidence limits their widespread clinical use.

Future strategies in DM management should advocate for precision medicine, developing treatments tailored to individual genetic backgrounds and pathological features to enhance treatment specificity and efficacy. Additionally, an integrated treatment approach combining pharmacological with non-pharmacological interventions, such as physical and psychological therapies, should be explored to improve patient quality of life. Lastly, a deeper understanding of the etiology and pathogenesis of DM is essential to develop more fundamental treatment methods.

Conclusions

DM is relatively rare and heterogeneous, with much of the primary evidence for clinical decisions derived from case reports and retrospective studies. DM, especially when refractory, remains one of the most challenging diseases in the field of rheumatology and immunology. With the evolving understanding of DM pathogenesis, ongoing refinement of skin damage and myositis assessment methods, and the accumulation of clinical evidence, a diversified and effective strategy combining novel therapies with traditional treatments will be explored to achieve personalized and precise treatment in the future.