Past, Present, and Future in Dermatomyositis Therapeutics

Abstract

Purpose of review:

This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review.

Recent findings:

There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam^® 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors.

Summary:

With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.

Introduction

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) defined by symmetrical proximal muscle weakness and distinct skin manifestations. The goals of managing DM are focused on treating muscle weakness, skin disease, as well as addressing any other underlying complications such as interstitial lung disease, arthritis, dysphagia, and/or calcinosis.

Few controlled studies are available to guide treatment strategies in DM and there are no international guidelines; thus, treatment recommendations are mostly based on case series, case reports, and expert opinion. While most medications are not approved for DM by the FDA, they are all approved for other uses and are used “off label” in myositis based on small clinical trials, expert experience, and individual reports in the literature of effectiveness in myositis. The recommended first-line therapy is glucocorticoids in combination with immunosuppressive therapies such as azathioprine, mycophenolate mofetil, or methotrexate, which are used as steroid-sparing agents to alleviate adverse effects of long-term steroids [1]. Selected patients with severe life-threatening weakness or dysphagia at risk for aspiration may also benefit from the addition of intravenous immune globulin (IVIg) [1,2]. Patients who do not respond satisfactorily to therapy with steroids and first-line steroid sparing agents are considered to have refractory disease. Depending on the organ manifestation that is active, treatment options for refractory disease include medications such as IVIg, calcineurin inhibitors such as cyclosporine or tacrolimus, rituximab, cyclophosphamide, or combination therapy with azathioprine and methotrexate [1–3].

Since patients with refractory DM may not respond to conventional treatment options, there is a strong unmet medical need for better therapeutic alternatives. Despite several challenges in conducting clinical trials in DM, including rarity and heterogeneity of the population, there are now many drug targets being explored as viable therapeutic options. Furthermore, the development and validation of more robust outcome measures in myositis have standardized the ability to assess treatment response (Table 1). In this review, we provide a review of current medications commonly used for DM, as well as an update on novel pharmacologic therapies in the pipeline for DM. Areas covered will include existing and FDA approved drugs for DM, along with new and emerging treatment targets. A summary of selected published clinical trials registered with clinicaltrials.gov within the past 5 years for the treatment of DM are shown in Table 2. Selected investigational therapies in the pipeline for DM are shown in Table 3.

Table 1.

Key response criteria and measures of disease activity in dermatomyositis.

Composite response criteria
IMACS Core Set Measures	1. Physician global activity
	2. Patient global activity
	3. Manual Muscle Testing
	4. Functional assessment tools (HAQ)
	5. Muscle enzymes (CK, Aldolase, AST, ALT, and LDH)
	6. Extramuscular assessment
IMACS Definition of Improvement (DOI)	Three of any six core set measures improved by ≥20%, with no more than 2 parameters worsening by ≥25%
2016 ACR/EULAR Myositis Response Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis	Absolute percentage changes in the six core set measures defined by IMACS are converted into an improvement score in a weighted manner. The Total Improvement Score (TIS) is the sum of all six improvement scares. The TIS is divided into minimal response (≥20 for DM/PM), moderate (≥40 for DM/PM), and major (≥60) for DM/PM.
Specific outcomes
Disease activity
Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI)	Validated skin-specific outcome measure used to determine the longitudinal course of disease. Higher scores indicate greater disease severity.
Muscle strength
1. Manual Muscle Testing	MMT by 0–10 point or expanded 0–5-point scale to include proximal, distal, and axial muscles
2. Dynamometry	Measurement of muscle strength using a dynamometer
Myositis Disease Activity Assessment Tool (MDAAT)	Tool to assess extramuscular organs, including constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, and cardiac activity
Laboratory assessment	At least two of the five muscle-associated enzymes (CK, Aldolase, AST, ALT, and LDH) is followed to assess degree
Pulmonary Function Test	Used to measure severity of interstitial lung disease.
Muscle MRI	Used to assess disease activity or damage
Patient-reported outcomes
HAQ	Validated patient questionnaire of activities of daily living to assess physical function
Functional Index-2 (Fi-2)	Observation of seven tasks to assess muscle endurance. The Functional Index-3 has been developed which decreases the number of tasks required to only 3.
Patient/physician global activity	Patient/physician global disease activity assessment by Likert or visual analog scale
Patient Reported Outcomes Measurement Information System physical function 20 (PROMIS-PF20)	Validated, patient-reported outcome measure developed by the NIH

Table 2.

Selected recently published pharmaceutical clinical trials on the treatment of dermatomyositis.

First author and year	Target	Drug	NCT	Phase	Country	Study Population	Intervention	Primary Outcome Measures	Results
Aggarwal 2018 [23]	ACTH analog	Repository corticotropin injection (RCI)	NCT01906372	Open label	USA	Refractory PM/DM (n=11)	RCI 80 units SC twice weekly for 24 weeks	IMACS DOI	Of 10 patients, 7 met DOI at median of 8 weeks. Muscle strength improved by >10% and physician global score improved by >40%. RCI was considered safe and tolerable in this open-label trial.
Paik 2021 [41]	JAK inhibitor	Tofacitinib	NCT03002649	Open label	USA	Refractory DM (n=10)	Tofacitinib 11mg ER	IMACS DOI	Of 10 patients, all met the primary outcome at 12 weeks, of whom 5 showed moderate improvement and 5 showed minimal improvement. CDASI score also significantly improved.
Tjärnlund 2018 [49]	T-cell costimulation blockade	Abatacept	NCT01315938	Phase IIb	Sweden, London, Czech Republic	Refractory PM/DM (n=20)	Subjects were randomized to abatacept IV for 6 months (active treatment) vs. delayed onset of treatment after 3 months.	No. of responders according to IMACS DOI at 6 months. Secondary outcome measures were MMT-8 and TIS scores.	Of 19 patients, 8 achieved DOI (2 with DM, 6 with PM). Muscle performance improved based on MMT-8 scores (P < 0.05). At 3 months, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm.
Aggarwal 2021 [17]	Intravenous immunoglobulins	Octagam 10%	NCT02728752	Phase III	International	DM with active disease and muscle weakness (n=95)	Subjects were randomized 1:1 to either high dose IVIg (2g/kg every 4 weeks) or placebo. After week 16, all patients on placebo and patients without clinical worsening on IVIG entered the open label Extension Period, receiving IVIg (2g/kg every 4 weeks) for an additional 24 weeks.	Proportion of responders with moderate improvement based on TIS at week 16 compared to baseline between the two arms.	Primary endpoint was met in the trial, with minimal improvement significantly higher in the IVIG group as compared to the placebo group (78.7% vs. 43.8, p=0.0008).

Table 3.

Investigational therapies in the pipeline for dermatomyositis.

Target	Drug	NCT	Phase	Country	Status	Primary Outcome Measures
JAK inhibitor	Baricitinib	NCT04208464	Phase 2a	UK	Not yet recruiting	Minimal, moderate, or major clinical response according to the IMACS criteria at 24 weeks
JAK inhibitor	Baricitinib	NCT04972760	Phase 3	France	Not yet recruiting	Moderate improvement based on TIS at 24 weeks without prednisone
JAK inhibitor	Tofacitinib	NCT04966884	Open Label	China	Recruiting	Number of responders by total improvement score at 12 months
Anti-interferon B monoclonal antibody	PF-06823859	NCT03181893	Phase 2	USA	Recruiting	CDASI Activity Score at 12 weeks
T-cell costimulation blockade	Abatacept	NCT02971683	Phase 3	USA	Active, not recruiting	IMACS DOI at 24 weeks
T-cell costimulation blockade	Abatacept	NCT04946669	Open label	China	Recruiting	IMACS DOI at 12 weeks
T-cell costimulation blockade	Abatacept	NCT03215927	Phase 2	USA	Recruiting	Forced Vital Capacity (FVC) % Change in 24 weeks
Complement inhibitor	Ravulizumab	NCT04999020	Phase 3	USA	Recruiting	Minimal improvement based on TIS at 26 weeks and 50 weeks

Past and current therapeutics used in clinical practice to treat dermatomyositis

Glucocorticoids are used in the acute management of DM for immediate treatment effect, while steroid sparing agents are used simultaneously or early in the course of disease to alleviate adverse effects of long-term steroids. The choice of immunosuppressants depends on several factors, such as underlying comorbidities, extracutaneous manifestations, patient tolerability, and side effects. In this section, we review key steroid sparing agents used in DM for the treatment of muscle and skin disease.

Methotrexate

Methotrexate inhibits several pathways including folic acid and purine metabolism, as well as adenosine signaling. Used as a first-line treatment for rheumatoid arthritis, methotrexate suppresses inflammation and improves function. Several case reports and studies have reported that DM patients respond well to methotrexate with improvement in skin and muscle strength, along with reduction or discontinuation of corticosteroid therapy [4–7]. Bohan et al. treated 25 patients with steroid-resistant DM and polymyositis (PM) with oral methotrexate, of whom 88% had significant disease improvement and 43% reduced their corticosteroid dose [8]. Methotrexate is commonly used as a first-line immunosuppressive therapy for DM, and can also be helpful for concomitant inflammatory arthritis.

Azathioprine

Azathioprine, a purine analog, blocks T cell and B cell proliferation. A randomized trial of 16 PM patients compared prednisone (60 mg daily) with azathioprine (2 mg/kg of body weight daily) or placebo. At 3 months, there was no difference in creatine kinase (CK) levels between the two groups. However, at 3 years, patients on combination therapy had better functional outcomes and required less prednisone as maintenance therapy (1.6 mg/day vs. 8.7 mg/day). This study showed that azathioprine can be effective for improving strength and tapering corticosteroids, although the response to azathioprine may take as long as 4–6 months. Combination therapy with methotrexate and azathioprine can also be effective at improving strength in myositis patients with inadequate responses to either drug alone [9].

Mycophenolate mofetil

Mycophenolate mofetil, an inhibitor of iosine monophosphate dehydrogenase (an enzyme in purine synthesis), is an effective immunosuppressive agent that blocks T and B cell proliferation. In a small case series of 6 patients with refractory myositis (2 DM, 3 PM, and 1 overlap myositis), mycophenolate mofetil was associated with improved muscle power, reduced CK levels, and diminished corticosteroid use (mean prednisolone dose tapered from 13.7 to 8.5 mg/day) [10]. In another retrospective series, 10 refractory DM patients were treated with mycophenolate mofetil. Manual muscle testing scores improved in 5 patients and glucocorticoids were tapered in 6 patients [11]. Mycophenolate mofetil has been used in myositis patients who have failed methotrexate or azathioprine, as well as those with interstitial lung disease. While studies have shown mycophenolate mofetil to be efficacious in refractory disease, it can be utilized as a first line agent for skin/muscle disease in clinical practice, especially in the absence of concomitant inflammatory arthritis.

Intravenous Immunoglobulin

Immunoglobulins, or blood products derived from large pools of donated human plasma that comprise of antibodies, can be given intravenously (IVIg) or subcutaneously (SCIg) for refractory DM patients. Several American and European neurology national guidelines for the treatment of DM have recommended use of IVIg as adjuvant treatment with continuation of immunosuppressive therapy and corticosteroids [12,13].

The efficacy of IVIg was first illustrated in 1993 in a double-blind, placebo-controlled trial of 15 DM patients with refractory disease [14]. Patients were continued on prednisone (mean dose 25 mg/day) and were randomly assigned to IVIg (2g/kg monthly) or placebo for 3 months, with allowance of crossover to the other arm for treatment failures. Of 12 patients who received IVIg, 75% had significant improvement in scores of muscle strength and neuromuscular symptoms, whereas patients assigned to placebo had no benefit and 5 deteriorated. In an open study of 35 refractory PM patients treated with IVIg (1g/kg daily for 2 days per month for 4–6 months), improvement in muscle strength occurred in 71% of patients, and serum CK levels decreased in all 33 patients with initially elevated levels [15].

While IVIg use had previously been used off-label for DM patients, the FDA recently approved the first and only IVIg product (Octagam^® 10%, Octapharma AG, Lachen, Switzerland) for use in adults with DM in July 2021. The approval was based on the ProDERM trial—a phase 3, randomized, prospective, double-blind, placebo-controlled, multicenter clinical trial that demonstrated the long-term safety and efficacy of IVIg in adults with DM among 95 patients [16,17]. Octagam^® 10% is a liquid intravenous polyvalent IVIg preparation prepared from human plasma containing highly purified normal human immunoglobulin G. The trial enrolled adults with definite or probable DM (based on Bohan & Peter criteria) with active disease and muscle weakness (MMT < 142/150). Patients were allowed to be on stable therapy with corticosteroids and/or maximally two immunosuppressants, or if they had previous failure of response or intolerance to corticosteroids and at least one additional immunosuppressive drug. Background medications including immunosuppressive drugs and corticosteroids were allowed if treatment was initiated at least 3 months prior to enrollment and maintained at a stable dose at least 4 weeks prior to enrollment.

During the first 16-week double-blind phase of the trial, adult patients were randomized 1:1 to receive IVIg (Octagam^® 10%) 2 g/kg every 4 weeks or placebo. The primary endpoint, defined as the proportion of responders according to the 2016 ACR/EULAR Myositis response [18] criteria of at least minimal improvement (Total Improvement Score [TIS] ≥ 20 points) at week 16, was met in the trial, with minimal improvement significantly higher in the IVIg group as compared to the placebo group (78.7% vs. 43.8, p<0.001). The mean TIS was also significantly higher in the IVIg arm compared to placebo (48.4 vs. 21.6) at week 16, indicating greater improvement with treatment. At week 16, moderate improvements were seen in 68.1% of the IVIg group compared with 22.9% of the placebo group (P<0.0001), and major improvements were observed in 31.9% versus 8.3% (P=0.0062).

The double-blind phase was followed by a 24-week open-label period where all patients received IVIg infusions of 2 g/kg every 4 weeks. After switching to open-label treatment at week 24, patients formerly on placebo showed dramatic improvements and ultimately had almost the same response rate by week 40 (71.1% in the IVIg group vs. 69.6% in the placebo/IVIg group).

Most related adverse events were infusion related/reactions and consistent with known side effects of IVIg, including mild headache (42% of subjects), pyrexia (19%), and nausea (16%) [19]. Premedication for infusions (ibuprofen, antihistamines, and Tylenol) were required in only 21% of patients prior to IVIg administration. Serious adverse events thought to be related to IVIg occurred in 7 patients, including thromboembolic events (i.e. deep vein thrombosis and pulmonary embolism) in 5 patients who also had other risk factors. The exposure-adjusted incidence rate for thromboembolic events was efficiently lowered (from 1.54 events per 100 patient months to 0.54) by reducing the maximum allowed infusion rate.

An alternative subcutaneous approach to the administration of IVIG in DM patients has also been used off-label. In a small case series of 7 patients (4 DM, 3 PM), the usual monthly dose was divided into weekly doses given subcutaneously through a programmable pump. Subcutaneous Ig (SQIg) treatment was safe and well-tolerated, with all patients demonstrating clinical improvement in muscle strength and decreased CK serum levels [20]. Advantages of SQIg included the convenience of home treatment, better quality of life, reduced cost, lack of the need for intravenous access, and lower incidence of adverse reactions compared to IVIg [20]. However, the dose of Ig can be substantial, making it challenging to logistically administer and requiring frequent injections per week. There is now an ongoing phase 3, multicenter, randomized, placebo-controlled, double-blind study to determine the efficacy, safety, and pharmacokinetics of IgPro20 (SCIg) treatment in adult patients with DM, with study completion anticipated in February 2024 (ClinicalTrials.gov Identifier: NCT04044690).

Rituximab

Rituximab is a chimeric monoclonal antibody against the CD20 antigen on B lymphocytes and leads to depletion of peripheral B cells. Many case reports, case series, and open-label trials have reported a beneficial effect of rituximab in patients with refractory myositis.

The largest randomized, double-blind, placebo-controlled trial so far regarding the efficacy of rituximab in adult and juvenile myositis is the rituximab in myositis (RIM) trial [21]. This trial included 195 individuals (72 DM, 75 PM, and 48 juvenile DM) refractory to glucocorticoids and at least one immunosuppressive agent. Patients were randomized to have either rituximab early (rituximab administered at weeks 0 and 1 and placebo infusions given at weeks 8 and 9) or late (placebo infusions at week 0 and 1 and rituximab at weeks 8 and 9). The primary endpoint compared the time to achieve the IMACS DOI between the two groups. Even though the primary endpoint of the trial was not met, most patients (83%) showed clinical improvement and a steroid-sparing effect during the trial. The presence of anti-Jo-1 and anti-Mi-2 antibodies were predictors of a more robust response to rituximab.

In a post-hoc analysis of the trial, there were significant improvements in cutaneous disease activity from baseline to the end of the trial after rituximab in both adult and juvenile DM subsets [22]. Cutaneous disease activity was assessed using a visual analog scale. The frequency of classic DM rashes (heliotrope or Gottron changes) decreased from 69% to 48% (p=0.009). Among other types of rashes, a significant decrease in frequency was seen in erythroderma, erythematous rash without secondary changes of ulceration or necrosis, periungual erythema, diffuse alopecia, and mechanic’s hands. Rituximab was overall well tolerated with infections being the most frequent cause of adverse events.

Repository corticotropin injection (RCI)

RCI, otherwise known as adrenocorticotropic hormone (ACTH) gel, is a long-acting full sequence ACTH thought to have anti-inflammatory and immunomodulatory effects through melanocortin receptors. RCI was originally approved by the FDA in 1952 for PM and DM, but this was based only on a few case reports. To further investigate its effectiveness, a prospective open-label clinical trial was performed in 2017 to evaluate the efficacy of RCI in PM and DM [23]. In this study, 10 patients with refractory disease (6 DM, 4 PM) completed treatment with RCI for 24 weeks. Treatment with RCI was effective in 70% of patients based on the primary end point of the International Myositis Assessment and Clinical Studies (IMACS) definition of improvement (DOI) at a median of 8 weeks. Furthermore, treatment was safe and tolerable and led to a steroid dose reduction at 24 weeks. No patients developed significant weight gain, cushingoid features, or an increase in hemoglobin A1C levels. Treatment with RCI may be an alternative to glucocorticoids; however, given the high cost it is unlikely to be used as a first-line treatment in myositis.

Promising Emerging Therapies for DM

Janus kinase (JAK) Inhibitors

Janus kinases are cytoplasmic protein tyrosine kinases that are important for signal transduction to the nucleus and downregulate downstream mediators of interferon activity. Tofacitinib was the first pan-JAK inhibitor to be FDA-approved for the treatment of rheumatoid arthritis, followed by the more selective JAK 1/2 inhibitor baricitinib and JAK 1 inhibitor upadicitinib.

The first case report to demonstrate early promise of JAK inhibitors for the use of refractory DM involved ruxolitinib, a JAK inhibitor used to treat neoplastic diseases [24]. A 72-year-old woman with long-standing, poorly controlled DM (manifested by active cutaneous and muscle disease despite treatment with high-dose glucocorticoids, azathioprine, and IVIg) was diagnosed with myelofibrosis. When her myelofibrosis was treated with ruxolitinib, her DM unexpectedly went into remission. However, the possibility that her DM was paraneoplastic, and therefore the treatment of the underlying disease was the cause for improvement of her DM, could not be excluded [25]. Following the initial case report, several case reports and series over the years demonstrated efficacy of JAK inhibitors (tofacitinib or ruxolitinib) for several DM manifestations [26], including skin rash [27–32], muscle weakness [27,29–32], arthropathy [27,29], pruritus [31,32], fatigue [31,32], alopecia [33], calcinosis [34,35], and interstitial lung disease [28,35–40].

In a single-center prospective open-label clinical trial by Paik et al., tofacitinib was safe and well-tolerated as a treatment of refractory DM in 10 patients who failed at least two steroid-sparing agents or high-dose steroids [41]. A wash-out period was required for all patients on immunosuppressive or immunomodulatory therapy, and a forced prednisone taper was instituted at 8 weeks for patients receiving prednisone at study entry. All patients met the primary outcome measure of interest, defined by the IMACS DOI at 12 weeks. The response rate was also measured by the 2016 ACR/EULAR Myositis Response Criteria, with half of subjects experiencing mild improvement and the other half experiencing moderate improvement. There were also statistically significant improvements in cutaneous findings as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) (28 ± 15.4 [baseline] vs. 9.5 ± 8.5 [12 weeks]; p = 0.0005). Furthermore, key chemokines such as serum CXCL 9/10 were downregulated with treatment. Four of 10 subjects received prednisone at study entry, of whom 3 (75%) of the 4 subjects were able to completely discontinue treatment with all steroids.

In an open-label treatment extension, 7 of 10 (70%) of patients entered the phase of this study, of which 6 of 7 (86%) continued to meet the IMACS DOI at 68 weeks, and there continued to be a statistically significant change in mean CDASI when compared to baseline (baseline: 25.4 ± 15.0, compared to 96 weeks: 4.71 ± 2.63, p=0.02) [42]. Two subjects required additional immunosuppression with low dose methotrexate up to 96 weeks, but no patients required any high dose steroid therapy or hospitalizations for flare-ups. Furthermore, there were no serious adverse events or study discontinuations related to tofacitinib.

Tofacitinib has also been used as a rescue option for patients with high-risk amyopathic anti-MDA5-positive amyopathic DM-associated interstitial lung disease (ADM-ILD), which can be a rapidly progressive and life-threatening disease. Japanese investigators reported the efficacy of tofacitinib as a rescue option for patients with high-risk anti-MDA5-positive ADM-ILD [40]. In a single-center, open-label clinical study in China, 18 consecutive patients with anti-MDA-5-positive ADM-ILD treated with combination tofacitinib and glucocorticoids had a significantly higher 6-month survival compared to historical controls [43]. Pulmonary function test parameters (forced vital capacity [FVC] % of predicted value and carbon monoxide diffusing capacity [DLCO] %) and imaging findings on high-resolution CT in the tofacitinib group also improved over time. In a literature review summarizing 32 published cases with anti-MDA-5 positive ADM-ILD, all cases survived during induction therapy with tofacitinib and glucocorticoids [44]. Among refractory or relapsing cases treated with glucocorticoid and immunosuppressive agents, 75% of cases and improved and survived by adding tofacitinib, although opportunistic infections were more frequent.

JAK inhibitors remain an incredibly promising treatment target for DM. Larger phase 2 and 3 studies are currently planned for baricitinib in the United Kingdom (ClinicalTrials.gov Identifier: NCT04208464) and France (ClinicalTrials.gov Identifier: NCT04972760) in both naïve and relapsing DM. Another clinical trial in China aims to investigate the efficacy and safety of tofacitinib in anti-MDA5 antibody-positive DM patients who are at risk of developing rapidly progressive ILD (ClinicalTrials.gov Identifier: NCT04966884).

Despite the potential benefits of JAK inhibitors, an approach of cautious optimism should be taken regarding the safety of the drug. In a recent FDA review of a large, randomized safety clinical trial in rheumatoid arthritis, tofacitinib was associated with an increased risk of heart attack or stroke, malignancy, thrombosis, and death associated with tofacitinib. As such, the FDA now requires new and updated warning labels for consumers and have extended the warnings to baricitinib and upadicitinib. It remains to be known whether this safety concern applies to patients with DM who clearly have a different disease process from rheumatoid arthritis.

Abatacept

Abatacept, a selective costimulation modulator, is a recombinant fusion protein comprised of the cytoplasmic T lymphocyte antigen 4 (CTLA4) and a fragment of the Fc region of immunoglobulin IgG1 that inhibits T cell activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Abatacept has been approved for use in rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis. In addition to downregulating T cells and directly affecting muscle inflammation in myositis, abatacept also decreases antigen-presenting capability of myocytes, inhibits macrophages, and decreases pro-inflammatory cytokines (e.g. IL-6, TNF alpha) that have been strongly implicated in DM [45].

A few clinical case reports have been published on the safety and efficacy of abatacept in patients with refractory juvenile DM with ulcerative skin disease [46] and calcinosis [46,47], and adult DM with refractory skin and oropharyngeal disease [48].

Abatacept was studied as a treatment for myositis in a randomized, phase 2b treatment delayed-start trial [49]. DM and PM patients with persistent inflammatory active disease despite treatment with glucocorticoids and on at least one immunomodulating drug for at least 3 months were randomized to either receive immediate active treatment with intravenous abatacept infusions or a delayed start after 3 months. The primary endpoint was the number of responders who met the IMACS DOI after 6 months of treatment. A secondary outcome measure was the number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Of the 17 participants included in the analysis, 8 achieved the DOI at 6 months, and there was significant improvement seen in muscle strength and in health-related quality of life in half of the patients. At 3 months after study start, 5 of 10 (50%) in the active treatment arm achieved the DOI compared to only 1 of 7 (14%) patients in the delayed onset arm. There were eight drug-related AEs, but none related to the drug.

There are also two ongoing clinical trials investigating the use of abatacept in adult IIM. The first is a large phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of abatacept in combination therapy compared with standard therapy alone in patients with active IIM excluding inclusion body myositis (ClinicalTrials.gov Identifier: NCT02971683). 148 participants with refractory IIM were allocated to receive subcutaneous abatacept or placebo for 24 weeks in addition to standard treatment, followed by a 28-week open label period. Patients were required to be on background standard treatment for IIM (including corticosteroids and/or immunosuppressive agents); medications had to be started at least 12 weeks prior to randomization with a stable dose for at least 4 weeks prior to randomization. The primary outcome will measure IMACS DOI at 24 weeks. Results from this trial have yet to be published.

Additionally, there is a phase 2, multi-center, randomized, placebo-controlled, 24-week proof of concept study to assess the efficacy, safety, and tolerability of abatacept in treating interstitial lung disease associated with anti-synthetase syndrome (ATtackMy-ILD, ClinicalTrials.gov Identifier: NCT03215927). The primary outcome measure will be the FVC % change from the baseline visit to 24 weeks between abatacept vs. placebo in addition to standard of care. This trial is actively recruiting patients.

Novel therapeutic agents under investigation for use in dermatomyositis

Complement C5 Inhibitors

The pathogenesis of DM is also thought to mediated by the complement pathway. Multiple studies have highlighted the vasculopathy of DM on biopsies (skin and muscle) resulting from a complement (C5b-9) mediated injury to endothelial cells, leading to depletion of the muscle capillary bed, muscle fibrosis necrosis, and perifascicular pattern of muscle fiber atrophy [50–52]. The use of eculizumab, a monoclonal antibody against C5 which blocks the generation of C5a and membrane attack complex assembly, has been reported with some success in two case reports [53,54]. Both involved young women with JDM who failed conventional disease-modifying antirheumatic drugs but had recovery with eculizumab. However, both cases were confounded by concomitant thrombotic microangiopathy with severe renal injury.

Ravulizumab is a complement C5 inhibitor that has been approved for the treatment for paroxysmal nocturnal hemoglobinuria and hemolytic uremic syndrome. There are currently plans to initiate a phase 2/3, double-blind, randomized, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of ravulizumab in adult DM patients (ClinicalTrials.gov Identifier: NCT04976140). Eligibility will include adult DM patients who have had an inadequate response to 2 or more immunosuppressive therapies. The primary outcome measure will be the proportion of participants with a ≥20-point improvement response on the TIS, with a goal enrollment of 180 participants. The clinical trial is still in its early phases and is not yet recruiting, but the estimated study completion date will be in 2026.

Apremilast

Apremilast is a phosphodiesterase-4 (PDE-4) inhibitor commonly used in the treatment of psoriasis, psoriatic arthritis, and Behçet disease. Apremilast was used successfully in treating three patients with refractory cutaneous DM without underlying malignancies [55]. Although the mechanism of action of apremilast in DM is unknown, it has been suggested that apremilast inhibits T helper-1 (Th1) and T helper-2 (Th2) immune pathways that play a fundamental role in DM [56]. Specifically, apremilast increases the level of cyclic adenosine monophosphate, resulting in decreased expression of proinflammatory cytokines including TNF-α and interferon-γ, thus inhibiting the Th1 response [57]. Apremilast may also block Th2 response by interfering with IL-6 secreted by macrophages [58]. With limited therapeutic options available for DM, investigators are evaluating the safety and efficacy of apremilast in the treatment of cutaneous disease in patients with recalcitrant DM in a phase 2, open label single arm study. Patients must have a diagnosis of DM on steroid-sparing agents and/or systemic steroids (maximum dose of prednisone 1mg/kg) still having cutaneous disease activity (≥5 points on CDASI) to be eligible for this trial. Immunosuppressive agents are allowed if patients are on stable doses for at least 4 weeks. The primary outcome measure is the number of participants experiencing at least a 4-point decrease in CDASI activity score at 3 months. While the clinical trial has concluded, results have not been published yet.

KZR-616

KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which modulates both innate and adaptive immune effector cells, resulting in decreased inflammatory T helper cell subsets (Th1 and Th17), increased regulatory cells, and decreased plasma cells and autoantibodies. Treatment with KZR-616 in a preclinical mouse model of PM demonstrated suppression of muscle inflammation and prevention of muscle weakness [59]. The preclinical improvement after KZR-616 supported the rationale for PRESIDIO, a phase 2, clinical trial of KZR-616 in patients with DM and PM currently under way (ClinicalTrials.gov Identifier: NCT04033926). This study will be a randomized, double-blind, placebo-controlled, crossover trial, with patients randomized to receive either KZR-616 subcutaneous injections or placebo for 16 weeks. Key eligibility criteria include adult patients with probable or definite DM or PM with active muscle disease who are intolerant or refractory to standard-of-care therapies. The primary outcome measure will be the mean change from start to end of KZR-616 treatment in the TIS.

Drugs directly targeting the IFN pathway (IFNs)

IFNs are cytokines produced during viral infections that are integral for regulating the immune system. Several studies have highlighted the activation of the innate immune system, including high expression of IFNs and IFN-regulated proteins, as an important pathological hallmark of DM. Type I IFNs have been identified as an important mediator in autoimmune diseases including DM, with upregulation of type I IFNs found in muscle tissue and peripheral blood cells [60] that correlate with disease activity.

Sifalimumab is an investigational anti-IFN-α (a type I IFN) monoclonal antibody that has been studied in clinical trials for use in systemic lupus erythematosus and plaque psoriasis. In 2013, a phase 1b randomized, double-blind, placebo controlled, multicenter trial was completed using sifalimumab in 48 IIM patients (27 DM and 21 PM) [61]. Patients at baseline were identified as having either high or low IFN gene expression profiles based on 13 type I IFN-inducible genes. Sifalimumab suppressed type I IFN expression by 66% in the blood and 47% in the muscle at day 98. Furthermore, patients with ≥15% MMT improvement showed greater neutralization of IFN signature than those with <15% improvement in both blood and muscle.

There has also been interest in investigating the efficacy of anti-IFN-β monoclonal antibodies in DM patients. PF-06823859 is an anti-IFN-β monoclonal antibody designed by Pfizer. Recruitment is ongoing for a phase 2 double-blind, randomized, placebo-controlled study of PF-06823859 in patients with moderate to severe DM, either defined as skin predominant (CDASI activity score ≥14) or muscle predominant (MMT ≤ 136/150) (ClinicalTrials.gov Identifier: NCT03181893). Participants with muscle predominant activity must have failed at least 2 courses of immunosuppressive or immunomodulatory agents and cannot exceed >20 mg of oral prednisone daily to be included into this trial. The primary outcome measure will be the change in CDASI activity score from baseline at 12 weeks.

Conclusions

Despite the many challenges in conducting clinical trials in DM, there has been significant progress in the research of potential treatments in DM. The recent FDA approval for Octagam^® 10% Immune Globulin Intravenous (IVIg) adds to the armamentarium of effective drugs for DM, and alternative formulations (such as SQIg or other companies’ products) are likely to follow suit. There are now several drug targets being explored as viable therapeutic options in phase 2 and phase 3 clinical trials. Biologic agents such as JAK inhibitors and abatacept are especially promising based on data from smaller trials. With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more pharmaceutical agents become available.