Version January 2024
INTRODUCTION — Classic dermatomyositis (DM) is an idiopathic inflammatory myopathy that most commonly presents with progressive, symmetric, proximal muscle weakness and a group of characteristic cutaneous findings. The cutaneous manifestations of DM may also develop in the absence of detectable muscle disease and can persist after the successful treatment of DM-associated myositis. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
Skin lesions of DM are often resistant to photoprotection and topical therapies alone, necessitating the initiation of systemic therapy (algorithm 1). Patients who fail to respond to antimalarials and methotrexate, or who relapse during therapy with these agents, require more aggressive immunosuppressive or immunomodulatory drugs. (See "Cutaneous dermatomyositis in adults: Overview and initial management".)
The management of patients with refractory cutaneous DM will be discussed here. The initial treatment of cutaneous DM, as well as the clinical manifestations, diagnosis, and management of the extracutaneous manifestations of DM and juvenile DM, are reviewed elsewhere. (See "Cutaneous dermatomyositis in adults: Overview and initial management" and "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults" and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations" and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis".)
APPROACH TO REFRACTORY DISEASE — DM is associated with characteristic cutaneous findings, most notably a pruritic, violaceous to erythematous eruption involving the scalp, face, neck, upper trunk, arms, and dorsal hands (picture 1A-F). Pruritus associated with DM can be severe, leading to significant detrimental effects on patient quality of life. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Skin findings in dermatomyositis'.)
For a subset of patients with skin manifestations of DM, trials of multiple therapies (in combination or sequentially) are required to identify the treatment regimen that produces satisfactory disease control. Because many patients fail to improve adequately with photoprotection, antipruritics, and topical corticosteroids or topical calcineurin inhibitors, the addition of systemic antimalarials or methotrexate is often necessary. Patients who fail to respond to these conventional interventions or who relapse after an initial response have refractory disease and require the initiation of more aggressive therapies (algorithm 1). (See "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Treatment'.)
Calcinosis cutis is a cutaneous complication of DM that also can be refractory to treatment. (See 'Calcinosis cutis' below.)
Choice of therapy — Although a wide variety of immunomodulatory and immunosuppressive medications have been used in the treatment of refractory cutaneous DM, few studies have investigated the efficacy and safety of these agents in patients with cutaneous DM.
Intravenous immune globulin (IVIG) and mycophenolate mofetil (MMF) are our preferred treatments for DM refractory to conventional therapy (photoprotection, topical agents, antimalarials, and/or methotrexate) (algorithm 1). Selection of these agents is based upon evidence that suggests efficacy and the knowledge that these are generally well-tolerated therapies. Although comparative studies have not been performed, clinicians with expertise in DM generally consider IVIG the most effective treatment and treatment of choice. However, the need for intravenous administration and the high cost of IVIG limit use of this agent in some patients. (See 'Intravenous immune globulin' below and 'Mycophenolate mofetil' below.)
Additional treatments for refractory cutaneous DM include systemic immunosuppressants (eg, azathioprine, cyclosporine, tacrolimus, sirolimus, cyclophosphamide, chlorambucil, Janus kinase [JAK] inhibitors, and rituximab), dapsone, and apremilast. Due to limited or conflicting evidence in support of the efficacy of these agents and the risks for serious adverse effects associated with some of these drugs, we generally reserve the use of these agents for patients who have failed or who are poor candidates for IVIG and MMF. The need for treatment of concomitant refractory muscle disease can also influence the choice of therapy. (See 'Other therapies' below and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)
PRIMARY THERAPIES — Intravenous immune globulin (IVIG) and mycophenolate mofetil (MMF) are our treatments of choice for refractory cutaneous DM (algorithm 1).
Intravenous immune globulin — IVIG is a product derived from pooled donor plasma that contains numerous immunoregulatory substances. IVIG has been used successfully for refractory extracutaneous manifestations of DM and appears to be beneficial in patients with cutaneous manifestations of DM who have failed to respond adequately to other therapies. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Intravenous immune globulin' and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Intravenous immune globulin'.)
Administration — In clinical practice, patients are usually treated monthly with 2 g/kg of IVIG given as infusions of 1 g/kg per day on two consecutive days every four weeks. Of note, in patients who develop intolerable side effects to this dosing schedule, the daily doses can be given two weeks apart (1 g/kg per day administered every two weeks), which is a frequently used dosing schedule for IVIG in children.
Clinical improvement is expected within two to three months, but the full benefit may not be realized for six months. Given the high cost of IVIG, the interval between treatments is typically progressively lengthened once the patient has achieved a complete or near complete clinical response (eg, in the traditional dosing schedule, adjusted to every five weeks, then every six weeks, etc). Relapse may occur upon treatment discontinuation; continued treatment may be necessary to maintain improvement.
Efficacy — Improvement in cutaneous DM has been reported in randomized trials designed to evaluate the efficacy of IVIG for muscle disease in DM [1,2]. In the largest trial, 95 patients with DM were randomly assigned to IVIG (2 g/kg body weight) or placebo given every 4 weeks for 16 weeks [2]. Treatment with IVIG was associated with a greater likelihood of at least minimal improvement in DM as defined by the change in the total improvement score at week 16 (79 percent in the IVIG group and 44 percent in the placebo group achieved minimal improvement). Assessment of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) total activity score also showed greater improvement in cutaneous disease in the IVIG group, with a mean change of -9.4 (95% CI -12.5 to -6.2) in the IVIG group compared with -1.2 (95% CI 3.3-1.0) in the placebo group.
Retrospective studies, case reports, and case series offer additional support for the use of IVIG in refractory DM [3-7]. Benefit from low-dose IVIG has been reported; in one woman with cutaneous manifestations of DM refractory to systemic glucocorticoids, five-day courses of IVIG (0.1 g/kg per day) given twice over the course of two weeks led to clinical improvement [5].
Adverse effects — Adverse effects of IVIG include hypersensitivity reactions, headaches, vasculitis, aseptic meningitis, renal failure, myocardial infarction, and thrombosis. (See "Intravenous immune globulin: Adverse effects".)
Mycophenolate mofetil — MMF is an immunosuppressive agent that reversibly inhibits inosine monophosphate dehydrogenase, an enzyme required for de novo purine synthesis. The dependency of T and B lymphocytes on this pathway for the production of DNA and RNA is responsible for the selective immunosuppressive properties of MMF. MMF is used for the treatment of myositis in DM, and the drug also appears to be beneficial for skin disease. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Mycophenolate mofetil'.)
Administration — MMF is typically given as 2 to 3 g per day in two divided doses. Patients are typically started on 500 mg twice daily for two weeks, followed by laboratory tests and clinical assessment to confirm tolerance of the medication. The dose is then titrated to 1 g given twice daily and, if tolerated, to 1.5 g twice daily in many patients. Improvement in skin disease is expected within two to three months of treatment. If the response is poor after three months, we transition patients to other treatments.
Given the relatively slow onset of action of MMF, overlapping treatment may reduce the risk for disease flares while awaiting the drug's onset of action and during titration of the MMF. In patients who are transitioning from methotrexate to MMF due to an inadequate response to methotrexate, we often continue methotrexate at a reduced dose (usually 10 to 15 mg per week) for several weeks to several months after starting MMF. Lowering the dose of methotrexate is intended to reduce cumulative immunosuppressive effects. In most patients, we taper and eventually discontinue methotrexate once clinical improvement is noted. However, in patients with particularly refractory disease, we may continue 10 to 15 mg per week of methotrexate in conjunction with MMF, with close monitoring for laboratory abnormalities and for infection. (See "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Methotrexate'.)
Efficacy — The use of MMF for the cutaneous manifestations of DM is supported by uncontrolled studies and a case series [8-11]. A prospective cohort study of 74 patients with moderate to severe cutaneous DM managed with various therapies found an association between treatment with MMF and clinical remission [8]. Furthermore, this study demonstrated that the majority of patients who achieved clinical remission with MMF were treated with 1.5 g twice daily, suggesting that higher doses may be required for effective treatment of DM skin disease.
In a retrospective study of 12 patients with cutaneous DM that was refractory to other systemic drugs, MMF given alone or as an adjunctive therapy resulted in improvement in 10 patients (83 percent) [11]. Most responses occurred within four to eight weeks, and all responses were attained at doses of 2 to 3 g per day. MMF also was effective in a series of four patients with skin lesions of DM that failed to respond to systemic glucocorticoids, hydroxychloroquine, and/or methotrexate [10].
Adverse effects — MMF has a favorable toxicity profile when compared with many other systemic immunosuppressants. Gastrointestinal distress is the most common adverse effect of the drug; additional side effects include teratogenicity and reversible cytopenias. Periodic monitoring of a complete blood count and liver and kidney function tests is recommended during treatment. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
It is unclear whether MMF leads to an increased risk for malignancy. In the retrospective study described above, one patient with a history of breast cancer developed cancer in the contralateral breast during treatment [11]. Another patient in the study developed an Epstein Barr virus-related B cell lymphoma of the central nervous system that resolved without further intervention following the discontinuation of MMF and methotrexate. (See 'Efficacy' above and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Neoplasia'.)
OTHER THERAPIES — Data on other therapies for cutaneous DM are limited. This lack of data and/or the potential for adverse effects with many of these alternative agents generally limit their use to patients who have failed or who cannot receive other treatments for refractory disease.
Janus kinase inhibitors and traditional immunosuppressants — There are limited but increasing data suggesting benefit of newer immunosuppressant agents, the Janus kinase (JAK) inhibitors, for recalcitrant cutaneous DM. We often use these agents following intravenous immune globulin (IVIG) and/or mycophenolate mofetil (MMF) in appropriately selected patients with refractory DM.
Case reports and small, uncontrolled studies suggest benefit of JAK inhibitors (eg, tofacitinib, ruxolitinib, baricitinib) [12-17]. A systematic review of the literature published in 2022 identified a total of 61 reports of treatment of refractory cutaneous DM in adults, all documenting improvement with JAK inhibitor treatment [18]. Examples of individual prospective studies include:
●In an open-label study of patients with refractory DM, 11 mg of extended-release tofacitinib was given daily for 12 weeks following a washout of all glucocorticoid-sparing agents. All 10 patients who completed the study achieved some improvement in disease activity at 12 weeks, and this improvement was primarily driven by skin disease. The mean change in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score was statistically significant and clinically meaningful (from 28±15.4 at study entry to 9.5±8.5 at week 12) [14].
●In an open-label study in which 12 patients with cutaneous DM were treated with baricitinib (2 mg twice daily) for 12 weeks with or without prednisone and/or hydroxychloroquine, nine patients achieved at least a 40 percent reduction in the CDASI activity score [16]. Pruritus (as measured by the visual analog scale itch score) also improved.
●In an open-label study of 16 patients with DM treated with JAK inhibitors (ruxolitinib or baricitinib with or without prednisone and/or IVIG), including 14 patients with active skin disease, the mean CDASI decreased from 27±13 at baseline to 14±11 at three months [17]. A statistically significant change in muscle symptoms (as measured by the Manual Muscle Testing 8) was not detected.
Azathioprine, cyclosporine, tacrolimus, sirolimus, cyclophosphamide, and chlorambucil have also been used for the treatment of refractory noncutaneous manifestations of DM [19-38]. Evidence for the efficacy of these agents for cutaneous disease is primarily limited to case reports and case series as documentation of clinical experience [39-44].
Safety concerns for the use of immunosuppressants include increased risk for infection and malignancy. Drug-specific safety monitoring should be performed.
Rituximab — Although available data suggest rituximab, a biologic immunosuppressant, may be beneficial for extracutaneous manifestations of DM, studies have yielded conflicting results on the efficacy of rituximab for cutaneous manifestations. Data on the effects of rituximab on extracutaneous manifestations of DM are reviewed in greater detail separately. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Rituximab'.)
Beneficial effects of rituximab on the cutaneous manifestations of DM were reported in an open-label study in which seven patients with DM were treated with four weekly infusions of rituximab (100 or 375 mg/m2 per infusion) [45]. Among the five patients in whom a cutaneous eruption of DM was documented at the start of the study, all exhibited improvement in skin disease with treatment [45]. In addition, hair regrowth occurred in two patients with alopecia secondary to DM. Treatment with rituximab was also beneficial as an adjunctive therapy in a retrospective study of juvenile DM; three out of four patients exhibited improvement in cutaneous and muscle disease [46].
In contrast, an open-label study in which rituximab (two 1 g doses separated by two weeks) was added to the treatment regimens of eight adults with DM did not detect improvements in skin disease following treatment [47]. Although all eight patients demonstrated sustained depletion of peripheral B cells on rituximab, a statistically significant change in the mean Dermatomyositis Skin Severity Index (DSSI) score was not detected.
A posthoc analysis of data from the Rituximab in Myositis trial, one of the largest studies to investigate rituximab for inflammatory myositis, suggested a beneficial effect on cutaneous disease in adult and juvenile DM [48,49]. However, lack of use of a validated cutaneous outcomes measure and lack of assessment of skin disease by dermatologists make it difficult to draw definitive conclusions from this analysis [49]. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Rituximab'.)
Additional studies using a validated skin score are necessary to determine the efficacy of rituximab, specifically for cutaneous DM, the ideal treatment regimen, and the patient population that might benefit most from rituximab. Given limited evidence of efficacy for cutaneous DM specifically, we rarely use rituximab as treatment for DM skin disease. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Rituximab'.)
Rituximab usually is well tolerated. However, the drug has been associated with nausea, serum sickness-like reactions [50], and infusion-related events, including hypotension, fevers, and rigors. In addition, a boxed warning on the drug label has been mandated by the US Food and Drug Administration (FDA) due to reports of fatalities from infusion reactions, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy due to JC virus in patients treated with rituximab. Sepsis is an uncommon complication. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Dapsone — Evidence from case reports suggests that dapsone may be of benefit in cutaneous DM [51,52]. Dapsone is usually initiated at a dose of 25 mg twice daily [39]. The dose can be increased to a total dose of 200 to 300 mg/day when necessary.
In one report, two patients with cutaneous DM unresponsive to combination therapy with hydroxychloroquine, quinacrine, prednisone, and other immunosuppressive medications had rapid improvement in skin lesions with the addition of dapsone [52]. The responses to dapsone correlated with treatment; skin disease worsened upon withdrawal of dapsone and improved after reinitiation. In contrast, failures to respond to dapsone have been documented in a patient with drug-induced amyopathic DM [53] and a patient with postmyopathic DM [54]. (See "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Amyopathic dermatomyositis' and "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Postmyopathic dermatomyositis'.)
Hemolysis and methemoglobinemia may occur in association with dapsone therapy. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at greater risk for hemolysis than the general population. Peripheral neuropathy, agranulocytosis, and a hypersensitivity syndrome are additional adverse effects of dapsone. (See "Drug eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms'.)
Apremilast — Findings from an open-label, phase 2a study suggest benefit of apremilast for cutaneous DM [55]. Apremilast (30 mg twice daily following an initial five-day dose titration period) was added to the treatment regimen of eight patients with refractory cutaneous DM (classic, amyopathic, or juvenile). At three months, seven patients had improvement in the CDASI, with a mean decrease of 12.9 points (standard deviation 6.3 points). An analysis of skin biopsies taken before and after three months of apremilast treatment revealed downregulation of multiple inflammatory pathways. The most common adverse effects were headache, nausea, and diarrhea.
Other systemic medications — Other systemic agents with limited evidence for efficacy include biologic tumor necrosis factor (TNF)-alpha inhibitors, leflunomide, thalidomide, and antiestrogens:
●Biologic TNF-alpha inhibitors – Biologic TNF-alpha inhibitor therapy for cutaneous DM is generally avoided outside of monitored clinical trials. Strong evidence for the efficacy of TNF-alpha inhibitors on cutaneous DM is lacking. Most reports documenting benefit of anti-TNF therapy in DM have focused on the effects on muscle disease [56-66]. Data on efficacy on cutaneous manifestations are sparse and contradictory, and induction or exacerbation of DM during TNF-alpha inhibitor therapy has been reported [67-72].
Moreover, the potential for adverse consequences of TNF-alpha inhibitor therapy also must be considered. It is unknown whether the baseline risk for malignancy associated with adult DM is augmented with the use of TNF-alpha inhibitors, mandating cautious use of these agents. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
●Leflunomide – Leflunomide, an immunomodulatory agent used in the treatment of rheumatoid arthritis, may be effective in some patients with cutaneous DM [54,73]. Leflunomide led to improvements in skin disease in a series of three patients with DM refractory to multiple other systemic therapies [54].
●Thalidomide – Patients in whom cutaneous DM improved during treatment with thalidomide, an agent believed to exert anti-inflammatory effects through inhibition of TNF-alpha, have been reported [53,74].
●Antiestrogens – Antiestrogens (tamoxifen or anastrozole) appeared to contribute to improvements in skin disease in two patients [75]. The mechanism through which antiestrogens could contribute to resolution of DM is unknown; a relationship between estrogen and the production of proinflammatory cytokines, such as TNF-alpha, has been postulated [75].
Total body irradiation — Total body irradiation was associated with improvements in myositis and skin disease in two patients with refractory DM [76]. Due to the potential for short- and long-term complications and the availability of other therapeutic options, total body irradiation generally is not recommended for the treatment of cutaneous DM.
Hematopoietic stem cell transplantation — Hematopoietic stem cell transplantation has been used in the treatment of severe and refractory autoimmune diseases, including DM [77-83]. In a child with juvenile DM, autologous peripheral hematopoietic stem cell transplantation was associated with improvements in muscle disease and the cutaneous manifestations of DM [79]. Resolution of DM-associated calcinosis cutis has also been reported following hematopoietic stem cell transplantation [77]. (See 'Calcinosis cutis' below.)
CALCINOSIS CUTIS — Calcinosis of the skin, soft tissues, muscle, or bone is a challenging complication of DM that is estimated to occur in at least 30 percent of patients with juvenile DM and occasionally develops in patients with adult DM. In juvenile DM, early therapeutic intervention may decrease the incidence or severity of calcinosis [84-90]. (See "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Calcinosis'.)
Cases in which calcinosis responded to diltiazem, low-dose warfarin, probenecid, aluminum hydroxide, alendronate, pamidronate, colchicine, intralesional corticosteroids, intravenous immune globulin, topical and intralesional sodium thiosulfate, or electric shock wave lithotripsy have been reported [84,91-106]. However, none of these therapies have been shown to be consistently effective for calcinosis secondary to DM. (See "Calcinosis cutis: Management".)
Resolution of calcinosis has also been reported in patients receiving treatment for DM with infliximab or hematopoietic stem cell transplantation [62,77,107,108]. Typically, smaller and more recently deposited calcinotic nodules respond more readily than long-standing, large plaques. Surgical excision can be used to remove cutaneous or subcutaneous lesions that are symptomatic and unresponsive to medical therapy [109]. Occasionally, calcinosis cutis regresses spontaneously [106]. (See "Calcinosis cutis: Management".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatomyositis and polymyositis".)
SUMMARY AND RECOMMENDATIONS
●Overview – Dermatomyositis (DM) is an idiopathic inflammatory disorder that is associated with a set of characteristic cutaneous findings. Patients who fail to respond to conventional therapies or who experience recurrence of disease with standard therapies require more aggressive immunosuppressive or immunomodulatory therapies for disease control (algorithm 1). (See 'Approach to refractory disease' above and "Cutaneous dermatomyositis in adults: Overview and initial management".)
●Primary therapies – Data are limited on treatments for refractory cutaneous DM. The limited efficacy data and concerns over drug safety, tolerability, and cost influence the selection of the most appropriate therapy.
For patients with cutaneous manifestations of DM that are refractory to topical therapies, antimalarials, and methotrexate, we suggest treatment with intravenous immune globulin (IVIG) or mycophenolate mofetil (MMF) based on evidence that suggests efficacy and the relative safety of these drugs (Grade 2C). (See 'Primary therapies' above.)
●Other therapies – Limited data suggest that oral Janus kinase (JAK) inhibitors may be beneficial for select patients with refractory cutaneous DM. (See 'Janus kinase inhibitors and traditional immunosuppressants' above.)
Other therapies used for refractory cutaneous DM include immunosuppressive agents (eg, azathioprine, cyclosporine, tacrolimus, cyclophosphamide, chlorambucil, and rituximab), dapsone, and apremilast. A lack of strong evidence in support of these therapies or risks of serious adverse effects associated with many of these therapies generally relegate use to patients who have failed or cannot receive IVIG and MMF. (See 'Other therapies' above.)
●Calcinosis cutis – Calcinosis cutis is a common cutaneous manifestation in patients with juvenile DM. Although a variety of agents have been used for this indication, none have shown consistent benefit. (See 'Calcinosis cutis' above.)
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