Dermatomyositis: current and future treatments

Abstract

Dermatomyositis (DM) is an idiopathic inflammatory myopathy traditionally characterized by a progressive, symmetrical proximal muscle weakness and pathognomonic or characteristic cutaneous manifestations. In some patients with DM, cutaneous disease exists in the absence of objective evidence of muscle inflammation, and these cases are referred to as amyopathic DM. Management of DM begins with careful investigation for the presence of muscle disease or of additional systemic involvement, particularly of the pulmonary, cardiac or gastrointestinal systems, and for the possibility of an accompanying malignancy. The presence of muscle or systemic involvement or the presence of malignancy alters the initial approach to management. Muscle disease and systemic involvement can be refractory and may require multiple sequential therapeutic interventions or, at times, combinations of therapies. In addition, even after these disease components are controlled, the cutaneous disease of DM can be particularly challenging to manage. Although the list of potential therapies for skin disease in DM is long, the number of rigorously conducted randomized, placebo-controlled trials in this area is extremely limited. This article will highlight therapeutic options used for cutaneous disease in DM, while also describing therapies for both muscle and systemic disease.

Keywords::

• amyopathic dermatomyositis
• dermatomyositis
• idiopathic inflammatory myopathies

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and Expert Reviews Ltd. MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. MedscapeCME designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/CME/expertreviews; (4) view/print certificate.

Learning objectives

Upon completion of this activity, participants should be able to:

• • Describe the clinical presentation of dermatomyositis

• • Prescribe effective primary treatments for dermatomyositis

• • Identify first-line oral treatments for dermatomyositis

• • Discriminate between immunomodulatory therapies for dermatomyositis

Financial & competing interests disclosure

CME AUTHOR: Charles P Vega, MD,Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.Disclosure:Charles P Vega has disclosed no relevant financial relationships.

EDITOR: Elisa Manzotti,Editorial Director, Future Science Group.Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

AUTHORS

Ruth Ann Vleugels,Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA.Disclosure:Ruth Ann Vleugels has disclosed no relevant financial relationships. No writing assistance was utilized in the production of this manuscript.

Jeffrey P Callen,Division of Dermatology, University of Louisville School of Medicine, 310 East Broadway Louisville, KY 40202, USA.Disclosure:Jeffrey P Callen has disclosed no relevant financial relationships. No writing assistance was utilized in the production of this manuscript.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy that is a distinct clinical entity with characteristic skin and muscle findings [1,2]. The muscle disease is typically defined by a slowly progressive, symmetrical proximal muscle weakness in the presence of elevated muscle-derived enzymes, an abnormal muscle biopsy, MRI or electromyogram (EMG). Cutaneous disease includes the pathognomonic changes of the heliotrope eruption and Gottron’s papules, as well as characteristic features including photoexposed violaceous erythema, violaceous erythema on the extensor surfaces, malar erythema, nonscarring alopecia with or without scaly poikilodermatous changes and cuticular/periungal changes [3]. Less common cutaneous lesions of DM include mechanic’s hands (hyperkeratosis of the lateral fingers and palms), panniculitis, cutaneous vasculitis, urticaria, a flagellate erythema, follicular hyperkeratosis, erosive or vesicobullous lesions and an exfoliative erythroderma [4]. Calcinosis can also be present, particularly in cases of juvenile DM, a subset of patients defined as typically having disease onset before 16 years of age.

Cutaneous disease in DM is frequently photodistributed and is often photoaggravated. In addition, pruritus may be a prominent feature in DM and may be helpful in clinically distinguishing this entity from lupus erythematosus. Quality of life impairment in DM is greater than in other skin diseases, including both psoriasis and atopic dermatitis, based on its cutaneous manifestations alone [5]. In addition, the cutaneous manifestations are often the component of disease most resistant to therapy. For these reasons, management of cutaneous disease often becomes an essential and challenging component of treating patients with DM.

There are a significant number of patients whose cutaneous findings are the only manifestation of their disease. Amyopathic DM (ADM), historically known as DM siné myositis, refers to the presence of cutaneous manifestations of DM in the absence of objective muscle inflammation (normal strength and normal muscle-derived enzymes) for at least 6 months. By definition, these patients must not have received two consecutive months or more of systemic immunosuppressive therapy in the first 6 months after skin disease onset and must not have received medications known to cause DM-like skin changes [6]. Although ADM presents with cutaneous disease indistinguishable from that of classic DM, it is considered a distinct entity rather than a group of patients in which muscle abnormalities are not yet detectable. In the largest systematic review of adult-onset clinically amyopathic DM, most patients had a normal EMG, muscle biopsy and/or muscle MRI when performed [7]. Using these criteria, 10–20% of patients with DM seen in academic health centers have amyopathic disease [8]. This percentage is as high as 40% when considering patients with DM seen specifically by dermatologists in a referral center [9].

In addition to patients with ADM, there is a potentially larger subset of patients whose muscle disease has been adequately treated with immunosuppressive therapy, yet their cutaneous disease remains active and is often difficult to manage. These patients may be characterized under the name ‘postmyopathic DM’ [10]. Hence, both postmyopathic DM and ADM patients are subsets of patients for whom the dermatologist should be involved as the primary physician managing the patient’s care.

Management of DM

Prior to deciding on a particular course of therapeutic intervention, patients with DM should have thorough evaluations to determine the presence and extent of muscle disease, the presence of other systemic involvement, including cardiac, pulmonary and/or gastrointestinal dysfunction, and the presence of malignancy [11]. Appropriate detection of an underlying malignancy in a newly diagnosed patient with DM is one of the most important therapeutic interventions; however, removal or treatment of an accompanying malignancy will not always result in a remission of the patient’s DM [12].

It is important to note that there are several limitations in assessing the therapeutic approaches to DM. First, there have been very few randomized controlled studies in the treatment of DM. In a Cochrane review article on DM, only four high-quality randomized controlled studies on DM were identified, and none specifically focused on its cutaneous manifestations [13]. Most information regarding therapy for DM in the literature is in the form of retrospective reviews. In addition, the incidence of the inflammatory myopathies is from two to seven per million, making these rare diseases challenging to study in a randomized controlled fashion [14]. In terms of treating the muscular disease specifically, DM was previously often combined in studies with polymyositis as being the same disease with additional skin manifestations. There is now mounting evidence that the pathogenetic mechanisms of polymyositis and DM differ significantly. In polymyositis, clonally expanded autoreactive CD8-positive T cells invade myocytes expressing MHC class I antigens and cause necrosis via the perforin pathway. In DM, autoantigens activate a humoral immune process in which complement is deposited in capillaries causing capillary necrosis and ischemia [11]. This information on the differing pathogenetic mechanisms limits the usefulness of data collected on combined pools of patients with polymyositis and DM.

In terms of treating the cutaneous disease of DM specifically, there are additional limitations in assessing therapeutic approaches. Given the refractory nature of the skin disease, patients are often already on agents for muscle disease at the time of initiation of additional therapies for cutaneous manifestations. Even in those without myositis, patients often have multiple simultaneous therapeutic interventions for their cutaneous disease. Data on true monotherapy, particularly off topical or systemic corticosteroids, is virtually nonexistent. In addition, many reports in the literature include cases of both adult and juvenile DM, as well as cases of both classic DM and ADM, making interpretation of results even more challenging. Finally, until recently there were no validated measures that might be utilized in studies of cutaneous DM.

Despite these challenges and given that the management of cutaneous DM is an essential component, often even a primary component, in disease management and patient quality of life, we will attempt to place particular emphasis in this review on the management of cutaneous disease (Box 1), while also including data on the treatment of myositis.

Therapeutic options for DM

Photoprotection

Given the photoexacerbated nature of the cutaneous disease, year-round daily use of a broad-spectrum sunscreen with a sun-protective factor of at least 30 is recommended [15]. Reapplication of sunscreen should occur every 3–4 h. Studies have demonstrated that both UVB and UVA are involved in the elicitation of certain forms of photosensitive cutaneous lupus erythematosus, and the same concept is thought to apply to DM, although studies are lacking [16]. One study did find that DM patients, similar to those with lupus erythematosus, showed a significantly reduced minimal erythema dose to UVB irradiation compared with healthy individuals [17]. In a study by Cheong et al., lesions of DM with solar-simulated radiation were only able to be reproduced in one out of six patients; however, five out of ten patients indicated that light would exacerbate their existing cutaneous lesions [18].

It should be emphasized to patients that their disease may be worsened by light even in very limited exposures [19]. Also, similar to lupus erythematosus, there have been cases reported involving flares of internal disease following solar irradiation in patients with DM [19]. Therefore, sun-protective clothing and wide-brimmed hats, as well as behavioral modification, should also be encouraged as the cutaneous disease is challenging to control without adequate photoprotection. Given the degree of photoprotection mandated in this patient population, consideration should be given to vitamin D status and possible vitamin D supplementation.

Topical corticosteroids

Topical corticosteroids are often used to reduce the erythema and pruritus associated with the cutaneous lesions of DM [12]. Class I topical corticosteroids are often used to treat the hands, extensor surfaces and scalp, while lower potency agents are often employed for the facial erythema and periorbital eruption. It has been recommended that these agents should be used under occlusion for refractory hyperkeratotic lesions, particularly those on the dorsal hands [10]. Although intralesional therapy is also occasionally used for refractory lesions or for the associated scalp dermatitis, this often is not practical given the extent of cutaneous disease [12].

Topical calcineurin inhibitors

Given the refractory nature of skin lesions in DM, patients are often on multiple therapeutic agents at any given time and studies of monotherapy are lacking. There have, however, been several cases and one pilot study in the literature regarding the efficacy of topical tacrolimus on refractory skin lesions in DM [8,20,21]. All patients were on additional therapeutic agents at the time of initiation of topical tacrolimus. In the pilot study, six patients (five adults and one pediatric patient) were followed for 6–8 weeks after initiation of topical tacrolimus. Two had greater than 90% improvement, one had 40–90% improvement and three had 20–40% improvement during this time period [22]. A side-by-side comparison in a different group of five patients, however, showed a lack of benefit with topical tacrolimus [23]. In another small group of patients with both lupus erythematosus and DM with facial lesions treated with topical tacrolimus, one of the two patients with DM had good response to topical tacrolimus while the other was refractory to this intervention [20]. In summary, topical tacrolimus is a reasonable agent to try for refractory cutaneous lesions of DM. Although there are no published reports on pimecrolimus, we have observed some limited success in patients using this cream.

Antipruritics

Pruritus can be a feature of disease that helps distinguish DM from lupus erythematosus. In fact, pruritus, in particular scalp pruritus, can be the initial presenting symptom in DM. Pruritus can interfere with sleep patterns and overall quality of life and should therefore be treated accordingly. Topical agents used for symptomatic relief include menthol, camphor, antihistamines, pramoxine and lidocaine [10]. Often more useful is the addition of oral antihistamines (hydroxyzine or doxepin), amitriptyline or other agents that can improve pruritus and overall quality of life.

Antimalarials

Since the 1950s, antimalarials have been reported to be of benefit in the cutaneous disease associated with DM. Initially, mepacrine was used, but given the risk of diplopia, a shift was made to the use of other antimalarials. Chloroquine medications have been reported to be effective as first-line therapy in the treatment of the cutaneous manifestations of DM [24].

Hydroxychloroquine in doses of 200–400 mg/day is effective in up to 75% of patients in partially controlling the cutaneous disease and allowing a decrease in the corticosteroid dosage. In an open study of seven patients with cutaneous lesions of DM that had not responded to topical therapy, the addition of hydroxychloroquine resulted in improvement in all of the patients, with total resolution of skin lesions in three patients and tapering of corticosteroid dosage in two patients [25]. Of note, therapy with hydroxychloroquine does not appear to have any beneficial effect on the myositis. The lack of effect of hydroxychloroquine on muscle disease suggests that the beneficial effects of this medication on the skin may be a result of photoprotection rather than systemic immunomodulation, or that the pathogenetic mechanisms differ in the skin and muscle disease, a concept that has been supported in a study published by Dalakas and Hohlfeld in 2003 [11,12].

Additional small studies demonstrated similar favorable results with hydroxychloroquine used for cutaneous disease in adult patients, including those with ADM, and in pediatric patients with DM [26–29]. In a pediatric study, however, three out of nine patients developed ocular side effects that mandated discontinuation of hydroxychloroquine [29]. In addition, one report has indicated worsening of rash in two children with DM after the initiation of hydroxychloroquine [30].

It appears that patients with DM have a greater potential to develop morbilliform drug reactions with hydroxychloroquine, and a pretreatment warning is helpful [31]. In addition, counseling regarding smoking cessation is essential as the efficacy of hydroxychloroquine appears to be reduced in patients who smoke.

Patients who do not respond well or fully to hydroxychloroquine can be switched to chloroquine therapy, 250–500 mg/day, or they can receive quinacrine 100 mg twice daily in addition. Chloroquine is used more frequently than hydroxychloroquine in Europe given possible increased efficacy. It does, however, carry an increased risk of irreversible retinopathy and is therefore used less frequently than hydroxychloroquine in the USA.

Quinacrine may be added on to either hydroxychloroquine or chloroquine given that it lacks ocular toxicity. It may not be available in all locations, however, and can only be obtained at special compounding pharmacies. One report by Ang and Werth supported the synergistic effect of combination antimalarials [32]. In this retrospective case series, seven out of 17 patients experienced at least near clearance in cutaneous symptoms with the use of antimalarial therapy alone (four required combination therapy of hydroxychloroquine–quinacrine or chloroquine–quinacrine, while three responded well to antimalarial monotherapy). This study suggested that a significant subgroup of patients may benefit from combination antimalarial therapy when monotherapy with an antimalarial has been ineffective. Of note, quinacrine can cause gastrointestinal upset as well as a reversible yellow discoloration to the skin that can be bothersome to patients.

The usual precautions regarding antimalarial therapy should be taken, including a careful ophthalmologic examination within several months of initiation of therapy and annually thereafter in follow-up [201]. Patients on quinacrine should undergo blood count monitoring given the risk, albeit rare, of aplastic anemia.

Corticosteroids

The mainstay of initial therapy for the myositis in DM is the use of systemic corticosteroids. Traditionally, prednisone is given in a dose of 0.5–1.5 mg/kg/day (maximum daily dose of 60 mg) as the initial therapy [33]. The treatment should continue for at least 1 month and until after the myositis has become clinically and enzymatically inactive. At this point, the dose is slowly tapered, generally over a period lasting 1.5–2-times as long as the period of active treatment.

However, aggressive corticosteroid therapy is not warranted in patients without clinical evidence of myositis. In our experience, systemic corticosteroids have varying degrees of efficacy for the skin lesions of DM with only a few patients having excellent responses at doses that do not cause toxicity. In addition, we have observed many patients on toxic doses of systemic corticosteroids without any apparent effect on their cutaneous disease or its associated symptoms. Therefore, treatment for amyopathic and postmyopathic DM can differ significantly from that of classic DM. Systemic corticosteroids are sometimes used for the initial treatment of the cutaneous manifestations of DM. However, given the many side effects of systemic corticosteroids as well as the refractory nature of the skin lesions in DM, systemic corticosteroids are not considered the mainstay in therapy for cutaneous disease.

There have been no randomized controlled studies comparing the use of various corticosteroid doses and taper rates and no controlled long-term studies assessing the hypothesis that, unlike systemic lupus erythematosus, patients with DM can often achieve long-term remission off therapy [14].

Methotrexate

Approximately 25–30% of patients with DM have muscle disease that will not respond to systemic corticosteroids or develop significant steroid-related side effects. In these patients, other immunosuppressive agents may be an effective means of inducing or maintaining a remission.

Methotrexate can be used on a weekly basis, given either orally or intravenously. It is traditionally administered in an empiric dose of 25–50 mg/week for the myositis of DM. The drug usually becomes effective within 4–8 weeks and therefore is not recommended for rapid control of a fulminant disease process.

Retrospective reviews and open-label studies support the usefulness of methotrexate in doses between 10 and 40 mg/week for the skin disease of DM. In a review of 22 patients treated with combined methotrexate and systemic corticosteroid therapy, 17 patients improved on methotrexate resulting in lowering of systemic corticosteroid dose [34]. Another review of 13 patients with skin disease and little-to-no muscle involvement treated with methotrexate 2.5–30 mg weekly for refractory cutaneous DM demonstrated complete clearance in four patients, near complete clearance in four patients and moderate clearance in all of the remaining patients. In addition, reduction and/or discontinuation of other therapies was enabled [35]. Another study demonstrated benefit in juvenile DM with the prevention of calcinosis formation. In this study, 12 pediatric patients with severe disease were treated with intravenous methylprednisolone and methotrexate. None of the six patients treated within 6 weeks of diagnosis developed calcinosis, whereas two out of the six patients treated over 5 months after diagnosis developed calcinosis [36].

Despite these positive reports, adverse effects including both liver and pulmonary toxicity must be considered. In one retrospective study by Zieglschmid-Adams et al., ten patients with DM (seven with classic DM and three with ADM) were treated with methotrexate (nine orally and one intravenously). Improvement of cutaneous disease occurred in seven (100%) of the patients with classic DM and in two (66%) of those with ADM, while myositis improved in four (57%) out of the seven patients with muscle disease. Systemic corticosteroid doses were able to be tapered effectively. Despite these promising results, methotrexate-related side effects occurred in six of the patients with classic DM and in one of the patients with ADM. Two of the four patients that had liver biopsies demonstrated mild hepatic fibrosis, resulting in discontinuation of methotrexate. Of note, both patients in whom fibrosis developed had pre-existing steroid-induced diabetes mellitus [37].

Overall, methotrexate is often considered first-line as a steroid-sparing agent in patients with DM. Both the myositis and cutaneous disease have demonstrated response to methotrexate although careful patient selection and monitoring for side effects is essential.

Azathioprine

Azathioprine has been used for the myositis of DM in a double-blind controlled trial with prednisone versus a group with prednisone and placebo. In a short-term analysis of 3 months, there were no differences between these two groups. However, in the open follow-up study 3 years later, a significantly lower steroid dosage was needed and significantly greater muscle strength was found in the patients who had been treated with azathioprine [38]. Azathioprine is administered orally in a dosage of 1–2 mg/kg/day depending on results of thiopurine methyl transferase testing in order to achieve efficacy yet avoid bone marrow suppression. There are data to show, however, that the myositis of DM may respond better to methotrexate than azathioprine [39]. Experience with azathioprine and skin disease is anecdotal, but suggests that some patients have cutaneous disease that responds to azathioprine and results in steroid-sparing.

Mycophenolate mofetil

Mycophenolate mofetil has been shown to be an effective therapeutic option for control of myositis in idiopathic inflammatory myopathy [40]. Retrospective reviews and open-label studies also support the usefulness of mycophenolate mofetil for the skin disease of DM [41–43]. One series of four cases demonstrated improvement of cutaneous lesions in four patients with refractory skin disease that had failed to respond to corticosteroids, hydroxychloroquine and/or methotrexate [42]. Another open-label retrospective review of the effectiveness of oral mycophenolate mofetil in patients with cutaneous lesions of DM recalcitrant to other therapies found improvement in ten out of 12 patients at doses of 500 mg–1 g twice daily. Most patients tolerated mycophenolate mofetil without side effects; however, one patient developed a B-cell lymphoma of the CNS and another developed elevated hepatic enzymes and urinary symptoms. Resolution of these side effects occurred with cessation of mycophenolate mofetil in both cases [43].

Cyclosporine

Several studies have supported the use of cyclosporine in both adults and children as a steroid-sparing agent to control either muscle disease or lung disease in DM [44–50]. In terms of its use for pulmonary disease, it has been shown that it should be considered for rapidly progressive interstitial lung disease (ILD). Once patients have developed respiratory failure, however, cyclosporine is ineffective [51,52]. In terms of its use in skin disease with DM, there are also reports of refractory skin necrosis responding to cyclosporine [53]. Other than this, however, data to support the use of cyclosporine as an adjunctive therapy for the cutaneous manifestations of DM are limited.

Tacrolimus

Oral tacrolimus (FK-506) has been reported to show benefit in the treatment of refractory ILD associated with DM and polymyositis [54–56]. In these reports, the patients had progressive disease despite conventional therapies including high-dose corticosteroids, cyclosporine, pulse cyclophosphamide and/or other agents, yet improved with oral tacrolimus. In the largest series of 13 patients with anti-aminoacyl-transfer RNA synthetase-associated ILD and idiopathic inflammatory myopathy treated with oral tacrolimus, all had improvement of pulmonary disease parameters and ten had improvement in muscle disease [56]. No data were reported on the effect of oral tacrolimus on skin disease in this series. Other cases have also reported improvement of refractory myositis in DM using oral tacrolimus after other agents failed [55,57].

Several cases have demonstrated improvement of cutaneous disease in children with refractory juvenile DM with oral tacrolimus [58–60]. Some of these children also had improvement in muscle disease whereas others did not.

Cyclophosphamide

Cyclophosphamide is used particularly for lung disease associated with DM, including rapidly progressive ILD [61–64]. There has been one case of refractory DM with cutaneous vasculitis resulting in ulcers that responded completely to repeated intravenous cyclophosphamide pulse therapy without high-dose corticosteroid therapy. No adverse effects were noted and repeat biopsy following treatment confirmed complete remission of vasculitis [65].

Chlorambucil

Several case reports have demonstrated the benefit of chlorambucil on muscle disease when used in conjunction with other agents [66–68]. There was, however, limited improvement in skin disease noted in these reports.

Dapsone

Case reports and a small series of patients with refractory cutaneous DM have shown response to oral dapsone therapy [69,70]. In the series, two patients with cutaneous DM unresponsive to combination therapy with prednisone, hydroxychloroquine, quinacrine and immunosuppressive medications had rapid improvement in skin lesions after the addition of dapsone to their therapeutic regimen. In addition, both demonstrated flaring of their cutaneous disease after discontinuation of dapsone and subsequent improvement after reinitiation of dapsone [70].

Thalidomide

Anecdotally, thalidomide has been helpful in the treatment of refractory cutaneous DM [71]. There is also a case of drug-induced cutaneous DM treated with initial success with thalidomide in the literature; however, no long-term follow-up is given in this case [72].

Adjuvant leflunomide

Several cases have reported benefit from leflunomide on the inflammatory myopathy associated with polymyositis or DM [73,74]. More recently, a case series demonstrated improvement in the cutaneous manifestations of DM with adjuvant leflunomide in three patients refractory to other systemic therapies [75].

Anti-TNF-α medications

There are numerous case reports demonstrating benefits from anti-TNF-α medications in both adult and pediatric cases of DM [76–85]. Several of these cases indicate improvement in cutaneous disease as well as muscle disease [77,83,84]. In one particular report, a patient had failed therapy with prednisone, methotrexate, mycophenolate mofetil and hydroxychloroquine, but eventually demonstrated improvement of cutaneous and muscular disease on combination therapy with methotrexate and etanercept. The patient then had continued disease remission off methotrexate and on etanercept alone for at least 6 months duration [77].

Despite these reports, a pilot study of infliximab for patients with refractory inflammatory myopathies demonstrated radiological and clinical worsening of muscle disease and activation of the type I interferon system in several cases [86]. In addition, a series of patients treated with etanercept all had exacerbation of muscle disease [87].

Some reports have even indicated the initiation of DM-like cutaneous eruptions on anti-TNF medications [88]. There has also been a report of DM with muscular, pulmonary and mild cutaneous changes occurring in a patient being treated with etanercept for seronegative rheumatoid arthritis [89].

Efalizumab

Prior to being removed from the market in the spring of 2009 for a potential increased risk of the demyelinating disease progressive multifocal leukoencephalopathy, efalizumab had shown promise in at least one case report of refractory DM [90]. After failing to improve on methotrexate and prednisolone, the patient in this case had improved skin disease after being started on efalizumab 1 mg/kg/week combined with prednisolone 40 mg/day. The patient was also started on azathioprine 50 mg/day after 1 month of therapy, along with a dose increase of efalizumab to 1.8 mg/kg/week. At 1 year of follow-up, this patient was still doing well clinically.

Rituximab

Many case reports have shown improvement in the muscle, pulmonary, cardiac and/or skin manifestations of DM with rituximab [91–97]. One case demonstrated remission of both skin and muscle disease for over 4 years [97]. A series of three patients with adequate control of muscle disease on other agents utilized rituximab specifically for worsening cutaneous disease [98]. All three patients had improved cutaneous DM following rituximab, with the heliotrope eruption and violaceous poikiloderma being the cutaneous changes demonstrating the best response.

In an open-pilot study of six patients with DM treated with rituximab, patients had increased muscle strength, decreased muscle enzymes, improved forced vital capacity in three patients with pulmonary disease and improved cutaneous disease in all patients, including hair regrowth in two patients with alopecia [99]. Despite these results, the largest open trial to date of rituximab for DM demonstrated modest improvement of muscle disease but limited effects on cutaneous disease [18]. In this trial of eight patients, three patients achieved partial remission at week 24, defined by a reduction in muscle deficit of at least 50%. Despite achieving sustained depletion of peripheral B cells, muscle enzyme levels and skin scores using the DM Skin Severity Index at week 24 were not significantly changed from those at baseline.

Another eight patients with presumed idiopathic inflammatory myopathy were also treated with rituximab, five in an open-label trial and three based on perceived medical need [100]. Although re-evaluation of the patients demonstrated that not all had polymyositis or DM, an interesting subset of two patients with Jo-1 antibody-positive DM both demonstrated greater than 30% improvement in creatine kinase (CK) along with improved clinical response. One of the patients had a normalized CK for 10 months, while the other had both normalized CK and stable pulmonary function tests for 36 months. Although Jo-1 antibody levels fell modestly in both patients, they remained detectable. In a retrospective review of four pediatric cases treated with rituximab, three patients, including one with positive myositis-specific antibody Mi-2 and two without positive myositis antibodies, improved following rituximab while one patient worsened [101]. We await the results of a randomized, placebo-controlled national trial of Rituximab for Inflammatory Myopathy (RIM).

Intravenous immunoglobulin

There are many cases of muscle disease in idiopathic inflammatory myositis responding to intravenous immunoglobulin (IVIg) [102–105]. One retrospective study indicated that patients treated with prednisone and cyclosporine, plus IVIg have an improved remission rate compared with patients treated with prednisone and cyclosporine alone [106]. Another retrospective study showed that IVIg is a safe and effective steroid-sparing agent as add-on treatment with mycophenolate mofetil for severe and refractory myositis [107]. A small series highlighted potential efficacy in lung disease, with benefit in two out of five patients [108]. Several reports have also demonstrated benefit in cases of juvenile DM [102,109,110].

With specific regard to skin disease, there has been a case described of cutaneous disease in an adult refractory to prednisone, methotrexate and hydroxychloroquine who responded to IVIg, with the formation of new cutaneous ulcerations ceasing 1–2 weeks after initiation of IVIg therapy [111]. In addition, it has been reported that patients with ADM may respond to one-tenth of the usual dose of IVIg [112].

Notably, high-dose IVIg has been tested in a randomized, placebo-controlled clinical trial [113]. A total of 15 patients were given an infusion of 2 g/kg of IVIg or placebo for 3 months with the option of crossover for an additional 3 months. After crossovers, nine out of 12 patients who received IVIg had major improvement with near return to normal function. Of the 11 patients receiving placebo, none had major improvement, three had mild improvement, three had no change and five had disease worsening. In addition to the myositis, skin disease also responded in patients in the treatment group. Some data has shown, however, that IVIg must be continued for longer-term effects given that the improvement of strength from IVIg usually lasts no longer than 4–8 weeks [114]. Although ongoing therapy is often beneficial, this can be a challenge given the high expense of this particular therapy.

Despite the favorable results of these case reports and single randomized controlled trial on IVIg in DM, a study of high-dose IVIg on molecular expression in muscle tissue of patients with inflammatory myopathies demonstrated limited benefit [115]. Of the 13 participants with treatment-resistant inflammatory myopathy in this study, four had DM and one had juvenile DM. Three patients had dramatic improvement in skin disease with IVIg. In terms of muscle disease, however, only three of the 13 patients improved by greater than 20% on the Functional Index (FI) in myositis score. Therefore, clinical improvement based on FI score was limited although statistically significant. Serum CK levels decreased significantly in five out of the 13 patients. Despite clinical improvement and decreased CK levels in some patients, there was no significant improvement of inflammation in muscle tissue based on numbers of T cells or macrophages, expression of MHC class I and II antigen on muscle fibers or endothelial cell activation. These results prompted the study’s authors to question the role of high-dose IVIg as an immune-modulating therapy for the idiopathic inflammatory myopathies [115].

Plasmapheresis & leukapheresis

A placebo-controlled study showed no benefit from plasmapheresis in DM [116]. In this controlled trial, despite significant reductions in the serum levels of muscle enzymes with plasma exchange, there were no significant differences in the final muscle strength or functional capacity of the patient groups. This study also demonstrated no benefit from leukapheresis. The conclusions of this study emphasized that plasma exchange and leukapheresis were no more effective for corticosteroid-resistant DM than sham apheresis.

In addition, another study indicated that plasmapheresis did not offer any advantage to patients being treated with other immunosuppressive medications [106]. In this study, the main finding was that patients receiving prednisone and cyclosporine, plus IVIg had a significantly higher probability of maintaining complete remission at the end of a 4-year follow-up period than those treated with prednisone and cyclosporine alone. They also found, however, that there was no additional benefit seen with the addition of plasma exchange in these patients. In summary, plasmapheresis is considered to be ineffective for both the myositis and cutaneous disease in DM.

Antiestrogen medications

Tamoxifen and anastrazole are antiestrogen medications that have been shown to improve the skin eruptions in two patients with DM. In one of the two patients, the rash worsened after discontinuation of tamoxifen. Tamoxifen has been found to have anti-TNF-α properties, and this was one mechanism postulated whereby this benefit may occur [117].

Total body irradiation

Two patients with DM refractory to traditional therapy were treated with 150 rad of total body irradiation over a period of 5 weeks [118]. Both had rapid improvement with minimal side effects and remained in remission at 18 and 42 months after treatment. Both cases also mention improved cutaneous aspects of disease.

Sirolimus

A case report of the first use of sirolimus (rapamycin) in a patient with DM demonstrated improved cutaneous and muscle disease within 4 weeks of treatment [119]. The patient’s prednisone dose was able to be successfully tapered. After 3 months, sirolimus was discontinued because of hypertriglyceridemia; however, even 4 months later the patient did not have worsening of skin or muscular disease. Another case has since demonstrated benefit in using a combination of rituximab and sirolimus to not only treat a case of post-transplant lymphoproliferative disorder, but also to maintain DM remission in the same patient [95].

Stem cell transplantation

There are increasing reports in the literature of the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe and refractory autoimmune diseases, including DM [120–125]. Several cases have demonstrated improvement in refractory interstitial lung disease after HSCT [123,125]. A case of refractory juvenile DM treated with HSCT has also been reported with improvement of both skin and muscle disease in a preschool-aged child [124].

Although there are no pooled data specific to patients with DM, there are compiled data for HSCT for autoimmune diseases. These data indicate a long-lasting improvement off of immunosuppression in approximately half of the patients who underwent HSCT for a severe and progressive autoimmune disease [120]. In addition, mortality related to HSCT has decreased in the past 5 years secondary to less intensive conditioning regimens as well as better initial patient selection. Autologous HSCT is preferred over allogenic HSCT given the increased morbidity and mortality associated with allogenic transplants [120].

Therapy for calcinosis

Although calcinosis will occasionally regress without therapy, DM patients with established calcinosis often require more than supportive therapy. Various therapies have been tried, including low-dose warfarin, colchicine, probenecid, diltiazem, aluminum hydroxide, alendronate, intravenous methylprednisolone and surgical excision [126–136]. Infliximab also showed benefit in some patients with juvenile DM and calcinosis in one study [82]. Despite IVIg showing benefit in cases of calcinosis associated with connective tissue disease, one report describes two patients with DM and progressive, extensive calcification despite several years of IVIg therapy [137].

Cutaneous calcinosis can be particularly problematic in children with DM and affects 29–70% of juvenile DM patients [138–140]. Aggressive and early therapy does seem to decrease the risk of development of calcinosis in children [36,135,140–144]. In addition, this early aggressive therapy is often warranted given that another retrospective study demonstrated improved outcomes and sustained remission of disease in children treated with this approach [145].

Exercise & rehabilitation

Although this review focuses on the treatments for cutaneous disease, the role of exercise and rehabilitation in the therapeutic regimen for patients with DM is significant. It is known that even in patients responding to pharmacologic interventions for muscle disease, a majority develop sustained disability [146]. Studies demonstrate that patients with inflammatory myopathy who participate in exercise and rehabilitation programs tolerate intensive resistance training, report reduced disease activity and have improved muscle strength and endurance [146–153]. Importantly, benefits have been demonstrated even in the course of active disease and have not been shown to induce disease flares [151]. In a study of children with juvenile DM, muscle inflammation did not increase after a single bout of exercise, suggesting that a moderate exercise program is also safe for children with juvenile DM [154].

Conclusion

Despite both the limitations in assessing the various therapies used to treat DM, as well as the challenges in treating the often refractory cutaneous disease, dermatologists have a significant role to play in treating this patient population and improving their overall quality of life. Although the incidence of DM is low, randomized controlled trials are needed to better assess the effectiveness of our therapeutic interventions. Regardless, therapeutic selection should be made only after careful consideration of a patient’s comorbidities, disease severity, presence of systemic involvement and search for a potentially associated malignancy.

Expert commentary

Our approach to caring for patients with DM emphasizes a rigorous investigation for malignancy, which should occur annually for at least 3 years. In addition, thorough evaluation for muscle disease and/or systemic involvement dictates our initial therapy, and the presence of either of these entities traditionally mandates high-dose systemic corticosteroids. Our steroid-sparing agent of choice is usually methotrexate, followed by mycophenolate mofetil. We have also had success with IVIg. Pilot studies indicate that the benefit of rituximab for skin disease is modest in many patients, and we await the results of the multicenter NIH-sponsored RIM, which has recently finished enrollment. All patients with muscle disease should have counseling regarding exercise programs, usually with the aide of a physical therapist.

In our experience, patients with poor prognostic features should be treated earlier with more aggressive therapy. Patients can have lasting remissions of their muscle and/or systemic disease if the initial therapy is aggressive. In addition, therapy should then be tapered slowly with prompt and complete suppression of any relapses.

Cutaneous disease in DM is often more refractory than the muscle disease and can become the most challenging component to manage effectively. With specific respect to cutaneous disease, we strongly emphasize to patients that exacerbation of skin disease often occurs with even modest sun exposure. Counseling includes behavior modification, wide-brimmed hats, sun-protective clothing and daily broad-spectrum sunscreen with sun-protective factor 50 or greater applied even on days spent indoors and reapplied regularly. We also treat patients’ pruritus, particularly scalp pruritus, aggressively given its impact on our patients’ quality of life.

Topical corticosteroids and occasionally topical calcineurin inhibitors are helpful for the skin disease of DM. Hydroxychloroquine is our first-line agent for cutaneous disease refractory to sun-protective measures and topical agents. We do counsel patients on smoking cessation. Our experience prompts discontinuation of hydroxychloroquine if a morbilliform eruption ensues given that the patient’s skin disease may koebnerize as a result. If hydroxychloroquine results in an inadequate response, we would typically add methotrexate as a next step. Other add-on therapeutic options that we often use include mycophenolate mofetil, IVIg and thalidomide, among others.

We would also like to emphasize our multidisciplinary approach to caring for patients with DM. Patients should be followed by an internist comfortable monitoring them for malignancy and systemic disease. We frequently collaborate with rheumatologists, neurologists and pulmonologists with regard to our patients’ muscle and systemic disease. Patients with juvenile DM also need to be followed by a pediatrician to monitor them for age-appropriate developmental milestones while on immunosuppressive therapy.

Five-year view

Although DM is a rare disease, it is essential that well-designed multicenter randomized, appropriately controlled clinical trials on therapeutic options be performed in the future. Several such trials are underway according to our search of ClinicalTrials.gov, including studies of rituximab, infliximab, methimazole, methotrexate, tacrolimus, etanercept, a monoclonal antibody directed against the fifth component of complement, and a product only known as MEDI-545 at present. Unfortunately, it is not clear that these studies are using validated measures to assess the skin disease in DM. In the next several years, there will be numerous immunosuppressive agents designed and approved to treat other systemic diseases that will potentially be investigated in DM. Our ability to perform these investigations in a rigorous fashion will benefit our understanding of the disease as well as the care of our patients. In addition, novel autoantibodies are being developed that will ideally allow clinicians to better predict which patients may or may not develop muscle disease or malignancy associated with their DM.

Box 1. Therapeutic ladder for cutaneous disease in dermatomyositis.

First line

Photoprotection including sunscreens

Topical corticosteroids

Topical tacrolimus

Antimalarials

Combination antimalarials (hydroxychloroquine or chloroquine plus quinacrine)

Second line

Methotrexate

Mycophenolate mofetil

Intravenous immunoglobulin

Third line

Dapsone

Thalidomide

Retinoids

Rituximab

Key issues

• • Cutaneous disease in dermatomyositis is often resistant to therapy.

• • Dermatologists have a unique role in caring for patients with skin disease in the absence of systemic and/or muscle involvement.

• • Screening patients with cutaneous dermatomyositis for the presence of muscle disease, systemic involvement and malignancy is critical.

• • Patients with dermatomyositis often require multiple therapeutic interventions for their cutaneous disease.

• • Most data regarding therapy for cutaneous dermatomyositis are in the form of retrospective reviews of small case series.

• • Emerging therapies for dermatomyositis are being reported in the literature, but randomized controlled trials are needed to better assess the effectiveness of these therapeutic interventions.

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Dermatomyositis: current & future treatments

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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1. Which of the following statements about the clinical presentation of dermatomyositis is most accurate?

• □ A Panniculitis is always part of the presenting symptom complex

• □ B Cutaneous disease is often photodistributed

• □ C Amyopathic dermatomyositis accounts for less than 0.01% of cases in academic centers

• □ D Cutaneous manifestations of dermatomyositis are the easiest element of the disease to treat

2. Which of the following statements about first-line treatment for dermatomyositis is most accurate?

• □ A Sunscreen should be applied at least twice daily

• □ B Intralesional corticosteroid therapy is preferred to topical corticosteroid therapy

• □ C Oral antihistamines have no role in therapy

• □ D Aggressive and early therapy can reduce the risk for calcinosis in children

3. Which of the following medications is considered first-line treatment for topical disease in dermatomyositis?

• □ A Combination antimalarials

• □ B Methotrexate

• □ C Retinoids

• □ D Mycophenolate mofetil

4. Which of the following statements about immunomodulating medications in the treatment of dermatomyositis is most accurate?

• □ A Aggressive oral corticosteroid therapy should be continued among patients without myositis but with persistent cutaneous lesions

• □ B There is more evidence that azathioprine is effective for cutaneous versus muscle disease

• □ C Anti-TNF-α has a poor record of efficacy in clinical trials and has been associated with dermatomyositis-like cutaneous eruptions

• □ D There is no evidence of the clinical efficacy of intravenous immunoglobulin for dermatomyositis