Dermatomyositis

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Dermatomyositis

Ruth Ann Vleugels and Jeffrey P. Callen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies characterized by cutaneous disease, including a heliotrope eruption, Gottron papules, a violaceous erythema on extensor surfaces in a photodistribution pattern, and/or periungual changes. Patients with cutaneous lesions of DM often have weakness of the proximal muscles, elevated enzymes such as creatine kinase or aldolase, or abnormal electromyograms or muscle biopsy findings. Some, however, have cutaneous disease that either precedes the onset of demonstrable muscle disease or occurs in its absence. In addition, many patients have persistent cutaneous manifestations long after their muscle disease is adequately controlled. DM in children and adolescents may be complicated by calcinosis, particularly when treatment is delayed. Adults with DM have a greater risk of having or developing a malignancy, usually within the first 3 years following diagnosis.

Management strategy

Prior to treatment the patient should be thoroughly evaluated to assess the severity of the disease, the presence of systemic involvement such as pulmonary, cardiac, or gastrointestinal involvement, and the presence of malignancy.

The goal of management is to reverse the weakness and allow the patient to return to normal functional status. The prevention of contractures is also a consideration, and the prevention or treatment of calcinosis is usually an issue in the management of children and adolescents, but may occur rarely in adults as well. Patients with cutaneous disease are troubled by intense pruritus and the appearance of their skin, and therefore request management even when the muscle disease has been effectively treated or is absent.

For the myopathy, systemic corticosteroids with or without an immunosuppressive agent are the standard treatment. Most patients respond to these agents, but for those who do not, high-dose intravenous immunoglobulin may be of benefit. Patients with cutaneous disease are photosensitive and are treated with sunscreens and behavior modification, topical corticosteroids, and occasionally topical calcineurin inhibitors, oral antimalarials, and often an oral immunosuppressant. High-dose intravenous immunoglobulin may also be used for recalcitrant cutaneous disease. Ultimately, the therapeutic goal is to provide patient relief from the cutaneous inflammation and associated symptoms utilizing a combination of topical and/or systemic medications selected after considering a patient’s comorbidities.

One of the problems with many of the reports published to date regarding therapeutic options for cutaneous DM is the lack of the use of a validated measure of activity to assess the activity of skin disease and response to therapy. To this end there are three measures that have recently been developed: the Dermatomyositis Skin Severity Index (DSSI) (Br J Dermatol 2008; 158: 345–350), the Cutaneous Dermatomyositis Area and Severity Index (CDASI) (Arch Dermatol Res 2008; 300: 3–9, and Br J Dermatol 2012; 162: 669–673), and a cutaneous assessment tool in juvenile dermatomyositis (Arthritis Rheum 2008; 59: 352–356). Unfortunately, none of these measures is routinely used in studies investigating therapeutic interventions for DM; however, the tools are being utilized more frequently and will ideally become incorporated as standard practice in the future as a means to assess cutaneous disease response.

Specific investigations

The value of malignancy evaluation in patients with dermatomyositis.

Callen JP. J Am Acad Dermatol 1982; 6: 253–9.

DM has been linked to internal malignancy in adults, but the value of an extensive malignancy evaluation in patients with DM is controversial. Fifty-seven patients who had DM with malignancies for whom data were available regarding the discovery of malignancy have been analyzed: 53 of these were reported previously. There were 67 malignancies in the 57 patients. The malignancy preceded (26 cases), followed (23 cases), or occurred with the DM (18 cases). A ‘blind’ (non-directed) malignancy search was not of value in any of the cases analyzed. Rather, the tumors were discovered in 40 cases by history (preceding tumor or abnormal symptoms), in 14 cases by physical examination, and in 12 cases by abnormal laboratory findings (e.g., chest radiograph, urinalysis, stool guaiac). One case was not discovered until autopsy (adenocarcinoma of the broad ligament). Analysis of tumor sites further negates the value of a malignancy work-up because most tumors (>90%) occur in areas not amenable to a ‘routine malignancy search.’ In several instances patients had an extensive search without having a complete physical examination.

Malignancy evaluations should be directed by abnormalities found on history, physical findings, or routine laboratory testing. However, since this paper was published, new, less invasive methods of malignancy search have been developed, and therefore the initial search should include CT scans of the chest, abdomen, and pelvis in most patients, and these scans should be repeated annually for at least 3 years. Malignancy screening should also include annual physical examinations.

A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.

Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. Medicine (Baltimore) 1991; 70: 360–74.

This study compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-signal recognition particle [anti-SRP], anti-Mi-2, and anti-MAS) to the standard clinical categories (polymyositis, DM, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms and prognosis in 212 adult patients. Compared to those without these antibodies, patients with anti-aminoacyl-tRNA synthetase autoantibodies (n = 47) had significantly more frequent arthritis, fever, interstitial lung disease, and ‘mechanic’s hands’; higher mean prednisone dose at survey; higher proportion of patients receiving cytotoxic drugs; and higher death rates. Those with anti-SRP antibodies (n = 7) had more frequent palpitations, myalgias, severe refractory disease, and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased ‘V-sign’ and ‘shawl-sign’ rashes and cuticular overgrowth, as well as a good response to therapy. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis.

These antibodies are less common in patients with DM than in patients with polymyositis, and currently only the anti-amino-acyl-tRNA synthetase autoantibodies are frequently incorporated into clinical practice.

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, Matsushita T, et al. Arch Dermatol 2011; 147: 391–8.

In this study of 376 adult Japanese patients with DM, anti-CADM-140 autoantibodies were associated with clinically amyopathic DM and rapidly progressive interstitial lung disease, whereas anti-155/140 autoantibodies were associated with malignancy. Anti-Mi-2 autoantibodies were associated with classical DM without either malignancy or pulmonary disease. The authors note that these autoantibodies define distinct clinical subsets and therefore are useful in predicting patient outcomes in DM.

The anti-CADM-140 and anti-155/140 autoantibodies are considered investigational at present and are not routinely available in commercial laboratories. They may, however, alter the screening practices for patients with DM in the future.

First-line therapies

For cutaneous disease
imageSunscreens E
imageTopical corticosteroids E
imageAntimalarials – hydroxychloroquine or chloroquine D
imageCombination antimalarial therapy E
For muscle disease
imageSystemic corticosteroids B
imageImmunosuppressive agents – methotrexate, azathioprine A

image

Combination antimalarials in the treatment of cutaneous dermatomyositis: a retrospective study.

Ang GC, Werth VP. Arch Dermatol 2005; 141: 855–9.

In this retrospective analysis, seven of 17 patients experienced at least near clearance of cutaneous symptoms with the use of antimalarial therapy alone: four of them required combination therapy (hydroxychloroquine sulfate 200 mg once or twice daily + quinacrine hydrochloride 100 mg daily; or chloroquine phosphate 250 mg daily + quinacrine 100 mg daily), and three of them responded well to antimalarial monotherapy. The median time required to efficacy was 3 months.

When considering combination antimalarial agents as a therapeutic option, it is critical to use quinacrine in addition to either hydroxychloroquine or chloroquine given that quinacrine lacks ocular toxicity. Hydroxychloroquine and chloroquine both have ocular toxicity and should not be given concurrently.

Second-line therapies

For cutaneous disease
imageTopical calcineurin inhibitors (tacrolimus or pimecrolimus) D
imageMethotrexate D
imageMycophenolate mofetil D
imageIntravenous immunoglobulin A
For muscle disease
imageOther immunosuppressive agents – cyclophosphamide, chlorambucil, mycophenolate mofetil, cyclosporine, tacrolimus D
imageIntravenous immunoglobulin A
imageRituximab A

image

Low-dose methotrexate administered weekly is an effective corticosteroid-sparing agent for the treatment of the cutaneous manifestations of dermatomyositis.

Kasteler JS, Callen JP. J Am Acad Dermatol 1997; 36: 67–71.

The records of 13 patients who received oral methotrexate in doses ranging from 2.5 to 30 mg weekly were reviewed. Their skin lesions had not been completely responsive to sunscreens, topical corticosteroids, oral prednisone, oral antimalarial therapy, or, in one patient each, chlorambucil and azathioprine. Four of these 13 patients had complete clearance of cutaneous manifestations, and another four had almost complete clearance. In the remaining five patients, methotrexate induced moderate clearing of their cutaneous lesions. In all patients, the addition of methotrexate allowed a reduction in or discontinuation of other therapies, including prednisone.

Mycophenolate mofetil in dermatomyositis: is it safe?

Rowin J, Amato AA, Deisher N, Cursio J, Meriggioli MN. Neurology 2006; 66: 1245–7.

These two open-label studies suggest that in 60–75% of patients with myositis, mycophenolate mofetil 1–1.5 g twice daily is an effective steroid-sparing agent for skin and muscle disease. The first report dealt only with patients with DM, whereas the latter included some with polymyositis. There was toxicity noted in these relatively small case series, including an Epstein–Barr virus-associated lymphoma of the central nervous system in the former study, which resolved upon cessation of therapy, and opportunistic infections in the latter study, one of which was fatal.

This agent, albeit seemingly useful, needs careful monitoring for the development of neoplasia and infection.

A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.

Dalakas MC, Illa I, Dambrosia JM. N Engl J Med 1993; 329: 1993–2000.

These authors conducted a double-blind, placebo-controlled trial of intravenous immunoglobulin in 15 patients with biopsy-proven treatment-resistant DM. The patients continued to receive prednisone (mean daily dose 25 mg) and were randomly assigned to receive one infusion of immunoglobulin (2 g/kg body weight) or placebo monthly for 3 months, with the option of crossing over to the alternative therapy for 3 more months. The eight patients assigned to immunoglobulin showed a significant improvement in scores of muscle strength (p < 0.018) and neuromuscular symptoms (p < 0.035), whereas the seven patients assigned to placebo did not. With crossovers, a total of 12 patients received immunoglobulin. Of these, nine with severe disabilities showed a major improvement to near normal function. Of 11 placebo-treated patients, none had a major improvement, three had a mild improvement, three had no change in their condition, and the condition of five worsened. Skin disease also responded in the treated patients with eight of 12 demonstrating ‘marked clearance’ of cutaneous disease as assessed through clinical photographs.

Chlorambucil. An effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis.

Sinoway PA, Callen JP. Arthritis Rheum 1993; 36: 319–24.

Five patients with recalcitrant DM were treated with oral chlorambucil, 4 mg daily, after discontinuation of another immunosuppressive agent (azathioprine or methotrexate). Three patients were treated with a combination of prednisone and chlorambucil, and two with chlorambucil alone. Beneficial effects were noted within 4–6 weeks in all five patients, and corticosteroids were eventually discontinued in four. The chlorambucil was stopped after 13–30 months of treatment in four patients, and their disease remained in remission. Minimal chlorambucil toxicity was noted, consisting of leukopenia in two patients.

Although chlorambucil was effective, its potential for subsequent malignancy makes it a less desirable choice.

Rituximab in the treatment of refractory adult and juvenile dermatomyositis (DM) and adult polymyositis (PM): a randomized, placebo-phase trial. (The RIM Study).

Oddis CV, Reed AM, Aggarwal R, Ascherman DP, Barohn RJ, Feldman BM, et al. Arthritis Rheum 2013; 65; 314.

An NIH-sponsored multicenter randomized controlled trial of 200 participants, including 76 with DM, 48 with juvenile DM, and 76 with polymyositis. Patients were randomized to either a ‘rituximab early’ arm, receiving drug at weeks 0 and 1 and placebo at weeks 8 and 9, or a ‘rituximab late’ arm, receiving placebo at weeks 0 and 1 and rituximab at weeks 8 and 9. The primary endpoint, time to achieve improvement based on specifically defined muscle parameters, was not met, nor were the secondary endpoints, which were also based on muscle involvement. Despite this, 83% of patients met the definition of improvement (DOI) by week 44. In addition, a steroid-sparing effect of rituximab was noted in both groups. The authors propose that the trial design, particularly the short placebo-phase of 8 weeks, may have reduced the ability to detect differences between the groups given the median time to DOI from rituximab. Of note, neither of the 2 validated indices for cutaneous dermatomyositis were utilized in the RIM Study.

The two pilot studies, along with other case reports, suggest that there might be a place for this agent in the treatment of dermatomyositis. Study design concerns with the RIM Study make recommendations regarding the use of rituximab in inflammatory myopathy, inlcuding DM, challenging. At this time, however, there is little data to support the use of rituximab for cutaneous dermatomyositis specifically.

Third-line therapies

imageDapsone for cutaneous disease E
imageThalidomide for cutaneous disease E
imageAnti-estrogen medication for cutaneous disease E
imageDiltiazem for calcinosis D
imageEtanercept A
imageInfliximab D
imageTotal body irradiation D
imageRituximab for cutaneous disease D
imageLeflunomide E
imageSirolimus E
imageStem cell transplantation D

A randomized, pilot trial of etanercept in dermatomyositis.

Amato A. Ann Neurol 2011; 70: 427–36.

In this randomized double-blind placebo-controlled trial of 16 participants with DM on prednisone (11 randomized to etanercept arm 50 mg subcutaneously weekly for 52 weeks and five to placebo arm), a steroid-sparing effect was demonstrated in five patients in the treatment arm. There was no statistically significant difference in skin disease response assessed by CDASI between the groups. In addition, cutaneous disease worsened in five etanercept-treated patients, and two of these also developed a positive anti-nuclear antibody during the study period.

In addition to the potential worsening of muscle disease in patients with DM treated with anti-TNF-α therapy, reports of TNF inhibitor-associated DM have also recently been reported (Tumor necrosis factor inhibitor-associated dermatomyositis. Klein R, Rosenbach M, Kim EJ, Werth VP, Dunham J. Arch Dermatol 2010; 146:780–784). For these reasons, anti-TNF therapy is utilized with caution in patients with DM.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Dermatomyositis

Ruth Ann Vleugels and Jeffrey P. Callen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies characterized by cutaneous disease, including a heliotrope eruption, Gottron papules, a violaceous erythema on extensor surfaces in a photodistribution pattern, and/or periungual changes. Patients with cutaneous lesions of DM often have weakness of the proximal muscles, elevated enzymes such as creatine kinase or aldolase, or abnormal electromyograms or muscle biopsy findings. Some, however, have cutaneous disease that either precedes the onset of demonstrable muscle disease or occurs in its absence. In addition, many patients have persistent cutaneous manifestations long after their muscle disease is adequately controlled. DM in children and adolescents may be complicated by calcinosis, particularly when treatment is delayed. Adults with DM have a greater risk of having or developing a malignancy, usually within the first 3 years following diagnosis.

Management strategy

Prior to treatment the patient should be thoroughly evaluated to assess the severity of the disease, the presence of systemic involvement such as pulmonary, cardiac, or gastrointestinal involvement, and the presence of malignancy.

The goal of management is to reverse the weakness and allow the patient to return to normal functional status. The prevention of contractures is also a consideration, and the prevention or treatment of calcinosis is usually an issue in the management of children and adolescents, but may occur rarely in adults as well. Patients with cutaneous disease are troubled by intense pruritus and the appearance of their skin, and therefore request management even when the muscle disease has been effectively treated or is absent.

For the myopathy, systemic corticosteroids with or without an immunosuppressive agent are the standard treatment. Most patients respond to these agents, but for those who do not, high-dose intravenous immunoglobulin may be of benefit. Patients with cutaneous disease are photosensitive and are treated with sunscreens and behavior modification, topical corticosteroids, and occasionally topical calcineurin inhibitors, oral antimalarials, and often an oral immunosuppressant. High-dose intravenous immunoglobulin may also be used for recalcitrant cutaneous disease. Ultimately, the therapeutic goal is to provide patient relief from the cutaneous inflammation and associated symptoms utilizing a combination of topical and/or systemic medications selected after considering a patient’s comorbidities.

One of the problems with many of the reports published to date regarding therapeutic options for cutaneous DM is the lack of the use of a validated measure of activity to assess the activity of skin disease and response to therapy. To this end there are three measures that have recently been developed: the Dermatomyositis Skin Severity Index (DSSI) (Br J Dermatol 2008; 158: 345–350), the Cutaneous Dermatomyositis Area and Severity Index (CDASI) (Arch Dermatol Res 2008; 300: 3–9, and Br J Dermatol 2012; 162: 669–673), and a cutaneous assessment tool in juvenile dermatomyositis (Arthritis Rheum 2008; 59: 352–356). Unfortunately, none of these measures is routinely used in studies investigating therapeutic interventions for DM; however, the tools are being utilized more frequently and will ideally become incorporated as standard practice in the future as a means to assess cutaneous disease response.

Specific investigations

The value of malignancy evaluation in patients with dermatomyositis.

Callen JP. J Am Acad Dermatol 1982; 6: 253–9.

DM has been linked to internal malignancy in adults, but the value of an extensive malignancy evaluation in patients with DM is controversial. Fifty-seven patients who had DM with malignancies for whom data were available regarding the discovery of malignancy have been analyzed: 53 of these were reported previously. There were 67 malignancies in the 57 patients. The malignancy preceded (26 cases), followed (23 cases), or occurred with the DM (18 cases). A ‘blind’ (non-directed) malignancy search was not of value in any of the cases analyzed. Rather, the tumors were discovered in 40 cases by history (preceding tumor or abnormal symptoms), in 14 cases by physical examination, and in 12 cases by abnormal laboratory findings (e.g., chest radiograph, urinalysis, stool guaiac). One case was not discovered until autopsy (adenocarcinoma of the broad ligament). Analysis of tumor sites further negates the value of a malignancy work-up because most tumors (>90%) occur in areas not amenable to a ‘routine malignancy search.’ In several instances patients had an extensive search without having a complete physical examination.

Malignancy evaluations should be directed by abnormalities found on history, physical findings, or routine laboratory testing. However, since this paper was published, new, less invasive methods of malignancy search have been developed, and therefore the initial search should include CT scans of the chest, abdomen, and pelvis in most patients, and these scans should be repeated annually for at least 3 years. Malignancy screening should also include annual physical examinations.

A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.

Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. Medicine (Baltimore) 1991; 70: 360–74.

This study compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-signal recognition particle [anti-SRP], anti-Mi-2, and anti-MAS) to the standard clinical categories (polymyositis, DM, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms and prognosis in 212 adult patients. Compared to those without these antibodies, patients with anti-aminoacyl-tRNA synthetase autoantibodies (n = 47) had significantly more frequent arthritis, fever, interstitial lung disease, and ‘mechanic’s hands’; higher mean prednisone dose at survey; higher proportion of patients receiving cytotoxic drugs; and higher death rates. Those with anti-SRP antibodies (n = 7) had more frequent palpitations, myalgias, severe refractory disease, and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased ‘V-sign’ and ‘shawl-sign’ rashes and cuticular overgrowth, as well as a good response to therapy. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis.

These antibodies are less common in patients with DM than in patients with polymyositis, and currently only the anti-amino-acyl-tRNA synthetase autoantibodies are frequently incorporated into clinical practice.

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, Matsushita T, et al. Arch Dermatol 2011; 147: 391–8.

In this study of 376 adult Japanese patients with DM, anti-CADM-140 autoantibodies were associated with clinically amyopathic DM and rapidly progressive interstitial lung disease, whereas anti-155/140 autoantibodies were associated with malignancy. Anti-Mi-2 autoantibodies were associated with classical DM without either malignancy or pulmonary disease. The authors note that these autoantibodies define distinct clinical subsets and therefore are useful in predicting patient outcomes in DM.

The anti-CADM-140 and anti-155/140 autoantibodies are considered investigational at present and are not routinely available in commercial laboratories. They may, however, alter the screening practices for patients with DM in the future.

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