Amyopathic dermatomyositis or dermatomyositis-like skin disease ...

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Amyopathic dermatomyositis (ADM) is characterized by the presence of dermatomyositis (DM) for 6 months or more in individuals who have normal muscle ...
Clin Rheumatol (2009) 28:979–984 DOI 10.1007/s10067-009-1152-9

BRIEF REPORT

Amyopathic dermatomyositis or dermatomyositis-like skin disease: retrospective review of 16 cases with amyopathic dermatomyositis Hua Cao & Tanvi N. Parikh & Jie Zheng

Received: 14 October 2008 / Revised: 24 February 2009 / Accepted: 25 February 2009 / Published online: 18 March 2009 # Clinical Rheumatology 2009

Abstract Amyopathic dermatomyositis (ADM) is characterized by the presence of dermatomyositis (DM) for 6 months or more in individuals who have normal muscle enzymes and no clinically significant muscle weakness. The aim of the study was to investigate the initial laboratory data, clinical manifestations, complications, and clinical outcomes of patients with the diagnosis of ADM. We reported 16 cases with the cutaneous findings of dermatomyositis without clinical or laboratory evidence of muscle disease for at least 2 years after onset of the skin manifestations in the Department of Dermatology and Rheumatology at Shanghai Ruijin Hospital between 1998 and 2004. All patients had Gottron’s papules, periungual erythema/telangiectasia, and violaceous discoloration of the face, neck, upper chest, and back at some time during the course of their disease. Follow-up of 1 to 10 years after diagnosis found muscle weakness in three patients (18.75%) within 5 years of diagnosis. One patient (6.15%) was rediagnosed as chronic cutaneous lupus erythematosus (CCLE). Four patients (25%) had associated malignancies. Twelve patients (75%) had radiographic evidence indicative of interstitial fibrosis irrespective of respiratory symptoms. Patients with ADM appear to be at risk for developing the same potentially fatal disease complications as those H. Cao (*) : J. Zheng Department of Dermatology and Rheumatology, Ruijin Hospital, Medical School of Shanghai Jiao Tong University, 197 Ruijin 2nd Rd, Shanghai 200025, China e-mail: [email protected] T. N. Parikh Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 430 East 67th Street, New York, NY 10021, USA

patients with DM (e.g., interstitial lung disease and internal malignancy). These cases further emphasize that the cutaneous manifestations of dermatomyositis are pathognomonic for DM and we propose the term dermatomyositislike skin disease as a better designation than amyopathic dermatomyositis to describe this distinctive subset of cutaneous symptoms. Dermatomyositis-like skin disease is a complex syndrome, which includes the characteristic cutaneous eruption of dermatomyositis without clinical evidence of muscle disease. Our findings suggest that patients diagnosed with this syndrome are at risk for fatal interstitial lung disease, malignancy, and/or delayed onset of DM or CCLE. Cautious systematic clinical trials should be considered for this group of patients. Keywords Amyopathic dermatomyositis . Dermatomyositis-like skin disease . Interstitial lung disease . Malignancy Dermatomyositis (DM) is classified as a connective tissue disorder with inflammation of the skin and muscles. Pearson [1] first informally described several cases that we would today categorize as amyopathic DM and suggested the term amyopathic dermatomyositis (ADM) in reference to several patients who had the classic cutaneous eruption of dermatomyositis with minimal to no muscle involvement. ADM is classified as a subset of dermatomyositis. Over the past decade, there has been significant controversy concerning the nomenclature of amyopathic dermatomyositis. Dermatomyositis sine myositis and cutaneous dermatomyositis have been used to designate this entity [2, 3]. In 1993, Euwer and Sontheimer [4] reported six patients who had the classic skin changes of dermatomyositis without initial muscle involvement and published four diagnostic criteria for amyopathic dermato-

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myositis: (1) cutaneous changes pathognomonic for dermatomyositis—Gottron’s papules are a minimal criterion (however, one patient in Euwer and Sontheimer’s study had violaceous erythema of the knuckles without discrete papule formation in association with a periorbital heliotrope and was therefore included), (2) skin biopsy findings indicative of dermatomyositis, (3) no clinical evidence of proximal motor weakness within 2 years of skin disease onset, and (4) normal serum skeletal muscle enzyme levels for 2 years after appearance of skin lesions. Euwer [5] subsequently reduced the interval from 2 years to 6 months for the diagnosis of ADM to include a greater number of patients whose illnesses were previously ill-defined. Additionally, the new parameters set by Euwer allow a provisional diagnosis of ADM for any patient with classical DM skin disease without evidence of muscle disease at presentation. However, given these new diagnostic criteria, many patients diagnosed with ADM have some evidence of clinically silent muscle inflammation on electromyography, muscle biopsy specimens, and magnetic resonance imaging (MRI). These laboratory findings beg the question, should patients with cutaneous manifestations of DM and longstanding clinically silent muscle inflammation be diagnosed with ADM even though the term amyopathic dermatomyositis implies the complete absence of muscle inflammation? Here, we review our findings on 16 patients diagnosed with ADM using the aforementioned classical criteria. The objectives of this study are to review the patients’ clinical situation, muscle-derived enzyme levels (creatine kinase and lactate dehydrogenase), skin and muscle biopsy (if available), electromyogram (if available), muscle MRI results (if available), antinuclear antibody (ANA) assay result, and management of internal malignancy or interstitial lung disease (if present). While analyzing the results of our study, we propose the name “dermatomyositis-like skin disease” as a better term than “amyopathic dermatomyositis” to describe this distinctive subset of patients.

lactic dehydrogenase (LDH), electromyogram (EMG), muscle and skin biopsy, and muscle MRI were used to evaluate the presence or absence of skin and muscle disease. Chest radiography, chest high-resolution computed tomography (CT), and pulmonary function testing were performed in all 16 patients. All patients underwent cancer screening, including detailed clinical examinations, chest radiography, and CT of the abdomen and pelvis. Women also underwent a gynecological examination. Follow-up information was available for all the patients.

Materials and methods

Muscle evaluation

We reviewed the charts of patients with dermatomyositis seen in the Dermatology Department of Ruijin Hospital Affiliated to the Medical School of Shanghai Jiao Tong University between 1998 and 2004. Patients were included in this review if they met the criteria proposed by Sontheimer [6], i.e., DM patients with no clinical muscle symptoms for more than 6 months to 2 years after the onset of skin manifestations. The most common initial diagnoses for the patients included in this report were contact dermatitis, lichen planus, and seborrheic dermatitis. In addition to standard physical examination, serum muscle enzymes such as creatine phosphokinase (CPK) and

In our patient samples, none had the subjective symptoms of skeletal muscle weakness with normal muscle enzymes CPK and LDH for at least 2 years after onset of skin manifestations. Six patients had an EMG evaluation. Functional metabolic changes were not observed in any of these six patients upon EMG testing. Additionally, a muscle biopsy was done on all 12 patients included in this study, which showed no signs of muscle involvement. Results of muscle MRI were available for nine patients. Six of these nine patients showed minimal subclinical muscle involvement without subjective and/or laboratory evidence of muscle weakness.

Results Epidemiology Our patients had skin disease for a mean duration of 4.5 years with a range from 2 to 10 years. The female/male ratio in our study was 4:3; the average age was 50.25 years (range from 18 to 77 years). The characteristics of the cutaneous eruptions seen in our patients are presented in Table 1. All of our patients had the Gottron’s papules, periungual telangiectases, and/or erythema. Of these 16 patients, 15 (94%) had a periorbital heliotrope and one (6%) had poikiloderma. None had scalp inflammation or calcinosis. Most of our patients had moderate to severe localized pruritus and photosensitivity. Lethargy and fatigue were present in nine patients. Arthralgias occurred in six patients. Histopathology Skin biopsy specimens from all patients were consistent with dermatomyositis as assessed by the dermatopathologist at our clinic. The histopathologic characteristics observed most frequently were hyperkeratosis, basal keratinocyte liquefaction degeneration, and a lymphohistiocytic perivascular inflammation.

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Table 1 Patients with skin lesions of dermatomyositis and follow-up information Patient no.

Gender

1 2 3 4 5 6 7 8 9 10 11 12 13

F M F F F F M F M F M F M

14 15 16

F F M

Age at onset (years)

Periorbital heliotrope

Periungual erythema

ANA

Interstitial fibrosis

Malignancy

69 48 37 22 38 52 64 18 51 71 50 47 50

+ + + + + + + + − + + + +

+ + + + + + + + + + + + +

− 1:160 − − − 1:160 − 1:80 − 1:80 − − −

+ + + + − − − + − + + + −

Pancreatic carcinoma

51 77 59

+ + +

+ + +

1:80 − −

+ + +

Only two of the 16 patients (12.5%) had clinically significant muscle weakness that presented 2 and 3 years, respectively, after onset of characteristic DM skin changes. A negative serum CPK was obtained in both of these patients at the onset of skin disease. However, an elevated CPK was found in these patients at the time of muscle disease. Interstitial lung disease Of the 16 patients we observed, 12 (75%) had radiographic changes indicative of interstitial fibrosis. Among the 12 patients, nine (75%) were free of respiratory symptoms, two (17%) developed interstitial lung disease (ILD) with symptoms of nonproductive cough and exertional dyspnea accompanied by bibasilar fine crackling rales, and one (8%) had rapidly progressive dyspnea and severe hypoxemia resistant to treatment and died after 3 weeks from the onset of respiratory symptoms. Pulmonary function tests of six patients (6%) showed a restrictive pattern of disease with reduced diffusion capacity. Internal malignancy Four patients (25%) in our study were found to have an internal malignancy (one with pancreatic carcinoma, one with metastatic adenocarcinoma of unknown primary origin, and two with nasopharyngeal carcinoma). In two patients, cancer was diagnosed at the same time as amyopathic dermatomyositis. The other two were found to have malignancies after the 2 year follow-up.

Metastatic adenocarcinoma

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma

Autoantibody Tests for antinuclear antibodies (human Hep-2 cells as substrate) were performed in a total of 16 patients, and five patients (31.2%) were positive. Speckled ANA patterns were seen. Only one patient had a positive antidouble-stranded DNA antibody. None of the patients had precipitating antibodies to Ro/SS-A, La/SS-B, Sm, or U1RNP within 2 years of skin disease onset. Only one patient who was refractory to treatment was subsequently diagnosed with chronic cutaneous lupus erythematosus (CCLE) because a positive antibody to Ro/SS-A and La/SS-B was detected after 2 years of skin disease onset. Management and prognosis Nine patients in our study were treated initially with prednisone (15–40 mg/day) for their symptomatic skin disease. Of these nine patients, two had stopped their medications and were experiencing a recurrence of their skin disease. The combination of a reduced dose of cortisone with other immunosuppressive therapy such as methotrexate or hydroxychloroquine relieved cutaneous symptoms in two patients. There were four cases with internal malignancy: two received chemotherapy and radiotherapy with slowly progressive pattern, one stopped the medication, and two died due to metastatic adenocarcinoma. Four patients were treated with hydroxychloroquine or southernwood in combination with emollients and topical antipruritics from the onset of skin disease; two of them got remission of the facial symptoms.

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Three of the patients who developed ILD started a treatment of methylprednisolone (80–200 mg/day) combined with methotrexate. In the three cases, two patients showed improvement in their cutaneous disease and respiratory symptoms after the above treatment. One patient, who had rapidly progressive dyspnea, had progressive hypoxemia treatment resistance and died after 3 weeks from the onset of respiratory symptoms. However, during the follow-up after 2 years of skin disease onset, one patient had clinically significant muscle weakness with an elevated CPK. One patient who was refractory to treatment was subsequently diagnosed with CCLE because a positive antibody to Ro/SS-A and La/SSB was detected after 2 years of skin disease onset. Additionally, one died from cancer.

Discussion There is a female-to-male predominance of approximately 2:1 in DM, while in adult onset, ADM was closer to 3:1[7]. Sontheimer’s group has compiled published data on 336 patients reported to have hallmark skin manifestations of dermatomyositis without muscle weakness for variable lengths of time. Of these 336 patients, 88% were female. The mean age was 43 years. The mean duration of skin disease was 4.5 years. However, a study from Hong Kong has reported a higher ratio of ADM (ten of 40 [25%]) in Chinese patients initially diagnosed as having DM [8]. Curiously, this group of patients was male predominant (8:2); most other series from the West have been female predominant [3]. In our study, the female/male ratio was 4:3. The average duration of skin disease was 4.5 years. In our study, all of our patients had the Gottron’s papules or Gottron’s syndrome, periungual telangiectasias, and/or erythema. Fifteen of the 16 patients had a periorbital heliotrope. One patient had poikiloderma. None had scalp inflammation or calcinosis. These highlight the importance of Gottron’s papules and periungual telangiectases in the clinical presentation of this disease. Most of our patients had moderate to severe pruritus and photosensitivity. Chronic skin involvement from DM, especially in certain parts of the body, such as the V area of the anterior neck and upper chest, back, and buttocks, can assume the appearance of poikiloderma indistinguishable from other causes of this multicomponent skin change [9]. A number of reports now indicated that a macular violaceous erythema overlying the extensor aspect of the upper extremities with or without fully formed Gottron’s papules is present more frequently than a periorbital heliotrope erythema in DM [10, 11]. In our study, all 16 patients had specific DM rashes persistent for more than 6 months to 2 years without clinical evidence of myopathy. Six of the

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patients had subclinical muscle abnormalities seen on MRI evaluation at the time of diagnosis. Only two patients developed clinical evidence of myositis which was observed after prolonged follow-up periods. They should also undergo very thorough muscle testing with EMG and MRI in order to identify the presence of a subclinical myopathy. MRI has now become the method of choice for the diagnostic imaging of muscle abnormalities in myositis patients. The incidence of ILD in DM has been estimated previously to range between 30% and 50% [12–14]. The published literature has also revealed that ILD is a major cause of morbidity and mortality among ADM patients [6]. In our series, nine patients had radiographic changes indicative of interstitial fibrosis but were free of pulmonary symptoms. Two of these patients developed ILD with symptoms of nonproductive cough and exertional dyspnea accompanied by bibasilar fine crackling rales. One patient presented with rapidly progressive dyspnea and progressive hypoxemia and died of respiratory failure within 3 weeks despite steroid therapy. Ideura et al. [15] suggested that ILD associated with ADM can be classified into two clinical subtypes based on the time course of pulmonary involvement. ILD were divided into acute (dyspnea within 1 month before diagnosis) or chronic types. Patients with rapid progression in respiratory symptoms should undergo intensive treatment as soon as possible to promote favorable outcomes. Patients with DM/polymyositis (PM) complicated by ILD had different clinical courses. It has been reported that the DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively [13]. Cyclosporine and cyclophosphamide have each been reported to be of value in severe complications of ILD in DM patients, especially when started before severe respiratory failure develops [16, 17]. Considerable controversy exists concerning the possible association of classic DM–PM with occult malignancy. Internal malignancy occurs in 20–25% of adult onset classical dermatomyositis patients within 2 years of the onset of dermatomyositis. In Caucasians, carcinomas of the breast and lung are the most commonly associated malignancies [18, 19], whereas Asian men most frequently develop nasopharyngeal carcinoma [20]. This association with malignancy has also been noted in “amyopathic” patients; thus, clinical surveillance is required for this group as well. In our study, the incidence of malignancy was 25% (one with pancreatic carcinoma, one with metastatic adenocarcinoma of unknown primary origin, and two with nasopharyngeal carcinoma). Three of these patients were found to have an internal malignancy when they initially presented with the classic skin changes of dermatomyositis without initial muscle involvement and one patient was

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found to have a malignancy after 2 year follow-up. Remission of facial erythema was obtained on treatment with radiation and chemotherapy. One patient denied treatment. El-Azhary group [21] concluded that an association with cancer appears to exist for amyopathic dermatomyositis to the same degree and in the same manner as for classic dermatomyositis. The malignancy could have occurred before, after, or at the time of skin disease onset. Several features of cutaneous dermatomyositis have been suggested to correlate positively with increased risk of malignancy. These features include corticosteroid resistance, a bright vascular flush of the skin of the shoulders, neck, face, and scalp, and cutaneous ulceration [22]. It is recommended that all patients with specific DM rashes undergo a complete physical evaluation with chest radiography and breast, rectal, and pelvic examinations. It appears that continued surveillance is necessary for patients with DM [23]. A positive ANA (human Hep-2 cells as substrate) was found in 25% of the 16 patients in our study. Speckled ANA patterns were observed. No patient had precipitating antibodies to Ro/SS-A, La/SS-B, Sm, or U1RNP within 2 years of skin disease onset. After further follow-up, one patient, who had DM skin disease refractory to treatment, had developed antibodies to Ro/SS-A and La/SS-B. Thus, we rediagnosed this patient with CCLE. Currently, there is no effective measure to distinguish ADM patients from cutaneous LE patients. A patient presenting with clinically amyopathic dermatomyositis refractive to therapy and anti-Ro/SS-A and anti-La/SS-B antibodies should be carefully evaluated for the possibility of having made a delayed transition to classical systemic lupus erythematosus. We hope that some autoantibodies can help prevent such confusion in the future. DM patients with a positive ANA, however, do not seem to produce myositis-associated antibodies (e.g., Jo-1 or Mi-2). Targoff et al. [24] reported that a unique pair of autoantibodies (155 kd and Se) might serve as serologic markers for ADM patients. Topical therapy with a broad-spectrum sunscreen, an anti-inflammatory, and an antipruritic should be used for DM or ADM. In our study, four patients were treated with hydroxychloroquine or southernwood in combination with emollients and topical antipruritics from the onset of skin disease, two of them got remission of the facial symptoms. Single-agent or combined aminoquinoline antimalarial therapy represents the safest form of preliminary systemic therapy for dermatomyositis-like skin disease occurring in any clinical setting; however, this approach, also used for patients with LE, tends to be less effective for treatment of DM. Euwer reported [4] that treating ADM patients, who suffer only from cutaneous manifestations of DM, with oral cortisone may prevent these patients from developing significant muscle involvement during the

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course of their disease. Thus, systemic corticosteroid therapy can benefit patients with cutaneous dermatomyositis. However, because of the severe side effects associated with long-term systemic corticosteroid use, we prefer to use such therapy only in patients who are refractory to treatment with antimalarials. Considerable controversy exists regarding the nomenclature of ADM. During the past decade, terms such as dermatoamyositis, dermatositis, dermasitis, and cutaneous dermatomyositis have been suggested. There might be some value to adopting the term dermatomyositis-like skin disease when referring to the biopsy-confirmed hallmark clinical cutaneous manifestations of DM, regardless of whether such manifestations are present in the context of clinically significant myositis or abnormalities in other organ systems [6]. Some patients who are diagnosed with amyopathic DM have evidence of clinically silent muscle inflammation, as seen on EMG or MRI. Because the muscle inflammation is clinically silent for long periods, the impact of such findings on the day-to-day treatment of ADM patients is uncertain. However, because the term ADM implies complete absence of muscle inflammation, it is understandable that controversy regarding nomenclature exists. Patients with ADM and hypomyopathic DM can certainly be considered to have orphan medical dermatologic disorders. All orphan diseases, once adopted by practicing clinicians, will inevitably assume their own unique designation. Dermatomyositis-like skin disease refers to a condition in which the typical cutaneous eruption of dermatomyositis is present but muscle disease may or may not be lacking. Taken together, the evidence currently suggests that a skin rash may precede onset of muscle disease by months to years, and in some cases, overt muscle disease may never occur or may remain extremely mild. Thus, the clinical circumstance of amyopathic dermatomyositis or dermatomyositis without myositis is therefore the focus of both interest and controversy. Dermatomyositis-like skin disease is a working functional designation for patients with the skin-only and skin-predominant subsets of DM, amyopathic DM, and hypomyopathic DM. This term was chosen to emphasize the fact that the major clinical discomfort experienced by such patients is skin disease rather than muscle weakness. Dermatologists are in an ideal position to initially diagnose Dermatomyositis-like skin disease and contribute greatly to the quality of life and overall management of these patients. The initial goal in treatment is to control cutaneous inflammation and symptoms with the safest forms of topical and/or systemic therapy available. Broad-spectrum systemic immunosuppressive/immunomodulatory therapy is reserved for patients experiencing disabling cutaneous symptoms or for those who develop clinically significant muscle weakness. Cautious systematic clinical trials for the treatment of dermatomyositis-like skin

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disease are needed. Additionally, ongoing vigilance by dermatologist is required for these patients due to the possibility of fatal interstitial lung disease, internal malignancy, delayed onset of muscle weakness from myositis, and complications of systemic drug therapy.

Disclosures None

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