Cutaneous changes of dermatomyositis in patients with normal muscle enzymes: Dermatomyositis sine myositis?

Cutaneous changes of dermatomyositis in patients with normal muscle enzymes: Dermatomyositis sine myositis? Marcus R. Stonecipher, MD, Joseph L. Jorizzo, MD, Wain L. White, MD, Francis O. Walker, MD, and Elizabeth Prichard, MD Winston-Salem, North Carolina Background: Dermatomyositis sine myositis may have various connotations. Controversyexists as to nomenclature, degree of evaluation required, therapy, and course (e.g., does true dermatomyositis of the skin only exist?). Objective: The purpose of this study was to assess prospectively patients with the clinicopathologic features of dermatomyositis and normal muscle enzyme serum levels to determine their course in terms of the onset of muscle disease. Methods: Thirteen patients were studied by complete history and clinical examination, laboratory studies, electromyography, and skin and muscle biopsy. They were observed for I to 6 years. Results: Patients were classifiable into three groups: (1) cutaneous changes only, (2) cutaneous changes only at baseline with subsequent development of myositis, and (3) cutaneous changes with normal muscle enzyme serum levels at baseline but with myositis demonstrated by electromyography and/or muscle biopsy specimens. Conclusion: Significantly different prognostic and therapeutic implications are present in patients with dermatomyositis with normal muscle enzyme serum levels depending on the results of electromyography, muscle biopsy, and clinical observation. (J AM ACAD DERMATOL 1993;28:951-6.)

Dermatomyositis is characterized by a typical cutaneous eruption and an inflammatory myopathy producing symmetric proximal muscle weakness. 1,2 In the absence of cutaneous disease the disorder is known as polymyositis. At initial presentation a patient may not have clinical evidence of both cutaneous and muscular disease because the cutaneous disease in dermatomyositis may often precede the development of muscle weakness. 3-6 The typical cutaneous manifestations may also precede or occur in the absence of laboratory or other diagnostic evidence (electromyography [EMG] or muscle biopsy) of an inflammatory myopathy. 6 The designations dermatomyositis sine myositis and more recently amyopathic dermatomyositis have been used to refer to patients who have typical cutaneous findings but no apparent myopathy. Some authors use these From Bowman Gray School of Medicine, Wake Forest University. Accepted for p\lblication Dec. 21, 1992. Reprint requests: Marc\ls R. Stonecipher, MD, Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157. Copyright ® 1993 by the American Academy of Dermatology, .Inc. 0190-9622/93 $1.00 +.10 16/1/45173

designations to describe patients who have no apparent or "minimal" muscle disease,6-g whereas others reserve these designations for patients who, after complete evaluation (e.g., muscle enzymes, EMG, and muscle biopsy), have no laboratory or other diagnostic evidence of an inflammatory myopathy. 8,9 The designation takes on major importance if aggressive therapy, such as with systemic corticosteroids and/ or immunosuppressive agents, is restricted to patients with documented myopathy. Published studies on dermatomyositis sine myositis are limited. Although not using this designation, an early report addressing this issue was published by Krain4 in 1975. In this report, six patients initially presented with typical cutaneous changes of dermatomyositis without apparent (not all patients had complete evaluations) muscle disease. All patients eventually either developed or were found to have evidence of an inflammatory myopathy. The term amyopathic dermatomyositis was proposed in 1979 by Pearson 8 who applied this to several patients who had the typical cutaneous findings with no or minimal muscle disease. Recently, Euwer and Sontheimer6 have reviewed this topic and reported six additional patients. These authors used the term amy-

951

952 Stonecipher et at.

Journal of the American Academy of Dermatology June 1993

Fig. 1. Patient 2. Typical eruption of dermatomyositis with erythematous plaques overlying joints of figures in a patient without evidence of muscle disease. Fig. 2. Patient 2. Typical Gottron's papules and periungual nailfold telangiectasia.

opathic dermatomyositis to refer to patients who have classic cutaneous findings and no clinical or laboratory evidence of muscle disease, although EMG and muscle biopsy were either not performed or not reported in most patients. Because patients may have the cutaneous changes of dermatomyositis without muscle weakness and with normal muscle enzyme serum levels, there may be confusion and delay in diagnosis and in the initiation of therapy. We present our evaluation and follow-up of 13 patients with the typical cutaneous findings of dermatomyositis but with normal muscle enzyme serum levels.

MATERIAL AND METHODS Patients were eligible for inclusion if the following criteria were met: (l) typical cutaneous changes of dermatomyositis (Figs. 1 and 2); (2) cutaneous biopsy specimen compatible with dermatomyositis; (3) normal muscle en-

zyme serum levels (creatine kinase, aldolase); and (4) consent for complete evaluation (e.g., EMG and muscle biopsy). Laboratory tests, EMG, and muscle biopsy were performed when patients demonstrated active cutaneous disease and were receiving no systemic therapy with corticosteroids or immunosuppressive drugs. Patients were then observed for 1 to 6 years.

RESULTS Baseline data The baseline data of our 13 patients are summarized in Table 1. Both patients with juvenile-onset disease were male; all remaining patients were women except for one 20-year-old man. All patients had the characteristic histopathologic changes of dermatomyositis. Patients 8 and 11 had mild subjective muscle weakness and equivocal results of muscle testing. All patients had a normal serum creatine kinase and aldolase at the time of enroll-

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953

Fig. 3. Patient 3. Sparse superficial perivascular lymphocytic infiltrate with extensive vacuolar change involving the keratinocytes along the dermoepiderma1 junction. There is slightly compact orthokeratosis. (Hematoxylin-eosin stain; X63.)

Table I. Patients with clinicopathologic dermatomyositis but with normal muscle enzyme serum levels Patient No.

\Veakness of clinical testing

Skin biopsy

1 2

20 37

M F

1988 1981

3 4 5 6 7 8 9 10

35 70 47 56 29 72 55 71

F F F F F F F F

1987 1984 1984 1991 1991 1991 1988 1991

11 12

72 14

F M

1989 1988

13

7

M

1985

AST, Aspartate aminotransferase;

CjWDM C jW DM; negative lupus band CjWDM CjWDM CjWDM CjWDM CjWDM CjWDM CjWDM Mild change CjWDM CjWDM Mild change CjWDM CjWDM

Enzymes

No No

WNL WNL

No No No No No

WNL WNL WNL WNL (SL WNL (SL WNL WNL WNL

±

No No No

±

WNL WNL

No

WNL

t AST) t LDH and AST)

qw; consistent with; DM, dermatomyositis; LDH, lactate dehydrogenase; WNL. normal.

ment into the study. A mild elevation of serum aspartate aminotransferase (AST) was present in patients 6 and 8; patient 8 also had a borderline increase in lactate dehydrogenase (LDH).

Skin biopsy findings All skin biopsy specimens were similar. They showed a superficial perivascular lymphocytic infiltrate with vacuolar interface changes. These ranged

from focal vacuolar degeneration along the dermoepidermal junction to extensive vacuolar involvement (Fig. 3) across the breadth of the specimen. In some cases more chronic changes of an indistinct, "smudgy," dermoepidermal junction and telangiectatic vessels were present. In all cases necrotic, apoptotic keratinocytes, from few to many, were present along the epidermal basement membrane zone. There was a range of slight epidermal hyper-

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954 Stonecipher et al. Table II. Evaluation and course of 13 patients Patient No.

Onset of clinical myositis

EMG

Muscle biopsy

WNL

Negative

2

WNL

Negative

3

WNL

Negative

4

Essentially WNL (nonspecific changes right upper extremity) Positive, C/W OM

Negative

5

1990 (6 yr after skin*-revealed only with EMG and muscle biopsy) 1991 (5 rno after skin)

WNL

Borderline slight type II atrophy Positive, C/W DM

1991 (2 rno after skin) 1992 (3 yr after skin)

Positive, C/W DM

Negative

Positive, C/W OM

Negative

10

1991 (4 rno after skin)

Positive, C/W OM

Positive, C/W OM

11

1990 (6 rno after skin) 1989 (6 mo after skin)

WNL

Patient refused

Pediatrician and patient refused

Pediatrician and patient refused

1988 (3 yr after skin)

Pediatrician and patient refused

Positive, C/W DM

6

7

8 9

12

13

t

(Enzymes 2 mo into flu)

WNL

Positive, C/W OM

Course

Skin disease only (at 4 yr) Skin disease only at 11 yr Skin disease only at 5 yr Skin disease only at 4 yr (no change 1 yr after EMG) Muscle enzymes never elevated but patient treated with prednisone and doing well Improved with hydroxychloroquine 2 mo into flu CK increased; asymptomatic; treated with hydroxychloroquine N/A Patient diagnosed with adenocarcinoma of breast; improved after surgery Patient diagnosed with adenocarcinoma of breast; improved after surgery Disease is controlled with prednisone Clinical myositis with increased enzymes developed and controlled with prednisone Enzymes never elevated; clinical myositis responding well to prednisone

EMG, Electromyography;.f7u, follow-up; N/A, not available; for other abbreviations see legend of Table I. *After skin: after onset of cutaneous disease.

plasia to focal atrophy and compact orthokeratosis. These features are characteristic of dermatomyositis. 10, 11 Evaluation and course The evaluation and course of each patient are summarized in Table II. The data in Table II allow

the classification of patients into three groups. This classification is presented in Table III. Other laboratory tests The following tests were within normal limits in all patients: erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor (except patient 11),

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Stonecipher et af. 955

Table III. Classification of patients Category I

Cutaneous changes only (4 patients [1-4])

Category II

Cutaneous changes only at baseline with subsequent evolution of myositis (7 patients [6-8, 10-13])

anti-Sjogren's syndrome A (SS-A, Ro), antiSjogren's syndrome B (SS-B, La), anti-Smith antibody, anti-ribonuclear protein, anti-Jo-l antibody, anti-double-stranded DNA, and anti-polymyositis scleroderma (PM-Scl) antibody. Antinuclear antibody tests performed on human substrate were positive in all patients except patient 1. All patients had a speckled pattern and titers were generally low; no patient had other clinical or laboratory evidence of systemic lupus erythematosus. With subsequent reevaluation there has been no evidence of lupus erythematosus in any of the patients. DISCUSSION

Additional longitudinal analysis might allow some patients in category I (cutaneous changes only) to be reclassified into category II (cutaneous changes only at baseline with subsequent evolution of myositis). However, ofparticular interest are patients 1through 4 who demonstrated no evidence of myositis after 4 to 11 years of evaluation. Previous studies suggested that muscle disease seems to appear in most patients after 2 years; our patients provide additional evidence that this is not always the case. Patients 1 through 4 provide strong support for the existence of true dermatomyositis sine myositis. Some may hold that such patients may have undetected subclinical muscle disease or that a myopathic process may subsequently evolve; however, given that the current follow-up periods are 4 to 11 years and that no myositis has been detected with complete evaluation by universally accepted diagnostic tests or criteria, it seems that, indeed, a small subset of patients with only cutaneous disease does exist. In all patients, except patient 12, the cutaneous involvement was the predominant feature of the disease process. Callen et a1. 12, !3 have recommended the appropriate evaluation of patients with dermatomyositis for occult malignancy. In our patients, screening evaluation for malignancy was negative in nine, but

Category III

Cutaneous changes with normal muscle enzyme serum levels; baseline diagnostic investigations revealed myositis (2 patients [5, 9])

patients 9 and 10 had a malignancy in close temporal association to their cutaneous eruption. In both patients cancer preceded the onset of muscle disease but was not detected until after the onset of the cutaneous eruption. This implies that patients with only cutaneous disease should probably be evaluated in the same manner as patients who also have myositis. Previous studies have deemphasized the importance of a complete muscle evaluation and suggest a common approach to therapy regardless of the detection ofsubclinical muscle disease. 6 The cutaneous eruption of dermatomyositis is often resistant to therapy.l4 Some authors have emphasized the importance of disassociating the cutaneous response to systemic corticosteroids from the response of the muscle disease so a reduction in dosage is not delayed. Therapy with hydroxychloroquine may be beneficial, especially when combined with a sunscreen and with mild topical corticosteroid therapy.15 Our approach has been to reserve systemic corticosteroid or other immunosuppressive therapy for patients in category II (i.e., begin prednisone therapy at the time of clinically evident myositis) or category III (begin prednisone therapy at the time of detection of subclinical myositis). Patients in category III present a therapeutic problem because muscle enzyme serum levels cannot be used as a guide to therapy in patients. The principles that guided the patient evaluation conducted in this study are those proposed by Bohan and Peter.! Future studies should assess noninvasive tests that could be performed sequentially in patients with dermatomyositis sine myositis. These tests could includemagnetic resonanceimaging,!6, 17 thallium scanning, 18,19 and muscle ultrasound. The results may be helpful in diagnosis and proper subcategorization of patients as well as evaluation of the response to therapy in category III patients. These tests along with immunohistochemical studies On

Journal of the American Academy of Dermatology June 1993

956 Stonecipher et aI, muscle tissue in category I patients may be helpful in further supporting or refuting the existence of a subset of patients with true dermatomyositis sine myositis,

11. 12.

REFERENCES I. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975;292:344-7. 2. Dalakas Me. Polymyositis, dermatomyositis and inclusion body myositis. N Engl J Med 1991;325:1487-98. 3. Bohan A, Peter JB, Borman RL, et al. A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 1973;56:255-86, 4. Krain LS: Dermatomyositis in six patients without initial muscle involvement. Arch DermatoI1975;3:241-5. 5. Rockerbie NR, Woo TY, Callen JP, et al: Cutaneous changes of dermatomyositis precede muscle weakness, J AM ACAD DERMATOL 1989;20:629-32. 6. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis (dermatomyositis sine myositis). JAM ACAD DERMATOL 1991 ;24:959-66, 7. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis. [Letter]. J AM ACAD DERMATOL 1992;26:506-8. 8. Pearson C. Patterns of polymyositis and their responses to treatment. Ann Intern Med 1963;59:827-38. 9. Callen JP, Jorizzo JL. Amyopathic dermatomyositis (dermatomyositis sine myositis) [Letter]. J AM ACAD DERMA. TOL 1992;26:505-6. 10. Janis JF. Winkelmann RK. Histopathology of the skin in

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18,

19.

dermatomyositis: a histologic study of 55 cases. Arch Dermatol 1968;97:640-50, Ackerman AB. Histologic diagnosis of inflammatory skin diseases. Philadelphia: Lea & Febiger, 1978, Callen JP, Hyla JF, Boles CG, et al. The relationship of dermatomyositis and polymyositis to internal malignancy. Arch Dermatol 1980;116:295-8, Callen JP. The value of malignancy evaluation in patients with dermatomyositis. J AM ACAD DERMATOL 1982; 6:253-9, Callen JP. Dermatomyositis, Dermatol Clin 1983;1:46173. Woo TY, Callen JP, Voorhees JJ, et al. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J AM ACAD DERMATOL 1984;10:592-600, Kaufman LD, Gruder BL, Berstman DR, et al. Preliminary observations on the role of magnetic resonance imaging for polymyositis and dermatomyositis. Ann Rheum Dis 1987;46:569-72. Park JH, Vansant JP, Kumar NG, et al. Dermatomyositis: correlative MR imaging and P-31 MR spectroscopy for quantitative characterization of inflammatory disease. Radiology 1990;177:473-9. Guillet GY, Guillet JA, Blanquet P, et al. A new noninvasive evaluation of muscular lesions in dermatomyositis: thallium 201 muscle scans. J AM ACAD DERMATOL 1981; 210:670-2, Guillet G, Guillet J, Sanciaume C, et al. Evaluation of muscular lesions in connective tissue diseases: thallium 210 muscular scans. J AM ACAD DERMATOL 1988;18:663-6,