Amyopathic Dermatomyositis a Review by the Italian Group of Immunodermatology

STUDY Amyopathic Dermatomyositis A Review by the Italian Group of Immunodermatology

Marzia Caproni, MD; Carla Cardinali, MD; Aurora Parodi, MD; Barbara Giomi, MD; Manuela Papini, MD; Mario Vaccaro, MD; Angelo Marzano, MD; Clara De Simone, MD; Marcello Fazio, MD; Alfredo Rebora, MD; Paolo Fabbri, MD

Objective: To analyze the average age, sex distribu- phenomenon in 4. An elevated erythrocyte sedimentation tion, duration of follow-up, clinical course, serologic ab- rate was detected in 6 patients, hepatitis B virus antigen in normalities, and incidence of possibly associated malig- 3, speckled antinuclear antibodies in 7, and anti-Ro and nancy in patients with amyopathic dermatomyositis. antimitochondrial antibodies in 1 case each. None of our patients had evidence of internal malignancy. Neither car- Design: Retrospective study. diopulmonary nor esophageal dysfunction was demonstrated. Electromyography showed a protopathic muscle Setting: University hospitals. abnormality in 3 patients. Muscle biopsy disclosed myositis and a neurogenic myopathy in another one. Patients: Thirteen patients with amyopathic dermatomyositis. Conclusions: Amyopathic dermatomyositis is a rare disease. So far, only 2 series of a few cases each have been Results: The 13 patients represented 8.2% of 157 pa- reported. The “amyopathic” subset of dermatomyositis tients with dermatomyositis seen retrospectively in a 10- is peculiar in that its cutaneous lesions are predominant year period by the Italian Group of Immunodermatology for long periods or even permanently, although they are of the Italian Society of Dermatology and Venereology. Got- indistinguishable from those of classic dermatomyosi- tron papules and sign and periungual telangiectasias were tis. The minimal or absent muscle disease and the rarity found in approximately 50% of cases (papules in 7 pa- of serum immunologic findings imply a favorable prog- tients, Gottron sign and periungual telangiectasias in 6), nosis in white patients. while periorbital violaceous erythema was seen in 70% (9 patients). Arthralgias occurred in 2 patients and Raynaud Arch Dermatol. 2002;138:23-27

HE TERM amyopathic derma- phenytoin, may induce DM-like reac- tomyositis(ADM)(orderma- tions,4 and the racial differences in the pub- tomyositis sine myositis) re- lished reports. In fact, 1 of the 2 series com- fers to patients who, after 2 prised only Chinese patients and the other years of biopsy-confirmed a mixed population of blacks and whites. Tclassic cutaneous manifestations of derma- To determine whether the conclu- tomyositis(DM),have“minimal”muscledis- sions of the 2 mentioned series could also ease1 (after complete evaluation with elec- apply to Mediterranean patients, the Ital- tromyography [EMG], muscle biopsy, and magneticresonanceimaging)ornoevidence For editorial comment of inflammatory myopathy.2,3 Amyopathic dermatomyositis is a rare see page 114 disease. Only 2 series of a few cases each have been reported so far. Rarity, how- ian Group of Immunodermatology of the ever, may be only apparent depending in Italian Society of Dermatology and Vene- part on the lack of qualitative differences reology reviewed retrospectively the cases in the clinical features and immunohisto- of ADM observed during the last 10 years. pathologic findings between the cutaneous manifestations of ADM and those of RESULTS classic DM.4 Other reasons are the diag- The affiliations of the authors nostic difficulty in patients in whom con- Gottron papules (Figure 1) and sign appear in the acknowledgment current treatment with drugs, such as hy- (Figure 2) were found in 7 (54%) and 6 section at the end of this article. droxyurea, alfuzosin hydrochloride, and (46%) of our patients, respectively. Among

(REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 23

Thirteen patients (12 women and 1 man; mean age, 53 years; range, 19-86 years) from the centers (Flo- rence, Genoa, Messina, Milan, Rome, and Terni) of the Italian Group of Immunodermatology were reviewed. They belonged to a series of 157 consecu- tive patients with DM (8.2%). A questionnaire with clinical, laboratory, and immunologic items was sent to the study centers. The recruited records were then examined. The diagnosis of DM was accepted when patients proved to fulfill Bohan and Peter’s clinico- pathologic criteria5 and satisfied the exclusion and Figure 1. Gottron papules prominent over joints on the dorsal aspects of the Sontheimer’s additional criteria.4 fingers and periungual nailfold telangiectasia. Eleven patients had had their skin disease for at least 2 years (confirmed ADM),4 while 2 had it for longer than 6 months but shorter than 24 months (provisional ADM).4 In the juvenile case, the disease had begun at age 13 years; no familial cases were included. All patients had the characteristic histopathologic changes of DM, with basal keratinocyte liquefaction degeneration and lympho- histiocytic inflammation of papillary dermis. Patients were observed during a mean follow-up of 6.8 years. Laboratory tests included erythrocyte sedimentation rate, serum muscle enzyme levels (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and aldolase), antinuclear antibodies, anti– double-strand DNA, anti-extractable nuclear antigens, and antimitochondria, anti–smooth muscle, and an- Figure 2. Gottron sign: symmetric violaceous erythema overlying the dorsal tithyroid antibodies. Serologic tests for hepatitis B and aspect of the hands. C virus were also performed. Electromyography was performed on deltoids and quadriceps in 8 of 13 patients. Muscle biopsy specimens were obtained from 2 cases. Complaints of Raynaud phenomenon and arthralgias were also recorded. Pulmonary investigations (x-ray films, car- bon monoxide diffusion capacity) and esophageal motility studies were performed in all patients. Search for neoplasia included clinical examina- tion, standard biological tests, and chest x-ray films. Specific investigations were also performed only if in- dicated by direct abnormal symptoms.

the characteristic skin lesions, periorbital violaceous erythema (Figure 3 and Figure 4) was seen in 9 patients (69%) and periungual telangiectasias (Figure 1) in 6 patients (46%). Poikiloderma was observed in only 1 case. Two patients complained of photosensitivity, while in 3 the cutaneous lesions were accompanied by severe pru- Figure 3. Facial erythema with periorbital edema. Periorbital changes ritus. Arthralgias occurred in 2 patients (15%) and represent heliotrope eruption. Raynaud phenomenon in 4 (31%). An elevated erythrocyte sedimentation rate was de- None of our patients had evidence of internal ma- tected in 6 patients (46%). Hepatitis B virus antigen was lignancy. Neither cardiopulmonary nor esophageal dys- present in 3 patients (23%). Speckled antinuclear anti- function was demonstrated. bodies were found in 7 patients (54%) with a titer rang- The EMG showed no signs of muscle involvement ing between 1:80 and 1:640. Anti-Ro and antimitochon- in 5 of the 8 cases in which it was performed, while a drial antibodies were found in 1 case each. Antithyroid protopathic muscle abnormality was demonstrated in 3 and anti–smooth muscle antibodies were detected in an- patients. Muscle biopsy showed myositis in 1 patient other one. who was not in the positive EMG group, while in

(REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 24

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 another case a neurogenic myopathy was demonstrated. Thus, 4 patients of 10 investigated with EMG and muscle biopsy showed minimal, subclinical muscle involvement without subjective and laboratory (normal serum levels of muscle enzymes) evidence of muscle weakness.

COMMENT

Only 8% of our 157 patients with DM had ADM. This prevalence is lower than reported elsewhere (10%-20%).6 Recently, an even higher incidence of ADM (25%) has been reported in a Chinese study.7 Apparently, ADM is less common in the Mediterranean area. Figure 4. Facial erythema with periorbital edema. Periorbital changes Most cases have been reported in middle-aged adults. represent heliotrope eruption. Until now, juvenile patients have been described only in case reports8 and small case series,1,9 but, in a recent study,10 27 juvenile-onset cases of ADM have been ana- between the presence of Raynaud phenomenon and lyzed. Elderly patients have also been described, includ- positive antinuclear antibodies, but only a fortuitous ing an 84-year-old man presenting with blisters on the association was made in 2 cases. neck and oral ulcers in association with the typical skin Anti–double-strand DNA autoantibodies were manifestations of DM.11 We observed an 86-year-old absent (as in other ADM reports1,7,9,17), and anti- woman. extractable nuclear antigen autoantibodies were found Most patients with ADM are said to be women9,12-14; in only 1 case. In addition, another patient had positive only the Chinese series showed a prevalence of men.7 In antithyroid and anti–smooth muscle autoantibodies. In our series, the female predominance was almost absolute fact, we had also found antithyroid antibodies in 2 of the (92%) (Table). The characteristic heliotrope erythema was 3 patients with ADM studied previously.9 Although other slightly more frequent than the pathognomonic Gottron authors have encountered several diagnostic autoanti- papules (69% vs 54%). Although the difference was not bodies (anti–Jo-1, anti–Mi-2, anti-PML, and anti-Ku) in statistically significant, we support Callen’s opinion12 that classic DM,18 we failed to do so. heliotrope erythema is a pathognomonic lesion. First Braverman19 and Bohan et al20 suggested the Periungual alterations affected only 46% of our pa- possible association with malignancy in patients with tients. In a previous study,9 periungual nailfold telangi- ADM, and later Stonecipher et al17 recommended exam- ectasias were present in the 3 cases studied. In contrast, ining patients with ADM, like those with classic DM. In all 6 patients described by Euwer and Sontheimer1 pre- fact, in the Chinese series,7 60% of patients had malig- sented with Gottron papules, periungual erythema tel- nancy. None of our patients had such evidence, in agree- angiectasias, and violaceous discoloration of the face, neck, ment with other Western series.1,21 In the Chinese se- and upper part of the chest, or had had them at some time ries, nasopharyngeal carcinoma was the most common during the course of the disease. Also, in the study by malignant disease. Chinese findings may be coinciden- Rockerbie et al,15 Gottron papules and heliotrope ery- tal given the small number of their ADM cases and the thema were the most frequent lesions (80%). On the con- fact that nasopharyngeal carcinoma is frequent in South- trary, in the patients with associated malignancies in the east Asia.8 Other cases of ADM have been reported in as- Chinese series,16 the most common cutaneous lesions sociation with breast cancer,13,22 transformed malignant (83%) were erythematous, violaceous macules or pap- lymphoma,23 and papillary serous ovarian cancer.14 We ules on the face, limbs, and trunk (Table). agree with other authors4 that the risk of malignancy All patients described by Euwer and Sontheimer1 had should be considered low in white patients. moderate to severe pruritus and complained of photo- Some patients with ADM have subclinical evidence sensitivity. These symptoms have been reported more of muscle inflammation if investigated thoroughly with rarely elsewhere and were uncommon in our series, with EMG, muscle biopsy, or noninvasive procedures that can 2 patients complaining of photosensitivity and 3 of se- assess muscle anatomy and physiology, such as ultra- vere pruritus. Arthralgias and Raynaud phenomenon (15% sound and magnetic resonance imaging.7 Four of 10 of and 31% of our cases, respectively) have not been pre- our patients who fulfilled the diagnostic criteria for ADM viously reported, except by Euwer and Sontheimer1 (1 underwent some of those investigations, demonstrating patient with arthralgias). minimal, subclinical muscle involvement without sub- As for the laboratory findings, positive antinuclear jective and laboratory (normal serum levels of muscle en- antibodies were found in half of our patients, in agree- zymes) evidence of muscle weakness. ment with previous data.1 In other series,14,17 however, These findings reveal the necessity of proper classi- they were positive in almost all patients. The speckled fication of these patients, and, in this regard, the use of pattern was prevalent in all of the studies, with lower ti- noninvasive tests might be helpful because a complete and ters only in Stonecipher and coworkers’ series.17 We con- reliable evaluation of muscle involvement is not possible firmed the speckled pattern of other reports and el- on the basis of only EMG and muscle biopsy. In fact, EMG evated titers as well.14,16 No correlation was demonstrated is a sensitive but not specific procedure,24 while muscle

(REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 25

Lam et al,7 Euwer and Current Fung et al,16 Caproni Dawkins Whitmore Stonecipher Sontheimer,1 Rockerbie Variable Study 1998 et al,9 1998 et al,13 1998 et al,14 1996 et al,17 1993 1991 et al,15 1989 Total population 157 40 . . . 65 19 . . . 50 . . . of DM No. (%) with 13 (8) 10 (25) 3 (. . .) 12 (18) 12 (. . .) 13 (. . .) 6 (11) 50 (. . .) ADM Age range, y 19-86 25-72 20-76 26-70 33-72 20-72 ND 2-83 Median age, y 53.0 ND 51.3 48.6 59.0 45.0 53.6 ND Juvenile cases, 10 1 1 02 1 ND No. Sex, No. M:F 12:1 2:8 3:0 11:1 10:2 10:3 5:1 3:1 Mean follow-up 6.8 y 20-90 mo 5 y 4.8 y 4.2 y 1-6 y 3 y ND Gottron papules, 7/13 4/6 3/3 ...‡ ...§ ...‡ 6/6 40/50 No./total (%) (53.8) (67)† (100) (100) (80) Heliotrope 9/13 2/6 3/3 ...‡ ...§ ...‡ 6/6 40/50 erythema, (69) (33)† (100) (100) (80) No./total (%) Periungual 6/13 4/6 3/3 ND 0 0 6/6 3/50 alteration (46) (67)† (100) (100) (6) (erythema, telangiectasia), No./total (%) Poikiloderma, 1/13 2/6 0 ND 0 0 2/6 5/50 No./total (%) (8) (33)† (33) (10) Positive ANA, 7/13 5/6 2/3 ND 11 or 12/13 3/6 ND No./total (%) (54) (83)† (67) 12/12‡ (92) (50) Positive 00 0 NDND0 0 ND anti–native DNA, No. Anti-ENA 1/13 00 ND000ND (Ro/SSA+) Antithyroid 1/13 ND 2/3 ND ND ND ND ND antibody, No./total Enzyme levels࿣ Normal Normal Normal Normal Normal Normal Normal ND Elevated ESR, 6/13 ND ND ND ND 0 3/5 ND No./total (%) (46) (60) Positive HBV, 3/13 ND ND ND ND ND ND ND No./total (%) (23) Frequency of 0 6/10 0 1/12 4/12 2/13 00 malignancy, (60) (8) (33) (15) No./total (%) EMG Normal ND No signs of Normal findings ND Positive C/W ND ND findings muscle DM in in 5/8 involvement 4/11 patients patients Muscle biopsy Myositis in 1 ND Low-grade Normal findings ND Positive C/W ND ND case and myositis in DM in neurogenic 1 case 4/11 myopathy patients in another Therapy ND Not Not Oral Not Not Oral Not described described hydroxychloroquine, described described corticosteroids described oral methotrexate, topical corticosteroids

*DM indicates dermatomyositis; ADM, amyopathic DM; ND, not determined; ANA, antinuclear antibody; ENA, extractable nuclear antigen; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; EMG, electromyogram; and C/W, consistent with. †Data referred to the 6 patients with malignancies. ‡Ellipses indicate patients had the typical cutaneous features of DM. §Ellipses indicate diagnosis made on the basis of pathognomonic cutaneous changes (heliotrope eyelid rash and Gottron papules). ࿣Enzyme levels included creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and aldolase.

biopsy may give confusing results because of sampling er- In conclusion, the amyopathic subset of DM is un- ror.7 In the absence of these important noninvasive pro- usual in that its cutaneous lesions are predominant for cedures, as in our study, we treated the patients conser- long periods or even permanently, although they are in- vatively without using immunosuppressive drugs. distinguishable from those of classic DM. The minimal

(REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 26

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 or absent muscle disease and the rarity of serum immu- 6. Sontheimer RD. Dermatomyositis. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. nologic findings all imply a favorable prognosis in the Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill Book Co; 1999:2008-2022. white population. 7. Lam WWM, Chan H, Chan YL, Fung JWK, So NMC, Metreweli C. MR imaging in amyopathic dermatomyositis. Acta Radiol. 1998;40:69-72. Accepted for publication May 24, 2001. 8. Schmid MH, Tru¨eb RM. Juvenile amyopathic dermatomyositis. Br J Dermatol. From the Dipartimento di Scienze Dermatologiche, 1997;136:431-433. Clinica Dermatologica II, Universita` degli Studi di Firenze, 9. Caproni M, Salvatore E, Bernacchi E, Fabbri P. Amyopathic dermatomyositis: report of three cases. Br J Dermatol. 1998;139:1111-1137. Florence (Drs Caproni, Cardinali, Giomi, and Fabbri); Se- 10. Plamondon S, Dent PB. Juvenile amyopathic dermatomyositis: results of a case zione di Dermatologia, Universita` di Genova, Diparti- finding descriptive survey. J Rheumatol. 2000;27:2031-2034. mento di Scienze Endocrinologiche e Metaboliche (DISEM), 11. Seno A, Tokuda M, Yamasaki H, Akiyama K. A case of amyopathic dermatomyo- Genoa (Drs Parodi and Rebora); Dipartimento delle Spe- sitis presenting blister and oral ulcer. Ryumachi. 1999;39:836-840. cialita` Medico-Chirurgiche, Sezione di Dermatologia di 12. Callen JP. Dermatomyositis. Lancet. 2000;355:53-57. 13. Dawkins MA, Jorizzo JL, Walker FO, Albertson D, Sinal SH, Hinds A. Dermatomyo- Terni, Universita` di Perugia, Perugia (Dr Papini); Istituto sitis: a dermatology-based case series. J Am Acad Dermatol. 1998;38:397-404. di Dermatologia, Universita` degli Studi di Messina, Mes- 14. Whitmore SE, Watson R, Rosenshein NB, Provost TT. Dermatomyositis sine myo- sina (Dr Vaccaro); Istituto di Scienze Dermatologiche, Is- sitis: association with malignancy. J Rheumatol. 1996;23:101-105. tituto di Ricovero e Cura a carattere Scientifico (IRCCS) 15. Rockerbie NR, Woo TY, Callen JP, Giustina T. Cutaneous changes of dermato- Ospedale Maggiore, Universita` degli Studi di Milano, Mi- myositis precede muscle weakness. J Am Acad Dermatol. 1989;20:629-632. 16. Fung JWK, Chan H, Lam WWM. Amyopathic dermatomyositis in Hong Kong: lan (Dr Marzano); Istituto di Dermatologia, Universita` Cat- association with nasopharyngeal carcinoma. Int J Dermatol. 1998;37:659- tolica del Sacro Cuore, Rome (Dr De Simone); and Istituto 663. Dermopatico dell’Immacolata—IRCCS, Rome (Dr Fazio), 17. Stonecipher MR, Jorizzo JL, White WL, Walker FO, Prichard E. Cutaneous changes Italy. of dermatomyositis in patients with normal muscle enzymes: dermatomyositis Corresponding author and reprints: Marzia Caproni, sine myositis? J Am Acad Dermatol. 1993;28:951-956. 18. Targoff IN. Dermatomyositis and polymyositis. In: Weston WL, MacKie RM, Pro- MD, Clinica Dermosifilopatica, Universita` degli Studi di vost TT, eds. Current Problems in Dermatology. St Louis, Mo: Mosby–Year Book; Firenze, Via degli Alfani 37, 50121-Firenze, Italy. 1991:131. 19. Braverman I. Connective tissue (rheumatic) diseases. In: Cutaneous Signs of Sys- temic Disease. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1981:300-310. REFERENCES 20. Bohan A, Peter JB, Bowman RL, Pearson CM. A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine. 1977;56:255- 1. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis (dermatomyositis sine 286. myositis). J Am Acad Dermatol. 1991;24:959-966. 21. Krain LS. Dermatomyositis in six patients without initial muscle involvement. Arch 2. Pearson C. Patterns of polymyositis and their responses to treatment. Ann In- Dermatol. 1975;3:241-245. tern Med. 1963;59:827-838. 22. Goyal S, Nousari HC. Paraneoplastic amyopathic dermatomyositis associated with 3. Callen JP, Jorizzo JL. Amyopathic dermatomyositis (dermatomyositis sine breast cancer recurrence. J Am Acad Dermatol. 1999;41:874-875. myositis). J Am Acad Dermatol. 1992;26:505-506. 23. Osman Y, Narita M, Kishi K, et al. Case report: amyopathic dermatomyositis as- 4. Sontheimer RD. Cutaneous features of classic dermatomyositis and amyo- sociated with transformed malignant lymphoma. Am J Med Sci. 1996;311:240- pathic dermatomyositis. Curr Opin Rheumatol. 1999;11:475-482. 242. 5. Bohan A, Peter JB. Polymyositis and dermatomyositis (2-part article). N Engl 24. Oddis CV, Medsger TA. Inflammatory myopathies. Baillieres Clin Rheumatol. 1995; J Med. 1975;292:344-348, 403-407. 9:497-514.

(REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 27