Treatment o[ dermatomyositis Therapy CYCLOSPORIN POR THE TREATMENT OF DERMATOMYOSITIS M. Marschalko, I. Papp, J. Biro, E. Jakob, P. Cserhalmi and A. Horvath ABSTRACT 2 patients with extreme severe dermatomyositis, 2 patients who were at risk because of corticosteroid side effects due to underlying diseases - and 1 patient with amyopathic dermatomyositis who was resistant to previous corticosteroid treatment were treated with 5 mg/kg/d cyclosporin A (CSP) and prednisone. CSP treatment has been shown to be beneficial in ali 5 patients. CSP treatment was discontinued after 3 and4 months in 2 of the patients with severe disease course because ofrenal side effects, which were reversible. In no cases were found underlying malignancies. CSP treatment seems to be a valuable second line drug in extreme severe cases of dermatomyositis, in cases who are at risk because of corticosteroid side effects, and in patients who are unresponsive to corticosteroid treatment. KEYWORDS cyclosporin A, dermatomyositis, renal side effects, malignancy INfRODUCTION Over the past years, cyclosporin A (CSP) has been used to treat a range of immunologically mediated dermatological diseases . The immunsosuppressive effects of CSP are the consequences of the inhibition of IL 2 and other lymphokine secretion by activated T cells. Its effect is established in severe chronic plaque type and pustular psoriasis (7, 8, 10, 11). Its use by dermatologists includes the treatment of psoriasis, Behcet's disease, pyoderma gangrenosum, atopic dermatitis, pemphigus vulgaris, pemphigoid bullosus, sys- temic lupus erythematosus, lichen planus, alopecia areata, ichthyosis (19) . acta dermatovenerologica AP A. Vol 2, 93, No 3 There is now increasing evidence suggesting that CSP is useful in the treatment of dermatomyositis. This is a report of uncontrolled studies in 5 patients who were treated with CSP and corticosteroids. CASE REPORTS Case l. A 52-year-old man presented with a history of myalgias and weakness and a non-pruritic erythematous rash for 5 weeks. He has had insulin-dependent diabetes mellitus for 5 years, and he has been on insulin therapy. Examination 87 Treatment of dermatomyositis revealed violaceous plaques on his neck, · forearms, chest, elbow, knee and periorbital area. Periungual erythema without teleangiectasia was noted. Baseline studies included the following detenninations (in ali cases): complete blood celi count, hemoglobin concentration, urinalysis, serum alkaline phosphatase, serum bilirubin, GOT, GPT, creatin kinase, lactic dehydrogenase, uric acid, total serum protein, blood glucose, serum creatinine, GFR clearance, BUN, antinuclear antibody test (on rat !iver), EMG, skin and muscle biopsy. Results of laboratory findings resulted in elevated creatin kinase (normal leve!: below 195 u/ml,) lactic dehydrogenase (normal leve!: 230-460 u/ml), GPT: 50 u/ml, blood glucose 15,1 mimol/1. Results of muscle biopsy and EMG were compatible with dermatomyositis. Prednisone at 30 mg/d dose was started; because of elevation in bloodglucose (19,8 mmol/1, 24,9 mml/1, 22,9 mmol/1, and aceton in urine the prednisone dosage was reduced rapidly to 20 mg/d and CSP at 5 mg/kg/dose was started. The prednisone dosage has been tapered to 14 mg/d in three weeks. CSP dosage has been subsequently tapered at monthly intervals. After 3 weeks of starting CSP treatrnent, muscle involvement improved. Skin symptoms seemed to be more resistant to treatment, but within 3 months of starting CSPtreatrnent the patient showed some improvement in the extent and severity of skin involvements. Maintenance has been achieved at 1,5 mg/kg/ d CSP and 7 mg/d prednisone. 11 months after starting the treatment he is in good general health but residual skin symptoms are stili to be seen. No serious side effects of CSP treatment were observed. Case 2. A 39-year-old man presented with muscle weakness, intennittent muscle pain in his proximal thighs, and skin lesions on his face, on his chest and on his hands of one month duration. His past medica! history included ulcus duodeni since 1983, haemorrhagia ventriculi approximately two years prior to adrnission and deep vein thrombosis 3 years prior to admission. Examination revealed periorbital heliotrope eruption, violaceous erythema of the neck, upper chest and Gottron's papules. Results of skin and muscle biopsy specimens were compatible with dermatomyositis. Ali laboratory tests were within normal leve! except elevated creatin kinase: 380 u/ml, lactic dehydrogenase: 603 u/ml and elevated serum bilirubin leve!: 31 mmol/1. Antinuclear antibody test was negative. An initial high dose of prednisone (125 mg/d) was followed by rapid rate tapering. After two weeks of starting the prednisone therapy additional CSP was started at 5 mg/kg/day dose. The patient began to respond within 4 weeks of treatment. CSP dosage was adjusted downward by 1 mg/kg/dat monthly intervals after an initial 1 month oftherapy. Maintenance has been achieved with 1,5 mg/kg/d CSP and 15 mg prednisone every other day. 10 months after starting the therapy the patient has signs of 88 neither skin nor muscle involvement. No serious side effects were noted. Serum bilirubin was rigorously monitored. The treatment did not cause further elevation of serum bilirubin leve!. Case 3. A 47-year-old female patient has had pruritic, widespread skin symptoms and muscle weakness with fatigue and lethargy. Erroneous initial diagnosis given our patient before seeing us were: contact dermatitis, viral infection, Lyell syndrome? She came to our clinic with severe proximal muscle weakness and pain in the shoulders, hips and thighs. She had severe dysphagia and respiratory muscle inv o! vement. She had widespread violaceous erythematous papules and plaques on her neck, back, chest, on back of her hands, on elbows, shoulders, buttocks, thighs and extensor arms, on some areas with subepidermal buli as and erosions. She had violaceous erythema on the face and scalp, including periorbital edema. Creatin kinase leve! was highly elevated, 2560 u/ml, lactic dehydrogenase 1309 u/ml, GOT 108 u/ml, blood sugar 10,8 mmol/1. Antinuclear antibody test was negative. Intravenous pulse steroid (1 g/d) was started as her lesions required urgent treatrnent. After 5 days when tapering the corticosteroid dose to 125 mg/d, CSP therapy was started, followed by monthly tapering. After 1 month of therapy moderate improvement was seen, creatin kinase was 258 u/ ml, lacticdehydrogenase 892 u/ml. After 2months oftherapy there was a marked improvement (creatin kinase 46 u/ml, lactic dehydrogenase 731 u/ml) both in skin and muscle involvement. 4 months after starting CSP serun1 creatinine levels rose to more than 30 % over baseline values. The dose was therefore reduced to 1,5 mg/kg/d, but the serum creatinine levels did not decrease so the CSP u·eaunent was stopped. The patient was subsequently controlled with prednisone. After 9 months after the start of the disease the patient had no skin disease, moderate muscle weakness and takes 30 mg prednisone daily. Her serum creatinine decreased to n01mal leve!. Case 4. This 45-year-old female patient presented with a 2-year history of dermatomyositis that had been previously u·eated with conicosteroids. 3 months before admission the patient stopped the treatment with no other medication anddeveloped a recurrence. Examination revealed violaceous erythema of the face, violaceous plaques on chest, on thighs, on aims with bullaformation, Gottron's papules, periungual teleangiectasia and erythema. There was severe proximal muscle weakness. Results of laboratory tests included increased creatin kinase leve!: 9530 u/ml, increased lactic dehydrogenase leve!: 1510 u/ml, increased GPT leve!: 141 u/ml. Antinuclear antibody test showed speckled type reactivity at 1/160 dil. High dose prednisone 250 mg/d was started then tapering the acta dermatovenerologica AP.A. Vol 2, 93, No 3 Treatment of dermatomyositis corticosteroid dose CSP at 5 mg/kg/d was given. After two months of treatrnent the patient's motor strength was much irnproved, muscle tendemess decreased, skin eruptions irnproved, dysphagia disappeared. Serum enzyme levels were as follows: creatinkinase 230 u/ml, lactic dehydrogenase 1101 u/rnl, GPT 69. 3 months after starting theCSPtheGFR clearance was 57 ml/min, therefore the CSP therapy was discontinued. After 11 months of this relapse she remains asymptomatic taking prednisone at a maintenance dose of 25 mg/d. Case 5. The 19-year-old female patient had been in good health until June 1991 when she noted discreeteruptions on the back ofher hands, later extensive joint tenderness with swelling of the joints: shoulder, knee and hip,_ DIP. 3 months later more extensive skin symptoms started on elbows and thighs. She was admitted to a medical departrnent. Laboratory findings revealed normal creatinkinase ( 40 u/ml), lactic deh ydrogenase (423 u/ml) negative antinuclear antibody, anti-Sm, anti- RNP, dsDNA, Ro/SSA,La/SSB tests, normal total haemolytic complement, C3, C4 level. No classified autoimmune disease was suspected. 40 mg/d prednisone was started, latertapering the dose to 20 mg/d. Joints complaints markedly improved but skin symptoms continued to be resistant to treatrnent. 1 year after the start of the disease she was adrnitted to our clinic. Examination revealed large, hyperkeratotic violaceous plaques on elbows with ulceration and calcinosis of soft ti- ssue. On thighs violaceous plaques, on the face heliotrope eruption with edema and Gottron's papules were seen. Muscle strength was normal. Skin biopsy was compatible with dermatomyositis. Ali laboratory tests - included creatin kinase and lactic dehydrogenase -werewithinnormal limits. The diagnosis of amyopathic form of dermatomyositis was made. The corticosteroid dose was increased to 60 mg/d. Skin symptoms did not respond, theref ore CSP was staited at 5 mg/kg/d with reduced dose of prednisone. After 1 month of starting therapy dramatic irnprovement was seen both in skin and joint inv olvements. The CSP dose was reduced at monthl y interval s. She has taken CSP at a maintenance dose of 2 mg/ kg/d and prednisone at dose of 15 mg/d. for 7 months then CSP therapy was stopped. No serious side effects were seen. The patient has remained symptom-free for more than 10 months after CSP therapy was discontinued. fu two cases were found underlying malignancies. DISCUSSION There are several anecdotal reports on the beneficial effect of low dose CSP in dermatomyositis . Zabel reported a 15- year-old girl with extreme severe disease who was treated with CSP after prednisone and azathioprine proved to be acta dermatovenerologica AP A. Vol 2, 93, No 3 ineffective. It was suggested that CSP treatrnent is justified in unusually severe cases of dermatomyositis unresponsive to conventional therapy (20). A 14-year-old boy has been successfully treated with CSP and low dose prednisone. The treatrnent resulted in complete remission (9). 14 patients with chronic active juvenile dermatomyositis were successfully treated with CSP. It was possible to stop steroids or reduce the steroid dose in all patients (13). Dantzig reported good response after CSP treatrnent of a 4 year-old girl (5). These experiences suggest that CSP may be valuable in treatingjuvenile dermatomyositis patients because it avoids the sequele of prolonged steroid use. Casato and his coworkers treated an adult patient with CSP and corticosteroids who responded dramatically to the treatrnent (2). Danko and her coworker treated 10 patients with CSP at 5 mg/kg/d, ali of whom responded to the treatrnent. (2 of them were unresponsive to previous corticosteroid therapy) ( 4 ). Mehregan et al successfull ytreated one case of dermatomyositis and one case of polymyositis/ scleroderma overlap who did not respond to previous corticosteroid treatrnent ( 17). Similarly good response was observed in cases of polymyositis. (1, 12, 16). However there have been treatrnent failures. The case of Levi did not respond to 4 weeks of CSP treatment (This patient was resistant to steroids and azathioprin too) (15). No serious side effects were observed in these cases. fu most studies CSP was administered with corticosteroids as in our cases. Ali five patients responded well to CSP a11d corticosteroid treatrnent. fu two of our patients with extreme severe disease form (Patients Number 3, 4) CSP was added to high dose prednisone aiming to a rapid clinical control of the disease. Both patients showed dramatic improvement after 2 months of therapy. Two of our patients (Patients Number 1, 2) were atrisk for corticosteroid treatrnent because of under-lying diseases. fu them the CSP treatrnent enabled to control the disease with lower corticosteroid doses a11d we could reduce the dose more rapidly then usual in this disease. Pa-tient Number 5 who was unresponsive to previous corti- costeroid therapy showed marked improvement after CSP was added to corticosteroids. The u·eatrnent was discontinued after 4 and 3 months of therapy in cases 3 and 4 because of renal side effects, which were reversible. However the early aggressive treatrnent with CSP andhighdose of corticosteroids of these extreme severe cases resulted in rapid conu·ol of active disease. Dermatomyositis is an illness which often responds well to early aggressive therapy with corticosteroids. Neve1theless there are cases which are resistant to treatrnent, or serious side effects to continue the treatrnent. There is no clear agreement about the use of second-line drugs such as cytotoxic agents . To broaden the additive u·eatrnent modalities seems to be 89 Treatment of dermatomyositis reasonable. Our experience as well as the experiences of others suggest that CSP may be valuable as a second-line drug in the therapy of dermatomyositis. We advocate adding it to corticosteroid therapy if large doses of corticosteroids fail to control the disease over a reasonable period of tirne, or if steroid side effects are becoming troublesome or if a more rapid onset of action is desired. To determine the exact role of CSP in dermatomyositis therapy more tirne and well controlled trials are needed. In patients on CSP development of malignancies ·has been reported (3, 14, 18). The question arises if CSP treaunent does not alter the risk of eventual late development of malignancy in dermatomyositis patients. Long-term experience and conu·olled studies are lacking to answer this question. REFERENCES l. Bendzten K, Tvede N, Andersen V, Bendixen G.: Cyclosporin for polymyositis. Lancet, 1984; 1 :792 2. Casato M, Bonomo L, Caccavo D. et. al: Clinical effects of cyclosporine in dermatomyositis. Ciin Exp Dermatol 1990; 15:121-123 3. Cockburn ITR, Krupp P .: The risk of neoplasms in patients treated with cyclosporine A J Antoimmun 1989; 2:723-731 4. Danko K, Szegedi Gy .: Cyclosporin A treaunent of dermatomyositis. Arthritis Rheumatism. 1991; 34:933-934 5. Dantzig P .: Juvenile dermatomyositis treated with cyclosporin J Amer Acad Dermatol 1990; 22:310-311 6.EjstrupL: Severedermatomyositis treated withcyclosporine A. Ann Rheum Dis 1986; 45:612-613 7. Ellis CN, DC, Hamilton TA. et.al: Cyclosporine improves psoriasis in a double blind study. JAMA 1986; 256:3110- 3116 8. Ellis CN, Fradin MS, Messana JM. et. al: Cyclosporine for plaque-type psoriasis: Results of a multi-dose double-blind trial. New Engl J Med 1991; 324:277-284 9. Girardin E, Dayer JM, Paunier L.: Cyclosporine for juvenile dermatomyositis. J Pediatr 1988; 112: 165-166 10. Griffiths CEM, Powles A V, Leonard JW. et al: Clearance of psoriasis with low dose cyclosporine. Brit Med J 1986; 293:731-732 11. Griffiths CE.: Systemic and local administration of cyclosporine in the treaunent of psoriasis. J Amer Acad Dermatol 1990; 23: 1242-1247 12. Gruhn WB, Diaz-Buxo JA.: Cyclosporine treaunent of steroid resistant interstitial pneumonitis associated with dermatomyosi tis/po 1 ym yositis. J Rheumatol 198 7' 14: 1045- 1047 13. Heckmatt J, Hasson N, Saunders C. et. al: Cyclosporine in ju venile dermatomyositis. Lancet 1989; I: 1063-1066 14. Koo YK, Kadonaga JM, Wintroub BV, et al.: The development of B-cell lymphoma in a patient with psmiasis treated with cyclosporine. J Amer Acad Dermatol 1992; 26:836-840 15. Levi S, HodgsonHJF.: Cyclosporinefor dermatomyositis Ann Rheum Dis. 1989; 48:85-86 16. Meer Vander S, Imhof JW, Borleffs JCC.: Cyclosporine for polymyositis. Ann Rheum Dis 1986; 45:612 17. MehreganDr, Daniel Su WP.: Cyclosporine u·eaunentfor dermatomyositis/polymyositis. Cutis, 1993; 51 :59-61 18. Merot Y, Miescher PA, Balsinger F et al.: Cutaneous malignantmelanomas occuring under cyclosporin A therapy: A report oftwo cases. Brit J Dermatol 1990; 123:237-239 19. Peter RU, Ruzicka T.: Cyclospmin A in der Therapie entzundlicher Dermatosen. Hautarzt, 1992; 43:687-694 20. Zabel P, Leimenstoll G, Gross WL.: Cyclosporine for acute dermatomyositis. Lancet, 1984; I: 343 AUTHORS' ADDRESSES 90 M. Marschalko, M.D., Ph. D. professor of dermatology Dept. of Dermatology, Semmelweis Medica! School, Budapest, 1085 Maria u 41. Hungary I. Papp M.D. same address J. Biro M.D. same address E. Jakob M.D. same address P. Cserhalmi M.D. same address A. Horvath M.D. same address acta derniarovenerologica AP.A. Vol 2. 93 . No 3