Penicillamine-Induced Juvenile Dermatomyositis: A Rare Clinical Encounter

Dear Editor, Juvenile dermatomyositis (JDM) is an autoimmune connective tissue disorder characterized by skin manifestations and proximal muscle weakness. Dermatomyositis (DM) can develop in a genetically predisposed individual following an environmental trigger such as infections, vaccines, drugs, physical exertion, ultraviolet radiation, emotional stress, etc.[1] Although many drugs are being implicated in the development of DM, the pathogenesis of drug-induced DM is not well established yet. We describe here a rare presentation of penicillamine-induced DM in a 7-year-old girl with Wilson's disease. A 7-year-old girl with Wilson's disease, presented with complaints of reddish itchy rash on both the cheeks and ears with aggravation of the rash on sun exposure for a duration of 1 month. Also, she had red raised lesions on her elbows, knees, and knuckles for the past one month. The patient also experienced difficulty in standing up from a squatting position and combing her hair. Her 2 older siblings were diagnosed with Wilson's disease and died of liver failure. There was no history of dyspnea, dysphagia, and weight loss. The patient has been taking one tablet of penicillamine 250 mg once daily since one and a half years. On a general physical examination, her vital parameters were within normal limits. Cutaneous examination showed an erythematous to violaceous rash on both the cheeks and pinnae, and multiple erythematous papules on both the knees, elbows, and metacarpophalangeal joints, proximal and distal interphalangeal joints of both the hands (Gottron's papules) [Figure 1]. Musculoskeletal examination revealed mild to moderate tenderness and power grade - 3/5 in proximal muscles of both the upper and lower limbs. Investigations revealed hemoglobin – 9.3 g/dl, aspartate aminotransferase (AST) level – 78 U/l. The rest of the complete blood count, liver, and renal function tests were within normal limits. Muscle enzymes like creatine phosphokinase (CPK) – 314 U/l (N: <154 U/l), lactate dehydrogenase (LDH) – 479 U/l (N: 105-333 U/l), and aldolase – 13.7 U/l (N: 1 – 7.5 U/l) were raised. Other investigations like 24-hour urinary protein – 415 mg (N: <140 mg) and 24-hour urinary copper – 197 mg (N: <53 mg) were also raised. Antinuclear antibodies (ANA) titer was 1:1000; however, the ANA blot was negative. Biopsy from an erythematous papule from the right elbow showed basal cell layer vacuolar degeneration and mucin deposition in the dermis [Figure 2]. Magnetic resonance imaging (MRI) showed hyperintensity in proximal muscles of both the upper and lower limbs, signifying muscle edema [Figure 3]. Based on clinical, biochemical, histopathological, and radiological features, the patient was diagnosed with penicillamine-induced juvenile dermatomyositis. As per the pediatrician's opinion, tablet penicillamine was stopped, and the tablet trientine hydrochloride 333 mg twice daily was started. The patient was treated with a tablet prednisolone 15 mg once daily, a tablet hydroxychloroquine 100 mg once daily, and a tablet methotrexate 5 mg weekly. After 3 months of receiving immunosuppressive therapy, the patient experienced marked improvement in both muscle weakness and cutaneous manifestations. Notably, the patient remains in complete remission, even though immunosuppressants were discontinued three months ago.Figure 1: (a and b) Erythematous to violaceous rash on both the cheeks and pinnae, (c and d) Multiple erythematous papules on both the knees and elbows (Gottron's papule)Figure 2: (a) Basal cell layer vacuolar degeneration (yellow circle) and mucin deposition (black circle) in the dermis (b) Basal cell layer vacuolar degeneration with pigment incontinence (blue rectangle) (H & E, 40x) (c) Alcian blue Mucin deposition is seen in the dermis (black arrow) (40x)Figure 3: (a-c) MRI (T2 weighted) showed hyperintense signaling in proximal muscles of both the upper and the lower limbs (yellow arrow)JDM is a systemic, idiopathic, inflammatory connective tissue disease, mainly affecting the skin and the muscles and starts before 16 years of age. Rarely, DM can also be caused by drugs. Drug-induced DM is also called drug-induced dermopathy, pseudodermatomyositis, and dermatomyositis-like eruption. A review of 70 case reports of drug-induced DM by Siedler and Gotlieb concluded that hydroxyurea, hydroxymethylglutaryl (HMG) Co-A reductase inhibitors, and penicillamine are the most common drugs implicated in the causation of DM. A total of 10 cases of penicillamine-induced DM were reported in this study.[2] Other drugs include non-steroidal anti-inflammatory drugs (niflumic acid, diclofenac, and phenylbutazone), anti-infective agents (penicillins, sulphonamides, and isoniazid), anti-neoplastic (tegafur, cyclophosphamide, etoposide, and imatinib), lipid-lowering drugs (statins and fibrates), Bacillus Calmette–Guérin vaccine, terbinafine, omeprazole, interferon α-2b, phenytoin, and alfuzosin.[3] Although the pathogenesis of drug-induced DM is not yet clear, it has been hypothesized that drugs induce autoimmunity by promoting apoptosis and intensifying the innate immune response, and this leads to the displacement of various cellular antigens resulting in a state of neo-antigenicity and anti-endothelial cell antibody formation.[4] Penicillamine has been used in the long-term treatment of Wilson's disease. The occurrence of penicillamine-induced dermatomyositis is not dependent on the dose or on the duration of treatment. There are 40 reported cases of penicillamine-induced DM in the literature.[3] Drug-induced dermatomyositis can present as a classic dermatomyositis, amyopathic dermatomyositis, myositis without cutaneous findings, elevated creatine kinase without cutaneous findings, or obvious muscle disease. Serology for anti-Jo-1 antibodies is usually negative. However, the ANA titer could be either positive or negative.[2] Muscle and skin biopsies reveal the same changes seen in dermatomyositis and, thus, cannot be used as differentiating features. Polymyositis/Dermatomyositis induced by penicillamine is sometimes found to be fatal, due to associated myocardial damage.[5] Hence, careful attention is required to be given for early diagnosis and prompt treatment of PM/DM induced by penicillamine therapy. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.