Scleromyxedema: A Complete Response to Prednisone

Case Report

Scleromyxedema: A Complete Response to Prednisone DANIEL RAYSON, M.D.,* JOHN A. LUST, M.D., PH.D., ALAN DUNCAN, M.D., AND W. P. DANIEL Su, M.D. Scleromyxedema is a disorder characterized by a typical rash due to the accumulation of mucin in the dermis. It is always associated with a monoclonal protein in the serum and can have a wide variety of systemic manifestations. We describe a 40-year-old woman who had scleromyxedema associated with a monoclonal G Aprotein. Severe systemic symptoms included fatigue, esophageal dysmotility, and myopathy. Symptoms resolved completely with oral prednisone therapy, and she remained in elini-

cal remission 24 months after use of prednisone was discontinued. Scleromyxedema is commonly treated with alkylating agents, which have been associated with pronounced morbidity and mortality. We suggest that oral corticosteroid therapy may be a reasonable initial choice for treating this disease and that alkylating agents be reo served for corticosteroid-refractory disease. Mayo Clin Proc 1999;74:481-484

S

cleromyxedema is a rare acquired cutaneous mucinosis that can have various systemic manifestations. It is associated with a paraproteinemia, the importance of which remains to be elucidated. Treatment of this condition is difficult. Several therapies have been used with varying degrees of success. Because of the coexistence of the monoclonal protein, investigators have suggested that scleromyxedema may be related to or may be a variant of multiple myeloma. Consequently, alkylating agents, either alone or in combination with corticosteroids, have been the systemic agents most frequently used in managing the disease. Long-term follow-up has shown that alkylating agents can produce substantial benefit in certain patients; however, overall, therapy-related morbidity and mortality are substantial. We describe a patient with severe cutaneous and systemic manifestations of scleromyxedema who had a complete response to oral prednisone therapy.

and antecubital fossae bilaterally. She also noted diffuse skin thickening and tightness and had been forced to remove her rings. Her earlobes had thickened to the point that she was unable to wear earrings. She could not completely open her mouth. Skin biopsy specimens (Fig. 1 and 2) demonstrated marked mucin deposition in the dermis along with an increase in fibroblasts and collagen, findings consistent with a diagnosis of sc1eromyxedema. The patient was treated with isotretinoin, 40 mg daily, but during the following month, she experienced progressive proximal muscle weakness and fatigue. In addition, she had difficulty swallowing both solids and liquids, and she experienced frequent choking episodes. Her rash worsened. The dosage of isotretinoin was increased to 80 mg daily; no response occurred. She was referred to Mayo Clinic Rochester in January 1996. At that time, the patient's complaints were profound muscle weakness to the point that she was unable to climb stairs. The dysphagia had resulted in numerous choking episodes, and she had lost 7 to 9 kg. Her skin had become more thickened, and she was unable to flex her fingers completely. Her only medication was isotretinoin, 40 mg twice daily. Physical examination of the patient was remarkable for innumerable flesh-colored papules (l to 2 rom) over the dorsum of her hands, antecubital fossae, face, and back of her neck. Her earlobes had increased to approximately 3 times that of normal. She had proximal arm weakness and weakness of the neck flexors with intact sensation and reflexes. Her skin demonstrated a diffuse thickening, most prominently on the dorsum of her hands and the glabella. Findings on the rest of the physical examination were normal. Laboratory results are summarized in Table 1. Findings on a metastatic bone survey were normal. A bone marrow

REPORT OF CASE A 40-year-old woman sought assessment at her local medical facility in the summer of 1995 because of upper extremity arthralgias and myalgias. She was treated with lowdose prednisone for 1 month and had complete resolution of her symptoms. Shortly thereafter, she noted a papular skin eruption affecting primarily the dorsum of her hands From the Division of Hematology and Internal Medicine (D.R., J.A.L.), Division of General Internal Medicine (A.D.), and Department of Dermatology (W.P.D.S.), Mayo Clinic Rochester, Rochester, Minnesota. *Current address: Ontario, Canada.

London Regional Cancer Centre, London,

Address reprint requests and correspondence to Dr. J. A. Lust, Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1999;74:481-484

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Fig. 1. Photomicrograph showing mucinousdeposit in upper and middle dermis and proliferation of fibroblasts. (Hematoxylineosin; original magnification, x50.)

Fig. 2. Photomicrograph of skin biopsy specimen, showing pronounced deposit of mucin associated with increase in fibroblasts and collagen. (Hematoxylin-eosin; originalmagnification, x200.)

aspirate and biopsy showed normal trilineage hematopoiesis with less than 5% plasma cells. An esophageal motility study demonstrated pronounced weakness of the lower esophageal sphincter, with a mean pressure of II mm Hg, which is compatible with a neuromuscular process. Electromyographic examination showed normal nerve conduction, but profuse fibrillations were seen in all muscle groups with electrophysiologic features of myonecrosis. A muscle biopsy demonstrated an active inflammatory myopathy. The patient was treated with prednisone, 60 mg daily, and Pneumocystis carinii pneumonia prophylaxis with trimethoprim-sulfamethoxazole DS (double strength) was given twice weekly. At l-month follow-up, she reported improvement in her swallowing and no further choking spells. Her arm strength had returned to normal, and she was exercising on a treadmill daily. The physical examination was remarkable for softer skin, partial regression of the skin lesions, and normal muscle strength. The creatine kinase level had normalized, and the monoclonal protein had decreased to 0.19 g/dL. The dosage of prednisone was slowly tapered, and all treatment was discontinued on Nov. 17, 1996. Sequential laboratory test results are listed in Table 1. Management was complicated by solitary episodes of herpes zoster, oral candidiasis, bronchitis, and a urinary tract infection, all of which were easily treated. Seven months after discontinuation of the prednisone therapy, the patient's skin lesions had completely resolved. Electromyographic studies showed resolution of the myopathic process, and she remained systemically well. She was last seen in November 1998, 24 months after use

of prednisone was discontinued, and she was still in clinical remission. DISCUSSION Scleromyxedema is characterized by the accumulation of mucinous material consisting of acid glycosaminoglycan in the dermal layers of the skin. Characteristic histologic features of this disease include focal deposition of mucin in the papillary and reticular dennis and increased numbers of fibroblasts. The predominant glycosaminoglycan is hyaluronic acid. 1 Deposition of this substance leads to various dennatopathologic manifestations, which were initially classified in 1953 by Montgomery and Underwood.' Cutaneous manifestations associated with scleromyxedema range from discrete areas of tiny flesh-colored papules to a diffuse infiltrative dermopathy that results in a generalized thickening of the skin. Common complaints are restriction in movement of the fingers and difficulties in completely opening the mouth. Involvement of the face ~an result in a characteristic leonine facies.s" Although dennatologic manifestations may be similar to those in systemic sclerosis, the absence of Raynaud' s phenomenon, calcinosis cutis, and nail bed capillary proliferation suggests a diagnosis of sclerornyxedema,? Common extracutaneous abnormalities include esophageal motility disturbances, proximal myopathies, and central nervous system disorders. Esophageal dysfunction is mainly localized to the upper esophagus and is most commonly found in patients with an associated myopathy.' Muscle biopsy specimens have revealed a necrotizing and vacuolar myopathy.9.11 Neurologic manifestations range

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Table I.-Laboratory Test Results, Stratified by Date, in 40-Year-Old Woman With Scleromyxedema* Normal

Date

Determination

range

1/96

2/96

12/96

6/97

4/98

Hemoglobin (gldL) Leukocytes (XI091L) Platelets (XI091L ) Aspartate aminotransferase (UIL) Calcium (mg/dL) Creatinine (mg/dL) Creatine kinase (UIL) Aldolase (UIL) Monoclonal protein (lgG A, g/dL) Sensitive thyroid-stimulating hormone (mIUIL) Urinary protein immunoelectrophoresis

12.0-15.5 3.5-10.5 150-450

13.0 4.7 242

14.6 11.7 231

13.4 5.2 228

12.3 5.9 251

12.1 6.1 250

12-31 8.9-10.1 0.6-0.9 38-176 <7.4

48 9.0 0.7 648 12.7

24 9.3 0.6 157 ND

14 9.3 0.9 79 ND

17 9.8 0.7 73 ND

ND ND ND 99 ND

0.42

0.19

ND

0.24

ND

3.3

ND

ND

ND

ND

Neg

ND

ND

ND

ND

0.3-5.0

*ND =not done; Neg =negative.

from median nerve entrapment neuropath y and other peripheral sensory neuropathies to a fulminant organic brain syndrome.P-" Histologic examination, however, has failed to demonstrate direct neuronal or cerebral involvement with the mucinous process." The existence of a paraproteinemia associated with scleromyxedema was first reported by McCarthy and assoelates" in 1964. They suggested that scleromyxedema was a systemic disease related to multiple myeloma with the skin as the targ et organ and that the clinical mani festations were a result of tissue deposition of an abnormal immunoglobulin. Since that report, the coexistence of a monoclon al protein with scleromyxedema has been repeatedly verified and represents the most common laboratory abnormalit y associated with this disease. Hill and colleagues" prop osed that the presence of a paraproteinemia was one of the defining features of the disease. A monoclonal IgG A. protein is most commonly isol ated in patients with scleromyxedema, but IgG K, IgM A., and biclonal monoclonal gammopathies have also been described." The monoclonal IgG protein is most often found in the slow gamma region on serum protein electrophoresis. Thi s electrophoretic pattern differs from that in most other ca ses of monoclonal gammopathies or multiple myeloma and has been suggested to support the diagnosis of scleromyxedema. " Scleromyxedema coexi sting with multiple myeloma has been described,'? but most cases do not evolve into nor are they associated with a plasma cell dyscrasia. The role of the monoclonal protein in the cause and clinical manifestations of scleromyxedema remains uncertain.P'P

Tr eatment of sclero my xedcma is difficult. Various therapies have been used . Localized skin involvement ha s been treated with external beam irradiation 16 and topically applied corticosteroids." More generalized invol vement has led to the use of extracorporeal photochemotherapy," psoralen plus ultraviolet A,25 and retinoids;" success has varied. For advanced disease with systemic invo lvement, plasmapheresisv-" and various chemotherapeutic agents have been used , including cyclophosphamide," met hotrexate," chlorambucil," and 2-chlorodeoxyadenosine.30 Rarely, spontaneous remi ssion has been obs erve d." In 1969, Feldman and coworkers" reported a dramatic response to melphalan. This was the first documented success of systemic therapy for this disease. In 1979, Harris and associates" described a series of eight patients treated with melphalan . Four had an excellent clinical response, but two died of therapeutic com plications. Recently, Dinneen and Dicken' ? described the largest series of patients treated with this agent to date . Of 17 patients treated with melphalan, 6 (35% ) died of therapeutic com plications, 4 (24 %) died of sepsis, and 2 (12%) died of acute leuk emia. Of the 17 patients, 12 responded to therapy; 8 responses were transient and limited to improvement in the skin. Corticosteroids have been used alone and in combination with alkylating agents or plasmapheresis. They have been shown to result in occasional abatement of the myopathic and dermatologic features of the disease. I I Our patient had an excellent clinical response, but the duration remains to be determined. Morbidity due to therapy was limited to several easily treated infectious complications.

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Although finn treatment recommendations cannot be generated from a solitary case, we suggest that oral corticosteroid therapy may be a reasonable initial choice for this disease, particularly in young patients, and that alkylating agents be reserved for corticosteroid-refractory or progressive disease.

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