A Patient with a Severe Scleroedema diabeticorum, Partially Responding to Low-Dose Methotrexate

Cutaneous signs accompanying diabetes mellitus (DM) are numerous and varied. According to Gilgor and Lazarus [1], 30% of patients with DM develop a skin disorder that is an early indicator of yet undiagnosed diabetes or a complication of known diabetes. A relatively underestimated complication of diabetes is scleroedema diabeticorum. It forms a distinct clinical entity and can be differentiated from scleroedema adultorum of Buschke, which develops at any age, frequently after an upper respiratory infection and spontaneously clears in months or years [2].Scleroedema diabeticorum is preceded by long-existing, poorly regulated insulin-dependent DM and is often limited to the upper back, neck and shoulders [3, 4, 5]. In this case report, we describe a patient with an unusual widespread and disabling form of scleroedema diabeticorum, partially responding to treatment with low-dose methotrexate (MTX).A 40-year-old woman presented with a 10-year history of a progressive thickening and induration of the skin of the neck and shoulders. This had gradually extended down the upper arms and back and also involved the face, presternal area and upper legs. She has been suffering from insulin-dependent DM since the age of 3 years. Previous complications of her long-existing, poorly controlled insulin-dependent diabetes included polyneuropathy, cataract and a symmetric carpal tunnel syndrome. There was no history of Raynaud phenomenon or dysphagia.Physical examination showed an obese woman with symmetric thickening and induration of the skin of her face, posterior neck, shoulders, back, presternal area, upper arms and upper legs. It was not possible to pinch or move the skin of these parts of the body. There was no sclerodactyly or telangiectasia. The joints showed no signs of arthritis or arthrosis. While standing relaxed, her arms were not stretched but remained in flexure (fig. 1).Laboratory investigations including full blood count, ESR, renal and liver functions showed no abnormalities. HbA1c was 8.9%. Positive antinuclear antibodies and antibodies to histones were found. No other auto-antibodies were detected and in addition chest X-ray and pulmonary function tests were normal. Histology revealed a thickened dermis with large swollen collagen bundles, separated by fenestrations, containing minimal deposits of mucin. The epidermis was normal and only a few skin adnexae were seen. Because improvement of sclerotic skin changes by MTX has previously been shown in a double-blind placebo-controlled study in patients with systemic sclerosis [6], MTX in a dose of 15 mg/week was administered. The skin of the face and upper trunk became less indurated after 2 months of treatment. Although we continued therapy for another 4 months, no further improvement was achieved. Physiotherapeutic treatment was started to improve mobility.Scleroedema diabeticorum is preceded by a long-existing, insulin-dependent difficult to control DM. Patients are usually of middle age, obese and have diabetic complications [7, 8, 9]. The onset is insidious. The lesions are typically confined to the face, neck, upper part of the trunk and proximal upper extremities. Histologically, scleroedema is characterized by a thickening of the dermis, due to an increase in hypertrophic collagen bundles which are separated by an accumulation of glycosaminoglycans [8, 10, 11]. In the literature, incidences of 2.5–14% in diabetic patients are reported [3, 12]. Although hyperglycaemia is thought to be important in the aetiology of scleroedema diabeticorum, it is feasible that poorly regulated diabetes is not sufficient alone to lead to scleroedema. Otherwise, scleroedema diabeticorum would be encountered more frequently.Treatment of scleroedema diabeticorum is disappointing. Therapy aimed at a strict regulation of blood glucose has no effect on the lesions, once they exist [7, 13]. Treatment with steroids, penicillamine, penicillin or intralesional insulin do not seem to improve the lesions [4, 8]. Physiotherapy or lymph drainage can be of benefit and induce slight improvement. Additional use of pentoxifylline may soften the lesions [7]. In a recent study, bath-PUVA appeared to be effective in 3 patients [14]. Our patient showed some improvement of the induration of her skin lesions after low-dose treatment with MTX. On the other hand, no resolution of the skin lesions was achieved.The pathogenetic mechanism of the induration of the skin is not totally unravelled. It is postulated that the hyperglycaemia leads to irreversible glycation of collagen [3]. The glycation process (non-enzymatic glycosylation) can be divided into 3 stages: first the formation of the Amadori product, which is an irreversible product significantly increased in diabetic patients, then spreading with glyco-oxidation reactions and finally the formation of advanced glycation end products [15, 16]. This action causes an increase in cross-linking and alteration in packing and impaired collagen resorption, rendering the collagen fibres resistant to degradation by collagenase. This abnormal collagen accumulates in the dermis and forms the substrate for the induration in the skin. With levels of hyperglycaemia in vivo, the process of glycation probably takes several months or years to become biochemically important [3].It is therefore conceivable that once the glycation is started, this slow process will continue for years despite a regulation of the blood sugar level to normal. The process of cross-linking and modification of collagen structure will progress, which could explain the fact that strict control of diabetes does not seem to affect the course of the disease once it is started [7, 13]. The partial improvement of skin lesions of scleroedema diabeticorum suggests interference of MTX with this process, although the exact mechanism of action of MTX in this disorder is not known.This patient, in whom the scleroedema diabeticorum is widespread, illustrates a severe form of a relatively common complication of DM which often remains unrecognized. As no curative treatment is available, further controlled trials are necessary to establish the importance of a tight regulation of blood glucose to prevent this skin disorder.