Rheumatology Advance Access originally published online on October 30, 2007
Rheumatology 2007 46(12):1862-1863; doi:10.1093/rheumatology/kem272
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Relapse of skin thickening after discontinuation or decrease of azathioprine therapy in a patient with diffuse cutaneous systemic sclerosis
Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden
Correspondence to: A. Scheja, Department of Rheumatology, Lund University Hospital, S-221 85, Lund, Sweden. E-mail: agneta.scheja{at}med.lu.se
SIR, Skin thickening in diffuse cutaneous systemic sclerosis (dcSSc) is reported to reach its maximum early in the course of disease, usually within 1–3 yrs from the onset of skin involvement, during which period internal organ involvement mainly arises [1]. Here we report on a male patient with dcSSc who had two periods of relapsing skin involvement occurring after discontinuation or decrease of azathioprine therapy. The relapses were registered by palpation and by ultrasound (US) assessment.
A man born in 1931 with a history of hypertension, macroscopic haematuria and a diagnosis of benign prostate hyperplasia was admitted in October 1995 with a 1-yr history of Raynaud's phenomenon. In addition, he had developed swelling and stiffness of hands and feet for half a year and complained of fatigue. Skin palpation revealed thickening over fingers, arms and feet but not proximal to elbows and knees. A diagnosis of limited cutaneous systemic sclerosis (lcSSc) was established, with involvement of skin (skin score 15 points with a modified Rodnan skin score [2]), gastrointestinal tract and lungs [vital capacity (VC) 76% of predicted value (%p) and carbon monoxide diffusing capacity (DLCO) 64%p]. High-resolution computed tomography (HRCT) was not available at the time at our department but chest radiography was normal. Because of the pulmonary involvement, evidenced by decreased pulmonary function despite short disease duration, oral cyclophosphamide therapy was started in November 1995. Clinical assessment in December 1995 showed progression of skin involvement (Fig. 1A), which by then was also present proximal of the knees, and the diagnosis was revised to dcSSc. The cyclophosphamide therapy was stopped after only a few weeks due to haematuria. The patient was admitted to the urology service where the haematuria was assessed and associated to the benign prostate hyperplasia. Transurethral prostatectomy was performed and the cyclophosphamide therapy was restarted with three i.v. pulses (500, 700 and 700 mg) during March and April 1996 followed by oral therapy. Assessment in October 1996 showed stabilized VC 79%p, with DLCO 52%p and normal X-ray of the chest. The cyclophosphamide therapy was discontinued and azathioprine was started in February 1997 at which time the patient had been treated for 1 yr with cyclophosphamide. At repeated assessments, the skin involvement decreased and the pulmonary function remained stable. The gradual decrease in skin thickness was verified by high-frequency (20 MHz) US [3, 4] (Fig. 1B), which also showed an increase in echogenicity compared with that in 1995. In September 2000, the skin score was only 1 point and in June 2001, the azathioprine therapy was discontinued. Five months later, in November 2001, stiffness of hands and arms had recurred and the skin score was now assessed as 20 points (Fig. 1A). The increase in skin thickness was verified by US (Fig. 1B) that also showed lower echogenicity. No decrease in pulmonary function was noted and HRCT was normal. Azathioprine was reintroduced at a dosage of 150 mg/day. Subsequently, the skin involvement again regressed. In December 2003, after 2 yrs of azathioprine treatment, the dose was tapered to 100 mg/day and in September 2005, after another 18 months, further to 50 mg/day. However, at the yearly check up in September 2006, a new skin worsening was noted by the patient. The examination showed increased skin score and US indicated increased skin involvement. The azathioprine dose was again increased to 150 mg daily. At the most recent visit to the out-patient clinic in April 2007, the patient reported that the skin stiffness had disappeared. The skin score and the US assessment showed a modest improvement. The pulmonary function tests remained stable.
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Several open reports [5, 6] and two controlled studies [7, 8] have shown a beneficial effect of cyclophosphamide in patients with interstitial lung disease in SSc. One of the controlled studies in addition reported an improved skin score compared with the placebo group [8]. Due to the risk for serious dose-related side-effects, most centres try to restrict cyclophosphamide therapy to between 6 and 12 months. This is then followed by maintenance therapy with e.g. azathioprine or more recently with mycophenolate mofetil [9]. There are no agreed recommendations for how long the maintenance therapy should be continued. We show in the present case report that relapses of skin involvement can occur after more than 10 yrs of disease. Although the assessments were not blinded, to the patient's perception of the skin involvement, the relapses were confirmed by two different methods performed by three different examiners (ultrasound by M.W. and skin score by A.S. or A.Å.), which add substance to the report. This case also suggests that azathioprine should be subjected to controlled trials in SSc.
Disclosure statement: The authors have declared no conflicts of interest.
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[Abstract/Free Full Text]
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