Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura in the setting of adult-onset Still's disease

Sir, Adult-onset Still’s disease (AOSD) is a systemic autoimmune disorder of unknown aetiology and pathogenesis, characterized by high spiking fever, a salmon-pink evanescent rash and polyarthritis. Although the aetiology and pathogenesis of this disease are not fully understood, several lines of evidence suggested that immunological mechanism play important roles in the pathogenesis [1]. Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disorder characterized by haemolytic anaemia, consumptive thrombocytopenia, disturbance of consciousness, fever and renal damage. A major breakthrough in the understanding of the pathogenesis of TTP is the discovery of deficient activity of the von Willebrand factor-cleaving protease (vWF-CP), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-13 [2–4], Severe ADAMTS13 deficiency is an important pathogenetic factor for many cases of classical TTP. TTP is occasionally associated with various systemic autoimmune diseases such as systemic lupus erythematosus and Sjogren’s syndrome [5, 6]. However, TTP is rarely reported occurring with AOSD. Here, we describe the first case report of AOSD that developed TTP with the detection of diminished ADAMTS-13 activity. A 23-yr-old woman with a 4-yr history of AOSD was admitted to our hospital complaining of nausea, vomitting and gross haematuria. Since her onset of AOSD, the patient had had three exacerbations of spiking fever and polyarthritis in the past. She was administered prednisolone for recurrent spiking fever and polyarthrits at another hospital. Though D-penicillamine and methotrexate were also used at one point, they were discontinued owing to adverse effects. At the time of this current admission, renal function (serum creatinine was 0.7 mg/dl) and platelet count (36 × 104/μ1) were normal. However, her disease activity and polyarthritis had not been well-controlled with prednisolone only. She first visited our clinic in 1998, and three weeks after prednisolone was tapered from 15 to 14 mg/day, severe polyarthritis and low-grade fever appeared, and she was admitted to Tokyo Women’s Medical University Aoyama Hospital in May 2000 (Fig. 1). Fig 1 Clinical course. Onset of AOSD: spiking fever, salmon-pink evascent rash and polyarthritis repeatedly appeared as the dose of corticosteroid was decreased. These symptons were ameliorated with increasing dose of corticosteroid. Just before the onset of ... On admission, physical examination revealed pale and yellow sclera, epigastric tenderness, petechia on skin and active arthritis on bilateral hand joints and knee joints. Petechial haemorrhage on gastric mucosa was observed with gastrointestinal fibre-optic endoscopy. Although paralysis and pathologic reflex were not observed, floating disturbance of consciousness appeared on day 2. Laboratory data revealed haemolytic analemia [haemoglobin (Hb) 4.5 g/dl], thrombocytopenia (0.7 × 104/μl), elevated lactic acid dehydrogenase (LDH) (2548 IU/l), normal hepatic function (asparate aminotransferase (AST) 36 IU/l, alanine aminotransferase (ALT) 11 IU/l), normal renal function (serum creatinine was 1.1 mg/dl) and haematuria. Serum ferritin level was markedly elevated to 3500 mg/dl. Coombs test was negative, and red cell fragmentation was observed on peripheral blood smear. We made a diagnosis of TTP associated with AOSD, according to physical examination and characteristic laboratory data. The patient was treated with low-dose aspirin (100 mg/day), high-dose corticosteroid (1 g of methylprednisolone/day for 3 days followed by prednisolone 100 mg/day) and plasma exchange (total 10 times). After the first plasmapheresis was performed, the disturbance of consciousness disappeared rapidly, and haemolytic aneamia, thrombocytopenia and hepatic and renal function were completely ameliorated (Fig. 1). At the time of discharge, laboratory data revealed normal haemoglobin level (Hb 12.1 g/dl), platelet count (23.5 × 104/μl), LDH (269 IU/l) and renal function (serum creatinine was 0.7 mg/dl). The patient has had follow-up for 5 yrs, and to date, the disease activity has been fairly controlled with corticosteroid (10–20 mg/day) and ciclosporin A (200 mg/day) and no indications of TTP have become apparent thus far. In the plasma sample obtained before the plasma-exchange treatment, ADAMTS-13 activity of this patient was decreased to < 10% of that in the normal control plasma. The 2:1 mixing study revealed that plasma of this patient contained a suppressor function of ADAMTS-13 activity in normal plasma [2, 7]. In the clinical course of this case, just before the onset of TTP, prednisolone dose was decreased from 15 to 14 mg/day, symptoms of AOSD were exacerbated and serum ferritin level was increased. In this case, the onset of TTP coincided with the exacerbation of AOSD. Using the sample collected at the time of exacerbation of AOSD and the onset of TTP prior to plasma-exchange treatment, we conducted functional studies of ADAMTS-13 activity and found that it was suppressed by the presence of the plasma of this patient (data not shown). In the presence of ADAMTS-13 inhibitors, such as autoantibodies against ADAMTS-13, intravascular platelet thrombi develop and present as a clinical feature of TTP. A past report shows that autoantibodies inactivating ADAMTS-13 are not frequent in patients with autoimmune diseases without thrombosis [8]. Therefore, the presence of an autoantibody blocking ADAMTS-13 is not a common feature of autoimmune diseases, including AOSD. In our present case, epitope specificity of autoantibody might have changed during the course of the exacerbation of AOSD, and coincidently, the production of autoantibodies that could suppress the protease activity of ADAMTS-13 may have a role in the pathogenesis of TTP. To draw a clear picture of the pathogenesis of TTP in autoimmune diseases, further studies are needed to characterize anti-ADAMTS-13 autoantibodies.