CHU Toulouse, Pavillon Junod, 170 Avenue de Casselardit, 31300 Toulouse, France
SIR, We read with interest the recent case report by Trotta et al. [1] about long-lasting remission and the successful treatment of acquired factor VIII inhibitors using cyclophosphamide in a patient with systemic lupus erythematosus.
There is a recognized association between the development of acquired antibodies to factor VIII and a number of diseases with an autoimmune basis (bullous pemphigoid, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, temporal arteritis, ulcerative colitis, dermatomyositis and cryoglobulinaemia), which occur in about 12% of patients with acquired antibodies to factor VIII [2]. Such an association during the course of these diseases represents a real problem for treatment.
We report here the case of a woman with coexisting PM-Scl antibodies and antibodies to factor VIII. A 72-yr-old woman who had haematuria, and in whom spontaneous bleeding into muscles had occurred on several occasions, was suffering from an aortic aneurysm. The laboratory data before surgical treatment showed a prolonged activated partial thromboplastin time (70 s vs 30 s in control subjects) with a normal prothrombin time, revealing acquired haemophilia (an evaluation 1 yr previously was normal) with a concentration of factor VIII of 5 IU/ml, due to the presence of human factor VIII inhibitor antibodies at 76 BU/ml (Bethesda Unit) [3]. An underlying autoimmune disorder was suspected, with true sicca syndrome (salivary gland biopsy was not performed) and antinuclear antibodies with anti-polymyositis-scleroderma (PM-Scl) activity (immunofluorescence on Hep-2 cells and blotting). The patient refused steroid treatment, so her first-line therapy was with high-dose intravenous immunoglobulin (400 mg/kg per day for 5 days). After 4 months, the failure of this therapy and repeated spontaneous bleeding led us to initiate treatment with a steroid (prednisone 1 mg/kg per day) and cyclophosphamide (50 mg/day). This treatment was followed by a normal activated partial thromboplastin time and the complete disappearance of antibodies to factor VIII (5 BU/ml after 8 weeks), and factor VIII activity increased to 70% of normal. Corticosteroid treatment was stopped after 4 months and the patient remained in remission with cyclophosphamide alone. This last treatment was stopped after 10 months, and 8 months later the patient was still in remission. Sicca syndrome remained without modification, but antinuclear antibodies disappeared after 3 months.
The diagnosis of acquired haemophilia due to factor VIII inhibitor is consistent with most of the reported cases [2]: age >60 yr, spontaneous bleeding, prolonged activated partial thromboplastin time with a normal prothrombin time, and a low factor VIII level in relation to antibodies to factor VIII detected by the Bethesda method [2, 3].
The association with PM-Scl antibodies has not been reported previously. PM-Scl autoantibodies are a type of nucleolar autoantibodies. Three patterns of nucleolar staining are typically observed by indirect immunofluorescence in Hep-2 cells: speckled or punctate (RNA polymerase 1 specificity); clumpy (U3 RNP specificity); and homogeneous (PM-Scl specificity). PM-Scl antibodies are found in patients with overlap connective tissue disease characterized by the Raynaud phenomenon, scleroderma, myositis, arthritis and pulmonary restriction. The presence of PM-Scl antibodies is usually a good prognostic sign. With the exception of sicca syndrome, our patient did not present any clinical signs of connective tissue disease, and the true significance of these antibodies remains unknown [4].
Successful treatment of factor VIII inhibitors requires the immediate control of haemorrhage and long-term suppression of the autoantibody. Our patient's homeostasis status did not need symptomatic treatment, such as porcine factor VIII. With regard to immunosuppressive regimens, treatment with high-dose intravenous gamma globulin for the presence of factor VIII antibodies may or may not be successful [5]. It is not usually considered to be a first-line therapy, but may be useful in combination with other treatments. Many other immunosuppressive drugs have been proposed for long-term suppression. Corticosteroids and cyclophosphamide are the most widely used, and good effectiveness in the control of the level of factor VIII inhibitors has been reported [1, 6]. The complete effectiveness of these treatments in suppressing PM-Scl antibodies is surprising, but there are no reports of their effects on the underlying biological autoimmune markers.
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