Acquired inhibitors to factor VIII in non-hemophiliacs are rare, occurring in one of every five million individuals, and can lead to spontaneous hemorrhages.¹ They may develop in association with collagen vascular diseases such as systemic lupus erythematosus (SLE), which accounts for only 6% of cases, in malignancy, with certain drugs, and during pregnancy.² In nearly half of the patients, no underlying cause is apparent.² Significant bleeding, soft tissue hematoma and hemarthrosis are common complications, especially with strong inhibitors of more than 10 Bethesda units (BU)/ml.^2,3 Treatment consists of active control of bleeding, using high-dose human factor VIII, activated prothrombin complex or porcine factor VIII concentrates, together with aggressive immunosuppression to eliminate the inhibitor.³

More recently, recombinant activated factor VII (rF-VIIa) has been used for the control of bleeding due to inhibitors in hemophiliacs, and was shown to be equally effective in bypassing the inhibitory action in the management of non-hemophiliacs.⁴ Immunosuppression using cyclophosphamide (CYC) with or without corticosteroids is a well-established mode of treatment in the management of factor VIII inhibitors with severe bleeding complications.^5,6 Intravenous immunoglobulins (IVIG) were also reported to be successful in the management of acquired factor VIII inhibitor in SLE refractory to other modes of treatment.^7-9 We report the successful use of a combination of high-dose human factor VIII, CYC and prednisolone to eliminate factor VIII inhibitor in a patient suffering from documented childhood-onset SLE.

Our patient was a 16-year-old girl suffering from childhood-onset SLE. her symptoms started at the age of eight years, and she fulfilled the revised criteria of the American College of Rheumatology for the classification of SLE.¹⁰ She had a long history of non-erosive

From the Regional Laboratory and Blood Bank, Department of Haematology (Dr. Islam) and from the Department of Medicine, Rheumatology Division (Dr. Abdullah), Dammam Central Hospital, Dammam, Saudi Arabia.

Address reprint requests and correspondence to Dr. Islam: P.O. Box 6571, Dammam 31452, Saudi Arabia.

Accepted for publication 21 November 1998. Received 19 July 1998.

polyarthritis, pleuritis, mouth ulcers and positive antinuclear antibodies (ANA). titer at diagnosis was 1:1280 coarse speckled pattern. Our patient was initially treated with oral prednisolone. During a follow-up visit nearly eight years after the onset of symptoms, she reported easy bruising. Her only medication at the time was maintenance prednisolone 10 mg daily.

Physical examination revealed multiple ecchymoses on the arms, legs and trunk, and slight gum bleeding. Her father had died many years previously from undetermined causes, but her mother, brothers and sisters were all well. The presence of SLE familial element was suspected because two other members of her family, her first-degree maternal cousins, were also suffering from childhood-onset SLE. unfortunately, HLA phenotyping studies were not done. Her family reported that her two cousins who received follow-up in another hospital, also suffered from easy bruising. One of the cousins was an 11-year-old boy with cutaneous lupus (on topical Synalar 0.025% cream and coppertone 15 sunscreen, and later, prednisolone 10 mg/day), and the other was his five-year-old sister, who had been under treatment for SLE with prednisolone 10 mg/day and hydroxychloroquine 200 mg/day for over two years.

Physical examination of the patient's two cousins revealed only minor bruises on the legs, and both were on maintenance prednisolone 10 mg/day treatment. They both had slight reduction in aggregation response to adenosine diphosphate (ADP) and to epinephrine, which was different from our patient's aggregation response. Responses to the other agonists were normal, suggesting SLE or steroid-related mild acquired platelet dysfunction. They both had normal template bleeding time, PT, aPTT, TT, fibrinogen, platelet counts and RiCoF levels.

Our patient was initially managed conservatively with prednisolone 1 mg/kg/day, and two weeks later the inhibitor strength fell to 5 BU/ml, but did not disappear. At the end of the third week of prednisolone treatment and while still on 1 mg/kg/day, she was admitted with hemarthrosis in her left knee, with factor VIII:C level of 1.0%. The inhibitor strength was back again to 36 BU/ml. Activated prothrombin complex or porcine factor VIII concentrates were not available at the time and high-dose human factor VIII concentrates were used instead. The dose was 240 u/kg/day in three divided doses, and prednisolone was maintained at 1 mg/kg/day. She showed early response, with factor VIII:C pre-infusion levels rising to 15%, and by the end of the first week, the inhibitor strength had fallen back to 8 BU/ml. During the second week human factor VIII dose was reduced stepwise to reach 30 u/kg/day in three divided doses, and pre-infusion factor VIII:C levels were maintained around 10%. With resolution of her hemarthrosis, factor VIII infusion was stopped after two weeks of treatment, but she was maintained on prednisolone 1 mg/kg/day. The inhibitor did not go away, remaining at 6.0 BU/ml. Six weeks later, the inhibitor was back to the original level. In order to eliminate the inhibitor and prevent recurrence of bleeding, CYC at a dose of 2 mg/kg/day was added to prednisolone for an initial period of two weeks. The patient showed early response, factor VIII:C rising to 28% by the end of first week, and 50% by the end of the second week, with total disappearance of the inhibitor. After two weeks of treatment with CYC, the patient had a flare-up of her SLE symptoms with fever, moderate neutropenia, exacerbation of her mouth ulcers which were non-vesicular, non-crusting and painful ulcers with a diameter of 1-2 cm, and grand mal epileptic fits. She had normal blood pressure, was slightly confused but had no focal neurological signs. She had normal fundi, slight albuminuria, normal blood sugar and normal brain CT scan, but angiography was not available at the time.

Infection, agranulocytosis and possible central nervous system disease (neurolupus) were all suspected and CYC was stopped. The patient was kept on oral prednisolone and empirical intravenous antibiotics, phenytoin and antipyretic treatment were initiated. Septic screen, including serial blood cultures, urine and CSF examination, were all negative. Bone marrow examination showed the expected slight depressive effects of CYC but ruled out agranulocytosis. One week after CYC was stopped, factor VIII:C was 143.0% and the inhibitor was undetected. With cultures remaining sterile, and in view of the positive CMV serology, moderately raised anti-CMV IgG titer, but with IgM titer not available, a trial of intravenous acyclovir 10 mg/kg every 8 hours for five days was given (gancyclovir was not available). The patient settled down but continued to have intermittent fever, moderate neutropenia (0.8-1.0x10⁹/l), confusion, bleeding mouth ulcers, with platelet count 135x10⁹/l, and factor VIII:C at 143.0%. Phenytoin was changed to sodium valproate and pulse therapy with intravenous methyl prednisolone 500 mg daily for three days was attempted. The flare-up of SLE symptoms, namely the confusion, intermittent fever and moderate neutropenia, and her mouth bleeding and soft palate ulcers did not respond to pulse therapy with methyl prednisolone and it was decided that the patient might benefit from a combined course of plasmapheresis and immunosuppression. The patient was referred to King Faisal Specialist Hospital and Research Centre (KFSH&RC) in Riyadh, as plasmapheresis was not available at our hospital.

While she was at KFSH&RC, she had some respite from her symptoms, but she did not respond much to further management and remained in hospital for 5-6 weeks. Throughout her stay at KFSH&RC, the factor VIII:C was normal and the inhibitor was undetectable. The flare-up of her SLE symptoms was considered to be part of the natural history of her disease. We may have succeeded in eliminating her inhibitor, but unfortunately the patient died from the infective complications of uncontrolled SLE.

Minor bruising is a common complaint in patients with SLE, and is usually due to an acquired platelet dysfunction.^11,12 Sometimes, it heralds a more serious complication, such as immune thrombocytopenia, or as in our patient, the presence of an acquired inhibitor to coagulation factors, commonly to factor VIII. Efforts to suppress such acquired inhibitors with immunosuppressive agents are often successful.^5,6 There are many factors which appear to predict good patient response to treatment. These include a not-too-high inhibitor titer, the nature of the underlying disease as SLE which undergoes remission, and the concomitant infusion of factor VIII concentrate.³ The natural history of the underlying clinical condition is another important factor to consider when assessing the clinical outcome of therapy. Many inhibitors associated with pregnancy and those which are drug-induced tend to disappear on their own, a process known as spontaneous remission. On the other hand, those associated with SLE often require therapy. Corticosteroids alone may be effective in nearly 25% of all patients with acquired inhibitors to factor VIII.¹³ Those patients who are refractory to steroids alone can benefit from CYC administered alone or in combination with steroids.^5,6 More aggressive regimens using a combination of CYC, vincristine and prednisolone are reserved for patients refractory to CYC alone.³

There have been several case reports of acquired factor VIII inhibitor in the presence of SLE, although the criteria for the diagnosis of SLE were not always explicit. In 1981, Green and Lechner reported 10 cases of SLE among their large retrospective review of the treatment of 215 non-hemophiliac patients with acquired factor VIII inhibitors, and this remains the largest group in the literature.² All 10 patients received initial treatment with corticosteroids, with the addition of CYC (either IV or orally), or azathioprine (AZA) if no response to steroids alone was achieved. How many of the 10 patients actually received CYC or AZA was not clear. But the authors reported that the overall mortality was lower in treated patients (42%), compared with nontreated patients (62%), concluding that immunosuppressive therapy is warranted in such patients.

Adverse effects of the use of CYC include bone marrow suppression, hemorrhagic cystitis, impairment of fertility in the short term, and increased cancer risks in the long term. Carcinogenicity is very unlikely without prolonged treatment, and since treatment for elimination of factor VIII inhibitors is limited to no more than six weeks, it is considered to be an acceptable risk. There are very few reports on the use of intravenous immunoglobulin (IVIG) in the management of factor VIII inhibitors associated with SLE. It is reported to be beneficial, but its effect is incomplete and is to be reserved for patients who are refractory to, or who cannot tolerate, immunosuppressive treatment.^7-9

Our report was on the successful use of CYC and prednisolone combination in the management of a strong acquired factor VIII inhibitor in a patient with documented childhood-onset SLE with some adverse effects. Although the patient's bleeding episode was effectively controlled by prednisolone and high-dose human factor VIII concentrate treatment, elimination of the inhibitor was only achieved by the addition of CYC for a two-week period. We confirm that the combination of CYC and prednisolone is effective in the management of patients with acquired factor VIII inhibitor associated with SLE who are refractory to corticosteroid treatment alone.