Graham R.V. Hughes

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

BACKGROUND: The antiphospholipid-antibody syndrome is a thrombophilic disorder in which venous or arterial thrombosis, or both, may occur in patients with antiphospholipid antibodies. The optimal treatment of these patients is unclear. We assessed the efficacy of warfarin, low-dose aspirin, or both in the secondary prevention of thrombosis in patients with the syndrome. METHODS: One hundred forty-seven patients (124 [84 percent] of whom were female) with the antiphospholipid-antibody syndrome and a history of thrombosis were studied retrospectively. The syndrome was primary in 62 patients and was associated with systemic lupus erythematosus in 66 patients and lupus-like disease in 19. Each patient's history was reviewed. RESULTS: One hundred one patients (69 percent) had a total of 186 recurrences of thrombosis. The median time between the initial thrombosis and the first recurrence was 12 months (range, 0.5 to 144 months). Treatment with high-intensity warfarin (producing an international normalized ratio of > or = 3) with or without low-dose aspirin (75 mg per day) was significantly more effective (P < 0.001 by the log-rank test) than treatment with low-intensity warfarin (producing an international normalized ratio of < 3) with or without low-dose aspirin or treatment with aspirin alone in preventing further thrombotic events (recurrence rates per patient-year, 0.013, 0.23, and 0.18, respectively). The rate of recurrence of thrombosis was highest (1.30 per patient-year) during the first six months after the cessation of warfarin therapy. Complications involving bleeding occurred in 29 patients during warfarin therapy and were severe in 7 (0.071 and 0.017 occurrence per patient-year, respectively). CONCLUSIONS: The risk of recurrent thrombosis in patients with the antiphospholipid-antibody syndrome is high. Long-term anticoagulation therapy in which the international normalized ratio is maintained at or above 3 is advisable in these patients.

Drawing on our experience of 16 cases and a review of the English literature, we propose that CSS is under-diagnosed because of exclusive emphasis upon pathologic recognition of the disorder. The classical histological picture comprises a necrotizing vasculitis, eosinophilic tissue infiltration and extravascular granulomas, but it is only found in a minority of cases, and is not pathognomonic of the condition (69, 108). On the other hand, the clinical pattern of the disorder is most distinctive, and CSS can be readily identified on clinical grounds. Typically, it begins with allergic rhinitis, which is often complicated by nasal polyposis and sinusitis. Asthma and peripheral blood eosinophilia are essential features, often accompanied by pulmonary infiltrates. The systemic vasculitis of CSS resembles that of PAN, but severe renal disease is uncommon (the typical renal lesion is a focal segmental glomerulonephritis), and cardiac involvement accounts for 50% of deaths. Diagnostic difficulties arise from the close relationship of CSS to other granulomatous, vasculitic and eosinophilic disorders. CSS is usefully regarded as a point of overlap between these three disease spectrums (Fig. 5). Individual components of each spectrum can occur in the course of CSS; hence cases may be reported as PAN developing as a complication of Löffler syndrome or eosinophilic gastroenteritis (37, 57, 66). The hypereosinophilia of CSS tends to be less severe and more steroid-responsive than in HES, and evidence of eosinophil degranulation was not found in the patients we studied. Complement abnormalities are not a prominent feature of the disorder, and circulating immune complexes were detected in only two cases; both contained IgM. This may be of pathogenetic significance as IgM deposition was a dominant feature in four of the five cases with positive renal immunofluorescence. IgE levels were elevated in all patients studied during the vasculitic phase, and skin-prick tests were positive in 8 of 10 patients tested. CSS responds well to treatment with steroids, although some patients benefit from the addition of immunosuppressive agents. The vasculitic illness is usually of limited duration, but relapses can occur, and should be detected and treated early. Major problems in the post-vasculitic phase stem from hypertension and persisting peripheral nerve damage. Allergic upper and lower respiratory tract disease is an important cause of morbidity in the pre- and post-vasculitic periods.