Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium--the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.

We analyzed the clinical, radiologic, and immunologic characteristics of 50 patients with chorea and the antiphospholipid syndrome (APS) (6 from our clinics and 44 from a MEDLINE computer-assisted review of the literature from 1985 through 1995). Forty-eight (96%) patients were female and 2 (4%) were male. Twenty-nine (58%) patients had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 15 (30%) patients had "primary" APS. Mean age of patients in this series was 23 +/- 12 years (range, 6-77 yr); mean age at presentation of chorea was 21 +/- 12 years (range, 6-77 yr). In 11 (22%) patients, the onset of chorea was in childhood (6-14 yr), and in 2 (4%) patients it presented at 60 years or more. Six (12%) patients developed chorea soon after they started taking estrogen-containing oral contraceptives, 3 (6%) developed chorea gravidarum, and 1 (2%) patient developed chorea shortly after delivery. Most patients (66%) presented only 1 episode of chorea. Chorea was bilateral in 55% of patients. Computed tomography and magnetic resonance imaging scans reported cerebral infarcts in 35% of patients. The following antibodies were detected: lupus anticoagulant (92%), anticardiolipin antibodies (91%), antinuclear antibodies (82%), anti-DNA (59%), anti-Ro (10%), anti-RNP (8%), anti-La (2%), and anti-Sm (2%). The chorea in these patients responded to a variety of medications, for example, steroids, haloperidol, antiaggregants, anticoagulants, or a combination of therapy, usually prescribed in the presence of other manifestations of APS or SLE. However, many patients responded well to haloperidol and to the discontinuation of oral contraceptives if this was the precipitating factor.

Thyroid disease in primary Sjögren syndrome. Study in a series of 160 patients.

We studied 160 consecutive patients (147 female and 13 male) with primary Sjögren syndrome (SS) to determine the prevalence and clinical significance of thyroid disease in a large series of patients with primary SS from our unit and to compare the prevalence and significance with those in 75 individuals without SS from a primary care center. Serum levels of thyroid hormones (free thyroxine, triiodothyronine, and thyroid-stimulating hormone) and autoantibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) were measured in all SS patients and in 75 control patients. Fifty-eight (36%) of the 160 patients with primary SS had evidence of thyroid disease. Autoimmune thyroid disease (ATD) was diagnosed in 32 (20%) patients and nonautoimmune thyroid disease (NATD) in 26 (16%). No significant differences were found when these prevalences were compared with those in control patients. On the other hand, comparing those patients with altered hormonal profiles, patients with NATD showed mainly hyperthyroidism (10/17, 59% versus 2/20, 10% in patients with ATD, p = 0.001). Finally, when clinical and immunologic manifestations of SS were analyzed in patients with and without thyroid disease, respectively, we found that patients with thyroid disease had a higher prevalence of female gender (98% versus 88%, p = 0.03), antiparietal cell autoantibodies (33% versus 12%, p = 0.002), TgAb (30% versus 5%, p < 0.001), and TPOAb (40% versus 5%, p < 0.001). In conclusion, thyroid disease occurred in more than one-third of patients with primary SS; the main cause was ATD, which was present in 20% of the patients studied. We note that no significant differences were observed when the prevalence of thyroid disease (either ATD or NATD) was compared with that in a control group of similar age and gender. Our results indicate that middle-aged women (with or without SS) should be screened periodically for thyroid function.

Hepatitis C virus infection mimicking primary Sjögren syndrome. A clinical and immunologic description of 35 cases.

Hepatitis C virus (HCV) infection is emerging as an extremely common and insidiously progressive liver disease that is often associated with several extrahepatic manifestations. In 1992, a possible relationship between Sjögren syndrome (SS) and patients with HCV infection was first postulated. Subsequently, several studies demonstrated that a "true" SS, with similar clinical and histologic features to those observed in primary SS, may occur in some patients with chronic HCV infection. We report the clinical and immunologic characteristics of 35 patients with chronic HCV infection and a well-documented diagnosis of SS. Compared with 60 patients with primary SS who tested negative for HCV antibodies, SS-HCV patients showed a higher mean age (65.9 yr versus 61.5 yr, p = 0.04), a lower prevalence of parotidomegaly (17% versus 47%, p = 0.004), and a higher prevalence of liver involvement (94% versus 3%, p < 0.001). Moreover, those patients with HCV-related SS showed a higher prevalence of anti-parietal cell gastric antibodies (31% versus 13%, p = 0.03), antimitochondrial antibodies (14% versus 2%, p = 0.02), cryoglobulinemia (60% versus 10%, p < 0.001), hypocomplementemia (60% versus 8%, p < 0.001), and a lower prevalence of anti-Ro/SS-A (17% versus 38%, p = 0.03). The "true" SS observed in some patients with HCV may be considered 1 of the extrahepatic manifestations of HCV, and we suggest that HCV infection can be considered as an exclusion criterion for the diagnosis of primary SS.

Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients.

We analyzed the clinical and laboratory characteristics of 50 patients with catastrophic antiphospholipid syndrome (APS) (5 from our clinics and 45 from a MEDLINE computer-assisted review of the literature from 1992 through 1996). Thirty-three (66%) patients were female and 17 (34%) were male. Twenty-eight (56%) patients had primary APS, 15 (30%) had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 1 (2%) had rheumatoid arthritis. Mean age of patients in this series was 38 +/- 14 years (range, 11-74 yr). Three (6%) patients developed the clinical picture of catastrophic APS under the age of 15 years, and 11 (22%) were 50 years old or more. In 11 (22%) patients, precipitating factors contributed to the development of catastrophic APS (infections in 3, drugs in 3, minor surgical procedures in 3, anticoagulation withdrawal in 2, and hysterectomy in 1). The presentation of the acute multi-organ failure was usually complex, involving multiple organs simultaneously or in a very short period of time. The majority of patients manifested microangiopathy--that is, occlusive vascular disease affecting predominantly small vessels of organs, particularly kidney, lungs, brain, heart, and liver--with a minority of patients experiencing only large vessel occlusions. Thrombocytopenia was reported in 34 (68%) patients, hemolytic anemia in 13 (26%), disseminated intravascular coagulation in 14 (28%), and schistocytes in 7 (14%). The following antibodies were detected: lupus anticoagulant (94%), anticardiolipin antibodies (94%), anti-dsDNA (87% of patients with SLE), antinuclear antibodies (58%), anti-Ro/SS-A (8%), anti-RNP (8%), and anti-La/SS-B (2%). Anticoagulation was used in 70% of the patients, steroids in 70%, plasmapheresis in 40%, cyclophosphamide in 34%, intravenous gammaglobulins in 16%, and splenectomy in 4%. Most patients, however, received a combination of nonsurgical therapies. Death occurred in 25 of the 50 (50%) patients. In most, cardiac problems seemed to be the major cause of death. In several of these, respiratory failure was also present, usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Among the 20 patients who received the combination of anticoagulation, steroids, and plasmapheresis or intravenous gammaglobulins, recovery occurred in 14 (70%) patients. The use of ancrod and defibrotide appeared to be effective in the 2 respective patients in whom they were used.

Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus.

In the present study we assessed the frequency and characteristics of the main causes of morbidity and mortality in SLE during a 5-year period and analyzed the prognostic significance for morbidity and mortality of the main immunologic parameters used in clinical practice. We started in 1990 a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 5 years (1990-1995). Four hundred thirteen patients (41.3%) presented 1 or more episodes of arthritis, 264 (26.4%) had malar rash, 222 (22.2%) active nephropathy, 139 (13.9%) fever, 136 (13.6%) neurologic involvement, 132 (13.2%) Raynaud phenomenon, 129 (12.9%) serositis (pleuritis and/or pericarditis), 95 (9.5%) thrombocytopenia, and 72 (7.2%) thrombosis. Two hundred seventy patients (27%) presented infections, 113 (11.3%) hypertension, 75 (7.5%) osteoporosis, and 59 (5.9%) cytopenia due to immunosuppressive agents. Sixteen patients (1.6%) developed malignancies, with the most frequent primary localizations the uterus and the breast. Several immunologic parameters (anti-dsDNA or antiphospholipid antibodies) were found to have a predictive value for the development of SLE manifestations during the period of the study. Forty-five patients (4.5%) died; the most frequent causes of death were divided similarly among active SLE (28.9%), infections (28.9%), and thromboses (26.7%). A survival probability of 95% at 5 years was found. A lower survival probability (92%) was detected in those patients who presented at the beginning of the study with nephropathy.

Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients.

PURPOSE: To determine whether the features of the antiphospholipid syndrome (APS) are in any way influenced by the presence or absence of systemic lupus erythematosus (SLE). We followed up patients with 'primary' APS (PAPS) and APS secondary to SLE (APS plus SLE) with the objective of comparing laboratory and clinical events and of determining whether patients with PAPS would have evolution to SLE. PATIENTS AND METHODS: A total of 114 patients from 3 European referral centers were included in this study. Fifty-six had APS plus SLE and 58 had PAPS. Laboratory and clinical data were collected during an average 2-year period. RESULTS: Patients with PAPS and patients with APS plus SLE had similar clinical and laboratory profiles, with the exceptions of autoimmune hemolytic anemia, endocardial valve disease, neutropenia, and low C4 levels, all of which occurred more frequently in patients with APS plus SLE (p values: < 0.05, < 0.005, < 0.01, and < 0.001, respectively). On follow-up, 10 thrombotic episodes occurred in 10 patients, 8 of whom were receiving anticoagulant therapy. No patient with PAPS had either anti-DNA or anti-extractable nuclear antigen antibodies, and these patients had a significantly lower prevalence of antinuclear antibodies (41%) than patients with APS plus SLE (89%). CONCLUSIONS: Patients with APS plus SLE and PAPS have similar clinical profiles, although heart valve disease, hemolytic anemia, low C4 levels, and neutropenia seem to be more common in patients with APS plus SLE. Patients with APS may develop further thrombotic events despite anticoagulation therapy.

Effect of plasma from patients with primary antiphospholipid syndrome on platelet function in a collagen rich perfusion system.

The effect on platelet function of plasma from 9 patients with primary antiphospholipid syndrome (PAS) with previous thrombotic episodes was investigated under flow conditions. Five asymptomatic individuals with antiphospholipid antibodies (aPL) (A-aPL) and 14 normal controls were also studied. Patients and controls plasmas were added (1:20 v/v) to anticoagulated blood and perfused through annular chambers containing collagen rich vessel segments. The interaction of platelets with vessel subendothelium was morphometrically evaluated in thin sections. An increase in both covered surface and thrombi formation was observed in perfusions in the presence of PAS-plasma (mean +/- SD: 34.2% +/- 9.6% and 23.2% +/- 10.0% respectively) compared with control plasmas (21.4% +/- 7.3% and 10.1% +/- 7.7%, p < 0.01). Affinity purified anticardiolipin antibodies from one PAS patient showed a similar effect when added to normal blood. In contrast, A-aPL plasma had no effect on platelet-subendothelium interaction. In parallel studies, the same plasmas were incubated with isolated normal platelets before and after activation with ADP or collagen and the binding of immunoglobulins (Ig) was determined by flow cytometry. A significantly increased binding of Ig was observed in 8 out of 9 plasmas from PAS patients when platelets had been activated with collagen but not when resting or ADP activated platelets were used. No increased Ig binding to platelets was seen using A-aPL individuals plasma. These observations might help to explain the pathophysiology of the thrombotic events occurring in patients with PAS.

Cytopenia and past human parvovirus B19 infection in patients with primary Sjögren's syndrome.

OBJECTIVES: To determine the clinical significance of human parvovirus B19 infection in patients with primary Sjögren's syndrome (SS) and to investigate the immunologic and hematologic features related to B19 infection. METHODS: We included 80 consecutive patients with primary SS (74 women and 6 men), with a mean age of 62 years (range, 24 to 87 years) that were seen in our Unit. All patients fulfilled the European Community criteria for SS. As controls, we included 140 consecutive sera samples analyzed for B19 antibodies in our Microbiology Department and obtained from adult inpatients and outpatients of our Hospital. Serum from all patients and controls was tested for antibodies to B19 by enzyme-linked immunosorbent assay (ELISA). Additionally, the presence of B19 DNA in serum and in circulating leukocytes was investigated by nested polymerase chain reaction (PCR). RESULTS: Serological evidence of past B19 infection (positive IgG antibodies without IgM antibodies) was present in 28 (35%) patients with primary SS. None of these patients showed evidence for B19 viremia, and B19 virus DNA was not detected in the circulating leukocytes of IgG-B19(+) patients. Positivity for IgM antibodies to B19 was not detected in any patient. When compared with patients without evidence of past B19 infection, those with primary SS and past B19 infection showed a higher prevalence of cytopenia (57% v 15%; P < .001), and, specifically, of leukopenia (36% v 4%; P < .001). Additionally, when compared with controls positive for IgG-B19, SS patients with these antibodies had a higher prevalence of cytopenia (57% v 13%; P < .001), leukopenia (36% v 3%; P < .001) and thrombocytopenia (21% v 0%; P = .003). CONCLUSIONS: Serological evidence of past B19 infection is associated with the presence of cytopenia in our patients with primary SS. A possible relationship between B19 infection and the presence of cytopenia in primary SS may occur in some patients immunologically or genetically predisposed.

Cryoglobulinemia in primary Sjögren's syndrome: prevalence and clinical characteristics in a series of 115 patients.

OBJECTIVES: To determine the prevalence and nature of cryoglobulins in a large series of patients with primary Sjögren's syndrome (SS) and identify the clinical and immunologic features related to their presence. METHODS: In a cross-sectional study, we investigated 115 consecutive patients (107 women and eight men) with primary SS. All patients fulfilled four or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993. Serum cryoglobulinemia was measured in all patients. Serum samples were obtained at 37 degrees C, and cryoglobulinemia was estimated by centrifugation after incubation at 4 degrees C for 7 days. The type of cryoglobulinemia was identified by agarose gel electrophoresis and immunofixation. RESULTS: Cryoglobulins were detected in the sera of 18 (16%) of our patients with primary SS; most were IgMkappa monoclonal/IgG polyclonal. When compared with patients without cryoglobulins, those with cryoglobulins presented a higher prevalence of leukocytoclastic cutaneous vasculitis (56% v8%, P < .001), hypocomplementemia (75% v 2%; P < 0.001) and antibodies to hepatitis C virus (HCV) (47% v8%, P < .001). Liver involvement (clinical signs, biochemical features, or ultrasound/histological data of liver disease) was present in all patients (100%) with cryoglobulins and HCV infection but in only 11% of patients with cryoglobulins without HCV infection (P < .001). CONCLUSIONS: Leukocytoclastic cutaneous vasculitis, hypocomplementemia, and HCV infection are associated with the presence of cryoglobulins in the sera of patients with primary SS. Testing for HCV infection is recommended for patients with SS and cryoglobulinemia because of its high prevalence and its strong association with liver disease.

Association of antiphospholipid antibodies with retinal vascular disease in systemic lupus erythematosus.

OBJECTIVES: To study the prevalence and characteristics of retinal vascular disease in patients with systemic lupus erythematosus (SLE) and to analyze their relationship with antiphospholipid antibodies (aPL) and other serological markers. PATIENTS AND METHODS: Eighty-two consecutive patients (77 women and 5 men; mean age, 36 years) were studied. All patients fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. Ophthalmologic examination included assessment of best corrected visual acuity, tonometry, slit-lamp biomicroscopy, and fundus examination. Serologic studies included determination of anticardiolipin antibodies (aCL) (ELISA), lupus anticoagulant (LA) (coagulation tests), antinuclear antibodies (indirect immunofluorescence), anti-DNA (Farr's test), and anti-ENA antibodies (counterimmunoelectrophoresis). RESULTS: Retinal vascular disease was detected in 13 (15%) of 82 SLE patients. The retinal lesions consisted of retinal vascular occlusions in six patients (five arterial and one venous), cotton-wool spots in three, optic disc edema in three, retinal hemorrhages in three, and ischemic optic neuropathy in one. Antiphospholipid antibodies were detected in 10 (77%) of these 13 patients: nine had aCL and two had the LA. When compared with patients without retinal vascular disease, patients with retinopathy had a higher prevalence of aPL (77% v. 29%, P = .005). CONCLUSIONS: Retinal vascular disease is frequent in patients with SLE. The presence of aPL is associated with a higher prevalence of retinal abnormalities in SLE patients.

Antiphospholipid antibodies and thrombophilic factors in giant cell arteritis.

OBJECTIVES: To evaluate the prevalence of thrombophilic risk factors known to induce intravascular clotting and to assess their relationship with ischemic manifestations in giant cell arteritis (GCA). METHODS: Eighty consecutive patients with established GCA were included: 36 with isolated temporal arteritis (TA), 14 with isolated polymyalgia rheumatica (PMR), and 30 with TA and PMR. Forty-four patients (67%) had ischemic phenomena due to GCA. Twelve patients (15%) had thrombotic events unrelated to GCA (6 strokes, 5 deep venous thrombosis, and 1 myocardial infarction). A control group of 100 age- and sex-matched individuals without autoimmune disease, bleeding disorders, thrombosis, or clinical picture of TA or PMR also was analyzed. All participants were tested for the antiphospholipid antibody (aPL) profile, protein C, protein S, antithrombin activity, factor V Leiden mutation, and prothrombin gene G20210A mutation. We also studied fibrinolysis parameters: plasminogen, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, type-1 plasminogen activator inhibitor (PAI-1) antigen, PAI-1 activity, and the 4G/5G polymorphism of the promoter region of the PAI-1 gene. RESULTS: Eleven patients (18%) tested positive for lupus anticoagulant, 24 (30%) for anticardiolipin antibodies, 9 (11%) for anti-beta 2-glycoprotein I antibodies, and 29 (36%) for antiprothrombin antibodies. No relationship was found between these autoantibodies and ischemic manifestations. None of the patients had decreased protein C, protein S or antithrombin activity. Two patients and 2 controls were heterozygous for factor V Leiden, and only 1 patient and 2 controls were heterozygous for the prothrombin gene G20210A mutation. No statistically significant correlation was found between any thrombophilic factor and GCA-related or GCA-unrelated ischemic events. CONCLUSION: GCA patients have a high prevalence of aPL that is not related to ischemic manifestations. Moreover, GCA-related or GCA-unrelated ischemic manifestations do not appear to be due to congenital thrombophilic risk factors. Semin Arthritis Rheum 31:12-20.

Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics in a series of 122 patients.

OBJECTIVES: To determine the prevalence and nature of cryoglobulins in 122 patients with systemic lupus erythematosus (SLE) and identify the clinical and immunologic features related to their presence. METHODS: In a cross-sectional study, we investigated 122 consecutive patients (106 women and 16 men) with SLE who fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. All patients had documented medical histories and underwent a medical interview as well as a routine general physical examination by a qualified internist, and their clinical and serologic characteristics were collected on a protocol form. Serum samples were obtained at 37 degrees C, and cryoglobulinemia was estimated by centrifugation at 4 degrees C after incubation for 7 days in all patients. The type of cryoglobulinemia was identified by agarose gel electrophoresis and immunofixation. RESULTS: Cryoglobulins were detected in the sera of 31 SLE patients (25%): 20 patients (65%) had a cryocrit lower than 1%, 8 (26%) had percentages ranging between 1% and 5%, and only 3 patients (9%) had a cryocrit over 5%. Only cutaneous vasculitis (39% v 16%; P = .01) was more prevalent in patients with than in those without cryoglobulins. Rheumatoid factor (RF) (42% v 15%; P = .002) and low CH50 levels (84% v 49%; P <.001) were more prevalent in SLE patients with cryoglobulins. Hepatitis C virus (HCV) infection was investigated in 24 of the 31 cryoglobulinemic SLE patients and was detected in 5 (21%). In comparison, 4 (5%) of the 75 noncryoglobulinemic SLE patients studied were positive (P = 0.035; odds ratio, 4.67). Patients with a cryocrit greater than 1% showed a higher frequency of HCV infection than those with a cryocrit less than or equal to 1% (46% v 0%, P = .01). CONCLUSIONS: Cutaneous vasculitis, RF, hypocomplementemia, and HCV infection were associated with cryoglobulins in SLE patients. Testing for HCV infection is therefore recommended for patients with SLE and cryoglobulinemia to identify this subset of patients for prognostic and therapeutic reasons.

Clinical study and follow-up of 100 patients with the antiphospholipid syndrome.

OBJECTIVES: To study the clinical characteristics at diagnosis and during follow-up of patients with the antiphospholipid syndrome (APS) and to analyze the influence of treatment on their outcome. PATIENTS: One hundred patients with APS were included (86% female and 14% male; mean age, 36 years). Sixty-two percent had primary APS and 38% had APS associated with systemic lupus erythematosus (SLE). The median length of follow-up was 49 months. RESULTS: Fifty-three percent of the patients had thromboses, 52% had thrombocytopenia, and 60% of the women had pregnancy losses. Patients with APS associated with SLE had a higher prevalence of hemolytic anemia (P = .02), thrombocytopenia (platelet count lower than 100 x 10(9)/L) (P = .004), antinuclear antibodies (P = .0002), and low complement levels. Fifty-three percent of the patients with thrombosis had recurrent episodes (86% in the same site as the previous thrombotic event). Recurrences were observed in 19% of the episodes treated with long-term oral anticoagulation, in 42% treated prophylactically with aspirin, and in 91% in which anticoagulant/antiaggregant treatment was discontinued (P = .0007). Multivariate analysis showed that prophylactic treatment and older age had an independent predictive value for rethrombosis. Prophylactic treatment during pregnancy (usually with aspirin) increased the live birth rate from 38% to 72% (P = .0002). CONCLUSIONS: Patients with APS have a high risk of recurrent thromboses. Long-term oral anticoagulation seems to be the best prophylactic treatment to prevent recurrences. Prophylactic treatment with aspirin during pregnancy reduced the rate of miscarriages remarkably.

Antiendothelial cell antibodies in patients with the antiphospholipid syndrome.

Antiendothelial cell antibodies (AECA) have been detected in 20 out of 30 patients (67%) with thrombosis associated with antiphospholipid antibodies. Seven patients had systemic lupus erythematosus and 13 had the "primary" antiphospholipid syndrome. Seven patients had both IgG and IgM AECA, 9 had IgG AECA only, and 4 had only IgM AECA. None of 30 control patients with thrombotic events not related to antiphospholipid antibodies had a positive titre of AECA (P less than 0.001). No correlation between AECA, antinuclear antibodies, anti-dsDNA antibodies, anti-neutrophil cytoplasm antibodies, precipitating antibodies to soluble nuclear and cytoplasmic antigens or complement components was found. The possible role of these AECA in the pathogenesis of thrombotic events is discussed.

The 'primary' antiphospholipid syndrome: antiphospholipid antibody pattern and clinical features of a series of 23 patients.

Twenty-three patients with the 'primary' antiphospholipid syndrome were studied over 2-6 years. Twenty-two (96%) had antiphospholipid antibodies detected by ELISA (87% had antibodies to thromboplastin and 70% to cardiolipin), and 18 out of the 21 tested patients (86%) had lupus anticoagulant activity by coagulative assays. Mean age of the cohort was 29.9 years and the sex ratio (female:male) 4.75:1. Eleven patients presented 18 venous and/or arterial thrombosis and 13 had 25 foetal losses (84% occurred during the second and third trimester). Other clinical features were migraine, livedo reticularis, and epilepsy. Three patients had relatives with systemic lupus erythematosus. Thrombocytopaenia was seen in 33%, antinuclear antibodies in low or moderate titre in 30%, and haemolytic anaemia in 13%. During the follow-up, two patients presented recurrent thrombosis despite anticoagulant therapy, one of them dying because of recurrent pulmonary thromboembolism. Four patients achieved successful term pregnancies after treatment with aspirin and a further patient after treatment with aspirin and low dose prednisolone. No patient developed systemic lupus erythematosus or any other definable connective tissue disease. The 'primary' antiphospholipid syndrome may exist as a distinct clinical entity and all younger patients presenting with thrombotic events, foetal losses and/or thrombocytopaenia, without any evidence of a well defined disease, should be tested for antiphospholipid antibodies in order to rule out this syndrome.

Cardiovascular risk factors and the long-term outcome of lupus nephritis.

We evaluated cardiovascular risk factors, morbidity and mortality in patients with lupus nephritis (LN). We prospectively studied 70 consecutive patients with LN, and 70 age- and sex-matched controls with systemic lupus erythematosus (SLE) but no evidence of nephropathy, from 1988 to 1998. Patients were evaluated at entry for hypertension, diabetes, hyperlipidaemia, smoking, menopause and antiphospholipid syndrome. The LN patients (64 women, 6 men) had a mean age of 35 years (SE 1.7, range 11-67). During the 10 years, 15 (21%) LN patients and 18 (25%) of the controls were lost to follow-up. Compared with controls, LN patients had a higher prevalence of hyperlipidaemia (44% vs. 2%, p<0.001), hypertension (44% vs. 9%, p<0.001) and antiphospholipid antibodies (45% vs. 22%, p=0.01) at study onset. At the last visit, 37 (67%) LN patients had normal plasma creatinine, 13 (24%) had renal failure and only five (9%) end-stage renal failure. Hyperlipidaemia (78% vs. 27%, p<0.001) and hypertension (67% vs. 32%, p=0.01) at study onset were associated with development of renal failure. Nine LN patients and one control died (16% vs. 2%, p=0.02). These patients showed more antiphospholipid syndrome (56% vs. 17%, p=0.03) and hyperlipidaemia (78% vs. 37%, p=0.03) at study onset. The main causes of death in LN patients were vascular complications (cardiovascular or cerebrovascular events) in five patients (four of whom had antiphospholipid antibodies) and sepsis in three.

Antibodies to thromboplastin in systemic lupus erythematosus: isotype distribution and clinical significance in a series of 92 patients.

We determined the prevalence and relationship with clinical manifestations of antibodies to thromboplastin (aTP) in 92 patients with systemic lupus erythematosus (SLE). Thirty-two (35%) patients had aTP: 13 (14%) were positive for IgG aTP, 13 (14%) for IgM aTP, and 6 (7%) for both. Patients with aTP had an increased incidence of thrombosis (p = 0.01), thrombocytopenia (p < 0.001), hemolytic anemia (p < 0.001), and fetal losses (p = 0.03). When the IgG and IgM aTP isotypes were analysed separately, the IgG aTP were found to be associated with thrombosis (p < 0.001), thrombocytopenia (p < 0.001), and fetal losses (p = 0.02). The IgM aTP were associated with hemolytic anemia (p < 0.001). A correlation was found between the titers of aTP and those of anticardiolipin antibodies, in both IgG (p < 0.01, r = 0.6) and IgM (p < 0.01, r = 0.64) isotypes, and between the titers of IgG aTP and the diluted Russell's viper venom time used to detect the lupus anticoagulant (p < 0.001, r = 0.42). This test is a reliable, reproducible and sensitive assay for the detection of antiphospholipid antibodies, specially in those patients under anticoagulant therapy.

Late thrombotic events in patients with temporal arteritis and anticardiolipin antibodies.

IgG and IgM isotypes of anticardiolipin (aCL) antibodies were measured in a group of 40 patients with biopsy-proven temporal arteritis (TA), 13 of them with ischemic complications related to the disease. High levels of aCL antibodies were found in only 3 (7.5%) patients. Two had high titres of both IgG and IgM isotypes and the third had high titres of the IgM isotype. No relationship between aCL antibody positivity and the development of any of the classical early occlusive complications of TA was found. However, 2 out of the 3 patients with positive aCL antibody titres later developed ischemic phenomena on conventional corticosteroid treatment. This finding suggests that aCL antibodies could perhaps have a role in the development of the late ischemic complications that occasionally occur in adequately treated TA patients.

Isotype distribution and clinical significance of antibodies to cardiolipin, phosphatidic acid, phosphatidylinositol and phosphatidylserine in systemic lupus erythematosus: prospective analysis of a series of 92 patients.

OBJECTIVE: To determine the prevalence and correlation with clinical manifestations of the IgG and IgM isotypes of antibodies to cardiolipin (aCL), phosphatidic acid (aPA), phosphatidylinositol (aPI) and phosphatidylserine (aPS) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical and laboratory features of 92 consecutive unselected patients with SLE were prospectively studied over two years. aCL, aPA, aPI and aPS were determined by ELISA. RESULTS: aCL were detected in 34 (37%) patients, aPA in 26 (28%), aPI in 22 (24%), and aPS in 29 (32%). A significant association was found between the appearance of thrombosis and the presence of IgG aCL (p < 0.001) and IgG aPS (p < 0.05). A significant association was also found between thrombocytopenia and the presence of IgG aCL (p < 0.001), IgG aPA (p < 0.01), IgG aPI (p < 0.05), and IgG aPS (p < 0.001). The development of hemolytic anemia was associated with the detection of IgM aCL (p < 0.001), IgM aPA (p < 0.05), IgM aPI (p < 0.001), and IgM aPS (p < 0.01). CONCLUSION: We found a relatively high prevalence of aCL, aPA, aPI and aPS in our SLE population and confirmed the presence of a correlation between the IgG isotype of these antibodies and thrombosis and thrombocytopenia, and also between the IgM isotype and hemolytic anemia. These results demonstrate the variety of antiphospholipid antibodies that can be detected in SLE patients, as well as their association with the clinical manifestations of the antiphospholipid syndrome.