Gerard Espinosa

Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients.

The antiphospholipid syndrome (APS), originally defined as the combination of venous or arterial thrombotic events, recurrent fetal loss, and, frequently, a moderate thrombocytopenia in association with antiphospholipid antibodies (aPL), was subsequently greatly expanded to include diverse conditions, for example, heart valve lesions, adrenal insufficiency, and pulmonary syndromes such as acute respiratory distress syndrome (ARDS), “capillaritis,” and pulmonary alveolar hemorrhage, among others (16, 17). It was then realized that several “microangiopathic syndromes” also existed, as opposed to large vessel occlusive disease. Single organs, such as the kidneys, heart, skin, and brain, have been affected by this “thrombotic microangiopathy” in the context of the “classic” or “simple” APS. The temporal occurrence of thrombotic events in patients with this classic APS usually extends over months or years. In 1992, the existence of a new “subset” was described in which multiple vascular occlusive events, usually affecting small vessels supplying organs and presenting over a short period of time, were the outstanding features. This subset was termed the “catastrophic” APS. Although large vessel occlusions were also present, their prevalence did not in any way approach that in patients with the classic APS. The occlusions occurred over days to several weeks, and more than 50% of patients usually succumbed despite seemingly adequate therapy, including anticoagulation, steroids, etc. (6). In 1998, a comprehensive review article with the clinical and laboratory description of 50 such patients was published (8). In the present paper we describe the clinical and serologic features of the largest series of patients with catastrophic APS hitherto reported, including 30 new cases from interested physicians in many different countries, as well as a comprehensive literature review of 50 additional recently published case reports with this syndrome. This new series, comprising a total of 80 patients, enables us to analyze further and clarify not only the clinical importance of this syndrome, but also its pathogenesis. 0025-7974/01/8006-0355/0 MEDICINE® 80: 355-77, 2001 Vol. 80, No. 6 Copyright

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients

Objectives To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. Methods In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. Results 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. Conclusions Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults

OBJECTIVE To define the pattern of disease expression in patients with childhood onset systemic lupus erythematosus (SLE). METHODS Prospective analysis of clinical manifestations and immunological features of 34 patients in whom the first manifestations appeared in childhood from a series of 430 unselected patients with SLE. RESULTS Thirty one (91%) patients from the childhood onset group were female and three male (9%) (ratio female/male, 10/1, with no difference compared with the adult onset group). Mean age of this group at disease onset was 11 years (range 5–14) compared with 32 years (15–48) for the remaining patients. The childhood onset patients more often had nephropathy (20%v 9% in adult onset SLE, p=0.04; OR:2.7; 95%CI:1.1, 7), fever (41% v 21%, p=0.006; OR:2.6, 95%CI:1.2, 5.7), and lymphadenopathy (6%v 0.5%, p=0.03, OR: 12.3, 95%CI: 1.2, 127.6), as presenting clinical manifestations. During the evolution of the disease, the childhood onset patients had an increased prevalence of malar rash (79% v 51%, p=0.002; OR:3.7; 95%CI:1.5, 9.5) and chorea (9% v 0%, p<0.0001). This group exhibited a higher prevalence of anticardiolipin antibodies (aCL) of the IgG isotype when compared with the remaining patients (29% v 13%, p=0.017; OR:2.9, 95%CI:1.2, 6.8). No significant differences were found among the other antibodies between the two groups. Childhood onset patients more often received azathioprine (15% v 6%, p=0.00004; OR:11.2; 95%CI:2.8, 44.9) but no differences were detected between the groups concerning side effects or drug toxicity. CONCLUSIONS The presentation and the clinical course of SLE varied in this series of 430 patients depending on their age at disease onset. Nephropathy, fever, and lymphadenopathy were more common in childhood onset patients as presenting clinical manifestations, while malar rash, chorea, and detection of IgG aCL were more common during the evolution of the disease.

Morbidity and mortality in the antiphospholipid syndrome during a 5-year period

Objectives: To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance. Methods: The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed. Results: 200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected. Conclusion: Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).

Vascular involvement in Behçet’s disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin

PURPOSE Thrombosis, usually venous, occurs in 10% to 25% of patients with Behçets disease, but its pathogenesis is poorly understood. We evaluated parameters of hemostasis and their relation with thrombosis in a series of patients with Behçets disease. SUBJECTS AND METHODS We studied 38 patients with Behçets disease (13 with venous thrombosis), 38 patients with venous thrombosis without thrombophilia, and 100 control subjects. Levels or presence of protein C, protein S, antithrombin, methylenetetrahydrofolate reductase C677T, factor V Leiden, prothrombin gene G20210A, antiphospholipid antibodies, plasminogen, tissue-type plasminogen activator (tPA), type-1 tPA inhibitor (PAI-1), PAI-1 4G/5G polymorphism, prothrombin fragment 1+2, plasmin/alpha(2)-antiplasmin complexes, thrombomodulin, and activated factors VII and XII were determined. RESULTS There were no deficiencies in protein C, protein S, antithrombin, or factor V Leiden in the patients with Behçets disease, nor was there evidence of most other thrombotic abnormalities. Compared with control subjects, however, the Behçets disease group had elevated mean (+/- SD) levels of prothrombin fragment 1+2 (2091 +/- 1323 pmol/L vs. 804 +/- 398 pmol/L, P <0.001), plasmin/alpha2-antiplasmin complexes (410 +/- 220 microg/L vs. 214 +/- 92 microg/L, P <0.001), and thrombomodulin (37 +/- 24 ng/mL vs. 27 +/- 10 ng/mL, P <0.001). These levels did not differ between patients with or without thrombosis. CONCLUSIONS Thrombophilic factors do not seem to explain most thromboses in Behçets disease. There is increased thrombin generation, fibrinolysis, and thrombomodulin in Behçets disease, but these abnormalities are not related to thrombosis.

The lung in the antiphospholipid syndrome

Patients with antiphospholipid syndrome (APS) may develop a broad spectrum of pulmonary disease. Pulmonary thromboembolism and pulmonary hypertension are the most common complications, but microvascular pulmonary thrombosis, pulmonary capillaritis, and alveolar haemorrhage have also been reported. Clinicians should seriously consider these types of vascular injury when evaluating patients with APS who present with dyspnoea, fever, and infiltrates on chest radiography.

Failure of intravenous immunoglobulin to prevent congenital heart block: Findings of a multicenter, prospective, observational study

OBJECTIVE Congenital heart block (CHB) is presumed to be caused by transplacental passage of maternal immunoglobulin against Ro and La ribonucleoproteins. The recurrence rate in subsequent pregnancies following the birth of a child with CHB is approximately 19%. The purpose of this study was to determine whether intravenous immunoglobulin (IVIG) therapy could prevent the development of CHB in the fetuses of high-risk pregnant women. METHODS A total of 24 pregnancies in 22 women who had a previous pregnancy in which CHB developed, were over the age of 18 years, were <12 weeks pregnant, and had anti-Ro, anti-La, or both antibodies were monitored in this multicenter, prospective, observational study. Fifteen patients received infusions of IVIG. The 9 pregnancies in the remaining 7 patients served as controls. IVIG was administered at a dose of 400 mg/kg at weeks 12, 15, 18, 21, and 24 of pregnancy. Echocardiograms were performed at least every 3 weeks from week 15 to week 30 of gestation. Electrocardiograms were obtained at birth. The outcome measure was the development of third-degree CHB detected by fetal echocardiogram. RESULTS CHB developed in 3 babies among the 15 pregnancies in the treatment group (20%) and in 1 baby among the 9 pregnancies in the control group (11%). CHB was detected at weeks 18, 23, and 26, respectively, in the 3 babies in the treated group and at week 19 in the baby in the control group. Three of the affected pregnancies ended in termination; 2 for reasons related to the fetal disease and 1 for reasons related to both maternal (severe pulmonary hypertension) and fetal disease (at 21 weeks of gestation). CONCLUSION IVIG at the dose and frequency used in this study was not effective as prophylactic therapy for CHB in high-risk mothers.

Long term outcome of catastrophic antiphospholipid syndrome survivors

Background: Catastrophic antiphospholipid syndrome (APS) is defined as life threatening multiple organ thromboses developing simultaneously or over a short period. The survival rate of catastrophic APS is about 50%, but the long term outcome of patients who survive is unknown. Objective: To determine the long term outcome of patients with catastrophic APS and provide further information on patients who survived. Patients and methods: The clinical characteristics and outcomes of 130 patients with catastrophic APS have been reported previously. Six new cases were recently added to this series. Based on these publications, the authors who reported patients who had survived were contacted. Each author was asked (a) what treatment they gave their patients after the catastrophic APS; (b) if their patients had any further thrombosis. Results: 63/136 (46%) patients died at the initial event. Of the remaining 73 patients, information was available for 58 (79%). Thirty eight (66%) patients did not develop further APS related events during an average follow up of 67.2 months. Eleven (19%) patients developed further APS related events but were still alive. No patients developed further catastrophic APS. Nine (16%) patients died: due to multiple organ failure (three patients); myelofibrosis (one); pneumonia (one); and APS related events (four). Conclusion: Sixty six per cent of patients who survive an initial catastrophic APS event remained symptom free with anticoagulation during an average follow up of 67.2 months. Twenty six per cent of the survivors developed further APS related events and the mortality rate of these patients was about 25%.

Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients.

To describe the clinical and immunologic characteristics of patients with adrenal involvement and antiphospholipid syndrome (APS), we conducted a computer-assisted (PubMed) search of the literature to identify all cases of primary adrenal insufficiency associated with antiphospholipid antibodies published in English, French, and Spanish from 1983 (when APS was first defined) through March 2002.We reviewed 86 patients (80 from the literature plus 6 from our cohort); 55% were male, and the mean age at presentation was 43 ± 16 years. Sixty-one (71%) patients had primary APS, and 14 (16%) had systemic lupus erythematosus. In 31 (36%) patients, adrenal insufficiency was the first clinical manifestation of APS. Abdominal pain was present in 55% of patients, followed by hypotension (54%), fever (40%), nausea or vomiting (31%), weakness or fatigue (31%), and lethargy or altered mental status (19%). The main finding in imaging techniques was compatible with adrenal hemorrhage (59%) and in histopathologic study was a hemorrhagic infarction with vessel thrombosis (55%). Lupus anticoagulant was detected in 97% of patients and the anticardiolipin antibodies titer was positive in 93% of patients. Most patients (95%) were positive for the IgG isotype of anticardiolipin antibodies, whereas 40% were positive for the IgM isotype. Baseline cortisol levels were decreased in 98% of patients, ACTH hormone levels were increased in 96% of patients, and the cosyntropin stimulation test was positive in 100% of patients tested. Steroid replacement therapy was the most frequent treatment (84%), followed by anticoagulation (52%) and aspirin (6%). Thirty-two of 35 (91%) patients with prolonged anticoagulant therapy were in good health with a mean follow-up of 25 months, whereas 25 of the 69 (36%) patients with outcome data available had died.The results of the present review stress the clinical importance of systematic screening for lupus anticoagulant and anticardiolipin antibodies in all cases of adrenal hemorrhage or infarction. An initial screening for hypoadrenalism is mandatory in any antiphospholipid antibody-positive patient who complains of abdominal pain and undue weakness or asthenia.

Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab.

The catastrophic variant of the antiphospholipid syndrome (APS) is characterized by thrombosis in multiple organs developing over a short period of time. First-line treatment for the catastrophic APS is the combination of anticoagulation plus corticosteroids plus plasma exchange and/or intravenous immunoglobulin. Despite this regimen, the mortality remains high and new treatment options are needed. By a systematic review of the Catastrophic APS Registry (CAPS Registry), we identified 20 patients treated with rituximab. The purpose of this study is to describe the clinical manifestations, laboratory features, and outcomes of rituximab-treated CAPS patients. In addition, the rationale for using rituximab in catastrophic APS is discussed.