Poliklinik für Rheumatologie, Universitätsklinikum Lübeck, Medizinische Universität Lübeck and Rheumaklinik Bad Bramstedt, Oskar-Alexander-Straße 26, 24576 Bad Bramstedt,
1 Abteilung Nephrologie, Carl Neuberg Straße 1, Medizinische Hochschule Hannover, 30625 Hannover,
2 DIARECT AG, Wipperstraße 2, 79100 Freiburg, Germany
SIR, In primary systemic vasculitides such as Wegener's granulomatosis (WG), vasculitis involving veins has been implicated as a contributory factor for thrombosis, although systematic studies of this problem are still lacking [1]. Other determinants for thrombosis have not been evaluated in WG so far.
Conventional anticardiolipin antibody (ACLA) assays detect both ß2-glycoprotein I (ß2GPI)-dependent antibodies as well as ß2GPI-independent antibodies. ß2GPI acts as a cofactor for the interaction between ACLA and phospholipids. Antibodies solely directed to ß2GPI have been reported to represent a subset of ACLA with a stronger association with thrombosis than conventional ACLA in systemic lupus erythematosus (SLE) [2].
We studied 87 sera from 67 patients with generalized WG to determine the prevalence of IgM-, IgG- and IgA-ACLA and IgM-, IgG- and IgA-ß2GPI antibodies and the relationship to a history of thrombosis. This cohort of patients was a random selection of 200 patients with generalized WG. Eleven patients with WG had had previous venous thrombosis. For comparison, 11 patients with SLE and a history of previous venous thrombosis were also investigated. Diagnosis was based on standard definitions [35]. IgM-, IgG- and IgA-ACLA and IgM-, IgG- and IgA-ß2GPI antibodies were detected with commercially available specific enzyme-linked immunosorbent assay (ELISA) tests (ACLA: Pharmacia & Upjohn, Freiburg, Germany; ß2GPI antibodies: Varelisa ß2GPI Antikörper, Elias, Freiburg, Germany). Thrombosis was diagnosed when characteristic clinical findings were supported by either ascending contrast venography and/or Doppler or duplex ultrasonic examination. Prolonged immobilization, pregnancy, malignant diseases, antithrombin III, protein C or protein S deficiency and the coagulation factor V Leiden mutation were routinely excluded. The extent of organ involvement was denoted as the disease extent index (DEI) [6]. Data analysis was performed using the MannWhitney U-test and the Wilcoxon matched-pairs test if appropriate.
There was no statistically significant difference in the prevalence of ACLA and/or antibodies to ß2GPI between patients with WG with and without previous thrombosis. In general, levels of ACLA and antibodies to ß2GPI tended to be low in patients with WG irrespective of the history of former thrombosis. Patients with SLE and previous thrombosis had significantly higher levels of IgG-ACLA (21.4 ± 9.7 vs 5.1 ± 2.3; P < 0.01) and IgM-ß2GPI antibodies (7.5 ± 4.1 vs 3.1 ± 2.4) as compared with the 11 WG patients with former thrombosis.
There was no statistically significant difference between the 11 patients with WG and previous thrombosis and the remainder of the 56 WG patients without known thrombosis with regard to C-reactive protein (CRP), DEI, maximum DEI, duration of the disease, serum levels of IgM-, IgG- and IgA-ACLA and IgM-, IgG-and IgA-ß2GPI antibodies (Table 1). However, serial serum samples drawn from 11 patients with generalized WG without previous thrombosis revealed that serum levels of IgG-ACLA (11.1 ± 5.7 vs 4.6 ± 1.9, P < 0.01), IgA-ACLA (12.8 ± 6.5 vs 7.7 ± 4.0, P < 0.05) and IgA-ß2GPI (7.8 ± 6.6 vs 4.3 ± 2.6, P < 0.05) antibodies (ACLA and ß2GPI antibody measured in U/ml) differed significantly between active disease (DEI = 8.6 ± 3.3) and after partial or complete remission (DEI = 2.6 ± 2.1) had been induced by immunosuppressive therapy with oral cyclophosphamide according to the FAUCI (2 mg/kg cyclophosphamide p.o.) regimen [6] (DEI of active disease vs DEI during remission: P < 0.01). Gammaglobulin levels did not significantly differ between active disease and remission (11.8 ± 3.6 g/l vs 10.0 ± 2.6; P = 0.2).
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Our results are in agreement with a recent report of Manna et al. [7], who found a high prevalence of ACLA (51.5%) in patients with giant cell arteritis (GCA), but failed to demonstrate a correlation with vascular complications and thrombosis. Furthermore, Manna et al. [7] found an inverse relationship between ACLA and haemoglobin levels. We extended their findings in primary systemic vasculitis (PSV) by also testing for the presence of ß2GPI antibodies in WG, which seemed worthwhile against the background of ß2GPI antibody detection in ACLA-negative patients with SLE and a history of thrombosis [8]. If anaemia was ascribed to the disease activity in GCA, Manna's findings would resemble ours with respect to the association of higher values of ACLA and ß2GPI antibodies with active disease stages of WG. Thus, the presence of ACLA and ß2GPI antibodies in PSV might represent secondary events due to the vasculitis and consecutive vascular damage rather than being related to thrombotic events as in primary and secondary antiphospholipid syndromes, e.g. in SLE [9, 10].
Notes
Correspondence to: P. Lamprecht.
References