Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener's): long-term followup of a multicenter longitudinal cohort.

OBJECTIVE: An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. METHODS: The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. RESULTS: Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup. CONCLUSION: The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.

The frequency of anticardiolipin antibodies and genetic mutations associated with hypercoagulability among patients with Wegener's granulomatosis with and without history of a thrombotic event.

OBJECTIVE: Venous thrombotic events (VTE), including both deep venous thrombosis and pulmonary emboli, are now recognized as an important complication of Wegener's granulomatosis (WG), but the mechanism(s) of this occurrence is unclear. The frequency of anticardiolipin antibodies (aCL), anti-beta2-glycoprotein antibodies (anti-beta2-GP), and several genetic hypercoagulable factors were examined in a large cohort of patients with WG. METHODS: One hundred eighty patients with active WG had serum and DNA samples collected upon entry into a clinical trial. Of the 180 patients, 29 patients had VTE -- 13 before trial entry, 16 during trial. aCL (IgG, IgM, and IgA) and anti-beta2-GP (IgG and IgM) were evaluated in 176 patients. Factor V Leiden (FVL), the prothrombin gene mutation (G20210A, PGM), and methylenetetrahydrofolate reductase (MTHFR) gene mutation were tested in the 29 patients with thrombotic events, and 36 patients without. RESULTS: aCL occurred with increased frequencies in patients with WG when compared to the general population (1%-5%): 12% had aCL and 3% had anti-beta2-GP. There was no difference in the prevalences of aCL or anti-beta2-GP based on clotting status. The prevalence of the genetic hypercoagulable factors examined in patients with WG was comparable to the reported rates in the general population. CONCLUSION: Although the incidence of clinically significant VTE is increased in patients with WG, this increased risk is not explained by increased prevalences of aCL, anti-beta2-GP, FVL, or mutations in PGM or MTHFR. These observations suggest a need to search for new genetic or acquired prothrombotic abnormalities to account for the increased thrombotic event rate in patients with active WG.

Antiendothelial cell antibodies in patients with Wegener's granulomatosis: prevalence and correlation with disease activity and manifestations.

OBJECTIVE: Previous studies in small cohorts of patients with Wegener's granulomatosis (WG) or antineutrophil cytoplasmic antibody (ANCA) associated vasculitis have yielded conflicting data regarding the prevalence of antiendothelial cell antibodies (AECA), ranging from 8% to 100%, and the use of AECA as a measure of disease activity. We examined a large, well-characterized cohort of patients with WG and active disease for the presence of AECA. METHODS: Serum from subjects with WG who participated in a clinical therapeutic trial was collected at baseline, when all subjects had active disease. Clinical manifestations and disease activity were documented using the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Serum AECA (IgG) was measured by cyto-ELISA using unfixed human umbilical vein endothelial cells (HUVEC). The AECA positivity cutoff was determined using 71 healthy control samples. Statistical analyses utilized Student's t test, chi-square and Fisher's exact tests, and linear regression. RESULTS: AECA were detected in 34 of 173 (20%) evaluated serum samples. Mean BVAS/WG did not differ between patients with (7.3 +/- 3.2) or without AECA (7.0 +/- 3.3) (p = 0.58). Among the 34 patients positive for AECA, the antibody titer did not correlate with disease activity (BVAS/WG; r = 0.09, p = 0.60). There were no statistically significant differences in the frequency of major clinical manifestations between patients with or without AECA. CONCLUSION: AECA, as measured using HUVEC, are not highly prevalent among patients with active WG, are not associated with specific clinical manifestations, and do not correlate with level of disease activity.

Analysis of a cluster of cases of Wegener granulomatosis.

BACKGROUND: Wegener granulomatosis is a chronic inflammatory autoimmune disease of unknown etiology. The sporadic occurrence, lack of familial or genetic associations, and rising incidence suggest possible exposure to environmental agents as causative for this disease. OBJECTIVE: The objective of this study was to examine possible environmental triggers of Wegener granulomatosis. METHODS: While conducting an environmental survey of potential precipitants of Wegener granulomatosis on a cohort of patients seen at Doylestown Hospital and at the University of Pennsylvania, we identified a cluster of cases in the Dublin, Pennsylvania, region. Through hospital records and patient contacts, we located 7 cases diagnosed in a 3-year period within a 10-mile radius of an Environmental Protection Agency (EPA) Superfund toxic waste site. The radius of inclusion represents a population of approximately 50,000 individuals. Assuming complete ascertainment of cases--which is unlikely given the methods used to acquire patients--the prevalence is 2- to 4-fold greater than the expected rate of 3 per 100,000. We identified toxins at or above "action level" within the demarcated geographic region using published data from the EPA. Furthermore, we queried patients regarding their particular chemical exposures. RESULTS: These patients with Wegener granulomatosis were possibly exposed to high levels of trichloroethylene (TCE), vinyl chloride, methyl tertiary-butyl ether (MTBE), dichloroethene (DCE), and chromic acid from several industrial waste sites within the area. Additionally, these patients reported a total of greater than 30 possible exposures, including the aforesaid chemical contaminants. Three of 5 patients whose water source is known had well water that exposed them to industrial runoff and necessitated EPA intervention. CONCLUSION: This data, along with other epidemiologic studies, suggest possible toxic exposures as potentially correctable risk factors for Wegener granulomatosis. We encourage clinicians to seek data that suggests an unusual environmental exposure and to solicit information that might implicate an industrial source for these exposures.