ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis.

BACKGROUND: The pathogenic significance of antineutrophilic cytoplasmic antibodies (ANCA) in Wegener's granulomatosis is controversial. Their presence is influenced by the extent, severity, and activity of the disease at the time of sampling. The objective of this study was to determine the frequency of ANCA in patients with active Wegener's granulomatosis and to assess the influence of disease severity on test results. METHODS: Baseline serum samples from the 180 participants in a multicentric prospective trial were tested for ANCA by indirect immunofluorescence, direct enzyme-linked immunosorbent assay (ELISA), and capture ELISA. Disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener's granulomatosis. All patients had active disease at enrollment. Patients were categorized as having severe (n=128) or limited (n=52) Wegener's granulomatosis. RESULTS: When all ANCA detection methods were combined, 166 patients (92%) were ANCA positive, including 96% with severe disease and 83% with limited disease. CONCLUSION: ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis, but approximately 1 of 5 patients with active limited disease are ANCA negative. Immunofluorescence and both direct and capture ELISAs are required for optimal detection, suggesting that ANCA are not recognized equally well by all testing methods.

Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial.

OBJECTIVE: Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients. METHODS: One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively. RESULTS: All 6 solid malignancies observed during the WGET occurred in the etanercept group (P = 0.01 versus placebo group); based on a comparison of age- and sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment. CONCLUSION: Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of WG, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.

Herpes zoster in immunocompromised patients: incidence, timing, and risk factors.

PURPOSE: To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis. SUBJECTS AND METHODS: We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. RESULTS: Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (+/- 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine > or =1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine > or =1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004). CONCLUSION: Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.

Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study.

BACKGROUND: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known. OBJECTIVE: To measure the incidence of VTEs in patients with Wegener granulomatosis. DESIGN: Prospective, observational cohort study. SETTING: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis. PATIENTS: 180 patients with Wegener granulomatosis enrolled during periods of active disease. MEASUREMENTS: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE. RESULTS: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4). LIMITATIONS: Although prospectively recorded, screening for VTEs did not occur. CONCLUSIONS: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.