Nancy B. Allen

Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegeners granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Efficacy of Remission-Induction Regimens for ANCA-Associated Vasculitis

BACKGROUND The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown. METHODS In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

A disease-specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score

OBJECTIVE To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegeners granulomatosis (WG). METHODS Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physicians global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearmans rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.

Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis.

The vasculitides are a heterogeneous group of syndromes characterized by blood vessel inflammation. Since Zeeks initial proposal of five separate types of vasculitis in 1952, many schemes have been developed to classify vasculitis according to the size of blood vessel involvement (that is, small arteries compared with medium-sized or large arteries) [1, 2], scope of involvement (limited compared with systemic) [3], or whether the vasculitis occurs secondary to other conditions [4]. To facilitate communication among researchers, the American College of Rheumatology (ACR) proposed classification criteria in 1990 for seven vasculitides, including Wegener granulomatosis, giant-cell arteritis, polyarteritis nodosa, and hypersensitivity vasculitis [5]. The ACR vasculitis criteria were developed and validated on the basis of multicenter data [6, 7]. Rheumatologists from 48 centers in the United States, Canada, and Mexico (including one of the authors) participated in this effort by contributing data from 1020 consecutive patients with a new diagnosis of vasculitis (established <2 years before study entry) to a central database between 1982 and 1987 [6]. The rheumatologists provided each patients diagnosis and information on symptoms; physical findings; and any relevant results of laboratory, biopsy, or angiographic studies that influenced the diagnosis of vasculitis [6]. Neither biopsy nor angiography was required for inclusion in the data set, although most patients had had biopsy [6, 8]. In fact, to increase the representativeness of the sample, the data set included some patients with vasculitis who had not had biopsy or had had a negative biopsy result [6, 8]. Thus, the referring rheumatologists diagnosis served as the gold standard in developing the ACR classification criteria [6, 7]. These criteria have been associated with sensitivities ranging from 71% to 94% and specificities ranging from 87% to 92% for each specific diagnosis compared with other forms of vasculitis. In general, the ACR criteria for rheumatologic syndromes [9-13], including the ACR vasculitis criteria sets [5], were developed as classification criteria for research. In particular, the ACR vasculitis criteria were established to distinguish a specific type of vasculitis among patients with various vasculitides, not to differentiate patients who have vasculitis from those who do not have vasculitis for diagnostic purposes [5]. However, clinicians, particularly nonrheumatologists, often apply ACR classification criteria as diagnostic criteria for various rheumatologic syndromes in individual patients, particularly those with positive results on serologic tests [14]. This phenomenon is entirely understandable given the reported high sensitivity and specificity of ACR criteria sets for classification of patients. The operating characteristics of the ACR classification criteria for diagnosis have not been analyzed in patients who do not have a previously established diagnosis of vasculitis. Because clinicians often use the ACR classification criteria for diagnosis, it is important to conduct such a study in patients in whom vasculitis is suspected but who do not already have established diagnoses of vasculitis at the time of their evaluation. In this study, we applied ACR classification criteria for Wegener granulomatosis, giant-cell arteritis, polyarteritis nodosa, and hypersensitivity vasculitis to a prospective cohort of patients with an unknown diagnosis at the time of their initial rheumatologic evaluation for a possible vasculitis. This was done to determine the test performance of these criteria for these specific diagnoses. Methods Patients The institutional review boards of Duke University Medical Center and the Durham Veterans Affairs Medical Center approved this study. For all patients, an antineutrophil cytoplasmic antibody (ANCA) test was performed by indirect immunofluorescence in the Clinical Immunology Laboratory at Duke University Medical Center using standard techniques [15]. The patient sample was described in a previous report [15]. Briefly, 346 adult inpatients and outpatients, referred for evaluation of a possible vasculitis by rheumatologists at both medical centers, were eligible for the original study, a prospective study of the operating characteristics of ANCA for the diagnosis of Wegener granulomatosis [15]. In that study, we excluded patients who had previously diagnosed Wegener granulomatosis (n = 29) and patients who were receiving either immunosuppressive therapy or disease-modifying antirheumatic drugs (n = 65). For the current study, we further excluded patients who had a previously established vasculitis (n = 14) at the time of evaluation by the rheumatologist. Study Protocol Medical records of consecutive eligible patients were reviewed by a rheumatologist who was blinded to the patients diagnosis. A standard protocol form was completed to record baseline demographic information, comorbid conditions, symptoms, physical findings, and laboratory and radiographic results. A symptom or physical finding reported within the 6 months before the rheumatologic evaluation was considered present. If information on symptoms and physical findings was missing, it was considered absent. The same rheumatologist reviewed the medical records 2 to 8 months after the initial rheumatologic evaluation to collect information on laboratory, biopsy, or angiography results (where applicable) and final diagnosis. Patient Measures The clinicians recorded final diagnosis, made 2 to 8 months after the initial rheumatologic evaluation, along with histopathology or angiography results, was considered the gold standard. If a patient did not have follow-up visits at either medical center during this period, this information was obtained from the referring physician. If a patient died, available autopsy records were examined to determine the immediate cause of death. Our primary interest was to compare vasculitis diagnosed according to ACR classification criteria with the clinicians final diagnosis (as the gold standard). All patients for whom complete follow-up information was available were classified according to the 1990 ACR criteria for Wegener granulomatosis [16], giant-cell arteritis [17], polyarteritis nodosa [18], and hypersensitivity vasculitis [19] on the basis of initial presenting symptoms and physical findings. Wegener Granulomatosis Two of the following four criteria were required to meet ACR classification criteria for Wegener granulomatosis: 1) nasal or oral inflammation; 2) nodules, fixed infiltrates, or cavities on a chest radiograph; 3) microscopic hematuria or more than 5 erythrocytes per high-power field; and 4) granulomatous inflammation on biopsy [16]. These criteria have a reported sensitivity of 88.2% and a reported specificity of 92% for the classification of Wegener granulomatosis compared with other vasculitides [16]. Giant-Cell Arteritis Three of the following five criteria were required to meet ACR classification criteria for giant-cell arteritis: 1) age 50 years or older, 2) new-onset localized headache, 3) temporal artery tenderness or decreased temporal artery pulse, 4) erythrocyte sedimentation rate of at least 50 mm/h, and 5) abnormal artery biopsy specimen characterized by mononuclear infiltration or granulomatous inflammation [17]. These criteria have a reported sensitivity of 93.5% and a reported specificity of 91.2% for the classification of giant-cell arteritis compared with other vasculitides [17]. Polyarteritis Nodosa Three of the following 10 criteria were required to meet ACR classification criteria for polyarteritis nodosa: 1) weight loss of at least 4 kg; 2) livedo reticularis; 3) testicular pain or tenderness; 4) myalgias, weakness, or tenderness; 5) mononeuropathy or polyneuropathy; 6) diastolic blood pressure greater than 90 mm Hg; 7) elevated blood urea nitrogen or creatinine level; 8) hepatitis B virus infection; 9) arteriographic abnormality; and 10) biopsy specimen of small or medium-sized artery containing polymorphonuclear leukocytes [18]. These criteria have a reported sensitivity of 82.2% and a reported specificity of 86.6% for the classification of polyarteritis nodosa compared with other vasculitides [18]. Hypersensitivity Vasculitis Three of the following five criteria were required to meet ACR classification criteria for hypersensitivity vasculitis: 1) age at disease onset older than 16 years, 2) medication at disease onset as a precipitating factor, 3) palpable purpura, 4) maculopapular rash, and 5) biopsy specimen showing granulocytes around an arteriole and venule [19]. These criteria have a reported sensitivity of 71% and a reported specificity of 83.9% for the classification of hypersensitivity vasculitis compared with other vasculitides [19]. Statistical Analysis Descriptive analyses were done by using PC-SAS for Windows, version 6.11 (SAS Institute, Cary, North Carolina). Separate 2 2 contingency tables were constructed for patients who did and did not have a final clinical diagnosis of Wegener granulomatosis, giant-cell arteritis, polyarteritis nodosa, and hypersensitivity vasculitis compared with patients who did and did not meet ACR criteria for these four vasculitides. We constructed contingency tables for the entire cohort and for those patients with a final clinical diagnosis of vasculitis. The sensitivity, specificity, positive predictive value, and negative predictive value of ACR criteria for Wegener granulomatosis, giant-cell arteritis, polyarteritis nodosa, and hypersensitivity vasculitis were calculated for each of these scenarios. Results Patients One hundred ninety-eight patients who did not have a previously established diagnosis of vasculitis at presentation met the inclusion criteria for our study and at 2 to 8 months had complete follow-up information available for review. Sixty-eight percent of the patients were female, and 77% were white; the average a

The Role of Antineutrophil Cytoplasmic Antibody (c-ANCA) Testing in the Diagnosis of Wegener Granulomatosis: A Literature Review and Meta-analysis

Wegener granulomatosis is a serious systemic vasculitis that is uniformly fatal if untreated. In 1983, Fauci and colleagues [1] reported their success with a combination of corticosteroid and cyclophosphamide therapy in 85 patients with Wegener granulomatosis. Since then, the recognition among clinicians of Wegener granulomatosis and its expanded clinical spectrum has improved, making early diagnosis and treatment possible. Patients with the classic Wegener triad have necrotizing granulomatous vasculitis of the upper and lower respiratory tract associated with glomerulonephritis; patients with limited Wegener granulomatosis may have vasculitis limited to the respiratory tract [2]. Because of the potential clinical overlap with other diseases, the diagnostic algorithm for patients with suspected Wegener granulomatosis has traditionally included biopsy of the upper airway, lung, or kidney to confirm the diagnosis and to rule out other entities, such as systemic infections and malignancies, that may respond adversely to cyclophosphamide therapy [3]. Antineutrophil cytoplasmic antibody (ANCA), first described in 1982 in patients with systemic vasculitis and glomerulonephritis, has emerged as a new diagnostic tool and marker of disease activity for vasculitis [4, 5]. Originally thought to be a response to arboviral infection, ANCA was later identified as a seromarker for Wegener granulomatosis [4, 6]. It is currently believed that the presence of ANCA is an important factor in the pathogenesis of this disease [5]. Two ANCA patterns may be seen with indirect immunofluorescence of ethanol-fixed neutrophils: a cytoplasmic pattern (c-ANCA) and the artifactual perinuclear pattern (p-ANCA) [7, 8]. The major antigen for c-ANCA is a 29-kd serine protease, known as proteinase 3, which is found within the azurophilic granules of the neutrophil [9]. The major antigen for p-ANCA is myeloperoxidase, a lysosomal enzyme found in neutrophils [7, 10]. Some clinical overlap has been seen, but the two patterns have different disease associations. The c-ANCA pattern has predominantly been associated with Wegener granulomatosis, and p-ANCA has been associated with microscopic polyarteritis, other vasculitides, idiopathic necrotizing and crescentic glomerulonephritis, and other diseases [7, 11-13]. Early studies of c-ANCA in patients with Wegener granulomatosis, especially those with active disease, have been promising. Reported sensitivities and specificities have exceeded 90% [10-12, 14-18]. Because of the morbidity and expense associated with biopsy, c-ANCA has attracted interest as a rapid and noninvasive way to diagnose Wegener granulomatosis. In fact, some investigators advocate immunosuppressive therapy for patients with positive c-ANCA test results and symptoms compatible with Wegener granulomatosis, even in the absence of biopsy results [19-21]. The history of c-ANCA testing appears to mirror the natural history of many new diagnostic tests. Important and early pioneering studies of new tests are typically done in highly selected patients with confirmed disease to determine the tests operating characteristics. However, when the new test is subsequently applied to unselected populations, clinical experience and additional studies often provide a less optimistic picture of its diagnostic power. Several recent reports [22-27] document false-positive c-ANCA test results in patients with tuberculosis, Hodgkin lymphoma, human immunodeficiency virus infection, nasal septal perforation, monoclonal gammopathies, and drug-induced Wegener-like disease. Similarly, additional reports [28, 29] describe negative c-ANCA test results in patients with Wegener granulomatosis, even those with active disease. Given the current enthusiasm for a serologic diagnosis of Wegener granulomatosis, underrecognition of the rate of false-positive c-ANCA test results may lead to inappropriate immunosuppressive therapy in some patients who do not have Wegener granulomatosis. Conversely, underappreciation of the frequency of false-negative c-ANCA test results may delay therapy for patients who have clinical features compatible with Wegener granulomatosis. We did a literature review and meta-analysis to assess the utility of c-ANCA as a diagnostic marker for Wegener granulomatosis overall and in relation to disease activity. Methods As noted above, two ANCA patterns have been described in the literature, and each has separate disease associations. Patients with Wegener granulomatosis often have c-ANCA, whereas p-ANCA is found in patients with various syndromes with and without vasculitis [7, 30, 31]. Because c-ANCA is thought to have a higher test sensitivity than p-ANCA for the diagnosis of Wegener granulomatosis, we focused only on c-ANCA. Search Strategy We could not determine a systematic approach for identifying unpublished data on c-ANCA, and thus we selected only published articles for our literature review. We did a MEDLINE search for English-language studies done in humans and published between 1966 and June 1993. Three searches were done: 1) a textword and registry search for antineutrophil cytoplasmic antibody [ANCA], anticytoplasmic antibody, and antineutrophil antibody; 2) a combination of search terms antibodies, neutrophils and keywords such as pulmonary-renal syndrome, or Wegener granulomatosis, or vasculitis, or glomerulonephritis; and 3) a search using the keyword pulmonary-renal syndrome alone. Using this initial search strategy, we identified 720 citations. Manual examination of the reference lists of included articles and the bibliographies of review articles and standard texts yielded an additional 27 studies, for a total of 747. Article Selection To be included in the analysis, all articles had to pass through a four-stage review (Table 1). First, the titles and abstracts of the 747 articles were independently examined by two reviewers. One reviewer was a rheumatologist, and the other was a health services researcher with a PhD who had experience in the critical appraisal of medical literature. Articles were excluded at this stage if they were not pertinent to the topic (for example, if they addressed antineutrophil antibodies and malignancy) or if they did not present patient-level data (for example, if they were reports of tissue culture experiments). If a cited article did not have a published abstract but appeared to be relevant, or if either reviewer included it, it was retained for further review. Of the original 747 articles, 407 were excluded and 340 were retained for second-level review. Table 1. Summary of the Results of Protocol for Selection of Articles for Meta-analysis In stage 2 of the review process, the complete articles were photocopied and reviewed by a rheumatologist. Articles were excluded if they were case reports (n = 64), reviews (n = 75), or letters to the editor (n = 58), or if they were irrelevant to our topic (n = 81). Sixty-two of the 340 articles remained for potential inclusion. In stage 3, a rheumatologist (JKR) and an investigator with a PhD reviewed the methods section of each article in detail. The methodologic criteria required for inclusion at this stage were specification of the patient selection method and the use of standard reference criteria to define Wegener granulomatosis. For casecontrol and cohort studies, the authors had to have described a systematic method of patient selection (for example, consecutive patients or a random sample based on prespecified criteria) [32]. Thus, case-series studies (such as those defining persons with a common feature nonsystematically without the presence of a control group) were excluded. Authors also had to specify standard reference criteria for establishing Wegener granulomatosis exclusive of the c-ANCA test result. Acceptable reference criteria included the Ear, Nose, Throat, Lung, and Kidney staging system [2], the Fauci criteria [1], and the American College of Rheumatology criteria [33]. The Ear, Nose, Throat, Lung, and Kidney system and the American College of Rheumatology criteria require biopsy confirmation of Wegener granulomatosis, and the Fauci criteria are clinicopathologic in nature. Thirty-nine articles were excluded at this stage for the following reasons: case-series design (n = 24); the method of patient selection was not clearly stated (n = 4); a reference standard was not specified (n = 7); or the article was irrelevant to our review (n = 4). If either reader included an article, it was retained for further review. In stage 4, three physicians each independently read the remaining 23 articles. Articles were excluded at this stage if a 2 2 contingency table, needed to calculate the operating characteristics, could not be constructed from the results (n = 8). Thus, 15 articles remained for detailed review [10, 11, 14, 15, 28, 34-43]. For these 15 articles, 2 2 contingency tables were constructed for patients with and without Wegener granulomatosis compared with patients with and without positive c-ANCA test results. Disagreements between reviewers were resolved by consensus. Definition of Wegener Granulomatosis We included only those studies that specified standard reference criteria for defining Wegener granulomatosis independent of the patients c-ANCA test result [1, 2, 33]. Patients with Wegener granulomatosis can be further divided into two subtypes: those with classic and those with limited disease [2]. In classic Wegener granulomatosis, glomerulonephritis and inflammation of the upper or lower respiratory tract, or both, are present. In limited disease, the kidneys are not involved, but inflammation of the upper or lower respiratory tract, or both, is present. Only 6 of the 15 studies separated patients by subtype. Furthermore, 2 of these 6 studies did not separate the c-ANCA test results by Wegener granulomatosis subtype. Because of these inconsistencies, we considered a single classification (overall Wegener granulomatosis) to repres

Brief Communication: High Incidence of Venous Thrombotic Events among Patients with Wegener Granulomatosis: The Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study

Context Are patients with Wegener granulomatosis at increased risk for venous thrombotic events (VTEs)? Contribution This prospective observational study found 16 VTEs in 167 patients with Wegener granulomatosis who had no history of VTE. The incidence of VTE was 7 per 100 person-years of follow-up. Implications Patients with Wegener granulomatosis probably have an increased risk for VTE compared with healthy populations who have less than 1 VTE per 100 person-years offollow-up. The Editors Wegener granulomatosis is characterized by inflammation of small- and medium-sized vessels and granulomatous inflammation of various organs (1, 2). The involvement of the venous system in Wegener granulomatosis has received little attention in the past, with only a few reported cases of venous thrombosis (3-5), and textbooks and review articles do not mention an increased risk for venous thrombotic events (VTEs) (1, 6, 7). Early in the enrollment phase of a multicenter treatment trial for Wegener granulomatosis (8-10), several patients had VTEs, including both deep venous thromboses and pulmonary emboli. This observation led to our investigation of VTE incidence in patients with Wegener granulomatosis. Methods Patients and Visit Schedule The Wegeners Granulomatosis Etanercept Trial (WGET) is a multicenter, randomized, double-blind, placebo-controlled study of the efficacy of etanercept, 25 mg subcutaneously twice weekly, in addition to conventional immunosuppressive therapy with glucocorticoids and either methotrexate or cyclophosphamide. Details of the trial design and study results have been published (8, 10). All patients fulfilled the modified American College of Rheumatology Classification Criteria for Wegener granulomatosis, had no history of either exposure to inhibitors of tumor necrosis factor- or a malignant condition, and had no evidence of active infection upon enrollment (8). All patients in WGET were enrolled and randomly assigned to either the active experimental medication or placebo during a period of active vasculitis (flare). Patients were evaluated at study visits every 3 months. Data collection included a full interim medical history with determination of Wegener granulomatosis disease activity, physical examination, laboratory studies, and assessment and review of adverse events. We measured Wegener granulomatosis disease activity by using the Birmingham Vasculitis Activity Score for Wegeners Granulomatosis (BVAS/WG) (11), which considers all manifestations of active disease present during the 28-day period before the date of assessment. A score of 1 or greater indicates active disease, and a score of 0 indicates remission. Patients were required to have a score of 3 or greater to be enrolled in the trial. Investigators measured cumulative disease damage with the Vasculitis Damage Index (12). Severe disease was defined as having a life- or organ-threatening manifestation; other patients were considered to have limited disease (8). The patients who we observed for incidence of VTEs included all 180 patients enrolled in WGET. Details of the baseline demographic and clinical characteristics of this study cohort have been published (9). Diagnosis and Documentation of VTEs All VTEs in WGET were considered serious adverse events necessitating a separate written report documenting the event and outcome (8). A patient was considered to have had a VTE if the event was clinically apparent and was confirmed by diagnostic studies. Clinical evidence of VTEs included edematous or painful limbs, dyspnea, hypoxemia, chest pain, hemoptysis, or other features of deep venous thrombosis or pulmonary embolism. Diagnostic confirmation included results of vascular ultrasonography, impedance plethysmography, ventilationperfusion scanning, computed tomographic angiography, spiral computed tomograpy, venography, or angiography. Investigators collected detailed clinical data on VTEs on all patients for all events that occurred before and during WGET. A study physician completed a separate standardized thrombosis event form for each VTE on the basis of information obtained from patients, nonstudy physicians, and medical records review. The form included the date of event, clinical details of event, diagnostic test results, and determination of Wegener granulomatosis disease status at the time of event. We excluded thromboses of hemodialysis vascular accesses from these analyses. For our investigation of VTE incidence, the observation period started with the date of enrollment of the first patient (9 June 2000) and ended 3 months after the final patient was enrolled (31 December 2002). Statistical Analyses We evaluated differences among patient characteristics in the Wegener granulomatosis cohort at the start of the observation period with the Wilcoxon rank-sum test for continuous variables and with either chi-square or Fisher exact tests for categorical variables (SAS, version 8.0, SAS Institute, Inc., Cary, North Carolina). We calculated the incidence rate and 95% CIs for VTEs by using Stata, version 8.0 (cii command) (Stata Corp., College Station, Texas). The cumulative incidence curve is based on KaplanMeier estimates. Role of the Funding Sources The National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, the U.S. Food and Drug Administration Office of Orphan Products, and the Amgen Corporation supported this study. The Amgen Corporation provided the data on the incidence of VTEs among patients with rheumatoid arthritis. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication. Results Patients We included data from all 180 study patients enrolled in WGET in our study. Table 1 outlines key demographic characteristics and clinic data for the entire cohort and the VTE subgroups. Table 1. Baseline Demographic Characteristics and Clinical Data of Full Study Cohort and Venous Thrombotic Event Subgroups within Wegener Granulomatosis Cohort Incidence Rates of VTE in Wegener Granulomatosis and Comparison Groups At the end of the observation period, 29 of 180 patients (16%) with Wegener granulomatosis had had a VTE at some time: 13 (7.2%) had a history of VTE before WGET enrollment and 16 (8.9%) had first-time VTEs during WGET. The 16 new VTEs among the 167 patients with no history of VTE occurred over 228 person-years of observation, yielding an incidence rate of 7.0 per 100 person-years (95% CI, 4.0 to 11.4). The rates of VTEs did not differ between the etanercept and placebo groups. Clinical Characteristics of Patients with VTEs Appendix Tables 1 and 2 outline the clinical details of all VTEs among the Wegener granulomatosis study sample during and before WGET, respectively. The median time from WGET enrollment (active disease) to VTE in patients who experienced an event was 2.07 months (range, 0.07 to 21.13 months). The Figure shows the time to first VTE for the Wegener granulomatosis group. No participant had more than 1 VTE during WGET. Figure. Time to first venous thrombotic event (VTE) among patients with Wegener granulomatosis. Ten of 16 patients (63%) had active Wegener granulomatosis at the time of the event during WGET. In addition, 11 of the 16 patients (69%) were found to have active Wegener granulomatosis on the study visit before the event, including 3 of the 7 patients whose Wegener granulomatosis was not active at the time of the event. Visits for these 3 patients occurred 14, 33, and 49 days, respectively, before the event. Thus, for 13 of 16 patients (81%) who had VTEs during WGET, Wegener granulomatosis was active at the time of the event or within 2 months before the event. Before WGET enrollment, 18 VTEs occurred among 13 patients. Information on Wegener granulomatosis disease status was available for 12 of 13 first VTEs: Wegener granulomatosis was active in 10 of 12 cases (83%) at the time of the event. Seven of the 13 first VTEs occurred within the 3 months before WGET randomization, including 3 VTEs occurring less than 2 weeks before randomization. We excluded these 7 events from prospective calculation of incident VTE. There were few differences between the 16 patients who had VTE during WGET and the 151 WGET participants who had no history of VTE (Table 1). Compared with participants who did not have an event, those who had a VTE were older at baseline (mean age, 57.5 years vs. 48.6 years; P= 0.039). Aspirin use did not differ between patients with or without VTEs (2 of 16 patients vs. 14 of 151 patients; P> 0.2). Length of hospitalization (4.5 days vs. 6.0 days; P> 0.2) and the proportion of patients hospitalized (50.0% vs. 34.4%, P> 0.2) also did not differ between patients with VTE during WGET and those without a VTE. Discussion To our knowledge, our study is the first to investigate the incidence of VTE in Wegener granulomatosis using a large, well-characterized study cohort and to identify deep venous thrombosis as an important clinical feature of Wegener granulomatosis. Most VTEs in the WGET occurred either during periods of unequivocally active disease or within 2 months of a documented disease flare. Similarly, most VTEs that occurred before the start of the WGET observation period were also associated with active vasculitis. These results suggest that the increased risk for thrombosis bears an important relationship to disease activity in Wegener granulomatosis. Comparison against other groups of patients with VTEs is helpful to appreciate the magnitude of the increased incidence of VTEs in Wegener granulomatosis (Table 2). In a healthy, male, Swedish population, 65 VTEs occurred over 30 years of follow-up, totaling 21007 observation-years and resulting in an incidence rate of first VTE of 0.31 per 100 person-years (CI, 0.4 to 0.4 per 100 person-years) (13). Comparison with this group is relevant because the age of the sample was similar to that of the WGET cohort; the cli

RETROPERITONEAL FIBROSIS: A True Connective Tissue Disease

Retroperitoneal fibrosis, a disease that can occur at any age, is characterized by a periaortic fibrous mass that often surrounds the ureters, leading to ureteral obstruction. Patients who present with this disease may complain of flank pain and acute renal failure. There is a high correlation with atherosclerotic disease of the aorta, although the pathogenesis of this disease remains unknown. Although recommendations for therapy remain empiric, prednisone seems to be efficacious in treatment; tamoxifen also may be effective. Retroperitoneal fibrosis usually does not lead to long-term morbidity or affect survival.

A prospective study of antineutrophil cytoplasmic antibody (c-ANCA) and clinical criteria in diagnosing Wegener's granulomatosis

Antineutrophil cytoplasmic antibody (c-ANCA) has a reported sensitivity and specificity greater than 90% for active Wegeners granulomatosis in selected patients with previously-defined disease. Because of these reports, some clinicians believe that a positive c-ANCA result provides strong circumstantial evidence for the diagnosis of Wegeners granulomatosis in patients with compatible clinical symptoms. However, this approach has not been examined prospectively. We prospectively studied 346 consecutive patients suspected of having vasculitis; those with previously established Wegeners granulomatosis (n = 29) or receiving immunosuppressives other than corticosteroids (n = 65) at baseline were excluded. Measures included a baseline c-ANCA, blinded chart reviews to record symptoms, physical findings, and corticosteroid use at baseline, and 2 to 8 months later to record final diagnoses and biopsy results. Wegeners granulomatosis was defined using the 1990 American College of Rheumatology (ACR) criteria, which does not require a biopsy. Follow-up information was available for 212 (84%) of the 252 patients eligible for this study (no corticosteroids: n = 174; corticosteroids: n = 78). 25 patients with compatible symptoms were classified with Wegeners granulomatosis by ACR criteria; only 6 of the 25 had biopsy-proven disease. 14 of these 212 patients had positive c-ANCA results. The overall sensitivity and specificity of c-ANCA for ACR-defined Wegeners granulomatosis were 28% (95% CI, 10%-46%) and 96% (93%-99%) respectively. The positive and negative predictive values were 0.50 and 0.91. The specificity remained greater than 90% regardless of baseline corticosteroid use or disease activity; however, the sensitivity and positive predictive value remained poor. For Wegeners granulomatosis defined by biopsy criteria and compatible clinical symptoms, the sensitivity was 83% (53%-100%); however, the positive predictive value was 36%. These results raise serious questions about the use of positive c-ANCA tests in diagnosing Wegeners granulomatosis in patients with clinical symptoms alone.

Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis

PURPOSE Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy. PATIENTS AND METHODS We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy). RESULTS No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved. CONCLUSION Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.

Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

OBJECTIVE To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegeners Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.