Ulrich Specks

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

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.)

Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy

We report on the successful, compassionate use of the anti-CD20 chimeric monoclonal antibody rituximab in a patient with chronic, relapsing cytoplasmic antineutrophil cytoplasmic antibody (cANCA)-associated Wegeners granulomatosis (WG). The patient initially responded to treatment with glucocorticoids and cyclophosphamide. However, bone marrow toxicity during cyclophosphamide treatment of a relapse precluded its further use. Azathioprine and mycophenolate mofetil treatment had failed to maintain remission of the WG, and methotrexate was contraindicated. Because the patients 5-year course was characterized by close correlation of cANCA levels with disease activity, selective elimination of cANCA was deemed a treatment option for his latest relapse. He was given 4 infusions of 375 mg/M2 of rituximab and high-dose glucocorticoids. Complete remission was associated with the disappearance of B lymphocytes and cANCA. Glucocorticoid treatment was then discontinued. After 11 months, the cANCA recurred, and rituximab therapy was repeated, without glucocorticoids. At 8 months after the second course of rituximab (18 months after the first course), the patients WG has remained in complete remission. Elimination of B cells by rituximab therapy may prove to be an effective and safe new treatment modality for ANCA-associated vasculitis and possibly other autoimmune diseases. This modality warrants closer examination in a carefully conducted clinical trial.

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

Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists

PURPOSE To determine the association of antineutrophil cytoplasmic antibodies (ANCA) and leukotriene receptor antagonists with disease activity in a large series of patients with Churg-Strauss syndrome. METHODS Potential subjects were identified by a computerized search of the Mayo Clinic Rochester database for the years 1990 to 2000. Patients meeting one of three classification schemes for Churg-Strauss syndrome were included. RESULTS Ninety-one patients met the inclusion criteria. Clinical manifestations were similar to those in previous reports. Mortality was similar to that in the general population. ANCA testing was performed in 74 patients. Seventy-three percent (n = 22) of the 30 patients tested before therapy were ANCA positive, as were 75% (n = 12) of the 16 patients tested during a disease flare. In comparison, 16% (n = 8) of the 49 tested during remission were ANCA positive. Serial measurements indicated a correlation of ANCA levels with disease activity. Central nervous system involvement was the only clinical manifestation that correlated with ANCA status (P = 0.05). Twenty-three patients received leukotriene receptor antagonists, of whom 16 (70%) began treatment before diagnosis and 6 (27%) began during remission. Two of those treated after diagnosis relapsed. In 1 patient the relation between disease and leukotriene receptor antagonist use could not be determined. Use of leukotriene receptor antagonists did not affect the time between onset of asthma and manifestations of vasculitis, and was not correlated with organ manifestations, except sinus disease. CONCLUSION No one classification scheme identified all patients. Churg-Strauss syndrome has a better prognosis than other ANCA-associated vasculitides. ANCA status correlates with disease activity, whereas a pathogenic role for leukotriene receptor antagonists in the development of Churg-Strauss syndrome was not noted.

Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

Context Most patients with Wegener granulomatosis have antineutrophil cytoplasmic antibodies (ANCA). The role of ANCA testing in monitoring response to treatment is controversial. Contribution Using data from a large treatment trial, the authors found little association between disease activity and ANCA levels. Decreases in ANCA levels were not associated with remission, and increases were not associated with relapse. Caution Because follow-up duration differed by patient, standard measures of ANCA accuracy, such as sensitivity and specificity for detecting remission and relapse, could not be calculated. Implication Serial ANCA testing should not be used to monitor disease activity or to guide decisions about immunosuppressive treatment in patients with Wegener granulomatosis. The Editors Wegener granulomatosis is characterized by necrotizing granulomatous inflammation and vasculitis, most commonly affecting the respiratory tract and kidneys (1, 2). Remission can be induced in most patients by using glucocorticoids with cyclophosphamide or methotrexate (17), but most patients have relapse when immunosuppression is reduced or withdrawn (1, 2, 6, 8). Consequently, patients experience substantial illness and damage from both the disease and treatment toxicity (1, 9). Accurate assessment of disease activity and prediction of relapse remain the biggest challenges in management of Wegener granulomatosis (10). Most patients with Wegener granulomatosis have antineutrophil cytoplasmic antibodies (ANCA), which produce a cytoplasmic immunofluorescence pattern on ethanol-fixed neutrophils and react with the neutrophil serine protease proteinase 3 (PR3) (1115). Proteinase 3 is synthesized as a proenzyme (pro-PR3) containing an amino-terminal activation dipeptide that preserves PR3 in an inactive state (16). Subsequent cleavage of this dipeptide allows PR3 to assume its active enzyme conformation (mature-PR3) (16). The diagnostic value of ANCA is well established (17, 18); however, the role of serial ANCA measurements during follow-up and their utility in guiding treatment remain controversial (10, 19, 20). A recent study indicated that in individual patients with Wegener granulomatosis, ANCA against pro-PR3 had a stronger correlation with disease activity than did ANCA against mature-PR3 (21). Therefore, we sought to determine whether pro-PR3ANCA levels correlate more strongly with disease activity than do mature-PR3ANCA levels, whether a decrease in pro- or mature-PR3ANCA levels during remission-induction therapy is associated with a shorter time to sustained remission, and whether an increase in pro- or mature-PR3ANCA levels is associated with relapse. Methods This prospective study was done in the context of the WGET (Wegener Granulomatosis Etanercept Trial) (6, 22, 23), a randomized, placebo-controlled trial that evaluated etanercept for maintenance of remission in 180 patients with Wegener granulomatosis at 8 centers across the United States (Appendix 1). All patients met at least 2 of the 5 modified American College of Rheumatology criteria for classification of Wegener granulomatosis and had active disease within 28 days before enrollment and a Birmingham Vasculitis Activity Score for Wegener granulomatosis (BVAS/WG) of at least 3 (22, 24). Follow-up evaluations were done at baseline, after 6 and 12 weeks, and then every 3 months until the end of the trial. Two additional evaluations took place at 3 and 6 months after the end of the trial. During each visit, disease activity was measured by using the BVAS/WG, and serum samples were obtained, frozen, and stored at 80 C. Treatment Patients were treated in a protocol-defined manner with etanercept or placebo in addition to standard therapies. Patients with severe Wegener granulomatosis (life- or organ-threatening disease) received cyclophosphamide and glucocorticoids at enrollment (22, 24). Those with limited (that is, nonsevere) Wegener granulomatosis received methotrexate and glucocorticoids. Medication dosages were tapered according to protocol once disease activity was controlled (6, 22). Assessment of Disease Activity and Definitions of Sustained Remission and Relapse Disease activity was measured by using the BVAS/WG (24). This index considers all manifestations of active disease during the 28 days preceding the date of assessment. A BVAS/WG of 1 or greater is considered active disease, and a BVAS/WG of 0 indicates remission (24). Our analyses focused on first sustained remission and first relapse. Sustained remission was defined as a BVAS/WG of 0 for at least 6 months (6, 22). The PR3-ANCA level at the visit in the middle of this period was considered the PR3-ANCA level at sustained remission. Disease relapse was defined as an increase of at least 1 point in the BVAS/WG in patients who had sustained remission. ANCA Detection Methods A standard immunofluorescence assay and direct enzyme-linked immunosorbent assays (ELISAs) for PR3-ANCA and ANCA against myeloperoxidase were done as described elsewhere (25). Capture ELISA was used to measure PR3-ANCA (2527); levels are expressed as net absorbance, and a level of 0.10 or greater is considered positive (26, 27). The intra-assay and interassay coefficients of variation are 9% and 31%, respectively, for pro-PR3 capture ELISA, and 6% and 28%, respectively, for mature-PR3 capture ELISA. All baseline serum samples were screened at first thaw by using all methods. Patients whose baseline samples tested positive for perinuclear-staining ANCA or ANCA against myeloperoxidase (n= 24) were excluded from further analyses because of substantial differences in disease phenotype between patients positive for ANCA against myeloperoxidase and those positive for PR3-ANCA. In addition, the number of patients who were positive for ANCA against myeloperoxidase was too small for meaningful longitudinal analysis (5, 28, 29). Subsequently, all serum samples were tested for mature- and pro-PR3ANCA in parallel by using capture ELISA at first thaw (except for the baseline samples, which were retested at second thaw). To minimize variability, all serum samples from an individual patient were run at once in the same plate and the same lots of all reagents were used for all assays. Laboratory personnel were blinded to the clinical data. Increase and Decrease of PR3-ANCA Levels We defined an increase in PR3-ANCA levels a priori as an increase of at least 100% in the net absorbance over 6 months. An absolute increase of at least 0.4 was also required to ensure that small elevations were above the intra-assay coefficient of variation. We classified a negative-to-positive conversion of PR3-ANCA status as an increase only if the absolute increase was at least 0.4. Because 6 months corresponded to 3 clinical visits (except for the initial 6 months after enrollment, when it corresponded to 4 clinical visits), we compared the PR3-ANCA levels at each visit with those from the previous 2 to determine whether the criteria for increase were fulfilled. We first looked for an increase in PR3-ANCA 9 months after enrollment (the fourth visit), because that was the first time that a patient could meet the definition of sustained remission. Thus, the PR3-ANCA level at the fourth visit was compared with the levels at the third and second visits after enrollment. No increase in PR3-ANCA before the fourth visit after enrollment was analyzed (Appendix Figure 1). Appendix Figure 1. Diagram of the initial 4 clinical visits. The fourth clinical visit was the first point at which a patient could meet the study definition of sustained remission (SR) (a Birmingham Vasculitis Activity Score for Wegener granulomatosis [BVAS/WG] of 0 for 6 months) and was the first time we looked for an increase in proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels. We compared the net absorbance of PR3-ANCA at this visit with that of the previous 2 visits or the previous 6 months (curved lines). The same comparison was done at every subsequent visit. We defined a decrease in PR3-ANCA levels during the initial 6 months of follow-up as a decline of at least 50% in the net absorbance with an absolute decrease of at least 0.4; for values between 0.1 and 0.4, the capture ELISA needed to yield negative results. Statistical Analysis Descriptive data are summarized as mean (SD), median (interquartile range), or percentages. Groups were compared by using the t test (or the rank-sum test) or the chi-square test (or Fisher exact test), with 95% CIs calculated as appropriate. A P value less than 0.05 was considered statistically significant. We performed unadjusted and adjusted analyses. The adjusting variables were age, sex, disease severity (severe vs. limited Wegener granulomatosis), treatment group (etanercept vs. placebo), disease duration, baseline BVAS/WG, and clinical center (see Appendix 2 for additional details). PR3-ANCA Levels and Disease Activity The cross-sectional and longitudinal associations between the BVAS/WG and the levels of mature- and pro-PR3ANCA were estimated by using random-effect models. We constructed the models with BVAS/WG as the dependent variable and included a random effect for each patient (random intercept) and 2 terms for PR3-ANCA levelsone term for the value of PR3-ANCA level at baseline and the other for the change in PR3-ANCA level from baseline to time t. To assess the magnitude of the association between PR3-ANCA levels and the BVAS/WG, we estimated the relative reduction in the residual variance by comparing the residual variance of the model that included a random effect for each patient and 2 terms for PR3-ANCA levels with the residual variance of a model that only included the random effect for each patient. These analyses included only observations in which both BVAS/WG and PR3-ANCA level were available (9% of the observations had missing PR3-ANCA information). For patients who achieved sustained remission, the mature- and pro-PR3ANCA level

Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): Ten‐year experience at a single center

OBJECTIVE This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegeners) (GPA). METHODS We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. RESULTS Fifty-three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. CONCLUSION RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long-term remission merits further formal investigation.

Clinical studyChurg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists

PURPOSE To determine the association of antineutrophil cytoplasmic antibodies (ANCA) and leukotriene receptor antagonists with disease activity in a large series of patients with Churg-Strauss syndrome. METHODS Potential subjects were identified by a computerized search of the Mayo Clinic Rochester database for the years 1990 to 2000. Patients meeting one of three classification schemes for Churg-Strauss syndrome were included. RESULTS Ninety-one patients met the inclusion criteria. Clinical manifestations were similar to those in previous reports. Mortality was similar to that in the general population. ANCA testing was performed in 74 patients. Seventy-three percent (n = 22) of the 30 patients tested before therapy were ANCA positive, as were 75% (n = 12) of the 16 patients tested during a disease flare. In comparison, 16% (n = 8) of the 49 tested during remission were ANCA positive. Serial measurements indicated a correlation of ANCA levels with disease activity. Central nervous system involvement was the only clinical manifestation that correlated with ANCA status (P = 0.05). Twenty-three patients received leukotriene receptor antagonists, of whom 16 (70%) began treatment before diagnosis and 6 (27%) began during remission. Two of those treated after diagnosis relapsed. In 1 patient the relation between disease and leukotriene receptor antagonist use could not be determined. Use of leukotriene receptor antagonists did not affect the time between onset of asthma and manifestations of vasculitis, and was not correlated with organ manifestations, except sinus disease. CONCLUSION No one classification scheme identified all patients. Churg-Strauss syndrome has a better prognosis than other ANCA-associated vasculitides. ANCA status correlates with disease activity, whereas a pathogenic role for leukotriene receptor antagonists in the development of Churg-Strauss syndrome was not noted.

Rituximab therapy in idiopathic membranous nephropathy: a 2-year study.

BACKGROUND AND OBJECTIVES It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) × 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations. RESULTS Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow-up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX. CONCLUSIONS Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy.