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ObjectiveTo evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response.MethodsTreatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper.ResultsPR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis.ConclusionsPatients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV.Trial registration numberNCT00104299; post-results.

Noninvasive means for diagnosing acute rejection in kidney transplants are needed. This study prospectively measured mRNA in urinary cells from kidney-allograft recipients. A three-gene signature appeared to be diagnostic and prognostic of acute cellular rejection. Kidney transplantation is considered the best available treatment for patients with end-stage renal disease (ESRD), but acute rejection, a leading cause of new cases of ESRD, undermines its full benefits. 1 – 3 Acute rejection is diagnosed by means of needle biopsy. Over time, this invasive procedure has become safer, and biopsy interpretation more standardized. 4 Nevertheless, bleeding and subsequent graft loss still occur, and sampling errors and interobserver variability in biopsy reading remain problematic. 5 Repeated biopsies to assess the recipient's status pose challenges, including feasibility and cost. Immunosuppressive drugs effectively treat acute rejection; a noninvasive means of diagnosing this reversible cause of . . .

This study of ANCA-associated vasculitis compared a single course of rituximab with conventional immunosuppression with cyclophosphamide followed by azathioprine and showed similar results for the primary outcome of complete remission by 6 months, maintained through 18 months. Granulomatosis with polyangiitis (previously termed Wegener's granulomatosis) and microscopic polyangiitis are called antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides because they are frequently accompanied by autoantibodies against proteinase 3 or myeloperoxidase. 1 , 2 For nearly four decades, cyclophosphamide and glucocorticoids have been the standard therapy for the induction of remission. However, the primary results of the Rituximab in ANCA-Associated Vasculitis (RAVE) trial 3 and results from a European trial 4 showed that rituximab was as effective as cyclophosphamide for the induction of remission in patients with severe disease. Moreover, the rituximab-based regimen was superior in patients who had relapsing disease at 6 months. 3 Rituximab has . . .

This multicenter, randomized, double-blind, double-dummy, noninferiority trial compared rituximab with cyclophosphamide for remission induction in ANCA−associated vasculitis. Rituximab therapy was not inferior to daily cyclophosphamide treatment for remission induction in severe ANCA-associated vasculitis and may be superior in relapsing disease. Rituximab therapy was not inferior to daily cyclophosphamide treatment for remission induction in severe ANCA-associated vasculitis and may be superior in relapsing disease. Wegener's granulomatosis and microscopic polyangiitis are classified as antineutrophil cytoplasmic antibody (ANCA)−associated vasculitides because most patients with generalized disease have antibodies against proteinase 3 or myeloperoxidase. 1 , 2 The ANCA-associated vasculitides affect small-to-medium-size blood vessels, with a predilection for the respiratory tract and kidneys. 3 – 6 Cyclophosphamide and glucocorticoids have been the standard therapy for remission induction for nearly four decades. 7 , 8 This regimen transformed the usual treatment outcome of severe ANCA-associated vasculitis from death to a strong likelihood of disease control and temporary remission. 3 – 5 , 9 _ 11 However, not all patients have a remission with this combination of drugs, and those . . .

Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG)≥3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.

To the Editor: In the 18-month follow-up report of the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, Specks et al. (Aug. 1 issue) 1 reported a noninferiority of intravenous rituximab (375 mg per square meter of body-surface area administered weekly for 4 weeks) as compared with oral cyclophosphamide (taken daily) followed by azathioprine. Complete remission was maintained in 39% of the patients in the rituximab group and in 33% of the patients in the comparison group. As compared with the results of the CYCLOPS trial, the relapse rate in the control group exceeded expectations (20.8% in the CYCLOPS trial vs. 29% in . . .

Many phase I/II clinical trials in multiple sclerosis use gadolinium-enhanced lesions as the outcome measure. The best scanning interval and analysis for this outcome has not been determined. The objective of this study was to compare timing schemes and analysis techniques in terms of power for phase I/II clinical trials. Data were simulated under four scenarios assuming a negative binomial distribution for the number of new lesions and an exponential distribution for the duration of enhancement. The first scenario assumed an immediate treatment effect on the number of new lesions, while the second scenario assumed a delayed treatment effect. The third scenario assumed a higher proportion of patients had no new lesions, and the final scenario assumed an immediate treatment effect on the duration of enhancement. For each scenario, power for a six-month trial with 100 patients per arm was calculated using 10 analysis strategies. The scanning intervals tested were monthly scans, bimonthly scans and a single end-of-study scan. In addition, cost-effectiveness of each trial design and analysis was compared. Negative binomial regression models for the total number of new lesions were the most powerful analyses under an immediate treatment effect, and repeated measures models with a categorical time effect were the most powerful analyses under a delayed treatment effect. Although monthly scans generally provided most power, this design was also most costly. Designs with fewer scans per patient provide similar power and are more cost-effective. Negative binomial regression models are more powerful than non-parametric approaches.

The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG≥3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9-4.4) compared to healthy controls (1.2, 0.9-1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9-3.8, median change -0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25-0.41), and inversely with renal function (r = -0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity.

Islet β‐cell membrane excitability is a well‐established regulator of mammalian insulin secretion, and defects in β‐cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration–response relationship to mammalian β‐cells. However, zebrafish islet calcium transients are nor well coupled, with a shallower glucose‐dependence of cytoplasmic calcium concentration. We have also generated transgenic zebrafish that conditionally express gain‐of‐function mutations in ATP‐sensitive K+ channels (KATP‐GOF) in β‐cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations. KATP‐GOF fish become severely hyperglycemic, with slowed growth, and their islets lose glucose‐induced calcium responses. These results indicate that, although lacking tight cell‐cell coupling of intracellular Ca2+, adult zebrafish islets recapitulate similar excitability‐driven β‐cell glucose responsiveness to those in mammals, and exhibit profound susceptibility to diabetes as a result of inexcitability. While illustrating evolutionary conservation of islet excitability in lower vertebrates, these results also provide important validation of zebrafish as a suitable animal model in which to identify modulators of islet excitability and diabetes. We show that adult zebrafish islet β‐cell calcium levels rise in response to elevated extracellular [glucose], with similar concentration–response relationship to mammalian β‐cells. We have also generated transgenic zebrafish that conditionally express gain‐of‐function mutations in ATP‐sensitive K+ channels (KATP‐GOF) in β‐cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations.