Reanalysis of the Rituximab in ANCA-Associated Vasculitis trial identifies granulocyte subsets as a novel early marker of successful treatment

Abstract

IntroductionIn the present study, we sought to identify markers in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) that distinguish those achieving remission at 6 months following rituximab or cyclophosphamide treatment from those for whom treatment failed in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial.MethodsClinical and flow cytometry data from the RAVE trial were downloaded from the Immunology Database and Analysis Portal and Immune Tolerance Network TrialShare public repositories. Flow cytometry data were analyzed using validated automated gating and joined with clinical data. Lymphocyte and granulocyte populations were measured in patients who achieved or failed to achieve remission.ResultsThere was no difference in lymphocyte subsets and treatment outcome with either treatment. We defined a Granularity Index (GI) that measures the difference between the percentage of hypergranular and hypogranular granulocytes. We found that rituximab-treated patients who achieved remission had a significantly higher GI at baseline than those who did not (p = 0.0085) and that this pattern was reversed in cyclophosphamide-treated patients (p = 0.037). We defined optimal cutoff values of the GI using the Youden index. Cyclophosphamide was superior to rituximab in inducing remission in patients with GI below −9.25 % (67 % vs. 30 %, respectively; p = 0.033), whereas rituximab was superior to cyclophosphamide for patients with GI greater than 47.6 % (83 % vs. 33 %, respectively; p = 0.0002).ConclusionsWe identified distinct subsets of granulocytes found at baseline in patients with AAV that predicted whether they were more likely to achieve remission with cyclophosphamide or rituximab. Profiling patients on the basis of the GI may lead to more successful trials and therapeutic courses in AAV.Trial registrationClinicalTrials.gov identifier (for original study from which data were obtained): NCT00104299. Date of registration: 24 February 2005.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0778-z) contains supplementary material, which is available to authorized users.

Open Data Revolution in Clinical Research: Opportunities and Challenges

“…For instance, data repurposing initiatives from ImmPort (www.immpo rt.org), a data warehouse that includes clinical trial subject-level data from National Institute of Allergy and Infectious Diseases-funded immunology studies, facilitated the translation of new insights into discoveries. 38,39 Using ImmPort public data, Nasrallah et al 40 sought to identify biomarkers for patients with antineutrophil cytoplasmic antibody-associated vasculitis who failed treatment with cyclophosphamide or rituximab therapy. Their secondary analysis of rituximab-treated participants in the Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis RAVE trial revealed distinct subsets of granulocytes at baseline in patients with vasculitis who achieved a complete remission with cyclophosphamide or rituximab treatment compared with patients who failed to achieve remission.…”

“…Hence, this study suggested that profiling patients based on cell-based markers might help to make therapeutic decisions and inform future trial designs. 40 Another example of data repurposing includes the assessment of the post-donation conditions for living donors in solid organ transplantation included in the ImmPort database. A curated data set, immTransplant, with postdonation outcomes for kidney living donors were derived from 20 clinical studies (clinical trials and observational studies) in ImmPort.…”

Update Therapie der ANCA-assoziierten Vaskulitiden

“…Subgruppenanalysen der RAVE-Studie konnten ein besseres Ansprechen von RTX im Vergleich zu CYC bei Patienten mit Rezidiv und bei PR3-ANCA positiven Patienten demonstrierten [3,4]. Eine Posthoc-Analyse der RAVE-Studie identifizierte außerdem einen niedrigen "Granularity-Index" weißer Blutkörperchen als einen Indikator für das bessere Ansprechen auf CYC im Vergleich zu RTX [5]. Alle diese Subgruppen-bzw.…”

Solving Immunology?

“…Such raw data can be re-analyzed to defend the reproducibility of statistical testing from the original publication, and the aggregation of multiple studies through meta-analysis can be used to increase power to detect subtle signals. They could also be useful for new scientific discoveries, such as finding patient subsets that best respond to an intervention [76], or predicting why drugs might be succeeding or failing in clinical trials.…”