OP0027 TIME TO FLARE AND GLUCOCORTICOID EXPOSURE IN PATIENTS WITH NEW-ONSET VERSUS RELAPSING GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB OR PLACEBO PLUS PREDNISONE TAPERING: 3-YEAR RESULTS FROM A RANDOMIZED CONTROLLED PHASE 3 TRIAL

Background:In part 1 of the 52-week, double-blind GiACTA trial, tocilizumab (TCZ) every week (QW) or every other week (Q2W) + prednisone tapering reduced the risk for flare versus placebo (PBO) + 26-week prednisone tapering among patients with new-onset giant cell arteritis (GCA) at baseline. Among patients with relapsing GCA, TCZ QW but not Q2W + prednisone reduced the risk for flare versus both PBO groups, and there was separation in the time to flare between the TCZ QW and Q2W groups.1Objectives:To report time to first flare and potential cumulative glucocorticoid (GC) sparing over 3 years of the GiACTA trial (part 1 + 2-year open-label part 2) among patients with new-onset or relapsing GCA.Methods:At the end of part 1, patients entered open-label part 2, in which GCA therapy (including initiation/termination of open-label TCZ and/or GCs) was given at the investigator's discretion according to disease status. Time to first GCA flare during the 3-year study period was assessed using Kaplan-Meier analysis for patients in the intention-to-treat population according to disease onset status at baseline (new-onset/relapsing) based on their originally assigned treatment groups: TCZ QW, TCZ Q2W, or pooled PBO (PBO+26-week and PBO+52-week prednisone taper).Results:Among patients randomly assigned in part 1, 47 of 100 (47%) in the TCZ QW group, 26 of 49 (53%) in the TCZ Q2W group, and 46 of 101 (46%) in the pooled PBO group had new-onset GCA at baseline; the rest had relapsing GCA. Median time to first flare over 3 years was longer for patients assigned to TCZ treatment in part 1 than for patients assigned to PBO; Kaplan-Meier analysis showed a clear separation between the TCZ QW and the pooled PBO groups over 3 years for patients with new-onset and relapsing GCA (Figure 1A). Separation between the TCZ QW and TCZ Q2W groups was also observed over 3 years in patients with new-onset and relapsing GCA, although this was more evident in patients with relapsing GCA (Figure 1B). Higher proportions of patients in the TCZ QW group (new-onset, 49%; relapsing, 47%) than the pooled PBO group (new-onset, 28%; relapsing, 31%) and the TCZ Q2W group (new-onset, 27%; relapsing, 35%) remained flare-free during their entire treatment period. Cumulative prednisone dose over 3 years was lower for patients originally assigned to TCZ QW versus those originally assigned to PBO for patients with new-onset GCA and those with relapsing GCA at baseline (Figure 2).Conclusion:In this 3-year analysis of GiACTA parts 1 and 2, time to first flare favored TCZ QW over TCZ Q2W in patients with new-onset and relapsing GCA. TCZ QW delayed time to first flare and resulted in lower cumulative GC exposure compared with PBO in patients with new-onset and relapsing GCA, supporting TCZ QW dosing in patients with GCA regardless of disease onset.References:[1]Stone JH et al. N Engl J Med 2017;377:317-28.Disclosure of Interests:John H. Stone Grant/research support from: Roche, Consultant of: Roche, Helen Spotswood Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, Sebastian Unizony Grant/research support from: Genentech, Inc., Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Daniel Blockmans Consultant of: yes, Speakers bureau: yes, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG), Maria C. Cid Speakers bureau: Roche, Bhaskar Dasgupta Grant/research support from: Roche, Consultant of: Roche, Sanofi, GSK, BMS, AbbVie, Speakers bureau: Roche, Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Carlo Salvarani: None declared, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, Min Bao Shareholder of: Roche, Employee of: Genentec

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients

Peripheral CD5+B Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Objective. CD5(+) B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5(+) B cells as biomarkers in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods. The absolute and relative numbers (percentages) of CD5(+) B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA-Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse-free survival according to the percentage of CD5(+) B cells detected upon B cell repopulation. Results. CD5(+) B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5(+) B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5(+) B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5(+) B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5(+) B cells and induction treatment failure or disease severity. The dynamics of the CD5(+) B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5(+) B cells was not predictive of time to flare in RTX-treated patients. Conclusion. The percentage of peripheral CD5(+) B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type

Objective To 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. Methods Treatment 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. Results PR3-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. Conclusions Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV