Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients

Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a... Abstract Objectives To assess efficacy and safety of rituximab (RTX) induction and maintenance therapy for granulomatosis with polyangiitis (GPA) in a single-centre cohort study. Methods All patients with active GPA, not enrolled in trials, who received ⩾1 RTX infusion(s) for induction were included. At remission, protocolized maintenance RTX infusions were given every 6 months for 18 months. Kaplan–Meier curves were used to estimate survival rates. Univariable analyses identified factors associated with remission failure and relapse, and Cox models retained independent predictors of relapse. Results One hundred and fourteen adults with relapsing (65%), refractory/grumbling (22%) or new-onset (13%) GPA received RTX for induction; 100 were given ⩾1 RTX maintenance infusion(s) and 90 received 500 mg every 6 months. Median daily prednisone induction dose was 30 mg; 76% of patients were still receiving a median daily prednisone dose of 5 mg at 2 years. Median follow-up was 3.6 years. Respective 2-year relapse-free survival and RTX retention rates were 85 and 78%. Serious infection and serious adverse event rates were 4.9 and 8.1 per 100 patient-years, respectively. Refractory/grumbling vs new-onset and/or relapsing GPA (P < 0.01 for each individually; P < 0.001 vs the latter two taken together), pachymeningitis (P < 0.05), pure granulomatous disease (P < 0.05) or estimated glomerular filtration rate ⩾60 ml/min (P < 0.01) were associated with remission failure. Multivariate analyses retained refractory/grumbling GPA (P = 0.05), subglottic stenosis (P < 0.005), ENT involvement (P = 0.01) and skin involvement (P < 0.0005) as independent predictors of relapse. Conclusion RTX induction and low-dose preemptive maintenance can effectively and safely induce sustained remission in GPA in a real-life setting. granulomatosis with polyangiitis, rituximab, remission induction treatment, maintenance, glucocorticoids Rheumatology key messages In 114 granulomatosis with polyangiitis patients treated with rituximab induction and maintenance therapy, 2-year relapse-free survival was 85%. In granulomatosis with polyangiitis patients treated with rituximab for induction and maintenance therapy, RTX retention rate was 78%. Serious infection and serious adverse event rates in granulomatosis with polyangiitis were 4.9 and 8.1 per 100 patient-years, respectively. Introduction ANCA-associated vasculitides (AAVs) include several different commonly relapsing and potentially life-threatening diseases in which necrotizing vasculitis affects predominantly small-to-medium-sized vessels [1]. Granulomatosis with polyangiitis (GPA) is characterized by granulomatous inflammation, usually involving the upper and lower respiratory tract, with frequent necrotizing glomerulonephritis [2]. The development of a two-stage treatment strategy, using immunosuppressants and glucocorticoids (GCs) for induction and a less toxic immunosuppressive remission maintenance regimen to limit adverse events (AEs), was a major step forward in GPA management. Remission induction treatment of new-onset organ-threatening or life-threatening AAV usually combines GC and cyclophosphamide or rituximab (RTX) [1]. Remission maintenance therapy comprises low-dose GC and AZA, MTX, MMF or RTX [1]. Randomized controlled trials (RCTs) showed RTX’s non-inferiority to CYC for induction therapy of severe AAVs [3–5] and superiority over AZA to contain the relapse rate during maintenance [6, 7]. Because RTX use for AAVs is likely to increase, analysis of long-term RTX administration is of interest. However, data on the efficacy and complications of prolonged RTX use for AAVs are sparse in a real-life setting. Furthermore, RCTs enrolled GPA and microscopic polyangiitis (MPA) patients, who should perhaps be studied separately, selected patients with minor pre-existing comorbidities and provided only limited follow-up that precluded generalization. This study was undertaken to evaluate the efficacy and safety of RTX induction and maintenance therapy for GPA patients treated and followed in our centre. We also attempted to identify factors predicting failure to obtain remission and relapse. Methods Study population After obtaining approval from the Cochin Hospital Ethics Committee, we conducted a single-centre cohort study, including all adult patients with active and relapsing, refractory/grumbling or new-onset GPA who received ⩾1 RTX infusion(s) for induction at our National Referral Center for Vasculitis from April 2005 to December 2016. Data were censured 31 May 2017. Patients receiving RTX only as maintenance therapy were not included. Patients had to satisfy the ACR classification criteria [8] and/or revised Chapel Hill Nomenclature [2] for GPA. To ensure identification of all consecutive patients, potential participants were extracted from Cochin Hospital’s Central Pharmacy electronic database, which prepares all RTX infusions. Patients enrolled in prospective clinical trials were not included. Treatment protocol The remission induction regimen combined GC (i.v. methylprednisolone, 1 g/day for 1–3 days, before oral prednisone, if deemed necessary by the treating physician, and oral prednisone up to 1 mg/kg/day) and RTX. The scheduled prednisone tapering at our centre consisted of gradually tapering the daily dose to reach 20 mg at month 3, 10 mg at month 6 and 5 mg at month 12, and left thereafter to the treating physician’s discretion. The RTX regimen consisted of four infusions (375 mg/m2 of body surface area; 1/week) or sometimes two 1 g infusions, 2 weeks apart. Prior to infusion, all patients received methylprednisolone (100 mg), paracetamol (1 g) and dexchlorpheniramine (5 mg). Once RTX was initiated, all immunosuppressants, except GC, were discontinued. Our standard approach after achieving remission is to give preemptive RTX maintenance therapy (500 mg) every 6 months to all patients until month 24, according to a previously described regimen [6], modified with no reinfusion on day 15 following the first maintenance infusion. After having received a total RTX maintenance dose (2 g in four infusions) within 18 months, all patients were monitored every 3–6 months. During RTX induction and maintenance therapy, patients received trimethoprim–sulfamethoxazole prophylaxis against Pneumocystis jiroveci pneumonia. Ethical approval The Ethics Review Committee for publications of the Cochin University Hospital approved the study (decision no. AAA-2016-0600). Patient consent was not required. Definitions According to the EULAR recommendations [9]: remission is the absence of disease activity, with BVAS = 0; relapse is the recurrence or new onset of disease activity attributable to active vasculitis; major relapse is the recurrence or new onset of potentially organ- or life-threatening disease activity that cannot be treated with GC intensification alone and requires further therapeutic escalation; minor relapse is the recurrence or new onset of manifestations that are neither potentially organ- nor life-threatening. Vasculitis activity was evaluated with BVAS v3 [10, 11]. Serious AEs (SAEs) were defined as those that were life-threatening, required hospitalization, caused persistent disability or permanent damage, or were fatal. Serious infections were defined as those requiring hospitalization or i.v. antibiotics, or that were fatal. Hypogammaglobulinaemia was defined as serum gammaglobulin and/or low IgG <7 g/l, and significant hypogammaglobulinaemia as serum gammaglobulin and/or IgG <4 g/l. To compare RTX efficacies to treat GPA vasculitic manifestations (diffuse alveolar haemorrhage, glomerulonephritis and peripheral nervous system involvement) and granulomatous lesions (orbital granuloma, pulmonary mass, pachymeningitis or granulomatous ENT involvement), the two forms were differentiated. The phenotype was considered mixed when both lesion types were observed. Monitoring and parameters Patient evaluations were scheduled at each RTX infusion (1 month), at months 3, 6, 9 and 12, then every 3–6 months. Demographics and clinical information (including vasculitis activity, relapse frequency and severity, number and doses of RTX cycles, GC dose, AEs, B cell counts, PR3-ANCA and immunoglobulin levels at the different endpoints) were extracted from medical charts. Outcomes We evaluated RTX retention rate, percentages of patients initially achieving remission, 1- and 2-year remission rates, minor or major relapses, any SAEs, relapse-free survival at the different endpoints, numbers of deaths and their causes, numbers of patients taking GC and mean GC dose. Statistical analyses Follow-up began at the first RTX induction infusion (baseline) and continued until death, last medical update or 31 May 2017, whichever occurred first. Events were defined as death, relapses (major or not), serious infections and SAEs. Categorical variables, expressed as numbers (%), were compared with Fisher’s exact test while continuous variables are presented as medians and interquartile range (IQR). Crude relapse, SAE and serious infection rates were calculated by dividing the number of events during follow-up by the corresponding person-time at risk. All rates are presented as number of events per 100 person-years (95% CI). Kaplan–Meier curves were plotted to estimate event-free survival rates. Fisher’s exact test identified factors associated with remission failure 6 months after RTX induction, and univariable and multivariable Cox regression models identified independent predictors of relapses. Variables associated with outcome in univariable analyses with P < 0.2 were entered into the initial multivariable model of the backward selection procedure, with the significance threshold for selection set at P ⩽ 0.05. All analyses were computed with R Development Core Team version 3.1 [12]. Results Patient characteristics Between April 2005 and December 2016, 114 consecutive GPA patients received RTX induction therapy and were analysed (Fig. 1). Their characteristics are reported in Table 1. RTX was prescribed for relapsing (65%), refractory/grumbling (22%) or new-onset GPA (13%). Nearly half of the patients had pure granulomatous disease and 40% had one or more comorbidities. Ninety patients had previously received CYC with a cumulative median (IQR) dose of 7.6 (4.0–16.1) g. Table 1 Baseline characteristics of 114 patients with active granulomatosis with polyangiitis given RTX induction therapy Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) RTX: rituximab; IQR: interquartile range; GPA: granulomatosis with polyangiitis; eGFR: estimated glomerular filtration rate. Table 1 Baseline characteristics of 114 patients with active granulomatosis with polyangiitis given RTX induction therapy Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) RTX: rituximab; IQR: interquartile range; GPA: granulomatosis with polyangiitis; eGFR: estimated glomerular filtration rate. Fig. 1 View largeDownload slide Study flow chart M: month; RTX: rituximab. Fig. 1 View largeDownload slide Study flow chart M: month; RTX: rituximab. Induction therapy Eighty-nine (78%) patients received a weekly 375-mg/m2 RTX infusion (for 4 weeks) and 25 received 1 g (2 weeks apart) (Table 1), with combined GC for 111 (97%) of them. Their median (IQR) daily prednisone dose at first RTX infusion was 30 (20–51.3) mg (∼0.5 mg/kg). Maintenance therapy One hundred out of 108 (93%) GPA patients received RTX maintenance infusions, a median (IQR) of 6.5 (5.6–7.1) months after the first infusion; 90 received 500 mg every 6 months and 10 received another RTX maintenance regimen (Table 2). At month 6, the median (IQR) prednisone daily dose was 8 (5–10) mg. At 2 years, 76% of patients were still taking prednisone at a median (IQR) daily dose of 5 (2–5) mg. Table 2 Granulomatosis with polyangiitis patients’ maintenance regimens after glucocorticoid and rituximab induction therapy Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Four patients received associated AZA maintenance, one patient AZA and MTX, one patient MTX and one patient MMF. aTwo missing data. b One missing datum. M: month; IQR: interquartile range. Table 2 Granulomatosis with polyangiitis patients’ maintenance regimens after glucocorticoid and rituximab induction therapy Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Four patients received associated AZA maintenance, one patient AZA and MTX, one patient MTX and one patient MMF. aTwo missing data. b One missing datum. M: month; IQR: interquartile range. Remission Median (IQR) follow-up since the first RTX infusion was 3.6 (1.6–5.8) years and 41 (36%) patients were followed-up for >5 years. Among 108 patients who reached the month-6 evaluation, 91 (84%) were in remission. All three patients who did not receive GCs with RTX reached remission at month 6. Respective 1-, 2- and 3-year remission rates remained stable at 84, 86 and 79%. Relapse Overall, 40/91 (44%) patients relapsed, with 26 (29%) minor relapses and/or 18 (20%) major relapses, during the observation period, with median (IQR) time to flare 3.2 (1.5–4.5) years. In all, 12.3 (95% CI: 9.3, 16.1) flares per 100 patient-years occurred, with 8.1 (95% CI: 5.6–11.2) minor and 4.2 (95% CI: 2.5, 6.6) major relapses. The 2-year RTX retention rate was 78% (95% CI: 69.0, 85.0). Respective 1-, 2- and 3-year relapse-free survival rates were 93% (95% CI: 88.0, 98.0), 85% (95% CI: 78.0, 92.0) and 82% (95% CI: 75.0, 90.0) (Fig. 2A and B). Fig. 2 View largeDownload slide Kaplan-Meier estimates GPA patients' relapse-free (A), major relapse-free (B), serious adverse event-free (C) and any event-free survival (D). GPA: granulomatosis with polyangiitis. Fig. 2 View largeDownload slide Kaplan-Meier estimates GPA patients' relapse-free (A), major relapse-free (B), serious adverse event-free (C) and any event-free survival (D). GPA: granulomatosis with polyangiitis. Safety Thirty-one patients had 36 SAEs, including 22 serious infections in 20 patients (Table 3), for respective rates per 100 patient-years of 4.9 (95% CI: 3.1, 7.4) and 8.1 (95% CI: 5.6, 11.2). SAE-free survival is shown in Fig. 2C. Respiratory airways infections (n = 11) and sepsis (n = 5) were the most frequent. When identified, the causative agent was most often bacterial. Opportunistic pathogens (P. jiroveci, Aspergillus fumigatus, Actinomyces odontolyticus or Nocardia sp., each in one patient) also caused serious infections. The patient with Pneumocystis pneumonia did not take the recommended prophylaxis. No case of progressive multifocal leucoencephalopathy was reported. Table 3 Serious infections occurring in 114 granulomatosis with polyangiitis patients during rituximab induction and maintenance treatment Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Table 3 Serious infections occurring in 114 granulomatosis with polyangiitis patients during rituximab induction and maintenance treatment Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Four (3.5%) cancers (bladder, prostate, uterus or skin squamous-cell carcinoma) were diagnosed for an event rate of 0.9 (95% CI: 0.2, 2.3) per 100 patient-years. The bladder cancer developed in a patient who had received a cumulative CYC dose of 25 g. Among four patients developing hypersensitivity reactions to RTX one experienced anaphylaxis and discontinued RTX. Three patients suffered severe neutropaenia (necessitating RTX discontinuation for two, one developed neutropenia after the last RTX infusion); none had associated septic complications. Two patients died: a 72-year-old man, with severe gastrointestinal and renal vasculitis flare, succumbed to sepsis 3 months after the first RTX induction infusion; a 66-year-old woman died during a GPA flare at 6 months, 1 month after the first RTX maintenance infusion. The probability of developing a serious infection or SAE was not significantly higher for elderly vs younger patients, or those with relapsing/refractory/grumbling GPA vs those with new-onset disease, or with one or more major BVAS items at baseline vs without (data not shown). IgG and ANCA levels Before RTX induction, among the 79 patients with available data, 24 (30%) were already hypogammaglobulinaemic, including only 3 who subsequently developed serious infections. The only patient with significant hypogammaglobulinaemia pre-induction did not experience subsequent infectious complications. At month 6, among the 75 patients with available serum gammaglobulin and/or low IgG levels, 36 (48%) were hypogammaglobulinaemic and/or had low IgG, and 3 (4%) had significant hypogammaglobulinaemia and/or low IgG; respective values were 30/65 (46%) and 3/65 (5%) at month 12, and 26/45 (58%) and 3/45 (7%) at month 24. During serious infections, gammaglobulin and/or IgG levels were available for 18 patients: 8 (44%) were hypogammaglobulinaemic but none had gammaglobulins or IgG <4 g/l. At relapse, among ELISA-detected ANCA results for 14 patients, 10 (71%) were positive relapsing patients, while immunofluorescence was positive for 11/13 (85%). At that time, CD19+ B cells were undetectable in 3/15 (20%) patients with available results, with a median (IQR) count of 47 (5.5, 166.5) for the other 12. Factors associated with failure to achieve remission Among patients’ baseline characteristics, univariable analyses identified refractory/grumbling vs new-onset and/or relapsing GPA (P = 0.006 for each individually; P = 0.0003 vs the latter two taken together), pachymeningitis (P = 0.049), pure granulomatous disease (P = 0.017) or estimated glomerular filtration rate (eGFR) ⩾60 ml/min (P = 0.006) as factors associated with remission failure. The probability of achieving remission did not differ between relapsing vs new-onset GPA (P = 0.3). Predictors of relapse Univariable analyses identified baseline predictors of relapses (Table 4). The final multivariable model retained refractory/grumbling vs new-onset GPA, subglottic stenosis, ENT involvement and skin involvement as independent predictors of relapse. Table 4 Factors associated with granulomatosis with polyangiitis relapse in patients given RTX induction and maintenance therapy Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 RTX: rituximab; eGFR: estimated glomerular filtration rate. Table 4 Factors associated with granulomatosis with polyangiitis relapse in patients given RTX induction and maintenance therapy Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 RTX: rituximab; eGFR: estimated glomerular filtration rate. Discussion The results of this single-centre cohort study demonstrated that B-lymphocyte depletion with RTX induction and preemptive maintenance therapy, combined with GC, can effectively and safely achieve sustained remissions in GPA patients in a real-life setting. Patients’ 2-year relapse-free survival was 85%, with a high RTX retention rate, while serious infections or SAEs were infrequent. RCT outcomes showed that RTX is not inferior to CYC for remission induction of severe GPA or MPA [3, 4], and may be superior for relapsing disease [3]. Most of our patients received RTX at the licensed dose, but their median GC induction dose was only half that of the two RCTs [3, 4]. Despite this lower GC dose, almost 85% of our GPA patients achieved remission at 6 months with a daily median GC dose of 8 mg. In the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, 71% of RTX-treated patients achieved remission at 6 months, while taking <10 mg of prednisone/day [3]. In agreement with those results, our findings confirmed and extended that pivotal trial’s observations, even with a lower GC induction regimen. An RCT is ongoing to validate the latter GC regimen [13]. During the 18-month RAVE trial follow-up, without remission maintenance, only 39% of the RTX group patients had sustained complete remissions [3]. GPA patients with PR3-ANCA-positive results and relapsing disease were found to have the highest risk for relapse [5]. Those findings point the way to more effective disease control in those patients at high risk of relapse, which personifies our study population, half of whom satisfied all three characteristics. The MAINtenance of remission using RITuximab in Systemic ANca associated vasculitides (MAINRITSAN) trial results showed that, after having achieved remission with a CYC–GC induction regimen, more severe MPA or GPA patients had sustained remissions after RTX than AZA maintenance [6]. However, it remains unknown whether, after achieving RTX-induced remission, conventional maintenance therapy or repeated RTX B cell depletion more effectively prevents relapses [5]. All of our 114 GPA cohort patients received RTX induction therapy, followed by RTX maintenance every 6 months for 100/108, with no reinfusion 14 days after the first RTX maintenance dose. Our results indicate high efficacy of preemptive RTX maintenance therapy, even after RTX induction. They also suggest that RTX reinfusion 14 days after the first maintenance dose, as done initially, is probably unnecessary [6]. Although our findings warrant validation in trials, they agree with those of another RCT showing that AAV relapse rates did not differ significantly between patient-centred and systematic RTX regimens, despite individually tailored-arm patients receiving fewer RTX infusions [14]. RTX was well tolerated in our cohort, with a serious infection rate of <5/100 patient-years, predominantly pneumonia, as previously reported [15, 16] regardless of hypogammaglobulinaemia status. An interim analysis of the RTX in AAV Registry in 14 US centres revealed a serious infection rate of 9.1/100 patient-years for 97 patients [17], and the rate was 13/100 patient-years for a cohort of 53 relapsing GPA patients, most of whom received preemptive RTX remission maintenance cycles (two 1 g doses, 2 weeks apart) [15]. In another retrospective AAV study [16], the serious infection rate under RTX maintenance therapy (initially two 1 g doses i.v. separated by 2 weeks, followed by a 1 g i.v. every 4 months for 2 years, then 1 g i.v. every 6 months) was 8.5/100 patient-years; serious infections were independently associated with IgG <400 mg/dl, observed in ∼5% of the patients. Our use of low-dose RTX maintenance was associated with 85% 2-year remission, and might also explain the low numbers of infectious complications and significant hypogammaglobulinaemia, despite inclusion of patients with comorbidities and prolonged follow-up. According to our analyses, refractory/grumbling vs new-onset or relapsing GPA, pachymeningitis, pure granulomatous disease or eGFR >60 ml/min were associated with remission failure in this GPA cohort of patients who received an RTX induction regimen. Our results confirmed and extended previous findings that granulomatous manifestations (e.g. orbital granuloma and pachymeningitis) were more frequently refractory to RTX than vasculitis symptoms [18]. Further research should confirm whether RTX might be less effective to achieve remission in patients with higher eGFR. In the RAVE trial, no association was detected between the eGFR and week 2 RTX level or area under the curve. Furthermore, RTX levels at the different time points and area under the curve were not associated with time to relapse [19]. Our multivariable analyses also retained refractory/grumbling GPA, subglottic stenosis, ENT signs and skin involvement as independent predictors of relapse. It is of utmost importance to analyse factors predictive of relapse in a homogeneous population, as it was shown, for example, that an increased PR3-ANCA level associated with the subsequent relapse risk was affected by the disease phenotype and remission induction treatment [20]. Anti-PR3-ANCA-positivity and low serum creatinine levels did not carry significantly higher risks of relapse herein, as opposed to studies including patients with GPA, MPA and renal-limited AAV, who were not always managed with uniform treatment protocols [5, 20–28]. Future research will have to clarify whether those discrepancies resulted from too few patients in our cohort being PR3-ANCA-negative, having high creatinine levels or experiencing relapses to reach significance, or, alternatively, whether RTX induction and maintenance therapy was effective in patients who were PR3-ANCA-negative and/or with low creatinine levels, who are at high risk of relapse. At 2 years, approximately three-quarters of our patients were still taking low-dose GC. It remains controversial whether such GC use may play a role in controlling GPA, as suggested by two meta-analyses [29, 30]. RCTs are ongoing to help balance the risk of prolonged GC therapy against that of uncontrolled disease [31, 32]. Our study has several notable strengths. First, our large population enables firm conclusions to be drawn about the efficacy and safety of GC-combined RTX induction and low-dose preemptive maintenance for GPA patients in a real-life setting. Second, all the GPA patients received the same RTX regimen and standardized GC tapering. Third, all patients were evaluated by the same group of AAV experts. Fourth, our follow-up was longer than those of RCTs and the cohort included patients with comorbidities who would have not been eligible to participate in a trial. Our cohort study has inherent limitations, including open-label RTX administration and no protocolized collection of laboratory results. Second, AE capture may be incomplete. However, all those patients are regularly monitored in our department and it is highly unlikely that serious infections or SAEs were not brought to our attention by the patients or their physicians. In summary, our results, based on this large GPA population, illustrate that cohort studies and RCTs provide complementary information. The 85% 2-year relapse-free survival and 78% RTX retention rates confirmed, in this real-life setting, the efficacy and safety of GC-combined RTX induction and low-dose preemptive maintenance. Our findings have important implications for the design of future trials evaluating GC and low-dose preemptive RTX maintenance for AAV patients to assure optimal efficacy and long-term safety. Acknowledgements The authors thank Janet Jacobson for editorial assistance. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. X.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: X.P., M.I., A.L.C. and L.G. Acquisition of data: X.P., M.I., A.L.C., B.T., A.R. and P.C. Analysis and/or interpretation of data: X.P., M.I., A.L.C., A.V., C.L.J., L.M., P.R. and L.G. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: X.P. has declared speaking fees and honoraria (Pfizer, Laboratoire Français du Fractionnement et des Biotechnologies <$10 000), and a research grant (Pfizer). B.T. has declared consultancies, speaking fees and honoraria (Roche, LFB <$10 000). C.L.J. has received honoraria for advisory board participation (Roche, Astra Zeneca, Amgen <$10 000). L.M. has declared consultancies, speaking fees and honoraria (Roche <$10 000). All authors have been investigators in academic studies for which rituximab was provided by Roche Pharma. No other conflicts were reported. References 1 Yates M , Watts RA , Bajema IM et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis . Ann Rheum Dis 2016 ; 75 : 1583 – 94 . Google Scholar CrossRef Search ADS PubMed 2 Jennette JC , Falk RJ , Bacon PA et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides . Arthritis Rheum 2013 ; 65 : 1 – 11 . Google Scholar CrossRef Search ADS PubMed 3 Stone JH , Merkel PA , Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis . N Engl J Med 2010 ; 363 : 221 – 32 . Google Scholar CrossRef Search ADS PubMed 4 Jones RB , Tervaert JW , Hauser T et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis . N Engl J Med 2010 ; 363 : 211 – 20 . Google Scholar CrossRef Search ADS PubMed 5 Specks U , Merkel PA , Seo P et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis . N Engl J Med 2013 ; 369 : 417 – 27 . Google Scholar CrossRef Search ADS PubMed 6 Guillevin L , Pagnoux C , Karras A et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis . N Engl J Med 2014 ; 371 : 1771 – 80 . Google Scholar CrossRef Search ADS PubMed 7 Terrier B , Pagnoux C , Perrodeau E et al. Rituximab versus azathioprine to maintain remission of ANCA-associated vasculitides (MAINRITSAN): follow-up at 60 months . Ann Rheum Dis 2018 [Epub ahead of print]. 8 Leavitt RY , Fauci AS , Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis . Arthritis Rheum 1990 ; 33 : 1101 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Hellmich B , Flossmann O , Gross WL et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis . Ann Rheum Dis 2007 ; 66 : 605 – 17 . Google Scholar CrossRef Search ADS PubMed 10 Mukhtyar C , Lee R , Brown D et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3) . Ann Rheum Dis 2009 ; 68 : 1827 – 32 . Google Scholar CrossRef Search ADS PubMed 11 Suppiah R , Mukhtyar C , Flossmann O et al. A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis . Rheumatology 2011 ; 50 : 899 – 905 . Google Scholar CrossRef Search ADS PubMed 12 R Development Core Team. A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2017 . https://www.R-project.org/ (10 April 2014, date last accessed). 13 Walsh M , Merkel PA , Peh CA et al. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial . Trials 2013 ; 14 : 73 . Google Scholar CrossRef Search ADS PubMed 14 Charles P , Terrier B , Perrodeau E et al. Comparison of individually tailored vs systematic rituximab regimens to maintain ANCA-associated vasculitis remissions: results of a prospective, randomized-controlled, phase 3 trial . Ann Rheum Dis 2018 [Epub ahead of print]. 15 Cartin-Ceba R , Golbin JM , Keogh KA et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center . Arthritis Rheum 2012 ; 64 : 3770 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Cortazar FB , Pendergraft WF III , Wenger J et al. Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis . Arthritis Rheumatol 2017 ; 69 : 1045 – 53 . Google Scholar CrossRef Search ADS PubMed 17 Niles J , Allen N , Block JA et al. Safety following initiation of rituximab in granulomatosis with polyangiitis or microscopic polyangiitis: interim analysis of the Rituximab in ANCA-Associated Vasculitis Registry (RAVER) [abstract] . Ann Rheum Dis 2017 ; 76(Suppl 2) : 318 . 18 Holle JU , Dubrau C , Herlyn K et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations . Ann Rheum Dis 2012 ; 71 : 327 – 33 . Google Scholar CrossRef Search ADS PubMed 19 Cornec D , Kabat B , Mills JR et al. Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis . Rheumatology 2018 ; 57 : 639 – 50 . Google Scholar CrossRef Search ADS PubMed 20 Fussner LA , Hummel AM , Schroeder DR et al. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3 . Arthritis Rheumatol 2016 ; 68 : 1700 – 10 . Google Scholar CrossRef Search ADS PubMed 21 Hogan SL , Falk RJ , Chin H et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis . Ann Intern Med 2005 ; 143 : 621 – 31 . Google Scholar CrossRef Search ADS PubMed 22 Pagnoux C , Hogan SL , Chin H et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts . Arthritis Rheum 2008 ; 58 : 2908 – 18 . Google Scholar CrossRef Search ADS PubMed 23 Lionaki S , Blyth ER , Hogan SL et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis . Arthritis Rheum 2012 ; 64 : 3452 – 62 . Google Scholar CrossRef Search ADS PubMed 24 Stegeman CA , Tervaert JW , de Jong PE , Kallenberg CG ; for the Dutch Co-trimoxazole Wegener Study Group . Trimethoprim–sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis . N Engl J Med 1996 ; 335 : 16 – 20 . Google Scholar CrossRef Search ADS PubMed 25 Harper L , Morgan MD , Walsh M et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up . Ann Rheum Dis 2012 ; 71 : 955 – 60 . Google Scholar CrossRef Search ADS PubMed 26 Walsh M , Flossmann O , Berden A et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis . Arthritis Rheum 2012 ; 64 : 542 – 8 . Google Scholar CrossRef Search ADS PubMed 27 Puéchal X , Pagnoux C , Perrodeau É et al. Long-term outcomes among participants in the WEGENT trial of remission-maintenance therapy for granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis . Arthritis Rheumatol 2016 ; 68 : 690 – 701 . Google Scholar CrossRef Search ADS PubMed 28 Li ZY , Chang DY , Zhao MH , Chen M. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a study of 439 cases in a single Chinese center . Arthritis Rheumatol 2014 ; 66 : 1920 – 6 . Google Scholar CrossRef Search ADS PubMed 29 Walsh M , Merkel PA , Mahr A , Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis . Arthritis Care Res 2010 ; 62 : 1166 – 73 . Google Scholar CrossRef Search ADS 30 Rodrigues J , Collister D , Archer A et al. The Steroid Tapering in ANCA Vasculitis Evaluation Study (STAVE) 2: a systematic review and meta-analysis [abstract] . Arthritis Rheumatol 2017 ; 69(Suppl 10) . http://acrabstracts.org/abstract/the-steroid-tapering-in-anca-vasculitis-evaluation-study-stave-2-a-systematic-review-and-meta-analysis/ (25 April 2018, date last accessed). 31 Merkel PA, Krischer JP. The Assessment of Prednisone In Remission Trial - Centers of Excellence Approach (TAPIR). https://clinicaltrials.gov/ct2/show/NCT01940094? cond=Wegener+Granulomatosis&draw=3&rank=29 (23 January 2018, date last accessed). 32 Lega JC, Puéchal X. A prospective, multicenter, randomized, double-blind, placebo-controlled study to evaluate the remission maintenance using extended administration of prednisone in systemic anti-neutrophil cytoplasmic antibodies-associated vasculitis (MAINEPSAN). https://clinicaltrials.gov/ct2/show/NCT03290456?term=MAINEPSAN&rank=1 (16 October 2017, date last accessed). © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1462-0324
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1462-0332
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10.1093/rheumatology/key117
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Abstract

Abstract Objectives To assess efficacy and safety of rituximab (RTX) induction and maintenance therapy for granulomatosis with polyangiitis (GPA) in a single-centre cohort study. Methods All patients with active GPA, not enrolled in trials, who received ⩾1 RTX infusion(s) for induction were included. At remission, protocolized maintenance RTX infusions were given every 6 months for 18 months. Kaplan–Meier curves were used to estimate survival rates. Univariable analyses identified factors associated with remission failure and relapse, and Cox models retained independent predictors of relapse. Results One hundred and fourteen adults with relapsing (65%), refractory/grumbling (22%) or new-onset (13%) GPA received RTX for induction; 100 were given ⩾1 RTX maintenance infusion(s) and 90 received 500 mg every 6 months. Median daily prednisone induction dose was 30 mg; 76% of patients were still receiving a median daily prednisone dose of 5 mg at 2 years. Median follow-up was 3.6 years. Respective 2-year relapse-free survival and RTX retention rates were 85 and 78%. Serious infection and serious adverse event rates were 4.9 and 8.1 per 100 patient-years, respectively. Refractory/grumbling vs new-onset and/or relapsing GPA (P < 0.01 for each individually; P < 0.001 vs the latter two taken together), pachymeningitis (P < 0.05), pure granulomatous disease (P < 0.05) or estimated glomerular filtration rate ⩾60 ml/min (P < 0.01) were associated with remission failure. Multivariate analyses retained refractory/grumbling GPA (P = 0.05), subglottic stenosis (P < 0.005), ENT involvement (P = 0.01) and skin involvement (P < 0.0005) as independent predictors of relapse. Conclusion RTX induction and low-dose preemptive maintenance can effectively and safely induce sustained remission in GPA in a real-life setting. granulomatosis with polyangiitis, rituximab, remission induction treatment, maintenance, glucocorticoids Rheumatology key messages In 114 granulomatosis with polyangiitis patients treated with rituximab induction and maintenance therapy, 2-year relapse-free survival was 85%. In granulomatosis with polyangiitis patients treated with rituximab for induction and maintenance therapy, RTX retention rate was 78%. Serious infection and serious adverse event rates in granulomatosis with polyangiitis were 4.9 and 8.1 per 100 patient-years, respectively. Introduction ANCA-associated vasculitides (AAVs) include several different commonly relapsing and potentially life-threatening diseases in which necrotizing vasculitis affects predominantly small-to-medium-sized vessels [1]. Granulomatosis with polyangiitis (GPA) is characterized by granulomatous inflammation, usually involving the upper and lower respiratory tract, with frequent necrotizing glomerulonephritis [2]. The development of a two-stage treatment strategy, using immunosuppressants and glucocorticoids (GCs) for induction and a less toxic immunosuppressive remission maintenance regimen to limit adverse events (AEs), was a major step forward in GPA management. Remission induction treatment of new-onset organ-threatening or life-threatening AAV usually combines GC and cyclophosphamide or rituximab (RTX) [1]. Remission maintenance therapy comprises low-dose GC and AZA, MTX, MMF or RTX [1]. Randomized controlled trials (RCTs) showed RTX’s non-inferiority to CYC for induction therapy of severe AAVs [3–5] and superiority over AZA to contain the relapse rate during maintenance [6, 7]. Because RTX use for AAVs is likely to increase, analysis of long-term RTX administration is of interest. However, data on the efficacy and complications of prolonged RTX use for AAVs are sparse in a real-life setting. Furthermore, RCTs enrolled GPA and microscopic polyangiitis (MPA) patients, who should perhaps be studied separately, selected patients with minor pre-existing comorbidities and provided only limited follow-up that precluded generalization. This study was undertaken to evaluate the efficacy and safety of RTX induction and maintenance therapy for GPA patients treated and followed in our centre. We also attempted to identify factors predicting failure to obtain remission and relapse. Methods Study population After obtaining approval from the Cochin Hospital Ethics Committee, we conducted a single-centre cohort study, including all adult patients with active and relapsing, refractory/grumbling or new-onset GPA who received ⩾1 RTX infusion(s) for induction at our National Referral Center for Vasculitis from April 2005 to December 2016. Data were censured 31 May 2017. Patients receiving RTX only as maintenance therapy were not included. Patients had to satisfy the ACR classification criteria [8] and/or revised Chapel Hill Nomenclature [2] for GPA. To ensure identification of all consecutive patients, potential participants were extracted from Cochin Hospital’s Central Pharmacy electronic database, which prepares all RTX infusions. Patients enrolled in prospective clinical trials were not included. Treatment protocol The remission induction regimen combined GC (i.v. methylprednisolone, 1 g/day for 1–3 days, before oral prednisone, if deemed necessary by the treating physician, and oral prednisone up to 1 mg/kg/day) and RTX. The scheduled prednisone tapering at our centre consisted of gradually tapering the daily dose to reach 20 mg at month 3, 10 mg at month 6 and 5 mg at month 12, and left thereafter to the treating physician’s discretion. The RTX regimen consisted of four infusions (375 mg/m2 of body surface area; 1/week) or sometimes two 1 g infusions, 2 weeks apart. Prior to infusion, all patients received methylprednisolone (100 mg), paracetamol (1 g) and dexchlorpheniramine (5 mg). Once RTX was initiated, all immunosuppressants, except GC, were discontinued. Our standard approach after achieving remission is to give preemptive RTX maintenance therapy (500 mg) every 6 months to all patients until month 24, according to a previously described regimen [6], modified with no reinfusion on day 15 following the first maintenance infusion. After having received a total RTX maintenance dose (2 g in four infusions) within 18 months, all patients were monitored every 3–6 months. During RTX induction and maintenance therapy, patients received trimethoprim–sulfamethoxazole prophylaxis against Pneumocystis jiroveci pneumonia. Ethical approval The Ethics Review Committee for publications of the Cochin University Hospital approved the study (decision no. AAA-2016-0600). Patient consent was not required. Definitions According to the EULAR recommendations [9]: remission is the absence of disease activity, with BVAS = 0; relapse is the recurrence or new onset of disease activity attributable to active vasculitis; major relapse is the recurrence or new onset of potentially organ- or life-threatening disease activity that cannot be treated with GC intensification alone and requires further therapeutic escalation; minor relapse is the recurrence or new onset of manifestations that are neither potentially organ- nor life-threatening. Vasculitis activity was evaluated with BVAS v3 [10, 11]. Serious AEs (SAEs) were defined as those that were life-threatening, required hospitalization, caused persistent disability or permanent damage, or were fatal. Serious infections were defined as those requiring hospitalization or i.v. antibiotics, or that were fatal. Hypogammaglobulinaemia was defined as serum gammaglobulin and/or low IgG <7 g/l, and significant hypogammaglobulinaemia as serum gammaglobulin and/or IgG <4 g/l. To compare RTX efficacies to treat GPA vasculitic manifestations (diffuse alveolar haemorrhage, glomerulonephritis and peripheral nervous system involvement) and granulomatous lesions (orbital granuloma, pulmonary mass, pachymeningitis or granulomatous ENT involvement), the two forms were differentiated. The phenotype was considered mixed when both lesion types were observed. Monitoring and parameters Patient evaluations were scheduled at each RTX infusion (1 month), at months 3, 6, 9 and 12, then every 3–6 months. Demographics and clinical information (including vasculitis activity, relapse frequency and severity, number and doses of RTX cycles, GC dose, AEs, B cell counts, PR3-ANCA and immunoglobulin levels at the different endpoints) were extracted from medical charts. Outcomes We evaluated RTX retention rate, percentages of patients initially achieving remission, 1- and 2-year remission rates, minor or major relapses, any SAEs, relapse-free survival at the different endpoints, numbers of deaths and their causes, numbers of patients taking GC and mean GC dose. Statistical analyses Follow-up began at the first RTX induction infusion (baseline) and continued until death, last medical update or 31 May 2017, whichever occurred first. Events were defined as death, relapses (major or not), serious infections and SAEs. Categorical variables, expressed as numbers (%), were compared with Fisher’s exact test while continuous variables are presented as medians and interquartile range (IQR). Crude relapse, SAE and serious infection rates were calculated by dividing the number of events during follow-up by the corresponding person-time at risk. All rates are presented as number of events per 100 person-years (95% CI). Kaplan–Meier curves were plotted to estimate event-free survival rates. Fisher’s exact test identified factors associated with remission failure 6 months after RTX induction, and univariable and multivariable Cox regression models identified independent predictors of relapses. Variables associated with outcome in univariable analyses with P < 0.2 were entered into the initial multivariable model of the backward selection procedure, with the significance threshold for selection set at P ⩽ 0.05. All analyses were computed with R Development Core Team version 3.1 [12]. Results Patient characteristics Between April 2005 and December 2016, 114 consecutive GPA patients received RTX induction therapy and were analysed (Fig. 1). Their characteristics are reported in Table 1. RTX was prescribed for relapsing (65%), refractory/grumbling (22%) or new-onset GPA (13%). Nearly half of the patients had pure granulomatous disease and 40% had one or more comorbidities. Ninety patients had previously received CYC with a cumulative median (IQR) dose of 7.6 (4.0–16.1) g. Table 1 Baseline characteristics of 114 patients with active granulomatosis with polyangiitis given RTX induction therapy Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) RTX: rituximab; IQR: interquartile range; GPA: granulomatosis with polyangiitis; eGFR: estimated glomerular filtration rate. Table 1 Baseline characteristics of 114 patients with active granulomatosis with polyangiitis given RTX induction therapy Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) Characteristic Value Females, n (%) 64 (56) Age, years     At diagnosis, median (IQR) 45 (30–59)     At first RTX infusion, median (IQR) 52 (35–65)     ≥75 years at first RTX infusion, n (%) 12 (11) Patients with comorbidity, n (%) 46 (40)     Chronic lung disease 18 (16)     Chronic heart disease 10 (9)     Hypertension 17 (15)     History of cancer 4 (4)     Other 20 (18) Vasculitis profile, n (%)     Relapsing 74 (65)     Refractory/grumbling 25 (22)     New-onset 15 (13) Previous CYC therapy     n (%) 90 (79)     Cumulative dose, median (IQR), g 7.6 (4.0–16.1)     Cumulative dose >10 g, n (%) 44 (39) GPA phenotype, n (%)     Pure granulomatous 54 (47)     Pure vasculitic 11 (10)     Granulomatous and vasculitic 49 (43) Organ/system involvement, n (%)     Systemic (arthralgias, arthritis, fever) 37 (32)     Skin/mucous membranes 17 (15)     Eyes 21 (18)     ENT 64 (56)     Cardiovascular 2 (2)     Gastrointestinal 4 (4)     Lung 60 (53)     Renal 40 (35)     CNS 12 (11)     Peripheral nervous system 10 (9) Creatinine, median (IQR) μmol/l 81 (68–98) eGFR <60 ml/min, n (%) 29 (25) BVAS, median (IQR) 9 (6–14) PR3-ANCA, n (%) 86 (75) Hypogammaglobulinaemia, n (%)     <7 g/l 16/66 (24)     <7 g/l and/or IgG <7 g/l 24/79 (30)     <4 g/l and/or IgG <4 g/l 1/79 (1) Concomitant prednisone-induction therapy     Patients, n (%) 111 (97)     Dose, median (IQR), mg 30 (20–51.3)     Dose, median (IQR), mg/kg 0.47 (0.22–0.83) RTX induction regimen, n (%)     375 mg/m2 weekly for 4 weeks 89 (78)     1 g at 2-week interval 25 (22) Follow-up after the first RTX infusion, median (IQR), years 3.6 (1.6–5.8) RTX: rituximab; IQR: interquartile range; GPA: granulomatosis with polyangiitis; eGFR: estimated glomerular filtration rate. Fig. 1 View largeDownload slide Study flow chart M: month; RTX: rituximab. Fig. 1 View largeDownload slide Study flow chart M: month; RTX: rituximab. Induction therapy Eighty-nine (78%) patients received a weekly 375-mg/m2 RTX infusion (for 4 weeks) and 25 received 1 g (2 weeks apart) (Table 1), with combined GC for 111 (97%) of them. Their median (IQR) daily prednisone dose at first RTX infusion was 30 (20–51.3) mg (∼0.5 mg/kg). Maintenance therapy One hundred out of 108 (93%) GPA patients received RTX maintenance infusions, a median (IQR) of 6.5 (5.6–7.1) months after the first infusion; 90 received 500 mg every 6 months and 10 received another RTX maintenance regimen (Table 2). At month 6, the median (IQR) prednisone daily dose was 8 (5–10) mg. At 2 years, 76% of patients were still taking prednisone at a median (IQR) daily dose of 5 (2–5) mg. Table 2 Granulomatosis with polyangiitis patients’ maintenance regimens after glucocorticoid and rituximab induction therapy Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Four patients received associated AZA maintenance, one patient AZA and MTX, one patient MTX and one patient MMF. aTwo missing data. b One missing datum. M: month; IQR: interquartile range. Table 2 Granulomatosis with polyangiitis patients’ maintenance regimens after glucocorticoid and rituximab induction therapy Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Agent Value Prednisone     At M6         Number taking it/those with available data, n (%) 99/106 (93)a         Dose, median (IQR) mg 8 (5–10)         Dose, median (IQR) mg/kg 0.10 (0.07–0.15)     At M12         Number taking it/those with available data, n (%) 83/96 (86)a         Dose, median (IQR) mg 5 (5–5)         Dose, median (IQR) mg/kg 0.07 (0.05–0.09)     At M18         Number taking it/those with available data, n (%) 71/89 (80)b         Dose, median (IQR) mg 5 (4–5)         Dose, median (IQR) mg/kg 0.06 (0.04–0.08)     At M24         Number taking it/those with available data, n (%) 60/79 (76%)a         Dose, median (IQR) mg 5 (2–5)         Dose, median (IQR) mg/kg 0.06 (0.009–0.07)     Last visit         Number taking it/those with available data, n (%) 80/112 (71)a         Dose, median (IQR) mg 5 (0–6)         Dose, median (IQR) mg/kg 0.06 (0–0.09) Rituximab maintenance infusion         Number given first/those reaching M6 (%) 100/108 (93)         Number given second/those reaching M12 (%) 78/98 (80)         Number given third/those reaching M18 (%) 68/90 (76)         Number given fourth/those reaching M24 (%) 67/81 (83) Four patients received associated AZA maintenance, one patient AZA and MTX, one patient MTX and one patient MMF. aTwo missing data. b One missing datum. M: month; IQR: interquartile range. Remission Median (IQR) follow-up since the first RTX infusion was 3.6 (1.6–5.8) years and 41 (36%) patients were followed-up for >5 years. Among 108 patients who reached the month-6 evaluation, 91 (84%) were in remission. All three patients who did not receive GCs with RTX reached remission at month 6. Respective 1-, 2- and 3-year remission rates remained stable at 84, 86 and 79%. Relapse Overall, 40/91 (44%) patients relapsed, with 26 (29%) minor relapses and/or 18 (20%) major relapses, during the observation period, with median (IQR) time to flare 3.2 (1.5–4.5) years. In all, 12.3 (95% CI: 9.3, 16.1) flares per 100 patient-years occurred, with 8.1 (95% CI: 5.6–11.2) minor and 4.2 (95% CI: 2.5, 6.6) major relapses. The 2-year RTX retention rate was 78% (95% CI: 69.0, 85.0). Respective 1-, 2- and 3-year relapse-free survival rates were 93% (95% CI: 88.0, 98.0), 85% (95% CI: 78.0, 92.0) and 82% (95% CI: 75.0, 90.0) (Fig. 2A and B). Fig. 2 View largeDownload slide Kaplan-Meier estimates GPA patients' relapse-free (A), major relapse-free (B), serious adverse event-free (C) and any event-free survival (D). GPA: granulomatosis with polyangiitis. Fig. 2 View largeDownload slide Kaplan-Meier estimates GPA patients' relapse-free (A), major relapse-free (B), serious adverse event-free (C) and any event-free survival (D). GPA: granulomatosis with polyangiitis. Safety Thirty-one patients had 36 SAEs, including 22 serious infections in 20 patients (Table 3), for respective rates per 100 patient-years of 4.9 (95% CI: 3.1, 7.4) and 8.1 (95% CI: 5.6, 11.2). SAE-free survival is shown in Fig. 2C. Respiratory airways infections (n = 11) and sepsis (n = 5) were the most frequent. When identified, the causative agent was most often bacterial. Opportunistic pathogens (P. jiroveci, Aspergillus fumigatus, Actinomyces odontolyticus or Nocardia sp., each in one patient) also caused serious infections. The patient with Pneumocystis pneumonia did not take the recommended prophylaxis. No case of progressive multifocal leucoencephalopathy was reported. Table 3 Serious infections occurring in 114 granulomatosis with polyangiitis patients during rituximab induction and maintenance treatment Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Table 3 Serious infections occurring in 114 granulomatosis with polyangiitis patients during rituximab induction and maintenance treatment Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Type of infection Pathogen Patients, n Respiratory 11     Upper airways         Maxillary sinusitis Pseudomonas aeruginosa 1         Sinusitis Aspergillus fumigatus 1     Lower airways         Pneumonia Pneumocystis jiroveci 1         Pneumonia Pseudomonas aeruginosa 1         Pneumonia Actinomyces odontolyticus 1         Pneumonia Cytomegalovirus 1         Pneumonia Nocardia 1         Pneumonia Unknown 2         Pneumonia Unknown 2 Sepsis 4 Escherichia coli 1 Listeria monocytogenes 1 Unknown 2 Urinary tract 2         Pyelonephritis Unknown 1         Urinary Unknown 1 Other 5         Refractory otitis Unknown 1         Gastroenteritis Clostridium difficile 1         Septic arthritis Staphylococcus aureus 1         Axillary abscess Proteus mirabilis 1         Skin infection Herpes zoster virus 1 Four (3.5%) cancers (bladder, prostate, uterus or skin squamous-cell carcinoma) were diagnosed for an event rate of 0.9 (95% CI: 0.2, 2.3) per 100 patient-years. The bladder cancer developed in a patient who had received a cumulative CYC dose of 25 g. Among four patients developing hypersensitivity reactions to RTX one experienced anaphylaxis and discontinued RTX. Three patients suffered severe neutropaenia (necessitating RTX discontinuation for two, one developed neutropenia after the last RTX infusion); none had associated septic complications. Two patients died: a 72-year-old man, with severe gastrointestinal and renal vasculitis flare, succumbed to sepsis 3 months after the first RTX induction infusion; a 66-year-old woman died during a GPA flare at 6 months, 1 month after the first RTX maintenance infusion. The probability of developing a serious infection or SAE was not significantly higher for elderly vs younger patients, or those with relapsing/refractory/grumbling GPA vs those with new-onset disease, or with one or more major BVAS items at baseline vs without (data not shown). IgG and ANCA levels Before RTX induction, among the 79 patients with available data, 24 (30%) were already hypogammaglobulinaemic, including only 3 who subsequently developed serious infections. The only patient with significant hypogammaglobulinaemia pre-induction did not experience subsequent infectious complications. At month 6, among the 75 patients with available serum gammaglobulin and/or low IgG levels, 36 (48%) were hypogammaglobulinaemic and/or had low IgG, and 3 (4%) had significant hypogammaglobulinaemia and/or low IgG; respective values were 30/65 (46%) and 3/65 (5%) at month 12, and 26/45 (58%) and 3/45 (7%) at month 24. During serious infections, gammaglobulin and/or IgG levels were available for 18 patients: 8 (44%) were hypogammaglobulinaemic but none had gammaglobulins or IgG <4 g/l. At relapse, among ELISA-detected ANCA results for 14 patients, 10 (71%) were positive relapsing patients, while immunofluorescence was positive for 11/13 (85%). At that time, CD19+ B cells were undetectable in 3/15 (20%) patients with available results, with a median (IQR) count of 47 (5.5, 166.5) for the other 12. Factors associated with failure to achieve remission Among patients’ baseline characteristics, univariable analyses identified refractory/grumbling vs new-onset and/or relapsing GPA (P = 0.006 for each individually; P = 0.0003 vs the latter two taken together), pachymeningitis (P = 0.049), pure granulomatous disease (P = 0.017) or estimated glomerular filtration rate (eGFR) ⩾60 ml/min (P = 0.006) as factors associated with remission failure. The probability of achieving remission did not differ between relapsing vs new-onset GPA (P = 0.3). Predictors of relapse Univariable analyses identified baseline predictors of relapses (Table 4). The final multivariable model retained refractory/grumbling vs new-onset GPA, subglottic stenosis, ENT involvement and skin involvement as independent predictors of relapse. Table 4 Factors associated with granulomatosis with polyangiitis relapse in patients given RTX induction and maintenance therapy Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 RTX: rituximab; eGFR: estimated glomerular filtration rate. Table 4 Factors associated with granulomatosis with polyangiitis relapse in patients given RTX induction and maintenance therapy Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 Factor associated with relapse Univariable analysis Multivariable analysis (final model) Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Vasculitis profile 0.03 0.025     New-onset Ref. Ref.     Refractory/grumbling vs new-onset 2.36 (0.53, 10.42) 0.26 4.73 (1.04, 21.43) 0.05     Relapsing vs new-onset 0.95 (0.22, 4.11) 0.95 Alveolar haemorrhage 0.29 (0.07, 1.22) 0.09 Subglottic stenosis 5.39 (2.17, 13.43) <0.001 4.88 (1.79, 13.25) 0.002 ENT involvement 2.62 (1.30, 5.31) 0.01 2.91 (1.37, 6.20) 0.01 Skin involvement 3.47 (1.55, 7.79) <0.001 5.20 (2.18, 12.44) 0.0003 eGFR <60 ml/min 0.49 (0.19, 1.24) 0.13 Prednisone at first RTX infusion, mg/day 0.99 (0.97, 1.00) 0.08 RTX: rituximab; eGFR: estimated glomerular filtration rate. Discussion The results of this single-centre cohort study demonstrated that B-lymphocyte depletion with RTX induction and preemptive maintenance therapy, combined with GC, can effectively and safely achieve sustained remissions in GPA patients in a real-life setting. Patients’ 2-year relapse-free survival was 85%, with a high RTX retention rate, while serious infections or SAEs were infrequent. RCT outcomes showed that RTX is not inferior to CYC for remission induction of severe GPA or MPA [3, 4], and may be superior for relapsing disease [3]. Most of our patients received RTX at the licensed dose, but their median GC induction dose was only half that of the two RCTs [3, 4]. Despite this lower GC dose, almost 85% of our GPA patients achieved remission at 6 months with a daily median GC dose of 8 mg. In the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, 71% of RTX-treated patients achieved remission at 6 months, while taking <10 mg of prednisone/day [3]. In agreement with those results, our findings confirmed and extended that pivotal trial’s observations, even with a lower GC induction regimen. An RCT is ongoing to validate the latter GC regimen [13]. During the 18-month RAVE trial follow-up, without remission maintenance, only 39% of the RTX group patients had sustained complete remissions [3]. GPA patients with PR3-ANCA-positive results and relapsing disease were found to have the highest risk for relapse [5]. Those findings point the way to more effective disease control in those patients at high risk of relapse, which personifies our study population, half of whom satisfied all three characteristics. The MAINtenance of remission using RITuximab in Systemic ANca associated vasculitides (MAINRITSAN) trial results showed that, after having achieved remission with a CYC–GC induction regimen, more severe MPA or GPA patients had sustained remissions after RTX than AZA maintenance [6]. However, it remains unknown whether, after achieving RTX-induced remission, conventional maintenance therapy or repeated RTX B cell depletion more effectively prevents relapses [5]. All of our 114 GPA cohort patients received RTX induction therapy, followed by RTX maintenance every 6 months for 100/108, with no reinfusion 14 days after the first RTX maintenance dose. Our results indicate high efficacy of preemptive RTX maintenance therapy, even after RTX induction. They also suggest that RTX reinfusion 14 days after the first maintenance dose, as done initially, is probably unnecessary [6]. Although our findings warrant validation in trials, they agree with those of another RCT showing that AAV relapse rates did not differ significantly between patient-centred and systematic RTX regimens, despite individually tailored-arm patients receiving fewer RTX infusions [14]. RTX was well tolerated in our cohort, with a serious infection rate of <5/100 patient-years, predominantly pneumonia, as previously reported [15, 16] regardless of hypogammaglobulinaemia status. An interim analysis of the RTX in AAV Registry in 14 US centres revealed a serious infection rate of 9.1/100 patient-years for 97 patients [17], and the rate was 13/100 patient-years for a cohort of 53 relapsing GPA patients, most of whom received preemptive RTX remission maintenance cycles (two 1 g doses, 2 weeks apart) [15]. In another retrospective AAV study [16], the serious infection rate under RTX maintenance therapy (initially two 1 g doses i.v. separated by 2 weeks, followed by a 1 g i.v. every 4 months for 2 years, then 1 g i.v. every 6 months) was 8.5/100 patient-years; serious infections were independently associated with IgG <400 mg/dl, observed in ∼5% of the patients. Our use of low-dose RTX maintenance was associated with 85% 2-year remission, and might also explain the low numbers of infectious complications and significant hypogammaglobulinaemia, despite inclusion of patients with comorbidities and prolonged follow-up. According to our analyses, refractory/grumbling vs new-onset or relapsing GPA, pachymeningitis, pure granulomatous disease or eGFR >60 ml/min were associated with remission failure in this GPA cohort of patients who received an RTX induction regimen. Our results confirmed and extended previous findings that granulomatous manifestations (e.g. orbital granuloma and pachymeningitis) were more frequently refractory to RTX than vasculitis symptoms [18]. Further research should confirm whether RTX might be less effective to achieve remission in patients with higher eGFR. In the RAVE trial, no association was detected between the eGFR and week 2 RTX level or area under the curve. Furthermore, RTX levels at the different time points and area under the curve were not associated with time to relapse [19]. Our multivariable analyses also retained refractory/grumbling GPA, subglottic stenosis, ENT signs and skin involvement as independent predictors of relapse. It is of utmost importance to analyse factors predictive of relapse in a homogeneous population, as it was shown, for example, that an increased PR3-ANCA level associated with the subsequent relapse risk was affected by the disease phenotype and remission induction treatment [20]. Anti-PR3-ANCA-positivity and low serum creatinine levels did not carry significantly higher risks of relapse herein, as opposed to studies including patients with GPA, MPA and renal-limited AAV, who were not always managed with uniform treatment protocols [5, 20–28]. Future research will have to clarify whether those discrepancies resulted from too few patients in our cohort being PR3-ANCA-negative, having high creatinine levels or experiencing relapses to reach significance, or, alternatively, whether RTX induction and maintenance therapy was effective in patients who were PR3-ANCA-negative and/or with low creatinine levels, who are at high risk of relapse. At 2 years, approximately three-quarters of our patients were still taking low-dose GC. It remains controversial whether such GC use may play a role in controlling GPA, as suggested by two meta-analyses [29, 30]. RCTs are ongoing to help balance the risk of prolonged GC therapy against that of uncontrolled disease [31, 32]. Our study has several notable strengths. First, our large population enables firm conclusions to be drawn about the efficacy and safety of GC-combined RTX induction and low-dose preemptive maintenance for GPA patients in a real-life setting. Second, all the GPA patients received the same RTX regimen and standardized GC tapering. Third, all patients were evaluated by the same group of AAV experts. Fourth, our follow-up was longer than those of RCTs and the cohort included patients with comorbidities who would have not been eligible to participate in a trial. Our cohort study has inherent limitations, including open-label RTX administration and no protocolized collection of laboratory results. Second, AE capture may be incomplete. However, all those patients are regularly monitored in our department and it is highly unlikely that serious infections or SAEs were not brought to our attention by the patients or their physicians. In summary, our results, based on this large GPA population, illustrate that cohort studies and RCTs provide complementary information. The 85% 2-year relapse-free survival and 78% RTX retention rates confirmed, in this real-life setting, the efficacy and safety of GC-combined RTX induction and low-dose preemptive maintenance. Our findings have important implications for the design of future trials evaluating GC and low-dose preemptive RTX maintenance for AAV patients to assure optimal efficacy and long-term safety. Acknowledgements The authors thank Janet Jacobson for editorial assistance. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. X.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: X.P., M.I., A.L.C. and L.G. Acquisition of data: X.P., M.I., A.L.C., B.T., A.R. and P.C. Analysis and/or interpretation of data: X.P., M.I., A.L.C., A.V., C.L.J., L.M., P.R. and L.G. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: X.P. has declared speaking fees and honoraria (Pfizer, Laboratoire Français du Fractionnement et des Biotechnologies <$10 000), and a research grant (Pfizer). B.T. has declared consultancies, speaking fees and honoraria (Roche, LFB <$10 000). C.L.J. has received honoraria for advisory board participation (Roche, Astra Zeneca, Amgen <$10 000). L.M. has declared consultancies, speaking fees and honoraria (Roche <$10 000). All authors have been investigators in academic studies for which rituximab was provided by Roche Pharma. No other conflicts were reported. References 1 Yates M , Watts RA , Bajema IM et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis . Ann Rheum Dis 2016 ; 75 : 1583 – 94 . Google Scholar CrossRef Search ADS PubMed 2 Jennette JC , Falk RJ , Bacon PA et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides . Arthritis Rheum 2013 ; 65 : 1 – 11 . Google Scholar CrossRef Search ADS PubMed 3 Stone JH , Merkel PA , Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis . N Engl J Med 2010 ; 363 : 221 – 32 . Google Scholar CrossRef Search ADS PubMed 4 Jones RB , Tervaert JW , Hauser T et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis . N Engl J Med 2010 ; 363 : 211 – 20 . Google Scholar CrossRef Search ADS PubMed 5 Specks U , Merkel PA , Seo P et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis . N Engl J Med 2013 ; 369 : 417 – 27 . Google Scholar CrossRef Search ADS PubMed 6 Guillevin L , Pagnoux C , Karras A et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis . N Engl J Med 2014 ; 371 : 1771 – 80 . Google Scholar CrossRef Search ADS PubMed 7 Terrier B , Pagnoux C , Perrodeau E et al. Rituximab versus azathioprine to maintain remission of ANCA-associated vasculitides (MAINRITSAN): follow-up at 60 months . Ann Rheum Dis 2018 [Epub ahead of print]. 8 Leavitt RY , Fauci AS , Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis . Arthritis Rheum 1990 ; 33 : 1101 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Hellmich B , Flossmann O , Gross WL et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis . Ann Rheum Dis 2007 ; 66 : 605 – 17 . Google Scholar CrossRef Search ADS PubMed 10 Mukhtyar C , Lee R , Brown D et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3) . Ann Rheum Dis 2009 ; 68 : 1827 – 32 . Google Scholar CrossRef Search ADS PubMed 11 Suppiah R , Mukhtyar C , Flossmann O et al. A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis . Rheumatology 2011 ; 50 : 899 – 905 . Google Scholar CrossRef Search ADS PubMed 12 R Development Core Team. A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2017 . https://www.R-project.org/ (10 April 2014, date last accessed). 13 Walsh M , Merkel PA , Peh CA et al. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial . Trials 2013 ; 14 : 73 . Google Scholar CrossRef Search ADS PubMed 14 Charles P , Terrier B , Perrodeau E et al. Comparison of individually tailored vs systematic rituximab regimens to maintain ANCA-associated vasculitis remissions: results of a prospective, randomized-controlled, phase 3 trial . Ann Rheum Dis 2018 [Epub ahead of print]. 15 Cartin-Ceba R , Golbin JM , Keogh KA et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center . Arthritis Rheum 2012 ; 64 : 3770 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Cortazar FB , Pendergraft WF III , Wenger J et al. Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis . Arthritis Rheumatol 2017 ; 69 : 1045 – 53 . Google Scholar CrossRef Search ADS PubMed 17 Niles J , Allen N , Block JA et al. Safety following initiation of rituximab in granulomatosis with polyangiitis or microscopic polyangiitis: interim analysis of the Rituximab in ANCA-Associated Vasculitis Registry (RAVER) [abstract] . Ann Rheum Dis 2017 ; 76(Suppl 2) : 318 . 18 Holle JU , Dubrau C , Herlyn K et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations . Ann Rheum Dis 2012 ; 71 : 327 – 33 . Google Scholar CrossRef Search ADS PubMed 19 Cornec D , Kabat B , Mills JR et al. Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis . Rheumatology 2018 ; 57 : 639 – 50 . Google Scholar CrossRef Search ADS PubMed 20 Fussner LA , Hummel AM , Schroeder DR et al. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3 . Arthritis Rheumatol 2016 ; 68 : 1700 – 10 . Google Scholar CrossRef Search ADS PubMed 21 Hogan SL , Falk RJ , Chin H et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis . Ann Intern Med 2005 ; 143 : 621 – 31 . Google Scholar CrossRef Search ADS PubMed 22 Pagnoux C , Hogan SL , Chin H et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts . Arthritis Rheum 2008 ; 58 : 2908 – 18 . Google Scholar CrossRef Search ADS PubMed 23 Lionaki S , Blyth ER , Hogan SL et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis . Arthritis Rheum 2012 ; 64 : 3452 – 62 . Google Scholar CrossRef Search ADS PubMed 24 Stegeman CA , Tervaert JW , de Jong PE , Kallenberg CG ; for the Dutch Co-trimoxazole Wegener Study Group . Trimethoprim–sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis . N Engl J Med 1996 ; 335 : 16 – 20 . Google Scholar CrossRef Search ADS PubMed 25 Harper L , Morgan MD , Walsh M et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up . Ann Rheum Dis 2012 ; 71 : 955 – 60 . Google Scholar CrossRef Search ADS PubMed 26 Walsh M , Flossmann O , Berden A et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis . Arthritis Rheum 2012 ; 64 : 542 – 8 . Google Scholar CrossRef Search ADS PubMed 27 Puéchal X , Pagnoux C , Perrodeau É et al. Long-term outcomes among participants in the WEGENT trial of remission-maintenance therapy for granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis . Arthritis Rheumatol 2016 ; 68 : 690 – 701 . Google Scholar CrossRef Search ADS PubMed 28 Li ZY , Chang DY , Zhao MH , Chen M. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a study of 439 cases in a single Chinese center . Arthritis Rheumatol 2014 ; 66 : 1920 – 6 . Google Scholar CrossRef Search ADS PubMed 29 Walsh M , Merkel PA , Mahr A , Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis . Arthritis Care Res 2010 ; 62 : 1166 – 73 . Google Scholar CrossRef Search ADS 30 Rodrigues J , Collister D , Archer A et al. The Steroid Tapering in ANCA Vasculitis Evaluation Study (STAVE) 2: a systematic review and meta-analysis [abstract] . Arthritis Rheumatol 2017 ; 69(Suppl 10) . http://acrabstracts.org/abstract/the-steroid-tapering-in-anca-vasculitis-evaluation-study-stave-2-a-systematic-review-and-meta-analysis/ (25 April 2018, date last accessed). 31 Merkel PA, Krischer JP. The Assessment of Prednisone In Remission Trial - Centers of Excellence Approach (TAPIR). https://clinicaltrials.gov/ct2/show/NCT01940094? cond=Wegener+Granulomatosis&draw=3&rank=29 (23 January 2018, date last accessed). 32 Lega JC, Puéchal X. A prospective, multicenter, randomized, double-blind, placebo-controlled study to evaluate the remission maintenance using extended administration of prednisone in systemic anti-neutrophil cytoplasmic antibodies-associated vasculitis (MAINEPSAN). https://clinicaltrials.gov/ct2/show/NCT03290456?term=MAINEPSAN&rank=1 (16 October 2017, date last accessed). © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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RheumatologyOxford University Press

Published: May 2, 2018

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