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Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with a frequently relapsing/refractory course.1 2 Rituximab (RTX) is an established treatment in the other ANCA-associated vasculitides, but data on EGPA are scarce.3 4 Mohammad5 reported that RTX can be effective in EGPA, particularly in ANCA-positive patients.
We report the outcomes of 21 patients with EGPA who received RTX-induction (1 g 2 weeks apart, on top of ongoing immunosuppression) for refractory/relapsing disease in 2011–2017 (table 1). Starting from 2014, we scheduled RTX-maintenance (500 mg/6 months)6 7 in patients responding to RTX-induction. Nine patients received RTX-maintenance, the others received RTX only for relapses (a single, 1g infusion). Complete remission was defined as Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone ≤7.5 mg/day,3 partial remission as >50% BVAS reduction and prednisone ≤15 mg/day. Refractory disease was defined as failure to achieve remission, relapse as the recurrence/new onset of clinical manifestations requiring intensification of immunosuppression or increase in glucocorticoid dose >50%.8 All patients signed informed consent; the study was conducted in accordance with the Declaration of Helsinki.
Main clinical and laboratory parameters in the study cohort at different time points
All patients but one (who stopped RTX for infusion reaction) completed RTX-induction. Of the remaining 20, 15 (75%) achieved remission (complete in 5, partial in 10) at month 3. Of the five patients who proved refractory to RTX, two were ANCA-positive and three ANCA-negative; major disease manifestations were asthma in four and mononeuritis multiplex in one. After RTX failure, they received high-dose oral prednisone (n=5), omalizumab (n=3) or intravenous immunoglobulins (n=1). The remission rates at 6 months and 12 months are shown in table 1. There was a significant reduction in BVAS, prednisone dose and eosinophil count between month 0 and subsequent time points (figure 1).
(a) Kaplan-Meier relapse-free survival estimate of the 15 patients with eosinophilic granulomatosis with polyangiitis (EGPA) who achieved remission after induction with rituximab. (b) Comparison of relapse-free survival between patients who received protocolised maintenance rituximab (continuous line) and patients who did not (dashed line). (c) Birmingham Vasculitis Activity Score, (d) prednisone dose (or equivalent) and (e) eosinophil counts of all patients 0, 6, 12 and 18 months after rituximab induction. Differences in continuous variables within groups were analysed using Wilcoxon matched-pairs signed-rank test. Differences in survival curves were analysed using the log-rank test. A p value of <0.05 was considered statistically significant for all analyses.
Of the 15 patients in remission at month 3, 5 (33%) relapsed within a median of 6 months (range 5–12). Relapses occurred only in patients not receiving scheduled RTX-maintenance; relapse-free survival was significantly shorter in this subgroup (figure 1). The two treatment regimen subgroups were comparable, given the similar proportions of ANCA-positive and ANCA-negative patients (table 1) and of major organ involvement frequencies (asthma/lung 100% vs 83.3%, neuropathy 88.9% vs 66.7%, gastrointestinal 33.3% vs 33.3% in the scheduled vs non-scheduled subgroups, all p values not significant).
No statistically significant differences in relapse rates or time-to relapse were observed between ANCA-positive and ANCA-negative patients (data not shown). However, a greater proportion of ANCA-positive patients were in remission at months 6 and 12, although the difference was not statistically significant.
Treatment-related adverse events included pneumonia in two patients (months 6 and 12, respectively), and bronchitis in one (month 6). Two patients died, one from arrhythmia (month 18), the other from brainstem astrocytoma (month 24). At last follow-up (median 24 months, range 6–42), of the 21 patients who initially received RTX, 19 are alive: 11 are in remission (9 while on RTX-maintenance), and 8 are stable while receiving prednisone and immunosuppressants.
Our data suggest that RTX is effective and well tolerated in refractory/relapsing EGPA. It rapidly induced remission and allowed glucocorticoid reduction in most patients. Scheduled RTX-maintenance significantly reduced relapse rate as compared with RTX given ‘on demand’ for relapse. This observation must be taken cautiously given the small sample size and the retrospective nature of the study, though it parallels the experience with other ANCA-associated vasculitides.6 9
Another biological agent, mepolizumab (antiinterleukin-5), has recently proved effective in reducing relapse rates and sparing glucocorticoids in EGPA;10 however, half the trial cohort did not achieve remission, thus highlighting the need for patient-tailored treatments, taking into account the phenotypical diversity of EGPA.1 RTX effectively maintained remission in our retrospective cohort. Hopefully the ad hoc prospective trial which is currently underway will confirm our findings (MAINRITSEG, clinicaltrials.gov: NCT03164473).
Acknowledgments
The authors thank Dr Giusi Taurisano for her help in the collection of the data and Dr Lorenzo Emmi for his precious clinical advices.
Footnotes
GE and GMR contributed equally.
Contributors GE, GMR and AV designed the study, collected data, analysed results and wrote the manuscript. MG performed statistical analysis. MLU, ES and DP contributed to clinical data and analysed the results. All authors revised the manuscript critically for important intellectual content and approved the final version.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.