Rituximab for Induction Therapy of ANCA-Associated Vasculitis: Practical Issues in the Asia Pacific Region

Abstract

ANCA-associated vasculitis (AAV), comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), represents a group of small to medium vessel vasculitides that may affect multiple organ systems, leading to vascular-mediated damage, organ failure, and mortality. Untreated AAV patients have a 1-year mortality of up to 80% [1]. The introduction of glucocorticoids (GCs) and cyclophosphamide (CYC) as induction therapy in the 1960s has significantly improved the prognosis [2]. In the landmark CYCLOPS trial published in 2009, the mortality of AAV patients treated with GCs and CYC at month 18 was 9% [3]. From 1995 to 2012, the European Vasculitis Society (EUVAS) conducted seven randomized controlled trials (RCTs) to evaluate the efficacy of various induction therapies in AAV, including CYC, rituximab, mycophenolate mofetil, methotrexate, azathioprine, plasmapheresis, and pulse methylprednisolone. Pooled data from 848 patients in these studies revealed an overall survival rate of 88.2% at 1 year and 78.2% at 5 years from the time of diagnosis. Compared to the general population, excess mortality by 14% at 1 year and 20% at 10 years was observed, with infections, cardiovascular complications, and malignancies being the major causes of death [4].

AAV exhibits notable variations in clinical manifestations between the Asian and Caucasian populations. Data from the Diagnostic and Classification Criteria in Vasculitis (DCVAS) group highlight a significantly higher proportion of anti-MPO-positive patients in the Japanese and Chinese compared to Northern Europeans (81.3% vs. 45.4% vs. 24.6%, respectively) [5]. Apart from the anti-MPO predominance, Asian patients are also more likely to be classified as having MPA. A collaborative epidemiological study conducted simultaneously in Japan and the United Kingdom reported a much higher incidence of MPA in Japan (annual incidence per millions of adults: 18.2 vs. 6.5 in Japan and UK, respectively) despite a similar incidence of all subtypes of AAV [6]. Asian AAV patients have less otorhinolaryngologic and ophthalmic involvement but more renal disease [5].

A difference in mortality was also observed between Asian and Caucasian patients with AAV according to real-world data. A recent study reported a high standardized mortality ratio (SMR) of MPA and GPA patients in South Korea (5.58 and 3.53, respectively) [7]. The all-cause-mortality risk of MPA was higher than the GPA group after adjustment for age, sex, and comorbidities (HR 1.33, p = 0.009). The SMR in this study is much higher than those reported in the Caucasians which range from 1.8 to 2.84 [8-10]. The inter-ethnic differences in clinical manifestations, treatment response, and prognosis of AAV emphasize the need for personalized approach in the management of this condition.

A combination of high-dose GCs and CYC is the conventional treatment for organ-threatening AAV. However, CYC is associated with significant adverse effects, including myelosuppression, opportunistic infection, malignancy, and infertility, and the risk increases with repeated courses of CYC, particularly in patients with relapsing disease. Rituximab, a chimeric anti-CD20 biological agent, has emerged as an alternative option for the treatment of AAV. Pivotal RCTs that include RAVE and RITUXIVAS have established non-inferiority of rituximab to CYC for induction therapy [11, 12]. Rituximab may be more effective in specific patient subgroups. For instance, in the RAVE study, rituximab was shown to be superior to CYC in achieving remission at month 6 in patients with relapsing disease (67% vs. 42%, p = 0.01). The superiority of rituximab to CYC for the primary outcome in patients with relapsing disease persisted after adjustment for ANCA subtypes (OR 1.40 [1.03–1.91]). Post hoc analysis of the same trial also revealed that anti-PR3-positive patients treated with rituximab had higher remission rate compared to CYC (65% vs. 48%, p = 0.04). In a retrospective study of 194 GPA patients recruited in the French Vasculitis Study Group (FVSG) registry, rituximab was shown to be better than CYC in achieving remission at month 6 (OR 1.82 [1.22–2.73]). Superiority of rituximab to CYC was also demonstrable in newly diagnosed GPA patients (n = 165) [13].

One should be reminded that, in RAVE trial, patients with alveolar hemorrhage requiring ventilatory support and advanced renal dysfunction (serum creatinine levels > 4.0 mg/dL) were excluded [11]. As a result, the efficacy of rituximab cannot be extrapolated to this subset of patients. In a recent retrospective study from Japan involving 687 patients with life-threatening AAV (rapidly progressive glomerulonephritis and/or alveolar hemorrhage), no significant difference in in-hospital mortality between treatment with rituximab and CYC could be demonstrated (HR 1.06 [0.62–1.80]) [14]. Moreover, rituximab treatment was associated with a higher frequency of hemodialysis on discharge (HR 2.58 [1.02–6.91]). Thus, there is still no strong evidence to support the first-line use of rituximab in life-threatening AAV.

Major international major guidelines, including the European Alliance of Associations for Rheumatology (EULAR), American College of Rheumatology & Vasculitis Foundation (ACR/VF), and Kidney Disease Improving Global Outcomes (KDIGO), recommend either rituximab or CYC as first-line options for remission induction of AAV [15-17]. Rituximab is favored in patients with positive anti-PR3, relapsing disease, susceptibility to opportunistic infections or malignancy, and those who wish to preserve ovarian function.

Pivotal trials evaluating rituximab in AAV, such as RAVE and RITUXIVAS, primarily involved Caucasian participants, with only one of 197 participants in the RAVE trial being Asians [11, 12]. As Asian patients with AAV more frequently present with renal disease, more data on the efficacy and tolerability of rituximab are needed.

In an issue of International Journal of Rheumatic Diseases, Dr. Behrooz Izadi et al. [18] reported retrospectively the efficacy of rituximab and CYC for remission induction in 57 Iranian patients with GPA. In two propensity score-matched groups of GPA patients, 29 patients were treated with rituximab and 28 patients were treated with CYC, in conjunction with oral prednisolone (1 mg/kg/day). At month 6, a significantly higher rate of remission was observed in the rituximab than CYC group (89.7% vs. 67.9%, p = 0.04). This finding aligns with the post-marketing registry study of the FVSG as forementioned [13]. In terms of safety profile, the infection rates were similar in both groups during the 6-month follow-up period.

It should be noted that, in the study by Behrooz et al. [18], 30 (52.6%) of the AAV patients were PR3-positive, 9 (15.8%) were MPO-positive, and 18 (31.6%) were ANCA-negative. The rate of PR3 positivity was remarkably lower than that of Caucasian studies, but a favorable response to rituximab was still observed. Additionally, rituximab appeared effective in the ANCA-negative AAV patient subtype, which is also consistent with previous studies [19, 20].

Although the data from Behrooz et al. [18] have provided experience of rituximab in Asian AAV patients, there are several limitations. First, the small patient cohort and retrospective design may reduce the robustness of the results. Second, the study primarily included patients with less severe disease manifestations, as evidenced by the low proportion of life-threatening or organ-threatening disease. Only four (7%) patients had renal dysfunction and none experienced alveolar hemorrhage. As a result, their data cannot support superiority of rituximab to CYC in Asian patients with more severe AAV.

The cost-effectiveness of AAV therapies is a major issue in the Asia Pacific region. The cost of rituximab and its availability in less affluent countries remains problematic. However, the recent availability of the rituximab biosimilars has significantly altered the landscape. Recent retrospective studies have shown that rituximab biosimilar are equally effective in treatment of AAV in comparison to their bio-originator [21-23]. Notably, the FDA has granted approval for GPA and MPA indications across all rituximab biosimilars, including Riabni, Ruxience, and Truxima [24-26].

Although CYC is much less expensive than rituximab, administrative cost of using CYC may be considerable. An Italian study estimated the annual health cost for an AAV patient amounted to €6168 [27]. Among the cost of illness, drugs cost accounted for only 27.6%, while hospitalizations and outpatient visits constituted the remaining. CYC, with its need for frequent blood monitoring and inherent infection risk, may inadvertently contribute to higher overall healthcare costs due to intensive management of associated adverse events. This observation is confirmed by a recent UK study which showed a substantially higher administrative cost of CYC than rituximab in the treatment of AAV [28]. The total visit cost for CYC was higher than rituximab biosimilar (£44 000 vs. £14 000). The excess cost related to CYC was attributed to factors such as more frequent day unit admissions, consultant visits, and multidisciplinary team reviews preceding each infusion, and extra cost from blood monitoring and management of adverse events.

In summary, rituximab has been shown to be non-inferior to CYC in the treatment of AAV. Rituximab may be superior to CYC in patients with relapsing disease and those with PR3-ANCA subtype. The study by Behrooz et al. [18] has provided some reassuring data regarding the efficacy and safety of rituximab in Asian patients with AAV. However, their study had involved a very small proportion of patients with severe life-threatening disease. Therefore, there is still lack of strong evidence of the upfront use of rituximab in AAV patients with rapidly progressive glomerulonephritis and alveolar hemorrhage. With the availability of rituximab biosimilars, it is expected that more patients will be treated upfront with this biologic in AAV patients. CYC may better be reserved for those patients who present with life/organ-threatening disease. Further collaborative studies are warranted to study the efficacy of newer treatment modalities of AAV in the APLAR region.

The authors take full responsibility for this article.

The authors declare no conflicts of interest.