What evidence is available regarding the use of rituximab in CNS vasculitis?

Comment by InpharmD Researcher

The majority of data is focused on rituximab as a combination regimen for ANCA-associated vasculitis, which is generally considered to be effective and beneficial for consideration as remission therapy compared to other immunosuppressive therapy. Data specific to CNS vasculitis is more limited to patient cases or retrospective reviews, but similarly suggest that rituximab may also facilitate remission of symptoms.

Background

Rituximab, a CD20-directed cytolytic antibody, is indicated for both induction and maintenance therapy in two subtypes (granulomatosis with polyangiitis, GPA; microscopic polyangiitis, MPA) of ANCA-associated vasculitis (AAV). The 2020 expert consensus guidelines from the British Society for Rheumatology were developed in order to provide in-depth clinical guidance for rituximab’s use as a remission maintenance therapy. The guidelines suggest that for new and relapsing patients with GPA/MPA, rituximab is recommended for the maintenance of remission following successful rituximab or cyclophosphamide induction. The same recommendation applies for eosinophilic granulomatosis with polyangiitis (EGPA), the third subtype of AAV, despite limited evidence related to this relatively understudied phenotype of AAV. The guidelines state that the treatment response to rituximab in EGPA patients may differ, and steroidal cessation may present more challenges. [1]

The expert panel recommends fixed interval dosing for the rituximab maintenance regimen (either 500 mg or 1000 mg administered intravenously every 6 months for 2 years) over biomarker-guided dosing due to a lack of proven efficacy of biomarker-guided dosing, including the evaluation of long-term outcomes. Currently, there have been no direct studies comparing those two dosages in terms of efficacy and safety. Despite the paucity of data on rituximab maintenance therapy extending beyond two years, the panel suggests that the rituximab therapy may continue up to 5 years in select patients with high relapse risk. However, the optimal treatment approaches beyond 2 years are yet to be determined in these patients. Overall, the guidelines emphasize the importance of individualized rituximab maintenance therapy based on age, comorbidities, and history of AAV. [1]

Given the possible risk of side effects, the guidelines recommend the withdrawal of disease-modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, methotrexate, mycophenolate) once initiation of rituximab maintenance therapy. Glucocorticoids are recommended to be weaned off over the course of six to 12 months or over shorter tapering strategies if tolerated. Patients with the EGPA phenotype may have a harder time with steroid withdrawal and may experience inadequate symptom improvements. [1]

A 2023 evidence-based guideline on eosinophilic granulomatosis with polyangiitis (EGPA) developed by a panel of European experts emphasized a multidisciplinary approach for diagnosis and treatment. ANCA testing was advised for all patients suspected of EGPA, with MPO-ANCA positivity correlating with vasculitis features such as glomerulonephritis and neuropathy. For remission induction in patients with new-onset, active eosinophilic granulomatosis with polyangiitis (EGPA), the treatment approach is stratified based on disease severity. For severe disease, indicated by unfavorable prognostic factors like peripheral neuropathy or alveolar hemorrhage, glucocorticoids should be administered initially, optionally followed by cyclophosphamide or rituximab. Pulsed intravenous glucocorticoids, typically methylprednisolone, are advised for severe cases, transitioning to high-dose oral glucocorticoids. Cyclophosphamide is beneficial for longer relapse-free survival, yet the optimal duration of therapy remains unclear; usually, therapy continues until remission, potentially extending to 9-12 months for slowly improving patients. Rituximab has shown comparable efficacy to cyclophosphamide for remission induction, independent of ANCA status or disease onset and relapse. For maintenance therapy, the focus remains on minimizing glucocorticoid toxicity. In severe EGPA, rituximab, mepolizumab, or traditional DMARDs combined with glucocorticoids are recommended, with an emphasis on tapering glucocorticoids to the minimum effective dose. Rituximab has shown efficacy in maintaining remission and reducing glucocorticoid dependency, especially in those achieving remission on rituximab. Mepolizumab is predominantly used for chronic asthma control but could also benefit major organ involvement, suggesting its potential broader application in severe manifestations. For non-severe EGPA, glucocorticoids combined with mepolizumab are effective in maintaining remission, as observed in clinical trials and studies. This approach underscores a strategic shift towards reducing glucocorticoid exposure while maintaining therapeutic effectiveness. [2]

A 2021 multicenter, randomized, phase 3, controlled trial (REOVAS), published as a two poster abstracts, evaluated the long-term efficacy of rituximab (RTX) compared with conventional immunosuppressive therapy (glucocorticoids, alone or in combination with cyclophosphamide ) for remission induction in 105 patients with newly diagnosed or relapsing EGPA. Rituximab was given as the experimental intervention, while the comparator group received glucocorticoids alone or with cyclophosphamide, depending on disease severity. At day 180, 63.5% of patients in the rituximab arm achieved the primary endpoint of remission compared with 60.4% in the conventional strategy group (relative risk [RR] 1.05; 95% CI, 0.78 to 1.42; p=0.75). By day 360, remission rates were 59.6% and 64.2%, respectively (relative risk 1.08; 95% CI, 0.80 to 1.45; p=0.63). Mean remission duration was comparable between groups (16.4 vs 16.2 weeks). Daily glucocorticoid exposure remained similar, with cumulative doses of 4591 mg and 4453 mg, respectively. No significant differences in relapse rates or SF-36 scores were observed; however, numerical trends favoring rituximab were noted in the HAQ and Vasculitis Damage Index (VDI) at days 180 and 360, though these did not reach statistical significance. The findings suggest that rituximab was not superior to conventional therapy in inducing remission among patients with EGPA at both 180 and 360 days. [3]

Following the 12-month core REOVAS trial, in which RTX did not demonstrate superiority over conventional strategies for remission induction at 180 days, patients underwent extended follow-up with disease activity, medication use, and adverse events collected semiannually. The primary endpoint of the extended analysis was minor and major relapse-free survival, while major relapse incidence and asthma or ENT exacerbation-free survival were assessed as secondary endpoints. Of the 105 patients enrolled, 104 (99%) were successfully followed over a median of 45 months. Minor and major relapse-free survival was non-significantly higher in the RTX group than the conventional treatment group (63.5% vs. 50.9%; p=0.24). In contrast, major relapse-free survival favored RTX (90.4% vs. 79.2%; p=0.17). Subgroup analyses revealed notably higher efficacy of RTX in MPO-ANCA-positive patients, with relapse-free survival of 92.3% (95% CI, 66.7% to 99.6%) compared to 50% (95% CI, 58% to 72%) in the conventional treatment arm (p=0.02). Among patients who were not co-enrolled in the MAINRITSEG maintenance trial (n=66), the relapse-free survival also numerically favored RTX over conventional therapy, especially in ANCA-positive patients, where relapse-free survival reached 78.6% versus 35.7% (p=0.054). Notably, in MPO-ANCA-positive individuals within this subset, relapse-free survival was 100% in the RTX group compared to 22.2% in the conventional group (p=0.007), indicating a significant treatment benefit. These findings suggest that while long-term outcomes between RTX and conventional therapy are generally comparable in the overall EGPA population, RTX confers superior relapse prevention in ANCA-positive subgroups. [4]

Regarding data specific to central nervous system (CNS) vasculitis, rituximab is generally considered an effective alternative treatment option. However, the evidence appears primarily based on case reports of individual patients reporting a positive clinical response. A 2022 review recommends rituximab for either the induction, maintenance, or severe/refractory cases of CNS vasculitis, with evidence supported by individual cases. Various combination regimens with rituximab are also being evaluated. [5], [6], [7]

A 2024 systematic review evaluated rituximab in CNS vasculitis. A total of 27 studies were included for analysis. These comprised four case series, 15 non-randomized cohorts, and eight RCTs examining both the efficacy and safety of rituximab for CNS vasculitis and related conditions such as ANCA-associated vasculitis. However, all the included RCTs focused on ANCA-associated vasculitis. One retrospective study of primary CNS vasculitis involved 8.5% of their cohort population receiving a combination steroid plus rituximab regimen. Rituximab was administered as a 375 mg/m2 intravenous infusion once a week for four weeks, followed by a repeat infusion at six months, if required. Overall, the authors found that treatment with steroids and another immunosuppression led to potential improvements in CNS vasculitis. Despite these favorable results, the review acknowledges the varying relapse rates and the need to weigh rituximab’s use against potential adverse effects such as infections. [8], [9]

References:

[1] Tieu J, Smith R, Basu N, et al. Rituximab for maintenance of remission in ANCA-associated vasculitis: expert consensus guidelines. Rheumatology (Oxford). 2020;59(4):e24-e32. doi: 10.1093/rheumatology/kez640
[2] Emmi G, Bettiol A, Gelain E, et al. Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nat Rev Rheumatol. 2023;19(6):378-393. doi:10.1038/s41584-023-00958-w
[3] Dutertre M, Pugnet G, de Moreuil C, et al. 0854 Long-term Efficacy of Remission-induction Regimens for Eosinophilic Granulomatosis with Polyangiitis. ACR Convergence 2023; November 10-15, 2021; San Diego, CA. Accessed May 8, 2025. https://acrabstracts.org/abstract/long-term-efficacy-of-remission-induction-regimens-for-eosinophilic-granulomatosis-with-polyangiitis/
[4] Terrier B, Pugnet G, de Moreuil C, et al. L21 Rituximab versus Conventional Therapeutic Strategy for Remission Induction in Eosinophilic Granulomatosis with Polyangiitis: A Double-blind, Randomized, Controlled Trial. ACR Convergence 2021; November 5-9, 2021; Virtual. Accessed June 11, 2025. https://acrabstracts.org/abstract/rituximab-versus-conventional-therapeutic-strategy-for-remission-induction-in-eosinophilic-granulomatosis-with-polyangiitis-a-double-blind-randomized-controlled-trial/
[5] Kraemer M, Berlit P. Primary central nervous system vasculitis - An update on diagnosis, differential diagnosis and treatment. J Neurol Sci. 2021;424:117422. doi:10.1016/j.jns.2021.117422
[6] Hecker C, Welponer T, Herold M, Trinka E, Broussalis E, Killer-Oberpfalzer M. Update on treatment strategies for vasculitis affecting the central nervous system. Drug Discov Today. 2022;27(4):1142-1155. doi:10.1016/j.drudis.2021.11.020
[7] Nehme A, Boulanger M, Aouba A, et al. Diagnostic and therapeutic approach to adult central nervous system vasculitis. Rev Neurol (Paris). 2022;178(10):1041-1054. doi:10.1016/j.neurol.2022.05.003
[8] Alharthi AM, Aljundi Z, Alharbi FA, Alfaqih KE. Prognostic Factors and Outcome Measures After Rituximab Therapy in Central Nervous System Vasculitis: A Systematic Review. Cureus. 2024;16(9):e69936. Published 2024 Sep 22. doi:10.7759/cureus.69936
[9] Agarwal A, Sharma J, Srivastava MVP, et al. Primary CNS vasculitis (PCNSV): a cohort study. Sci Rep. 2022;12(1):13494. Published 2022 Aug 5. doi:10.1038/s41598-022-17869-7

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What evidence is available regarding the use of rituximab in CNS vasculitis?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-7 for your response.


 

Rituximab Versus Cyclophosphamide for ANCA-Associated Vasculitis

Design

Multicenter, randomized, double-blind, double-dummy, noninferiority trial

N=197

Objective

To compare rituximab with standard cytotoxic therapy for the induction of complete remission by 6 months in patients with severe ANCA-associated vasculitis

Study Groups

Rituximab (n=99)

Cyclophosphamide (n=98)

Inclusion Criteria

Severe ANCA-associated vasculitis who were ANCA-positive

Exclusion Criteria

Alveolar hemorrhage severe enough to require ventilatory support, advanced renal dysfunction (serum creatinine >4.0 mg/dL)

Methods

Patients were randomized (1:1) to receive either intravenous rituximab (at a dose of 375 mg/m² of body-surface area once weekly for 4 weeks) plus daily placebo-cyclophosphamide or placebo-rituximab infusions plus daily cyclophosphamide (2 mg/kg of body weight, adjusted for renal insufficiency). All participants received the same glucocorticoid regimens: 1-3 pulses of methylprednisolone (1000 mg each), followed by prednisone at a dose of 1 mg/kg/day. The dose was tapered so that by 5 months, all patients who had a remission without disease flares had discontinued glucocorticoids. 

Study visits occurred at baseline; at weeks 1, 2, 3, and 4; and at 2, 4, and 6 months. Disease activity was measured on the basis of the BVAS/WG and the physician's global assessment.

Duration

December 30, 2004, to June 30, 2008.

Outcome Measures

Primary outcome: A BVAS/WG of 0 and successful completion of the prednisone taper at 6 months.

Secondary outcomes: A BVAS/WG of 0 during treatment with prednisone at a dose of less than 10 mg per day, rates of adverse events.

Baseline Characteristics

 

Rituximab (n=99)

Cyclophosphamide (n=98)

p-Value

Age, years

54.0±16.8 51.5±14.1 p=0.26

Female

54% 46% p=0.29

White

92% 95% p=0.64

ANCA-associated vasculitis type

Wegener’s granulomatosis

Microscopic polyangiitis

Indeterminate

 

75%

24%

1% 

 

76%

24%

0%

p=0.61

 

 

 

Pre-enrollment disease duration in patients with relapsed disease, yr

6.5±6.7 5.3±7.4 p=0.31

Pre-enrollment exposure to cyclophosphamide in patients with relapsed disease

82% 74% p=0.10

Disease-assessment scores

BVAS/WG

Physician’s global assessment

Vasculitis Damage Index

 

8.5±3.2

5.7±2.4

1.4±1.8 

 

8.2±3.2

5.6±2.4

1.0±1.4

 

p=0.38

p=0.67

p=0.17

ANCA-positive at diagnosis

By immunofluorescence

All

C-ANCA

P-ANCA

 

 

98%

66%

33%

 

 

96%

62%

34%

 

 

 

 

Results

Sixty-three patients in the rituximab group (64%) reached the primary endpoint, as compared with 52 patients in the control group (53%) (95% confidence interval [CI], −3.2 to 24.3 percentage points; p=0.09), a result that met the criterion for noninferiority (p<0.001).

The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary endpoint (p=0.01). 

Seventy patients treated with rituximab (71%) reached the secondary endpoint of disease remission while receiving less than 10 mg per day of prednisone, as compared with 61 patients in the control group (62%; p=0.10).

Adverse Events

There were no significant differences between the treatment groups with respect to rates of adverse events.

More patients in the control group than in the rituximab group had one or more of the predefined selected adverse events (e.g., death [from any cause], cancer, grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, drug-induced cystitis, venous thromboembolic events, stroke, hospitalization, and infusion reactions): 32 (33%) control vs 22 (22%) rituximab (p=0.01).

Percentage that Discontinued due to Adverse Events: 14 (14%) vs 17 (17%) patients in the rituximab and control group, respectively. 

Study Author Conclusions

Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. 

InpharmD Researcher Critique

The generalizability of study findings is limited to the patients with severe ANCA-associated vasculitis who were ANCA-positive. The outcome data from this trial were reported only on the 6-month remission-induction period; thus, long-term data are lacking.



References:

Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. doi: 10.1056/NEJMoa0909905

 

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

Design

Open-label, two-group, parallel-design, randomized trial

N=44

Objective

To assess the treatment response and rates of associated severe adverse events with a rituximab-based regimen, as compared with a cyclophosphamide-based regimen, as induction therapy in patients with recently diagnosed, severe ANCA-associated vasculitis, in the hope that a rituximab-based regimen might be more effective and safer

Study Groups

Rituximab (n=33)

Cyclophosphamide (n=11)

Inclusion Criteria

A new diagnosis of ANCA-associated vasculitis, ANCA positivity, and renal involvement

Exclusion Criteria

Not specified

Methods

Eligible patients were randomized (3:1) to receive either rituximab 375 mg/m²/week, for 4 consecutive weeks plus intravenous cyclophosphamide 15 mg/kg with the first and third rituximab infusions or a validated regimen of intravenous cyclophosphamide for 3 to 6 months, followed by azathioprine. Rituximab patients did not receive azathioprine to maintain remission. Further treatment with rituximab or cyclophosphamide was permitted in cases of relapse.

Relapses occurring before a minimum of 6 months of sustained remission were considered failures with respect to the primary efficacy endpoint. Assessments were performed at 0, 1.5, 3, 6, 9, and 12 months and at the time of relapse. 

Duration

June 2006 to June 2007.

Outcome Measures

Primary endpoints: Sustained remission rates at 12 months and severe adverse events.

Secondary endpoints: Time to remission, change in the Birmingham Vasculitis Activity Score (BVAS) between 0 and 3 months, change in the GFR, prednisolone dose, score on the Medical Outcomes Study 36-Item Short Form (SF-36) questionnaire, and score on the Vasculitis Damage Index (scores for this index range from 0 to 64, with higher scores indicating more severe damage).

Baseline Characteristics

 

Rituximab (n=33)

Cyclophosphamide (n=11)

 

Median age, years (interquartile range, IQR)

68 (56-75) 67 (58-76)  

Male

17 (52%) 6 (55%)  

Diagnosis

Wegener’s granulomatosis

Microscopic polyangiitis

Renal-limited vasculitis

 

18 (55%)

12 (36%)

3 (9%)

 

4 (36%)

4 (36%)

3 (27%)

 

ANCA-positive labeling pattern

Cytoplasmic

Perinuclear

 

20 (61%)

13 (39%) 

 

5 (45%)

6 (55%)

 

Median Birmingham Vasculitis Activity Score (IQR)

19 (14–24) 18 (12-25)  
 Dialysis required at entry   8 (24%)

 1 (9%)

 
Median Intravenous methylprednisolone, g (IQR) 1 (1-1)

1 (1-1)

 

Results

A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (p=0.77).

A total of 31 severe adverse events occurred in 14 of the 33 patients in the rituximab group (42%) and 12 severe adverse events occurred in 4 of the 11 patients in the control group (36%). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (p=1.00).

The median increase in the GFR between 0 and 12 months was 19 mL/min in the rituximab group and 15 mL/min in the control group (p=0.14). The median time to remission was 90 days (IQR, 79 to 112 ) in the rituximab group and 94 days (91 to 100) in the control group (p=0.87).

Study Author Conclusions

A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events.

InpharmD Researcher Critique

This study is limited by its open-label design with small sample size. A longer duration follow-up (12 months) and inclusion of the elderly were noted in this trial; however, the sustained-remission rates were not superior in the rituximab group. In both groups, more than 90% of survivors had sustained remission. 

Although the same mortality rates (18%) were observed in both groups, this high rate of death early in the course of the disease is of great concern. 



References:

Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220. doi: 10.1056/NEJMoa0909169

 

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial

Design

Randomised controlled trial

N= 44

Objective

To assess the long-term outcomes and immunosuppression maintenance requirements after rituximab in ANCA-associated renal vasculitis

Study Groups

Rituximab (n= 33)

Control (n= 11)

Inclusion Criteria

Newly diagnosed ANCA-associated vasculitis with renal involvement

Exclusion Criteria

Not specified

Methods

Patients were randomized to receive glucocorticoids plus either rituximab (375 mg/m2/week×4) with two intravenous cyclophosphamide pulses or intravenous cyclophosphamide for 3-6 months followed by azathioprine.

Duration 24 months
Outcome Measures Primary: Composite of death, end-stage renal disease, and relapse Secondary: Time to death, ESRD, and relapse
Baseline Characteristics   Rituximab (n= 33)

Control (n= 11)

Age, median years 76 76
PR3-ANCA positive 61% 45%
MPO-ANCA positive 39% 55%
Results  

Rituximab (n= 33)

Control (n= 11) p-value

Composite outcome of death, ESRD, and relapse

Death

ESRD

Relapse

42%

18%

6%

21%

36%

27%

0

18%

1.00

0.66

1.00

1.00

Adverse Events

Not specified

Study Author Conclusions

At 24 months, the rates of the composite outcome of death, end-stage renal disease, and relapse did not differ between rituximab and cyclophosphamide groups. B cell return in the rituximab group was associated with relapse, suggesting the need for sustained B cell depletion for remission maintenance.

Critique

The study provides valuable insights into the long-term outcomes of rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. However, the small sample size and lack of detailed adverse event reporting may limit the generalizability of the findings. Additionally, the study was not powered for subgroup analysis on the effect of ANCA on relapse.

 

References:

Jones RB, Furuta S, Tervaert JW, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. Ann Rheum Dis. 2015;74(6):1178-1182. doi:10.1136/annrheumdis-2014-206404

 

Adding low dose cyclophosphamide to rituximab for remission-induction may prolong relapse-free survival in patients with ANCA vasculitis: A retrospective study

Design

Retrospective single-center cohort study

N= 62

Objective

To compare patients treated with a combination of rituximab (RTX) and low-dose cyclophosphamide (CYC) or with RTX only, both followed by tailored maintenance with RTX, with regard to long-term outcomes

Study Groups

RTX-CYC (n= 34)

RTX only (n= 28)

Inclusion Criteria

Patients with a new diagnosis of AAV or relapsing disease who were followed for at least two years

Exclusion Criteria

Not specified

Methods

Patients were treated with RTX (two doses of 1000 mg within two weeks) combined with CYC (two IV doses of 15 mg/kg within two weeks or an oral equivalent), or with RTX alone (two doses of 1000 mg within two weeks). All patients received methylprednisolone or prednisolone with a subsequent individualized tapering scheme. Maintenance therapy with RTX was tailored per patient and given in case of CD19+ B cell repopulation, combined with a meaningful rise in ANCA level and/or clinical symptoms.

Duration

March 2007 to January 2019, with follow-up until January 2021

Outcome Measures

Primary: Major relapse rate after two and five years

Secondary: Clinical data including infections, ESRD, malignancy, and mortality; laboratory parameters including renal function, MPO- or PR3-ANCA and immunoglobulin levels, and circulating CD19+ B cells

Baseline Characteristics  

RTX-CYC (n= 34)

RTX only (n= 28)
Age, years (IQR) 63 (48–70) 60 (55–69)
Male 17 (50%) 19 (67.9%)
Renal involvement, 29 (85.3%) 17 (60.7%)
Birmingham Vasculitis Activity score (IQR) 14 (11-18) 12 (7-17)
Results   RTX-CYC (n= 34)

RTX only (n= 28)

p-value

Major relapse rate within 2 years

1 (3%) 6 (24%) 0.032

Major relapse rate within 5 years

7 (20.6%) 7 (25%) 0.666

Mortality

14.7% 3.7% 0.214
Adverse Events

Infections (18% vs. 29%), hypogammaglobulinemia (62% vs. 39%), ESRD (3% vs. 4%), malignancy (3% vs. 7%)

None of these incidences were significantly different

Study Author Conclusions

Adding low-dose CYC to RTX is safe and may prevent major relapses in patients with severe AAV in the first two years after remission-induction. Randomized controlled trials that compare the efficacy and safety between RTX and a combination of RTX with CYC are needed.

Critique

The study provides valuable insights into the potential benefits of combining RTX with low-dose CYC for remission-induction in AAV. However, the retrospective design and small sample size limit the ability to generalize findings. The non-randomized treatment allocation and higher prevalence of renal involvement in the RTX-CYC group may introduce bias. Further randomized controlled trials are necessary to confirm these findings.

 

References:

Ysermans R, Busch MH, Aendekerk JP, Damoiseaux JGMC, van Paassen P. Adding low dose cyclophosphamide to rituximab for remission-induction may prolong relapse-free survival in patients with ANCA vasculitis: A retrospective study. J Transl Autoimmun. 2022;6:100178. Published 2022 Dec 15. doi:10.1016/j.jtauto.2022.100178

 

Combination Therapy With Rituximab and Cyclophosphamide for Remission Induction in ANCA Vasculitis
Design

Retrospective study

N= 129

Objective

To describe outcomes with a novel remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper

Study Groups

All patients (n= 129)

Inclusion Criteria

Newly diagnosed or relapsing ANCA vasculitis with a BVAS-WG score ≥3 and received a standardized remission induction regimen

Exclusion Criteria

Not specified

Methods

Patients received rituximab, a 2-month course of low-dose oral cyclophosphamide, and an accelerated prednisone taper. Rituximab was administered as two 1000-mg IV doses separated by 2 weeks, followed by one 1000 mg IV dose every 4 months. Cyclophosphamide was dosed at 2.5 mg/kg daily for 1 week, then 1.5 mg/kg daily for 7 weeks. Prednisone was tapered from 60 mg daily to 15 mg by week 5, then by 2.5 mg monthly. Plasma exchange (PLEX) and pulse IV glucocorticoids were added for severe cases.

Duration

June 2006 to January 2016

Outcome Measures

Primary: Complete remission (BVAS-WG of 0 and prednisone dose ≤7.5 mg/d)

Secondary: Time to remission, relapse rate, renal outcomes, serious adverse events

Baseline Characteristics   Overall (n= 129) MPO (n= 90) PR3 (n= 39)

Age, years (IQR)

64.9 (54.2-75.6) 66.2 (58.1-78.0) 57 (49.2-68.6)

Male

55 (42.6%) 38 (42.2%) 17 (43.6%)

Recurrent disease

11 (8.5%) 7 (7.8%) 4 (10.3%)

Initial BVAS-WG

6 (5-8) 6 (5-8) 7 (5-10)

PLEX

40 (31.0%) 28 (31.1%) 12 (30.8%)

Organ involvement

Constitutional

Pulmonary

Ear, nose, throat

Renal

 

53 (41.0%)

63 (48.8%)

61 (47%)

87 (67.4%)

 

34 (37.8%)

45 (50.0%)

33 (36.7%)

63 (70.0%)

 

19 (48.7%)

18 (46.2%)

28 (71.8%)

24 (61.5%)

Rapidly progressive glomerulonephritis

75 (58.1%) 55 (61.1%) 20 (51.3%)
Results   Overall (n= 129) MPO (n= 90) PR3 (n= 39) p-value

Complete remission by 5 months

109 (84%) - - -

Median time to remission, months (IQR)

4 (3.9-4.4) - - -

Increase in eGFR at 6 months, mL/min/1.73 m2

  5.6 16 0.028

Serious infection rate per month

0.022 - - -
Adverse Events

Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Neutropenia was an important adverse event, occurring in 8.5% of patients, often leading to serious infections.

Study Author Conclusions

Combination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.

Critique

The study's retrospective design and single-center nature limit its generalizability. The lack of a comparator group and the predominance of MPO-ANCA patients may affect the applicability of results to PR3-ANCA patients.

 

References:

Cortazar FB, Muhsin SA, Pendergraft WF 3rd, et al. Combination Therapy With Rituximab and Cyclophosphamide for Remission Induction in ANCA Vasculitis. Kidney Int Rep. 2017;3(2):394-402. Published 2017 Nov 14. doi:10.1016/j.ekir.2017.11.004

 

Rituximab Versus Cyclophosphamide for ANCA-Associated Vasculitis with Renal Involvement

Design

Post hoc analysis of the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial

N= 197 (102 with renal involvement)

Objective

To compare the efficacy of rituximab (RTX) versus cyclophosphamide (CYC) followed by azathioprine (AZA) for remission induction in ANCA-associated vasculitis (AAV) with renal involvement

Study Groups

RTX group (n= 51)

CYC/AZA group (n= 51)

Inclusion Criteria

Patients with ANCA-associated vasculitis and renal involvement, defined as biopsy-proven Pauci-immune glomerulonephritis, red blood cell casts in urine, or a rise in serum creatinine attributed to vasculitis

Exclusion Criteria

Patients with serum creatinine >4 mg/dl, pulmonary hemorrhage requiring mechanical ventilation, or positive anti-glomerular basement membrane (anti-GBM) antibody

Methods

Patients received RTX at 375 mg/m2 weekly for 4 weeks or CYC at 2 mg/kg/d, followed by AZA at 2 mg/kg/d after 3-6 months. Both groups received glucocorticoids. Complete remission was defined as BVAS/WG=0 off prednisone.

Duration

18 months follow-up

Outcome Measures

Primary: Complete remission (BVAS/WG=0 off prednisone)

Secondary: Sustained remission at 12 and 18 months, eGFR increase, rates of disease relapse, rates of severe adverse events

Baseline Characteristics  

RTX Group (n=51)

CYC/AZA Group (n=51)
Age, years 56 ± 15 54 ± 13
Male

47%

57%

Body mass index, kg/m2

28 ± 5 29 ± 6

Type of AAV

Granulomatosis with polyangiitis (GPA)

microscopic polyangiitis (MPA)

 

69%

31%

 

65%

35%

ANCA type

PR3

MPO

 

59%

41%

 

55%

45%

Newly diagnosed at enrollment

51%

63%
Serum creatinine, mg/dL

2.02 ± 0.92

1.71 ± 0.70
Results   RTX Group (n=51) CYC/AZA Group (n=51) p-value

Complete remission at 6 months

61% 63% 0.84

Complete remission at 18 months

41% 43% 0.84

Mean eGFR increase, mL/min/1.73 m2

8 7 0.05
Adverse Events

No significant differences in total adverse events, serious adverse events, or infections between groups. Four deaths occurred (two in each group)

Study Author Conclusions

Patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids. RTX is an appropriate and effective therapy for induction of remission in many patients with AAV with renal involvement.

Critique

The study provides valuable insights into the treatment of AAV with renal involvement, showing equivalent efficacy between RTX and CYC/AZA regimens. However, the study's post hoc nature and exclusion of patients with advanced renal dysfunction limit the generalizability of the findings. Additionally, the trial was not powered to detect differences in some subgroups, such as those with very low eGFR at baseline.

 

References:

Geetha D, Specks U, Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement. J Am Soc Nephrol. 2015;26(4):976-985. doi:10.1681/ASN.2014010046

Rituximab therapy for primary central nervous system vasculitis: A 6 patient experience and review of the literature
Design

Retrospective study

N= 6

Objective To assess the efficacy and safety of Rituximab (RTX) in adult primary central nervous system vasculitis (PCNSV)
Study Groups All patients (n= 6)
Inclusion Criteria Patients with PCNSV, refractory to high dose glucocorticoids and/or conventional immunosuppressants, or newly diagnosed and received RTX in combination with glucocorticoids
Exclusion Criteria Not explicitly stated
Methods

Retrospective assessment of RTX in 6 patients with PCNSV. RTX was administered as two infusions of 1000 mg, 15 days apart, in 4 patients, and four weekly infusions of 375 mg/m2 in 2 patients. Clinical evaluation, laboratory tests, and imaging modalities were performed at initial RTX administration and during follow-up. Treatment response was assessed using the treating physician's global opinion and the modified Rankin scale (mRS).

Duration Median follow-up duration: 51 months (range: 16–105 months)
Outcome Measures

Primary: Efficacy and safety of RTX in PCNSV

Secondary: Reduction in number of flares, modified Rankin scale (mRS) score, prednisone dosage

Baseline Characteristics Characteristic All patients (n= 6)
Median age at diagnosis, years 50.5 
Female 3
Median disease duration before RTX, months 15 
Results Endpoint All patients (n= 6)
Reduction in number of flares before/after RTX

18/3

Median mRS score before/after RT

3/2

Median prednisone dose before/after RTX, mg/day

50/12
Adverse Events

No serious adverse events such as severe infections or infusion-related reactions were reported.

Study Author Conclusions

RTX may be an effective and safe therapeutic option in patients with PCNSV refractory to conventional immunodepressants. It may also reduce the number of flares and allow tapering of glucocorticoids.

Critique

The study is limited by its retrospective nature, small sample size, and lack of control group. The rarity of PCNSV makes randomized controlled trials challenging, but further studies are needed to confirm these findings.

 

References:

Salvarani C, Brown RD Jr, Muratore F, et al. Rituximab therapy for primary central nervous system vasculitis: A 6 patient experience and review of the literature. Autoimmun Rev. 2019;18(4):399-405. doi:10.1016/j.autrev.2018.12.002