A meta‐analysis comparing first‐line immunosuppressants in neuromyelitis optica

A meta‐analysis comparing first‐line immunosuppressants in neuromyelitis optica

Description of included studies

First, the meta-analysis of Huang et al.13 identified 10 comparative studies covering at least two interventions among immunosuppressive drugs and monoclonal antibodies in NMO patients updated to 21 November 2018. Among them, we excluded two studies because they did not consider at least two immunosuppressants among RTX, MMF, and AZA.20, 21 Thus, eight studies were eligible for inclusion in our meta-analysis based on the studies identified in the review of Huang et al. (Fig. 1). Second, we updated this review. A total of 373 records were identified from the Medline, CENTRAL, Embase, and ClinicalTrials databases search, including 366 nonduplicated studies, which were screened on the basis of title and abstract. Among them, we identified five eligible studies. In total, we identified 13 eligible, observational studies, and we contacted the corresponding authors.

Flow diagram. RTX, rituximab; MMF, mycophenolate mofetil; AZA, azathioprine; NMO, neuromyelitis optica, anti-AQP4+, anti-aquaporin-4-positive.

Among the 13 eligible studies, 5 were excluded because insufficient data for the calculation of the HR [95% CI] for the time to first relapse were obtained, with no response from the corresponding author.2226 One study was excluded, Mealy et al. 2014,27 because a large part of the population was already included in another study, McCreary et al., 2018,19 included in this meta-analysis and because of the inability to retrieve data from nonduplicated patients. Finally, seven observational studies comparing at least two first-line immunosuppressants among RTX, MMF, and AZA were included in the meta-analysis of NMO patients: Xu et al., 2016,28 Chen et al., 2017,29 Jeong et al., 2016,18 McCreary et al., 2018,19 Yang et al., 2018,30 Stellmann et al., 2017,31 and Poupart et al., 2020,.32 Four studies were included for the analysis of NMO and anti-AQP4positive patients: Jeong et al., 2017,18 McCreary et al., 2018,19 Stellmann et al., 2018,31 and Poupart et al., 2020.32 For three studies, the HR [95% CI] for the time to first relapse was provided by the corresponding author: Jeong et al., 2016,18 McCreary et al., 2018,19 and Stellmann et al., 2018.31 The data of the publications of Jeong et al.18 and McCreary et al.19 were updated in 2020 with additional patients for the meta-analysis. For two studies, HRs were obtained directly from published data: Xu et al., 201628 and Poupart et al., 2020.32 For two studies, HRs were calculated from the published Kaplan–Meier curve, Yang et al., 2018,30 or published figure showing plots representing individual data, Chen et al., 2017.29

The characteristics of the included studies are described in Table 1. The level of evidence was grade 3 for these observational studies. These studies included 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). Among them, 717 (83.9%) were positive for anti-AQP4.

Table 1.
Characteristics of the studies included in the meta-analysis.
Reference Year Study design Level of evidence Phenotype IS Sample size Number of events, n (%)b Follow-up (months) Anti-AQP4 positivity, n (%) Age (years) Female gender, n (%) Pretreatment ARR Concurrent use of prednisone, n (%) Regimen
Jeong, et al.18 (Korea)a 2015 Monocentric, retrospective cohort 3 NMOSD RTX 52 18 (34.6) 41 [63] 52 (100) 33.8 ± 13 46 (88.5) 2.0 [1.65] 0 (0)

375 mg/m² infused once/w for 4 w

or 1000 mg infused twice at a 2-week interval for induction, then for maintenance 375 mg/m2 when memory B cells reemerged

MMF 45 13 (28.9) 31[32] 45 (100) 36.3 ± 10.4 40 (88.9) 1.0 [1.4] 0 (0) 1.5 g–2 g/d
AZA 47 26 (55.3) 17 [23] 47 (100) 32.8 ± 12.3 39 (83) 1.0 [0.94] 0 (0) 1.75–2.5 mg/kg/d
Chen, et al.29 (China) 2016 Multicenter, prospective cohort 3 NMO, NMOSD MMF 105 46 (43.8) 11 [13] 89 (84.8) 44.0 ± 12.1 97 (92.4) 1.2 (0.1–7.0) 49 (46.7) 20 mg/kg/d
AZA 105 50 (47.6) 16.5 [28.5] 91 (86.7) 41.6 ± 11.9 99 (94.3) 1.4 (0.2–14.6) 89 (84.8) 2 mg/kg/d

Xu Y, et al.28 (China)

2016 Monocentric, prospective cohort 3 NMOSD MMF 38 NA 15.2 33 (86.8) 31.6 ± 14 32 (84.2) 0.8 (0.0–3.8) 38 (100) 11.5 g/d
AZA 119 NA 16.3 110 (92.4) 39.7 ± 13.9 110 (92.4) 0.8 (0.0–8.0) 119 (100) 100 mg/d
Stellmann et al.31 (Germany) 2017 Multicenter, retrospective cohort 3 NMOSD RTX 62 23 (37.1) 6.0 [7.8] 54 (87.1) 43.7 ± 14.9 51 (82.2) NA 0 (0) Median dose 1000 mg [375–3000] every 6 months
MMF 8 5 (62.5) 1.9 [6.2] 7 (87.5) 48.1 ± 14.2 5 (62.5) NA 0 (0) Median dose 1.5 g/d [1.5–2]
AZA 42 11 (26.2) 8.2 [13.4] 36 (85.7) 39.2 ± 13.6 38 (90.5) NA 0 (0) Median dose 150 mg [50–300]
Yang et al.30 (China) 2018 Monocentric, prospective cohort 3 NMOSD RTX 20 7 (35)

28.5 [11.5]

10 (50.0) 40.7 ± 11.4 19 (95.0) 0.9 (0–5.2) 20 (100) 100 mg/w during 4 w for induction and maintenance when memory B cells reappeared
MMF 30 14 (46.7) 26.5 [15.3] 13 (43.3) 42.6 ± 11.7 26 (86.7) 0.9 (0–5.0) 30 (100) 1 g/d
AZA 22 12 (54.5) 24 [9.8] 8 (36.4) 39.6 ± 12.0 20 (90.9) 0.8 (0–4.5) 22 (100) 2 mg/kg/d
McCreary et al.19 (USA)a 2018 Multicenter, retrospective cohort 3 NMO, NMOSD RTX 36 13 (36.1) 8 [20.5] 30 (83.3) 44.4 ± 16.9 31 (86.1) 0.71 [1.9] 0 (0) NA
MMF 26 13 (50) 12.5 [26.25] 23 (88.5) 40.8 ± 14.9 23 (88.5) 0.28 [0.82] 5 (19.2) NA
AZA 35 21 (60) 12 [28.5] 28 (80) 40.7 ± 16.1 31 (88.6) 0.75 [1.35] 13 (37.1) NA
Poupart J, et al.32 (France) 2020 Multicenter, retrospective cohort 3 NMOSD RTX 62 11 (17.7) 31 [29] 48 (77.4) 41.8 ± 14.3 55 (88.7) 0.99 ± 1.46 3 (4.8) 1 g repeated at 15 days for induction and 1 g for maintenance every 6 months (or anticipated maintenance perfusions every 2–5 months, n = 4 according to memory B cells reappearance)
MMF 42 16 (38.1) 35 [38] 35 (83.3) 41.4 ± 17.6 31 (73.8) 0.71 ± 1.17 8 (19.1) 1 g–2 g/d
AZA 23 6 (26.1) 25 [26] 12 (52.2) 39.1 ± 14.2 16 (69.6) 0.67 ± 1.46 9 (39.1) 1–2 mg/kg/d
  • Follow-up, age, and ARR pre-treatment are described as mean ± standard deviation, median [interquartile range] or median (range).
  • AQP4, aquaporin-4; ARR, annualized relapses rate; AZA, azathioprine; CI, confidence interval; d, day; HR, hazard ratio; IS, immunosuppressant; MMF, mycophenolate mofetil; NA, not available; NMO: neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; RTX, rituximab; w, week.

  • a

    Data updated using the same methodology as published, provided by the authors.


  • b

    Number of patients presenting at least one attack after initiation of immunosuppressive treatment.

Quality of included studies

The overall quality of the included studies is summarized in Table 2. Three studies received eight stars, and four studies received nine stars, indicating a very good quality of the observational studies included in the meta-analysis.

Table 2.
Risk of bias assessment for observational studies.
Author, Year Selection Comparability Outcome Total score
1 2 3 4 1 1 2 3
Jeong et al., 201618 * * * * ** * * * 9
Chen et al., 201729 * * * * * * * * 8
Xu et al., 201628 * * * * * * * * 8
Stellmann et al., 201731 * * * * ** * * * 9
Yang et al., 201830 * * * * * * * * 8
McCreary et al., 201819 * * * * ** * * * 9
Poupart et al., 202032 * * * * ** * * * 9

Comparison of the efficacy of first-line immunosuppressants

The pooled HR [95% CI] for the time to first relapse after the start of first-line immunosuppression was estimated for every comparison of immunosuppressants. Five studies were used for the comparison between RTX and MMF. We observed a higher risk of first relapse in MMF-treated patients than in RTX-treated patients (HR = 1.55 [1.04, 2.31], p = 0.032, p for heterogeneity = 0.31) (Fig. 2). Five studies were used for the comparison between RTX and AZA. We did not observe a difference between groups (pooled HR = 1.42 [0.87, 2.30], p = 0.16, p for heterogeneity = 0.10, RTX as reference) (Fig. 3). Seven studies were used for the comparison between AZA and MMF. We did not observe a difference between groups (HR = 0.94 [0.58, 1.54], p = 0.82, p for heterogeneity = 0.004, AZA as reference) (Fig. 4).

image

Forest plot of the hazard ratio for the association between the time to first relapse and first-line immunosuppression using mycophenolate mofetil (MMF) or rituximab (RTX) (as reference) in NMO patients.

image

Forest plot of the hazard ratio for the association between the time to first relapse and first-line immunosuppression using azathioprine (AZA) or rituximab (RTX) (as reference) in NMO patients.

image

Forest plot of the hazard ratio for the association between the time to first relapse and first-line immunosuppression using mycophenolate mofetil (MMF) or azathioprine (AZA) (as reference) in NMO patients.

Publication bias was investigated through funnel plots. We did not observe a significant Egger test for any comparison between immunosuppressants (data not shown). Meta-regression did not show a significant effect of anti-AQP4 positivity (p = 0.58, p = 0.77, and p = 0.74), age (p = 0.11, p = 0.20, and p = 0.07), sex (p = 0.06, p = 0.61, and p = 0.60), pre-treatment ARR (p = 0.42, p = 0.42, and p = 0.80), or concurrent use of prednisone (p = 0.92, p = 0.51, and p = 0.36) for the comparisons RTX versus MMF, RTX versus AZA, and AZA versus MMF, respectively.

Meta-analysis in anti-AQP4-positive patients

We did not observe a difference between RTX and MMF (pooled HR = 1.45 [0.89, 2.39], p = 0.14, p for heterogeneity = 0.23, RTX as reference), RTX and AZA (pooled HR = 1.32 [0.70, 2.51], p = 0.39, p for heterogeneity = 0.047, RTX as reference), or AZA and MMF (pooled HR = 1.07 [0.42, 2.76], p = 0.89, p for heterogeneity = 0.003, AZA as reference) (Fig. 5A–C).

image

Forest plot of the hazard ratio for the association between the time to first relapse and first-line immunosuppression using (A) mycophenolate mofetil (MMF) or rituximab (RTX) (as reference), (B) azathioprine (AZA) or rituximab (RTX) (as reference), (C) mycophenolate mofetil (MMF) or azathioprine (AZA) (as reference), in NMO in patients positive for anti-aquaporin-4 antibodies.

Source: Online Library, Wiley

Share on facebook
Share on twitter
Share on whatsapp
Share on email

You may also like

subscribe to our newsletter

I expressly agree to receive the newsletter and know that i can easily unsubscribe at any time