Efficacy of mycophenolate mofetil in the treatment of neuromyelitis opticaL spectrum disorders: An update systematic review and meta-analysis
ABSTRACT
Background: Neuromyelitis opticaL spectrum disorders (NMOSD) is an autoimmune astrocyte disease that mainly affects the optic nerve and spinal cord resulting in blindness or paralysis. Mycophenolate mofetil (MMF) is one of the available immunotherapies with purported beneficial effects for patients with NMOSD. The present review aimed to conduct an update systematic review and meta-analysis for the efficacy of mycophenolate mofetil in the treatment of NMOSD and analyze main factors affecting the efficacy of mycophenolate mofetil.
Methods: The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Mycophenolic Acid; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic’s Disease, Devic Syndrome, Devic’s Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid Mor- pholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61,443, RS-61,443, RS61443; (note: literature retrieval operators “AND” “OR” “NOT” are used to link MeSH with Entry Terms.) 30 studies were included in this systematic review and 14 studies were included in meta-analysis. The main efficacy indicators were the difference of the annualized relapse rate (ARR) between before and after mycophenolate mofetil treatments.
Results: In 14 studies involving 930 patients (815 women, 115 men), the ARR were reduced by an average of —1.17 (95%CI, —1.28 to —1.07).
Conclusion: Our systematic review and update meta-analysis provide new evidences that mycophenolate mofetil can substantially reduce ARR ratio.
In addition, mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is a reversible, non-competitive inhibitor of inosine-5′- monophosphate dehydrogenase (IMPDH). MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their pro- liferation[5]. Therefore, treatment with MMF suppresses both cell-mediated immune responses and antibody formation[5].
Several studies have shown that MMF can effectively reduce the annual recurrence rate (ARR) of NMOSD [6-11].
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered on the international prospective register of systematic reviews (PROSPERO) (CRD42021240597). The following Medical Subject Headings (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) databases.
Inclusion and exclusion criteria for the literature
Read all the searched documents to assess the appropriateness of their inclusion in meta-analysis. Inclusion criteria: 1) Meet study objective; 2) Patients with NMOSD meet diagnostic for NMOSD[12], [13];3) English articles. Exclusion criterion: 1) Case reports and studies that included fewer than 2 patients; 2) Review, editorials or meta-analysis;3) Studies without interest population.
Primary efficacy outcome
In this systematic review and meta-analysis, the primary efficacy outcome is differences in the ARR ratio (mean [SD]) before and after MMF therapy.
Quality assessment
Methodological quality assessment of the included observational studies was performed using the Newcastle–Ottawa Scale (NOS)[14].
Statistical analysis
We analyzed ARR as continuous variables, and reported the differ- ence between the arithmetic mean before and after the intervention. In the meta-analysis of each outcome, we did sensitivity analyses. We assessed the likelihood of publication bias by constructing a funnel plot of the effect size of each trial versus the standard error. We used the Egger test to evaluate the asymmetry of the funnel plot, and defined a significant publication bias as p-value <0.1. The I2 test was used to assess the presence of between-study heterogeneity. I2 value close to 0% means that there is no heterogeneity between studies, close to 25% means low heterogeneity, close to 50% means moderate het- erogeneity, and close to 75% means high heterogeneity between studies [15]. The generated forest map can show the ratio and comprehensive impact of individual studies.
Meta regression analysis with random effect was used to evaluate the effect of covariates on ARR ratio. These covariates include: age of onset, follow-up time, duration of disease and AQP4-IgG serostatus. We used Stata (version 15.0) for all statistical analyses.
Results
Study identification and selection
Searching PubMed, Medline, Cochrane database for relevant English literature up to May 2021. 1194 related articles were searched from the database. After a series of screening, 30 articles were included in the systematic review and 14 articles were included in the present meta- analysis.
Demographic and clinical characteristics
We can obtain the following relevant information from the included literature: study design, treatment results, patient characteristics
4.Discussion
Our results show that MMF can effectively reduce the ARR in pa- tients. The efficacy of MMF in the treatment of NMOSD was not significantly correlated with sex, age of onset, course of disease, serum AQP4 antibody status and follow-up time.
Pathogenesis, diagnosis and treatment of NMO are rapidly growing areas of research as AQP4- IgG were first identified. NMOSD recipro- cation is closely related to disease progression. Severe clinical recur- rence can lead to permanent blindness and obstacles[24]. Therefore, patients with NMOSD should receive standardized and personalized immunotherapy as soon as possible. At present, the main treatment options are corticosteroids, immunosuppressants, included azathio- prine, mitoxantrone, mycophenolate mofetil, cyclophosphamide, etc., and blood purification, included plasma exchange and immu- noadsorption. The application of monoclonal antibodies, including rit- uximab[25], satralizumab[26], ineblizumab[4], eculizumab[27], in the treatment of NMOSD, has attracted more and more attention of clini- cians[28]. A number of clinical studies have shown that monoclonal antibodies can effectively reduce the ARR rate and EDSS score, but the treatment mechanism and safety evaluation of related drugs are still not very clear. At present, there are still many difficulties in finding new drugs to treat NMOSD.
Many studies have confirmed the effectiveness and good application prospect of MMF, the prodrug of mycophenolic acid, in the treatment of NMOSD. Other studies have also shown that MMF is more effective than AZA and causes fewer adverse reactions[7], [9], [17], [18], [29], [30]. Huang et al. compared MMF’s efficacy and safety with RTX, AZA, CYP, and cyclosporine A (CyA) and found that MMF was superior to AZA and CYP but inferior to RTX and CyA[31]. However, the efficacy and safety of MMF in the treatment of NMOSD is still controversial. We expect that this systematic review will benefit NMOSD patients, physicians, healthcare managers, and policy makers.
The limitations of this systematic review and meta-analysis are: 1) highly heterogeneous observational studies are included; 2) Secondly, the heterogeneity of the study population, especially ethnic differences, pre-treatment disability and recurrence frequency, reflects the severity of the disease and the use of different doses of MMF, which may lead to different treatment outcomes and adverse reactions; 3) although the retrieval conditions are relatively perfect, it cannot be ruled out that qualified literature has not been included in this study.
Conclusions
This systematic review and meta-analysis showed that receiving MMF as prophylactic treatment in patients with NMOSD was associated with a reduction in ARR compared with pre-treatment.