Abstract
Background
Immune thrombocytopenic purpura (ITP) is a challenging disease in its presentation and management as it may cause life-threatening hemorrhaging in vital organs and may resist several lines of treatment. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of mycophenolate mofetil (MMF) in treating patients with ITP.
Methods
We systematically searched four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials) from inception until 10 October 2022. We included all clinical trials, either controlled or single arm, and prospective and retrospective observational studies that evaluate the efficacy and safety of MMF in patients with ITP. We assessed the risk of bias using three tools (ROBINS-I, Cochrane ROB-2, and NIH), each for eligible study design.
Results
Nine studies were included in this meta-analysis, with a total of 411 patients with ITP. We found that MMF demonstrated an overall response rate of (62.09%; 95% CI = [43.29 to 77.84]) and the complete response rate was (46.75%; 95% CI = [24.84 to 69.99]). The overall proportion of adverse events was (12%; 95% CI = [6 to 24]). After the sensitivity analysis, the overall response rate became 50%; 95% CI = [38 to 63]) and the complete response rate became (32%; 95% CI = [24 to 42]). However, MMF did not appear to affect white blood cell counts or hemoglobin levels significantly.
Conclusion
This systematic review and meta-analysis demonstrate that MMF appears to be an effective and relatively safe treatment option for patients with ITP when combined with steroids and even in those who have not responded to standard therapies (steroid-resistant cases). Further research with well-designed studies is warranted to better understand the factors influencing treatment response and to refine the use of MMF in the management of ITP. An interactive version of our analysis can be accessed from here: https://databoard.shinyapps.io/mycophenolate_meta/
Graphical abstract
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Background
Immune thrombocytopenic purpura (ITP) is a disorder characterized by a reduced blood platelet count, which increases the risk of hemorrhage [1]. Platelets are blood cells that serve an essential function in clotting blood [2]. They are responsible for generating clots at the area of injury in order to stop bleeding [2]. In ITP, the immune system wrongly attacks platelets, destroying them and decreasing their blood concentration [3, 4].
ITP can affect people of all ages, although children and young adults are more susceptible [5]. In children, it typically develops after a viral infection and resolves spontaneously within a few weeks to months [6, 7]. However, it can be chronic and persist for years in adults [6]. As with most autoimmune diseases, ITP is more common in females [4]; however, it is more common in male children than females [7, 8]. Depending on the severity of the disease, the ITP symptoms may vary. Some people with mild cases of ITP may have no symptoms, while others may experience bruising, petechiae (red or purple skin patches), and mucosal bleeding (bleeding from the gums, nose, or digestive tract) [9,10,11,12]. In serious instances, patients might suffer life-threatening hemorrhaging into the brain or other vital organs and also can die from a hemorrhagic shock [10, 12,13,14].
ITP is treated according to the disease’s severity and the presence of manifestations [11]. Treatment may not be required in mild casesand the platelet count may increase spontaneously [10]. In more severe instances, corticosteroids [15], intravenous immunoglobulin (IVIG) [16], anti-D immunoglobulin [17], and immunosuppressive agents such as mycophenolate mofetil (MMF) [18] or rituximab [19] may be administered. Some studies also suggest the use of methotrexate in ITP patients, especially in steroid-resistant cases [20, 21]. In some instances, splenectomy may also be contemplated [22].
MMF is a prodrug that the body transforms into mycophenolic acid (MPA) [23]. MPA inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH) [24], which is implicated in the synthesis of guanosine nucleotides. This decreases the generation of T and B lymphocytes and the proliferation of activated lymphocytes [23, 25]. MMF is, therefore, able to suppress the immune response and has been used to treat a variety of autoimmune disorders [26], including ITP [18, 27].
This systematic review aimed to evaluate the safety and efficacy of MMF in treating patients with ITP.
Methods
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines when reporting this systematic review and meta-analysis [28]. All steps were done in strict accordance with the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions [29]. The protocol of this study was registered on PROSPERO (CRD42023422449).
Eligibility criteria
Studies were included in our review if they satisfied the following criteria:
-
Population: studies on patients with ITP (chronic or refractory)
-
Intervention: studies where the experimental (or exposed) group received MMF
-
Comparator: studies where the control group did not receive MMF or received the standard therapy
-
Outcome: studies reporting at least one of the following outcomes: drug response or adverse effect (headache or white blood cells (WBCs) and hemoglobin (Hb) side effects or gastrointestinal symptoms)
-
Study design: we included all clinical trials, either controlled or single arm. We also included prospective and retrospective observational studies.
We excluded studies whose data were not reliable for extraction and analysis, case reports, case series, reviews, editorials, studies that were reported as a thesis, and studies that were not published in the English language.
Information sources and search strategy
We performed a comprehensive search of four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials) from inception until 10 October 2022 using the following query: (“Idiopathic Thrombocytopenic Purpura” OR “Immune Thrombocytopenic Purpura” OR “Thrombocytopenic Purpura” OR “Immune Thrombocytopenia” OR “Thrombocytopenias” OR “Werlhof Disease” OR “Werlhofs Disease” OR (“Autoimmune Thrombocytopenic Purpura” OR “ITP”) AND (“Mycophenolate Mofetil” OR “Mycophenolate” OR “Mycophenolic Acid” OR “Morpholinoethyl Ester” OR “Mycophenolate Sodium” OR “Myfortic” OR “RS 61443”). Further, the references of the included studies were manually searched for any potentially eligible studies.
Selection process
Duplicates were removed using Endnote (Clarivate Analytics, PA, USA), and the retrieved references were screened in two steps: the first step was to screen titles/abstracts of all identified articles independently by all authors to assess relevance to this meta-analysis, and the second step was to screen the full-text articles of the identified abstracts for final eligibility to meta-analysis.
Data collection process and data items
Data were extracted into a uniform data extraction sheet. The extracted data included (1) a summary of the included studies (study ID, title, design, groups, country, inclusion criteria, exclusion criteria, main finding); (2) characteristics of the population of included studies (study ID, groups, number of participants, dose, age, gender (male), and follow-up); (3) risk of bias domains; and (4) outcome measures (drug response and adverse effects).
Assessing the risk of bias in and between the individual studies
We assessed the risk of bias using three tools each for eligible study design. For the non-randomized trial, we used the risk of bias in non-randomised studies—of interventions (ROBINS-I) tool [30]. The randomized control trial was assessed by Cochrane risk of bias (ROB)-2 [31], while single-arm clinical trials were evaluated using quality assessment for before-after (pre-post) studies with no control group according to the National Institutes of Health (NIH) tool [32].
In the present study, we could not assess the existence of publication bias by Egger’s test for funnel plot asymmetry, as according to Egger and colleagues [33, 34], publication bias assessment is unreliable for < 10 pooled studies.
Statistical analysis
Data analysis was performed using Rstudio (Version 4.2.2). To estimate the combined proportion and its 95% confidence interval (CI) for all analyzed outcomes, a random effect model was utilized. The meta prop function from the meta library within Rstudio was employed for this purpose. Examination of heterogeneity was accomplished by assessing I2 along with its corresponding p-value. In instances where statistically significant heterogeneity was detected, a sensitivity analysis was carried out to pinpoint the particular study responsible for introducing the heterogeneity.
For the meta-analytical approach, a random intercept logistic regression model was employed, employing maximum-likelihood estimation for tau^2. The calculation of random effects confidence intervals relied on the t-distribution, and a logit transformation was applied accordingly. Heterogeneity testing was performed using both Wald-type and likelihood-ratio tests. Notably, a continuity correction of 0.5 was implemented when dealing with studies containing zero cell frequencies, strictly for the purpose of computing individual study outcomes.
Results
Literature search results
Our literature search has shown 1229 studies. Regarding title and abstract screening, only 15 studies were included for full-text screening. Nine studies were eligible for our systematic review. No further studies were included following a manual search of the references. The PRISMA flow diagram shows all search results (Fig. 1).
Characteristics of the included studies
Of the nine included studies, one is a randomized controlled trial, seven are single-arm clinical trials, and one is a non-randomized, controlled clinical trial. Out of the nine included studies, six included steroid-resistant ITP cases [27, 35,36,37,38,39] and two [18, 40] investigated MMF plus steroids compared to the steroids alone. The summary and baseline of the included studies are shown in Tables 1 and 2, respectively. The quality assessment for the single-arm clinical trials showed five studies with good quality, and two with moderate quality (Table S1). The risk of bias for randomized and non-randomized controlled trials revealed good quality (Tables S2 and S3).
Response to MMF
We conducted a single-arm meta-analysis to evaluate the efficacy of mycophenolate for ITP. The primary outcome measure was the combined proportion of partial and complete responses.
For overall response, combining partial and complete response, the random effects model estimated a proportion of (62.09%; 95% CI = [43.29 to 77.84]) based on eight studies with 257 observations and 156 events. Heterogeneity was significant (I2 = 79.8%, p < 0.0001), suggesting considerable variation in treatment response across the studies (Fig. 2). Sensitivity analysis was done by removing the Arnold et al. 2009 [37] and Bradbury et al. 2021 [18] studies which resolved the heterogeneity (I2 = 39%, p = 0.15), while the effect size decreased to (50%; 95% CI = [38 to 63]) (Figure S1). The reason for these two studies introducing heterogeneity is that the intervention was MMF + glucocorticoids rather than MMF alone. This is why they had a relatively higher response rate.
Subgroup analysis based on response type revealed that the proportion of complete response was (46.75%; 95% CI = [24.84 to 69.99]) in eight studies, while the proportion of partial response was (17.27%; 95% CI = 9.53 to 29.27]) in six studies. The test for subgroup differences was statistically significant (Q = 8.54, df = 1, p = 0.0035), indicating a significant variation in response between the subgroups. There was statistically significant heterogeneity in the complete response group (I2 = 86%, p < 0.001) (Fig. 3). Sensitivity analysis was done by removing Arnold et al. 2009 [37] and Bradbury et al. 2021 [18] studies which resolved the heterogeneity (I2 = 0%, p = 0.77), while the effect size decreased to (32%; 95% CI = [24 to 42] (Figure S2).
Lastly, the proportion of non-response to mycophenolate was (33.14%; 95% CI = [21.43 to 47.39]) in seven studies with 198 observations and 66 events. The heterogeneity analysis indicated moderate heterogeneity (I2 = 61%, p = 0.02), implying some variation in non-response rates among the studies (Fig. 4).
Adverse events
Eight studies reported adverse events with MMF use in a total of 272 patients with ITP. The overall proportion of adverse events was (12%; 95% CI = [6 to 24]) with significant heterogeneity (I2 = 67%, p < 0.01). The subgrouping according to the type of adverse events showed that the gastrointestinal adverse events (diarrhea, nausea, abdominal pain) were the most common (18%; 95% CI = [8 to 35]), then the headache (4%; 95% CI = [1 to 21]). One study (Miano et al. 2015 [41]) reported gastrointestinal adverse events and headaches as a combination with a proportion of (8%; 95% CI = [7 to 35]) (Fig. 5 and Table 3). Three studies [36, 38, 39] measured the effects of MMF on the white blood cells and hemoglobin and showed that MMF treatment did not affect any of them with a 0% in all these studies (Table 3). Additionally, the poor quality of life was reported as an adverse event of MMF in the Bradbury et al. study [18], which found that MMF-treated patients reported worse quality-of-life outcomes regarding physical function and fatigue compared to glucocorticoids-treated patients, despite the lack of difference between them in any other adverse events.
An interactive summary of our study findings can be accessed from here: https://databoard.shinyapps.io/mycophenolate_meta/
Discussion
Significance of the study
This systematic review and meta-analysis aimed to evaluate the efficacy of MMF in treating patients with ITP, a challenging autoimmune disorder. Understanding the role of MMF in ITP management is crucial as it can potentially provide an alternative or adjunctive therapy for patients who are unresponsive to standard treatments.
Summary of findings
Our study included nine studies with a total of 411 patients with ITP. In our analysis, we found that MMF demonstrated an overall response rate (combining partial and complete responses) of 62.09%. This suggests that MMF may be effective in inducing a response in a significant proportion of ITP patients. Subgroup analysis revealed that the proportion of complete response was 46.75%, while the proportion of partial response was 17.27%, indicating a variation in treatment response, with the complete response being predominant. Furthermore, the proportion of non-response to mycophenolate was 33.14%. Regarding adverse events, MMF use was associated with an overall proportion of 12% adverse events, with gastrointestinal symptoms being the most common, followed by headaches. Notably, MMF did not appear to significantly affect white blood cell counts or hemoglobin levels.
Of the included studies, two were controlled studies [18, 40] and compared MMF and steroids in treating patients with ITP. Xu et al. [40] compared the MMF plus prednisone with prednisone alone and found that the combination significantly increased the platelet levels when compared to the prednisone alone (p < 0.05). Additionally, the time to reach the normal platelets level was shorter in the combination group. Bradbury et al. [18] also investigated the use of MMF in combination with glucocorticoids as a first-line therapy in the management of ITP compared with glucocorticoids alone, with a follow-up of 2 years. The authors found that the MMF-glucocorticoids group had fewer treatment failures than glucocorticoids alone. Additionally, the combination group had a greater response than the glucocorticoids alone group. However, the patients in the combination group had worsened quality-of-life outcomes in terms of physical function and tiredness.
Explanation of the finding and potential mechanisms of MMF in ITP
The observed overall response rate of 62.09% with significant heterogeneity indicates that MMF has a considerable impact on ITP management, but treatment response varies among individual patients. To understand the potential mechanisms by which MMF exerts its effects in ITP, we need to consider its pharmacological properties and its known immunomodulatory actions.
MMF is an immunosuppressive medication that inhibits IMPDH [23], an enzyme that is required for the de novo synthesis of guanosine nucleotides, specifically guanosine monophosphate (GMP) and guanosine diphosphate (GDP) [23, 25]. These nucleotides are essential for deoxyribonucleic acid (DNA) synthesis and cell proliferation, especially in rapidly dividing cells such as lymphocytes [42].
Suppression of B and T lymphocytes
Lymphocytes play an important part in the development of ITP [43], and MMF predominantly targets them [23, 44]. T and B lymphocytes are involved in the destruction of platelets in ITP, either directly or indirectly, by developing autoantibodies against platelet surface antigens [12]. MMF suppresses lymphocyte proliferation by lowering the availability of GMP and GDP, hence restricting DNA synthesis and cell division [23, 25]. This activity reduces the number of autoreactive lymphocytes, resulting in less platelet destruction and possibly higher platelet counts [44].
Autoantibody production modulation
Autoantibodies that target platelet surface antigens are produced by B lymphocytes in ITP patients, resulting in platelet destruction via the reticuloendothelial system [45,46,47,48]. MMF may inhibit the generation of autoantibodies against platelets by decreasing B cell proliferation and antibody synthesis, contributing to the stabilization or enhancement of platelet levels [49].
Immunomodulatory actions
MMF’s immunomodulatory activities go beyond the inhibition of lymphocytes [43, 44]. It also has an impact on other immune cells, such as dendritic cells and macrophages [50, 51], which play important roles in immune response and inflammation regulation [52]. MMF may help reduce the inflammatory component of ITP by slowing the activity of these cells, lowering platelet destruction, and increasing platelet survival.
Impact on regulatory T cells (Tregs)
Tregs are a type of T cell renowned for their immunosuppressive properties, including the suppression of autoreactive T cells [53, 54]. MMF therapy has been linked to an increase in Treg frequency, which could improve their suppressive action [55]. MMF may enhance immunological tolerance and alleviate the autoimmune response that causes ITP by fostering a more favorable Treg-to-effector T cell balance.
Anti-inflammatory effects
MMF has anti-inflammatory properties in addition to its direct immunosuppressive effects [56,57,58]. Pro-inflammatory cytokines and chemokines play a role in platelet destruction and decreased platelet synthesis in ITP [59,60,61]. The anti-inflammatory effects of MMF may aid in the reduction of inflammatory mediators, resulting in a more balanced immunological milieu and enhanced platelet homeostasis [56,57,58, 62].
Platelet-associated autoantigen reduction
Platelets may carry autoantigens on their surface in some cases of ITP, which are recognized by autoreactive T lymphocytes and cause their death [11, 63, 64]. MMF’s effect on B cells and autoantibody synthesis may indirectly diminish platelet coating with autoantigens, reducing identification and destruction by immune cells [49].
It is crucial to highlight that the precise processes by which MMF operates in ITP are not fully understood, and it is likely that a combination of the aforementioned mechanisms, as well as patient-specific factors, contributes to treatment response. Furthermore, the study’s great variation in response rates highlights the need for additional research to uncover predictive markers for MMF responsiveness in ITP.
First-line versus steroid resistant
Steroid-resistant ITP represents a complex subset of patients within the broader ITP population. These people do not have a satisfactory increase in platelet counts in response to normal corticosteroid medication [65], which is commonly used as first-line therapy for ITP [15]. Steroid-resistant ITP presents distinct challenges, necessitating a specialized approach to address the underlying immunological dysregulation that leads to recurrent platelet destruction [66,67,68]. When corticosteroids fail to provide the intended response, a variety of other therapeutic options are tried. One strategy involves studying several immunosuppressive drugs, such as MMF, which was the focus of this study [49, 67, 68]. MMF’s methods of action, which were described, make it a possible candidate for treating steroid-resistant cases. Out of the nine included studies, six included steroid-resistant ITP cases [27, 35,36,37,38,39], and two [18, 40] investigated MMF plus steroids compared to the steroids alone. When compared to the steroids, the combination of MMF plus steroids showed significantly increased platelet levels [40], a shorter time to reach the normal platelet level [40], fewer treatment failures, and a greater response rate [18].
A previous systematic review by Bylsma et al. reported the potential treatments used for ITP in a second-line setting; MMF was one of those potential drugs [69]. It was also reported as second-line therapy in the International Consensus Report [70] and the American Society of Hematology guidelines on managing primary ITP [71], but as medical therapy with less robust evidence. However, one of the additions of our study is highlighting MMF as a potential second-line therapy with more substantial evidence and even a potential first-line therapy combined with glucocorticoids.
Recommendations for future research and clinical practice
In order to better study the efficacy and safety of MMF in treating ITP, future research should focus on conducting well-designed randomized controlled trials with bigger sample sizes. These studies should also look into potential predictors of treatment response in order to identify patient subgroups most likely to benefit from MMF therapy. Long-term follow-up studies are also required to determine how long the response lasts and to track any late adverse events that may arise. Additionally, the future research should compare MMF with other agents that are highlighted as a second-line therapy. Moreover, there is a critical need to define the specific patient characteristics or biomarkers that can reliably predict the response to MMF or other therapeutic agents. By elucidating the predictive factors associated with treatment response, such as disease phenotype, immunological parameters, or genetic markers, future research can facilitate the implementation of personalized treatment approaches, thereby maximizing the therapeutic benefits and minimizing the risks for patients with ITP.
In clinical practice, the findings of this study can guide clinicians in considering MMF as a treatment option for ITP patients, especially in steroid-resistant cases, to avoid splenectomy or even to do a safe splenectomy. Furthermore, the integration of these findings into clinical practice has the potential to inform the development of evidence-based treatment guidelines and protocols, empowering healthcare providers to make informed, data-driven decisions and optimize the standard of care for patients with ITP.
Finally, MMF is highlighted as a low-cost [36], which ensures accessibility and affordability for patients, contributing to a more efficient healthcare approach, especially a low and middle income nations.
Strength points and limitations
To the best of our knowledge, this is the first systematic review and meta-analysis to evaluate the efficacy of MMF in treating patients with ITP. The inclusion of various study designs and the large sample size provide a comprehensive evaluation of MMF in ITP management. However, some limitations should be acknowledged. First, the included studies might have had inherent biases that could influence the overall results. Although efforts were made to assess the risk of bias using appropriate tools, the possibility of residual confounding cannot be entirely ruled out. Second, the significant heterogeneity observed in treatment response highlights the need for caution when interpreting the overall response rate. Third, the number of included studies may have been limited, with a sample size that may not be considered large sufficiently, which could affect the generalizability of the findings.
Conclusion
This systematic review and meta-analysis demonstrate that MMF appears to be an effective and relatively safe treatment option for patients with ITP when combined with steroids and even in those who have not responded to standard therapies (steroid-resistant cases). The findings support the potential use of MMF as an alternative or adjunctive treatment for ITP, but careful patient selection and monitoring for adverse events are essential for optimizing treatment outcomes. Further research with well-designed studies is warranted to better understand the factors influencing treatment response and to refine the use of MMF in the management of ITP.
Data Availability
The datasets used and/or analyzed during the current study are available as MS Excel (.xlsx) and RevMan files (.rm5) from the corresponding author on reasonable request.
Abbreviations
- ITP :
-
Immune thrombocytopenic purpura
- MMF :
-
Mycophenolate mofetil
- ROBINS-I :
-
Risk of bias in non-randomised studies—of interventions
- ROB :
-
Risk of bias
- NIH :
-
National Institutes of Health
- IVIG :
-
Immunoglobulin
- MPA :
-
Mycophenolic acid
- IMPDH :
-
Inosine monophosphate dehydrogenase
- PRISMA :
-
Preferred reporting items for systematic reviews and meta-analyses
- WBCs :
-
White blood cells
- Hb :
-
Hemoglobin
- CI :
-
Confidence interval
- GMP :
-
Guanosine monophosphate
- GDP :
-
Guanosine diphosphate
- DNA :
-
Deoxyribonucleic acid
- Tregs :
-
Regulatory T cells
References
Cines DB, Blanchette VS (2002) Immune thrombocytopenic purpura. N Engl J Med 346(13):995–1008. https://doi.org/10.1056/NEJMRA010501
Holinstat M (2017) Normal platelet function. Cancer Metastasis Rev 36(2):195–198. https://doi.org/10.1007/s10555-017-9677-x
Miyata S (2012) Recent advances in the pathogenesis, diagnosis, and treatment of immune heparin-induced thrombocytopenia. Japan J Thromb Hemost 23. https://doi.org/10.2491/jjsth.23.362
Audia S, Mahevas M, Nivet M, Ouandji S, Ciudad M, Bonnotte B (2021) Immune thrombocytopenia: recent advances in pathogenesis and treatments. Hemasphere 5. https://doi.org/10.1097/HS9.0000000000000574
Gernsheimer T (2009) Chronic idiopathic thrombocytopenic purpura: mechanisms of pathogenesis. Oncologist 14(1):12. https://doi.org/10.1634/theoncologist.2008-0132
Despotovic JM, Grimes AB (2018) Pediatric ITP: is it different from adult ITP? Hematol (United States) 2018(1):405. https://doi.org/10.1182/asheducation-2018.1.405
Faki Osman ME (2012) Childhood immune thrombocytopenia: clinical presentation and management. Sudan J Paediatr 12(1):27–39
Saeidi S, Jaseb K, Asnafi AA, Rahim F, Pourmotahari F, Mardaniyan S, Yousefi H, Alghasi A, Shahjahani M, Saki N (2014) Immune thrombocytopenic purpura in children and adults: a comparative retrospective study in IRAN. Int J Hematol Oncol Stem Cell Res 8(3):30–6
Lambert MP, Gernsheimer TB (2017) Clinical updates in adult immune thrombocytopenia. Blood 129(21):2829–2835. https://doi.org/10.1182/blood-2017-03-754119
Zitek T, Weber L, Pinzon D, Warren N (2022) Assessment and management of immune thrombocytopenia (ITP) in the emergency department: current perspectives. Open Access Emerg Med 14:25–34. https://doi.org/10.2147/OAEM.S331675
Zufferey A, Kapur R, Semple JW (2017) Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J Clin Med 6(2):16. https://doi.org/10.3390/jcm6020016
Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG (2018) Emerging concepts in immune thrombocytopenia. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00880
Audia S, Bonnotte B (2021) Emerging therapies in immune thrombocytopenia. J Clin Med 10(5):1004. https://doi.org/10.3390/jcm10051004
Rodeghiero F, Michel M, Gernsheimer T, Ruggeri M, Blanchette V, Bussel JB, et al. (2013) Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood 121. https://doi.org/10.1182/blood-2012-07-442392
Cuker A, Liebman HA (2021) Corticosteroid overuse in adults with immune thrombocytopenia: cause for concern. Res Pract Thromb Haemost 5. https://doi.org/10.1002/rth2.12592
Almizraq RJ, Branch DR (2021) Efficacy and mechanism of intravenous immunoglobulin treatment for immune thrombocytopenia in adults. Ann Blood 6. https://doi.org/10.21037/aob-20-87
Cheung E, Liebman HA (2009) Anti-RhD immunoglobulin in the treatment of immune thrombocytopenia. Biol 3. https://doi.org/10.2147/btt.s3166
Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J et al (2021) Mycophenolate mofetil for first-line treatment of immune thrombocytopenia. New England J Med 385(10):885–895. https://doi.org/10.1056/nejmoa2100596
Lucchini E, Zaja F, Bussel J (2019) Rituximab in the treatment of immune thrombocytopenia: what is the role of this agent in 2019? Haematologica 104(6):1124–1135. https://doi.org/10.3324/haematol.2019.218883
Al-Alfy MN, Hamdy A (2015) Methotrexate as a promising treatment for immune thrombocytopenia. Int J Intern Med 2015:14–16. https://doi.org/10.5923/j.ijim.20150401.03
Abdelwahab OA, Seif AM, Sherif MES (2023) Why should we consider methotrexate in future trials of steroid-resistant immune thrombocytopenic purpura? Correspondence. Immunol Lett 254:39–40. https://doi.org/10.1016/j.imlet.2023.01.008
Kojouri K, Vesely SK, Terrell DR, George JN (2004) Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 104. https://doi.org/10.1182/blood-2004-03-1168
Allison AC, Eugui EM (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacol 47(2–3):85–118. https://doi.org/10.1016/S0162-3109(00)00188-0
Naffouje R, Grover P, Yu H, Sendilnathan A, Wolfe K, Majd N et al (2019) Anti-tumor potential of IMP dehydrogenase inhibitors: a century-long story. Cancers (Basel) 11(9):1346. https://doi.org/10.3390/cancers11091346
Goldsmith D, Carrey EA, Edbury S, Smolenski RT, Jagodzinski P, Simmonds HA (2004) Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients. Clin Sci 107:63–68. https://doi.org/10.1042/CS20030331
Iaccarino L, Rampudda M, Canova M, Della Libera S, Sarzi-Puttinic P, Doria A (2007) Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases? Autoimmun Rev 6(3):190–195. https://doi.org/10.1016/j.autrev.2006.11.001
Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, Mcguckin S et al (2015) Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol 171(4):625–630. https://doi.org/10.1111/bjh.13622
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, The PRISMA et al (2020) statement: an updated guideline for reporting systematic reviews. The BMJ 2021:372. https://doi.org/10.1136/bmj.n71
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ et al (2021) Cochrane handbook for systematic reviews of interventions version 6.2 [updated February 2021]. Cochrane. Available from www.training.cochrane.org/handbook
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ (Online) 355:i4919. https://doi.org/10.1136/bmj.i4919
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I et al (2019) RoB 2: A revised tool for assessing risk of bias in randomised trials. The BMJ 366:l4898. https://doi.org/10.1136/bmj.l4898
NIH (2014) Quality assessment tool for before-after (pre-post) studies with no control group. https://www.NhlbiNih.Gov/Health-Topics/Study-Quality-Assessment-Tools. Accessed 16 Aug 2023
Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315(7109):629–634. https://doi.org/10.1136/bmj.315.7109.629
Terrin N, Schmid CH, Lau J, Olkin I (2003) Adjusting for publication bias in the presence of heterogeneity.[erratum appears in Stat Med. 2005 Mar 15;24(5):825-6]. Stat Med 22(13):2113–2126. https://doi.org/10.1002/sim.1461
Hou M, Peng J, Shi Y, Zhang C, Qin P, Zhao C et al (2003) Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura. Eur J Haematol 70(6):353–357. https://doi.org/10.1034/j.1600-0609.2003.00076.x
Čolović M, Suvajdzic N, Čolović N, Tomin D, Vidović A, Palibrk V (2011) Mycophenolate mophetil therapy for chronic immune thrombocytopenic purpura resistant to steroids, immunosuppressants, and/or splenectomy in adults. Platelets 22. https://doi.org/10.3109/09537104.2010.520372
Arnold DM, Nazi I, Santos A, Chan H, Heddle NM, Warkentin TE et al (2010) Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura. Blood 115(1):29–31. https://doi.org/10.1182/blood-2009-06-222448
Zhang WG, Ji L, Cao XM, Chen YX, He AL, Liu J et al (2005) Mycophenolate mofetil as a treatment for refractory idiopathic thrombocytopenic purpura. Acta Pharmacol Sin 26:598–602. https://doi.org/10.1111/J.1745-7254.2005.00088.X
Provan D, Moss AJ, Newland AC, Bussel JB (2006) Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura. Am J Hematol 81:19–25. https://doi.org/10.1002/AJH.20515
Xu J, Wang G, Tan S, Ge Y, Liu J, Rao M et al (2019) The clinical effect of prednisone in combination with Mycophenolate mofetil on idiopathic thrombocytopenic purpura (ITP) and its influence on the level of peripheral blood T lymphocytes and NK lymphocytes. Saudi J Biol Sci 26(8):2108–2112. https://doi.org/10.1016/j.sjbs.2019.09.013
Miano M, Scalzone M, Perri K, Palmisani E, Caviglia I, Micalizzi C, et al. (2015) Mycophenolate mofetil and sirolimus as second or further line treatment in children with chronic refractory primitive or secondary autoimmune cytopenias: a single centre experience. Br J Haematol 171. https://doi.org/10.1111/bjh.13533
Lane AN, Fan TWM (2015) Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 43(4):2466–2485. https://doi.org/10.1093/nar/gkv047
Lin X, Xu A, Zhou L, Zhao N, Zhang X, Xu J et al (2021) Imbalance of T lymphocyte subsets in adult immune thrombocytopenia. Int J Gen Med 14:937–947. https://doi.org/10.2147/IJGM.S298888
Karnell JL, Karnell FG, Stephens GL, Rajan B, Morehouse C, Li Y et al (2011) Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation. The J Immunol 187(7):3603–3612. https://doi.org/10.4049/jimmunol.1003319
McMillan R (2000) Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin Hematol 37(3):239–248. https://doi.org/10.1016/S0037-1963(00)90102-1
Aghabeigi N, Lindsey N, Zamani A, Shishaeyan B (2012) Identification and characterization of anti-platelet antibodies in idiopathic thrombocytopenic purpura patients. Iran J Public Health 41(2):53–62
Meabed MH, Taha GM, Mohamed SO, El-Hadidy KS (2007) Autoimmune thrombocytopenia: Flow cytometric determination of platelet-associated CD154/CD40L and CD40 on peripheral blood T and B lymphocytes. Hematol 12(4):301–307. https://doi.org/10.1080/10245330701383957
Fu L, Ma J, Cheng Z, Gu H, Ma J, Wu R ()2018) Platelet-specific antibodies and differences in their expression in childhood immune thrombocytopenic purpura predicts clinical progression. Pediatr Investig 2. https://doi.org/10.1002/ped4.12097
Lv Y, Shi H, Liu H, Zhou L (2022) Current therapeutic strategies and perspectives in refractory ITP: what have we learned recently? Front Immunol 13. https://doi.org/10.3389/fimmu.2022.953716
Čolić M, Stojić-Vukanić Z, Pavlović B, Jandrić D, Stefanoska I (2003) Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells. Clin Exp Immunol 134. https://doi.org/10.1046/j.1365-2249.2003.02269.x
Zaza G, Leventhal J, Signorini L, Gambaro G, Cravedi P (2019) Effects of antirejection drugs on innate immune cells after kidney transplantation. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.02978
Katholnig K, Linke M, Pham H, Hengstschläger M, Weichhart T (2013) Immune responses of macrophages and dendritic cells regulated by mTOR signalling. Biochem Soc Trans 41. https://doi.org/10.1042/BST20130032
Wan YY (2010) Regulatory T cells: Immune suppression and beyond. Cell Mol Immunol 7. https://doi.org/10.1038/cmi.2010.20
Corthay A (2009) How do regulatory t cells work? Scand J Immunol 70. https://doi.org/10.1111/j.1365-3083.2009.02308.x
Furukawa A, Wisel SA, Tang Q (2016) Impact of immune-modulatory drugs on regulatory T cell. Transplantation 100. https://doi.org/10.1097/TP.0000000000001379
Al-Hizab F, Kandeel M (2021) Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing. Peer J 9. https://doi.org/10.7717/peerj.11360
Beduschi MG, Guimarães CL, Buss ZS, Dalmarco EM (2013) Mycophenolate mofetil has potent anti-inflammatory actions in a mouse model of acute lung injury. Inflammation 36. https://doi.org/10.1007/s10753-013-9599-x
Lv QK, Liu JX, Li SN, Gao YJ, Lv Y, Xu ZP, et al (2015) Article mycophenolate mofetil modulates differentiation of Th1/Th2 and the secretion of cytokines in an active Crohn’s disease mouse model. Int J Mol Sci 16. https://doi.org/10.3390/ijms16112598
Liu Q, Liu Y (2022) Role of IL-10 and IL-22 cytokines in patients with primary immune thrombocytopenia and their clinical significance. J Clin Lab Anal 36. https://doi.org/10.1002/jcla.24573
Goelz N, Bosch AMS, Rand ML, Eekels JJM, Franzoso FD, Schmugge M (2020) Increased levels of IL-10 and IL-1Ra counterbalance the proinflammatory cytokine pattern in acute pediatric immune thrombocytopenia. Cytokine 130. https://doi.org/10.1016/j.cyto.2020.155078
Zhao Y, Ni X, Xu P, Liu Q, Sun T, Liu X, et al (2020) Interleukin-37 reduces inflammation and impairs phagocytosis of platelets in immune thrombocytopenia (ITP). Cytokine 125. https://doi.org/10.1016/j.cyto.2019.154853
Monguilhott Dalmarco E, Mendes De Córdova CM, Fröde TS (2011) Evidence of an anti-inflammatory effect of mycophenolate mofetil in a murine model of pleurisy. Exp Lung Res 37. https://doi.org/10.3109/01902148.2011.570416
Nelson VS, Jolink ATC, Amini SN, Zwaginga JJ, Netelenbos T, Semple JW et al (2021) Platelets in ITP: victims in charge of their own fate? Cells 10. https://doi.org/10.3390/cells10113235
Provan D, Semple JW (2022) Recent advances in the mechanisms and treatment of immune thrombocytopenia. EBioMedicine 76. https://doi.org/10.1016/j.ebiom.2022.103820
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113. https://doi.org/10.1182/blood-2008-07-162503
Onisâi M, Vlădăreanu AM, Spînu A, Găman M, Bumbea H (2019) Idiopathic thrombocytopenic purpura (ITP) - new era for an old disease. Rom J Intern Med 57. https://doi.org/10.2478/rjim-2019-0014
Miltiadous O, Hou M, Bussel JB (2020) Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood 135. https://doi.org/10.1182/blood.2019003599
Psaila B, Bussel JB (2008) Refractory immune thrombocytopenic purpura: current strategies for investigation and management. Br J Haematol 143. https://doi.org/10.1111/j.1365-2141.2008.07275.x
Bylsma LC, Fryzek JP, Cetin K, Callaghan F, Bezold C, Mehta B et al (2019) Systematic literature review of treatments used for adult immune thrombocytopenia in the second-line setting. Am J Hematol 94. https://doi.org/10.1002/ajh.25301
Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, et al (2019) Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 3. https://doi.org/10.1182/bloodadvances.2019000812
Neunert C, Lim W, Crowther MA, Cohen A, Solberg L. The American Society of Hematology (2011) evidence-based practice guideline for immune thrombocytopenia. Blood 2011:117. https://doi.org/10.1182/blood-2010-08-302984
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).
Author information
Authors and Affiliations
Contributions
OAA developed the idea, wrote the first draft, and finalized the manuscript. A.M., SG, FH, HK, and DI were involved in screening and data extraction. YS searched the databases and was involved in the analysis and supervision. ME was involved in the analysis and revision of the manuscript. All authors approve the final draft of this manuscript and are responsible for all aspects of the manuscript.
Corresponding author
Ethics declarations
Disclosures
None.
Ethics approval and consent to participate
This article does not contain any studies with human participants or animals performed by any of the authors.
Consent for publication
NA.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Protocol Registration: The protocol of this study was registered on PROSPERO (CRD42023422449) .
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Abdelwahab, O.A., Mechi, A., Gahlan, S. et al. Efficacy and safety of mycophenolate mofetil in patients with immune thrombocytopenic purpura: a systematic review and meta-analysis. Clin Rheumatol 43, 621–632 (2024). https://doi.org/10.1007/s10067-023-06820-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-023-06820-4