Mycophenolate Mofetil Group Research Articles

Clinical Outcomes of Everolimus With Reduced-Dose Tacrolimus vs Mycophenolate Mofetil With Standard-Dose Tacrolimus in De Novo ABO-Incompatible Kidney Transplant Recipients: 1-Year Follow-up

One of the major barriers for long-term renal graft survival is considered to be calcineurin inhibitor nephrotoxicity, contributing to chronic graft dysfunction. Thus, recent immunosuppressive strategies are focused on regimens that can reduce or avoid exposure to calcineurin inhibitors. Herein, we carried out a small-scale pilot study to assess whether everolimus (EVR) with reduced-dose tacrolimus (Tac) is an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant compared with mycophenolate mofetil (MMF) with standard-dose Tac. This retrospective single-center cohort study included patients who underwent ABO-incompatible kidney transplant at our institution between January 2016 and December 2019. Those whose immunosuppressive regimen was changed by reasons other than rejection during the 1-year follow-up period were excluded. A total of 24 patients were enrolled in this study: 10 patients who received an EVR with reduced-dose Tac regimen and 14 patients who received an MMF with standard-dose Tac regimen. Tac trough levels in the EVR group were significantly lower than those in the MMF group (P < .001). No patients died or lost their grafts during the follow-up period. There were no significant differences in renal function, proteinuria, and prevalence of hyperlipidemia between the 2 groups at 1 year after transplant. There were no significant differences in the incidence of rejection (acute cellular rejection, steroid-resistant acute cellular rejection, acute antibody-mediated rejection) and infection (cytomegalovirus viremia, cytomegalovirus disease, BK viremia, BK virus nephropathy) between the 2 groups. Comparable with MMF with standard-dose Tac, EVR with reduced-dose Tac might be an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant.

EFFICACY OF MYCOPHENOLATE MOFETIL VERSUS CYCLOPHOSPHAMIDE IN THE TREATMENT OF LUPUS NEPHRITIS

Objective: Despite the prevalence of SLE, lupus nephritis (LN) is the primary cause of morbidity and mortality. This study objective was to assess the efficacy and safety of the induction treatment with mycophenolate mofetil (MMF) and cyclophosphamide (CYC). Methods: This was a prospective observational study enrolled 100 LN patients who were treated with MMF and cyclophosphamide. In this study, 6 male and 44 female patients were treated with MMF and 3 male and 47 female patients were treated with cyclophosphamide. To estimate drug efficacy, patients were evaluated for 24-h urinary protein excretion estimation, serum creatinine, protein-creatinine ratio (PCR), Proteinuria, Serum complement C3, Serum complement C4, and Serum albumin. The primary end point was a prespecified decrease in urine PCR and stabilization of serum creatinine. Secondary end points were complete renal remission, systemic disease status and safety. Results: The results indicated a potential small advantage of MMF over CYC although the results were not significant. Serum creatinine, 24-h urine protein, and serum albumin were also similar between the MMF and CYC groups after induction therapy. Leukopenia was significantly reduced in MMF treated patients. Both groups suffered from upper gastrointestinal symptoms, but the MMF group’s symptoms were mild and self-limited. MMF therapy was effective in reducing proteinuria and boosting serum complement levels. Conclusion: MMF and CYC were not significantly different in remission induction therapies for LN. Clinical improvement was seen in most patients in both treatment groups.

Associations Between Cessation of Second-Line Therapies and Relapse Rates of Childhood Refractory Minimal-Change Nephrotic Syndrome: A Single-Center, Retrospective Chart Review

BackgroundMost patients (≥85%) with minimal-change nephrotic syndrome (MCNS) respond to corticosteroid treatment. However, about 10% to 20% of patients with MCNS have steroid-resistant nephrotic syndrome and 25% to 43% of patients have steroid-dependent nephrotic syndrome or frequent-relapse steroid-sensitive nephrotic syndrome. Patients with refractory MCNS are treated with various second-line therapies.ObjectivesThis study aimed to evaluate the associations between the use of various second-line therapies and relapse rates in Chinese patients with childhood refractory MCNS.MethodsIn this study, patients with childhood nephrotic syndrome renal biopsy proved to be “minimal change” from a single tertiary-care center between January 2002 and July 2018 were identified. A Total of 56 medical charts of patients treated with 1 of these second-line immunosuppressors: cyclophosphamide (CYC), mycophenolate mofetil (MMF), or tacrolimus (TAC) were reviewed. Patients were divided into CYC (n = 24), MMF (n = 20), and TAC (n = 12) groups according to the second-line therapy administered. Baseline characteristics, immune status, immunocomplex deposition in the renal tissue, and treatment outcomes were analyzed.ResultsThe ratio of patients with steroid-resistant nephrotic syndrome and steroid-dependent nephrotic syndrome in the CYC, MMF, and TAC groups did not differ significantly (P = 0.721). The immunofluorescence assay did not show any significant differences in immunocomplex deposition identified in renal biopsy specimens among the 3 groups. The rate of steroid-free remission in the TAC group (75%) was higher than that in the MMF (55%) and CYC (25%) groups (P = 0.012). At the last follow-up, two-thirds of children in the TAC group had a relapse following discontinuation of therapy. In the TAC group, patients for whom steroids were withdrawn had significantly higher levels of immunoglobulin G at the onset of nephrotic syndrome than those for whom steroids were continued (P = 0.017). In the MMF group, children with relapse had a significantly higher percentage of CD16+CD56+-positive cells than those without relapse (P = 0.042). The relapse rate after treatment discontinuation was significantly different among the 3 groups (P = 0.035). Notably, the relapse rate after treatment discontinuation in the CYC group was lower than those in the other 2 groups (P = 0.035).ConclusionsIn this small population of Chinese patients with childhood refractory MCNS, the relapse rate following TAC therapy was higher than that following MMF or CYC therapy. Different proportions of CD16+CD56+-positive cells might be associated with relapse rates in patients with MCNS receiving MMF treatment. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

Comparative efficacy and safety of mizoribine and mycophenolate mofetil for treating systemic lupus erythematosus: a retrospective cohort study.

Background:Mizoribine (MZR) is an immunosuppressive agent that selectively inhibits inosine monophosphate dehydrogenase; its actions are considerably similar to those of mycophenolate mofetil (MMF). This study aimed to clarify whether MZR can be a good treatment option for systemic lupus erythematosus (SLE) and to compare the efficacy and safety of MZR and MMF in patients with active SLE.Methods:We retrospectively compared the efficacy, continuation rate, and safety of MZR (52 patients) and MMF (31 patients) after adjusting for stabilized inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were as follows: cumulative incidence of lupus low disease activity state (LLDAS) or remission attainment and flares and change in prednisolone dose over 2 years. Drug continuation rates were defined as the time from drug initiation to discontinuation for any cause, owing to the lack of efficacy, or owing to adverse events. The safety endpoint was the frequency of adverse events.Results:Overall, 25 (48.1%) and 13 (25.0%) patients in the MZR group and 18 (58.1%) and 15 (48.3%) in the MMF group achieved LLDAS and remission during the follow-up period, respectively; thus, the cumulative incidence of LLDAS and remission attainment of the two groups was similar after adjustment. Prednisolone dose was steadily reduced in both the groups, and the change in prednisolone dose was nearly identical between the two groups. Drug discontinuation rate due to adverse events and the frequency of all adverse events and infections were higher in the MMF group than in the MZR group, albeit without significance after adjustment.Conclusion:MZR is as effective as MMF in controlling SLE activity. The adverse events of MZR, whose profile differs from MMF, are comparable to or less than those of MMF. MZR may be a valuable option as an immunosuppressive agent for SLE, as well as MMF.

Effective Rituximab Treatment in Patients with Neuromyelitis Optica Spectrum Disorders Compared with Azathioprine and Mycophenolate.

IntroductionAs an autoimmune central nervous system disease characterized by inflammation and demyelination, neuromyelitis optica (NMO) has been extensively investigated. A specific antigenic target, astrocytic water channel aquaporin-4 (AQP4) has already been identified, and it can be recognized explicitly by the autoantibody marker NMO-IgG. Along with the immune attacks, clinical disabilities would gradually accumulate. As there has been no validated and well-recognized therapy for NMO till now, preventing and postponing attack using immunosuppressive therapies is the primary treatment option.MethodsIn the current retrospective study, the effect of immunosuppressive agents was investigated through a long-term follow-up. To assess the long-term effectiveness and safety of rituximab (RTX), azathioprine (AZA), and mycophenolate mofetil (MMF) therapies, all 129 patients with NMO spectrum disorders (NMOSD) who received at least one of these treatments were studied, including 55 seropositive for AQP4-Ab and 74 seronegative for AQP4-Ab.ResultsThe median post-treatment annualized relapse rate (ARR) was lower than the pre-treatment rates in all AQP4+Ab groups (from 1.0 to 0.7 in RTX, from 0.8 to 0.3 in AZA, and from 0.85 to 0.35 in MMF). Meanwhile, the ARR also decreased in all AQP4−Ab groups (from 0.3 to 0.2 in RTX, from 0.9 to 0.5 in AZA, and from 0.9 to 0.4 in MMF). Disability condition improved in the Expanded Disability Status Scale (EDSS) in all AQP4+Ab groups (from 4.0 to 2.75 in RTX, from 3.5 to 2.5 in AZA, and from 3.0 to 2.0 in MMF) and in all AQP4−Ab groups (from 3.0 to 2.5 in RTX, from 3.0 to 2.5 in AZA, and from 3.5 to 2.0 in MMF). There was no statistically significant difference between the post-treatment and pre-treatment changes of EDSS and ARR in the RTX, AZA, and MMF groups (P > 0.05). However, according to Kaplan–Meier survival analysis, RTX-treated patients were more likely to be relapse-free after long-term follow-up than those who received AZA or MMF therapy. Meanwhile, adverse effects were noted in three out of 23 patients with RTX treatment, five of 32 with AZA treatment, and three of 21 with MMF treatment. No serious adverse events were observed in all treatment groups during the study.ConclusionsRTX, AZA, and MMF therapies efficiently lowered the relapse frequency and disability in both of the AQP4-Ab seropositive or seronegative patients with NMO. Furthermore, low dosage of RTX is recommended for the patients with NMO owing to its long-term effectiveness and safety.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00298-5.

How Effective Are the Immunosuppressive Therapies Rituximab and Mycophenolate Mofetil in Immune Thrombocytopenia? Real World Evidence from the UK ITP Registry

Immune thrombocytopenia (ITP) is a rare condition characterized by thrombocytopenia and variable bleeding severity. After acute management with steriods and intravenous immunoglobulin (IVIG), the next line therapies include medical treatments: immunosuppressive therapy such as rituximab, mycophenolate mofetil (MMF), thrombopoietin receptor agonists or surgical treatments. The choice of therapy depends on the time course of the disease, severity, patient choice and comorbidities. The evidence for comparative efficacy between different treatment modalities is lacking in the literature, in particular the immunosuppressive therapies MMF and rituximab.The UK ITP registry is a national registry of primary ITP, capturing demographics, clinical features, treatments and comorbidities. As of July 2021, it has 4402 participants from 90 acute NHS Trusts across the UK. We analyzed data from the UK adult ITP registry to assess responses to rituximab and MMF therapy. All patients entered into the registry from 1st January 2010 were included in this analysis. Internationally recognized definitions of response based on platelet count were used: partial response (PR) platelets >30 x10 9/L and double baseline, complete response (CR) platelets >100 x10 9/L; No response - absence of CR and PR. In addition, we reviewed use of rescue therapy and use of additional therapies following treatment.A total of 844 patients were included in the analysis, of these 486 had received rituximab and 358 had received MMF since 2010. The median follow up before treatment was 230.5 weeks for rituximab and 195 weeks for MMF. At the time of commencing rituximab (and within 4 weeks of starting), 26.1% patients were receiving prednisolone, 10% IVIG, 3% dexamethasone, 3.2% MMF, 2.95% romiplostim and 2.36% eltrombopag. At the time of commencing MMF (and within 4 weeks of starting), 39.2% patients were receiving prednisolone, 12.74 IVIG, 3.86% dexamethasone, 3.6 rituximab, 5.6% romiplostim and 3.86% eltrombopag.The total number of patients achieving platelet response at each time response are listed in table 1. Of those receiving rituximab with baseline platelets <30 x10 9/L at starting therapy, 40% had at least PR by 4 weeks, 50% at 12 weeks and 30% at 12 months. For MMF, these percentages were 30%, 30% and 18% respectively, however, the numbers of patients in the MMF group were lower.The median duration of response was 44 weeks for rituximab and 27 weeks for MMF. Where new therapies were required, the median number of weeks until therapy was switched was 18 weeks for rituximab and 15 weeks for MMF. 77% patients and 80.7% patients who received rituximab and MMF respectively changed treatment during their follow up. Overall 284 (58.4%) patients received rescue medication during follow up, of those that received MMF 234 (65.36%) received rescue medication. The main rescue therapies were prednisolone (589 episodes in rituximab group and 520 in MMF group) and IVIG (482 in rituximab group and 321 in MMF group).In conclusion, this is one of the first studies, using real world data and long term follow up, to compare outcomes after immunosuppression. Both rituximab and MMF are often administered with additional therapies at the outset, predominantly steroids and IVIG, but also other therapies such as the thrombopoietin receptor agonists. The use of rescue therapies during follow up, suggesting treatment failure or a need to augment the response, is common with most patients in both groups ultimately having treatment change during follow up. Extension of this study to include other therapies and identifying groups most likely to respond will support optimization of treatment for patients with ITP. [Display omitted] DisclosuresMcDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Loughlin: FIECON: Current Employment. Laws: FIECON: Current Employment. Stacey: Grifols: Current Employment. Spears: Grifols: Current Employment. Hill: Apellis: Consultancy, Honoraria; Argenx: Consultancy; Novartis: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Sanofi: Consultancy; ReAlta: Consultancy; Alexion: Honoraria; Amgen: Honoraria. Cooper: UCB: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Other: Research support; Rigel: Honoraria, Other: Research support; Principia: Honoraria; Amgen: Honoraria; Grifols: Honoraria; Sobi: Honoraria. Makris: Freeline: Consultancy. Bradbury: BMS Pfizer: Honoraria, Speakers Bureau; Bayer: Honoraria, Other: support to attend conferences, Speakers Bureau; Amgen: Honoraria, Other: support to attend conferences, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support to attend conferences, Speakers Bureau; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees. Newland: Octapharma: Research Funding; Roche: Speakers Bureau; UCB Biosciences: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; GSK: Consultancy, Research Funding, Speakers Bureau; BMS: Research Funding; Argenx: Consultancy, Speakers Bureau; Angle: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure:rituximab - immune thrombocytopenia mycophenolate - immune thrombocytopenia

Comparison between high-dose, low-dose cyclophosphamide and mycophenolate mofetil in treatment of proliferative lupus nephritis (an Egyptian multicenter retrospective study)

Background Proliferative lupus nephritis (LN) is an aggressive pathological lesion of LN. Corticosteroids, cyclophosphamide (CYC) pulse therapy either by high dose; National Institute of Health (NIH) CYC or low dose; European cyclophosphamide regimen (EURO-CYC), and mycophenolate mofetil (MMF) are the best valid lines for treatment, but the choice between them is still challenging. The objective of this study was to compare the efficacy of both CYC regimens and MMF in the treatment of proliferative LN patients. Patients and methods We retrospectively collected the data of 225 biopsy-proven proliferative LN patients (adults and juveniles) from five tertiary centers. Forty four of patients received low-dose regimen, 124 received high-dose regimen, and 57 received MMF. All demographic data, laboratory tests, activity markers, and systemic lupus disease-activity index were recorded and compared at initial presentation and at 3, 6, 12, and 24 months of follow-up. Results After 6 months of treatment, 61.2% of NIH-CYC group reached complete response, while the rate was 40.9% of EURO-CYC group and 52.7% for MMF group, and the results were in favor for the NIH group over EURO group, while there was no difference between NIH and MMF groups, but at the end of 12th, 18th, and 24th months of follow-up, the outcomes of the three groups were comparable in efficacy and safety. Conclusion For induction treatment of proliferative LN, high-dose CYC shows a better and rapid complete response after the sixth month of treatment in adults and juvenile LN patients, but after the first year of therapy, the three regimens have comparable efficacy and safety.

Efficacy of azathioprine, mycophenolate mofetil, and rituximab in the treatment of neuromyelitis optica spectrum disorder and analysis of prognostic factors.

The study aims to compare the efficacies of the immunosuppressants most commonly prescribed for patients with neuromyelitis optica spectrum disorder (NMOSD). The predictors, which might be associated with relapse and disability in NMOSD, were also analyzed. This retrospective study included NMOSD patients treated with azathioprine (AZA), mycophenolate mofetil (MMF), and rituximab (RTX). The annual relapse rate (ARR) and the incidence rates of adverse events were compared. Cox proportional-hazards model calculated the potential predictors of NMOSD relapse and disability. A total of 83 patients were included. The median treatment time of AZA group (n = 34), MMF group (n = 20), and RTX group (n = 29) were 19.5, 15.5, and 12months, respectively. ARR of the three groups reduced significantly after treatment. In the three groups, 55.9%, 50%, and 79.3% of patients, respectively, were free from relapse. However, the difference among the three groups was of no statistical significance, possibly due to the small sample size. During the treatment, 32.4%, 15%, and 24.1% of patients experienced adverse events in the AZA group, MMF group, and RTX group, respectively. Additionally, the multivariate Cox analyses indicated that history of a severe attack and disease duration were associated with the risk of relapse after immunotherapy. Late-onset (≥ 50years old) NMOSD patients were probably more susceptible to motor disability, and those with optic neuritis at onset were more likely to develop visual disability. AZA, MMF, and low-dose RTX were all effective in reducing the relapse rate in NMOSD. The age at onset, disease duration, history of severe attacks, and primary syndromes might be significant prognostic predictors in NMOSD.

Altered effect of killer immunoglobulin-like receptor-ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation.

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.

Mycophenolate mofetil versus methotrexate for vulvar lichen planus: A 10-year retrospective cohort study demonstrates comparable efficacy and tolerability

Mycophenolate mofetil versus methotrexate for vulvar lichen planus: A 10-year retrospective cohort study demonstrates comparable efficacy and tolerability

Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia

BackgroundImmune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks.MethodsIn this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events.ResultsA total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P=0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group.ConclusionsThe addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.)

Efficacy and safety of modified reduced-dose rituximab in Chinese patients with neuromyelitis optica spectrum disorder: A retrospective cohort study

ObjectiveTo evaluate the long-term efficacy and safety of a modified reduced-dose rituximab (mRTX) regimen compared with azathioprine (AZA) and mycophenolate mofetil (MMF) in Chinese patients with neuromyelitis optica spectrum disorder (NMOSD). MethodsIn this retrospective cohort study, 71 patients with NMOSD were treated with AZA (n = 24), MMF (n = 18), or mRTX (n = 29). The primary outcome was initial relapse after first-line immunosuppressant therapy. The annualized relapse rate (ARR), expanded disability status scale (EDSS) score, activities of daily living (ADL) scale score, and treatment-related adverse events were compared between groups. ResultsSignificant ARR reductions were observed in the three groups, with relapse-free rates of 37.5%, 72.2%, and 79.3% in the AZA, MMF, and RTX groups, respectively. Compared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. Relapse within 1 year before immunosuppressant therapy or ARR before immunosuppressant therapy increased the NMOSD relapse risk. mRTX and MMF were superior to AZA in reducing the EDSS score and increasing the ADL score, but there was no significant difference between the mRTX and MMF groups. Additionally, mRTX-treated patients were less likely to use steroids concurrently than those treated with AZA and MMF. The adverse event rate in the AZA group was relatively higher than that in the MMF and mRTX groups, though no significant difference was noted among the three groups. ConclusionsCompared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. mRTX-treated patients presented less concomitant steroid use than those treated with AZA and MMF, fewer adverse events, and better tolerance.

Research in Brief

Rituximab may be superior to mycophenolate mofetil for the treatment of pemphigus vulgaris, according to the results of a randomised trial by Victoria Werth and colleagues. 135 patients with moderate-to-severe pemphigus vulgaris were randomly assigned (1:1) to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182; n=67) or oral mycophenolate mofetil (2 g daily; n=68), both in addition to tapered oral glucocorticoids. At week 52, sustained complete remission (defined as a Pemphigus Disease Area Index activity score of 0 for at least 16 weeks without the use of glucocorticoids; the primary outcome) was achieved in 25 (40%) of 62 patients in the rituximab group versus six (10%) of 63 in the mycophenolate mofetil group (difference 31%, 95% CI 15–45; p<0·001). 15 (22%) of 67 patients in the rituximab group had an adverse event versus 10 (15%) of 68 in the mycophenolate mofetil group.

Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris

BackgroundRituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials.MethodsIn a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment).ResultsOf the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, −1595 mg; 95% CI, −2838 to −353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was −8.87 points and −6.00 points, respectively (difference, −2.87 points; 95% CI, −4.58 to −1.17; P=0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group.ConclusionsRituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann–La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.)

Efficacy of mycophenolate mofetil versus cyclophosphamide in systemic sclerosis-related interstitial lung disease: a systematic review and meta-analysis.

This study systematically compares the efficacy and adverse events of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). The EMBASE and PubMed databases were systematically searched to find all relevant studies. Quality assessment, study selection, and data extraction were independently conducted by two reviewers. The mean changes in forced vital capacity (FVC)% and diffusing capacity for carbon monoxide (DLco)% of the patients were selected to be primary outcome measures. Stata software was used for the pooled analysis. Among 284 titles screened from multiple databases, six studies met the inclusion criteria (one randomized controlled trial, three prospective observational studies, and two retrospective observational studies). The summary weighted mean difference (WMD) of FVC change in the MMF group compared with the CYC group was - 1.17 (95% CI: - 2.713, 0.373; P = 0.137), and the summary WMD of DLco change in the MMF group compared with the CYC group was 2.245 (95% CI: 0.258, 4.232; P = 0.027). Studies enrolled showed that adverse events were less common in the MMF group. The efficacy of MMF with respect to FVC and DLco improvement is comparable to that of CYC, and MMF is preferred on the basis of the occurrence of adverse events. Key Points • A systematic review and meta-analysis was conducted to compare the efficacy and adverse events of mycophenolate mofetil and cyclophosphamide in patients with systemic sclerosis-related interstitial lung disease. • The efficacy of MMF with respect to FVC and DLco improvement is comparable to that of CYC, and MMF is preferred on the basis of the occurrence of adverse events.

Steroid resistant focal segmental glomerulosclerosis: effect of arterial hyalinosis on outcome: single center study.

Background. Few data with adequate evidence exists as regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment.Material and methods. Thirty-seven adults with primary FSGS patients resistant to steroid therapy consecutively randomized to treatment with either MMF or cyclosporine. Low dose prednisolone added to both groups. Glomerular filtration rate (GFR) and blood pressure (BP) were determined at all examinations and a second renal biopsy was taken 12 months after treatment with either of cyclosporin and mycophenolate mofetil.Results. GFR significantly increased in MMF group p < 0.01 after 6 months and unchanged after 12 months. On the other hand, GFR significantly decrease in CsA group p < 0.001 after 6 months and reduced more after 12 months p < 0.001 compared to base line levels. There was a significant difference of GFR between the 2 groups at 6 months p < 0.001. The extent of proteinuria decreased significantly in CsA group after 12 months p < 0.001. The extent of arteriolar hyalinosis increased significantly in CsA group (0.78 to 1.81 score, p < 0.001) but was unchanged in MMF group (0.93 to 0.96 score), whereas interstitial fibrosis increased to same level in both groups (grade 3).Conclusion. Conversion to MMF in those patients may be superior to CsA as regards GFR after 12 months after treatment in spite of the presence of greater level of protein excretion. The increased arteriolar hyalinosis during CsA treatment most likely results in higher BP compared to MMF treatment in patients with FSGS resistant to steroids.

Effect of Mycophenolate Mofetil Dosing on 6-month Risk of Acute Cellular Rejection, Leukopenia and CMV Viremia in Heart Transplant

<h3>Purpose</h3> Mycophenolate mofetil (MMF) is a cornerstone of heart transplant (HT) therapy. MMF dose is associated with leukopenia and infections (eg CMV). Despite widespread use, the optimal MMF dose to balance risk of rejection with leukopenia and infection is unknown. Our center recently transitioned from a high-dose (HD) 3g/day to low-dose (LD) 2g/day MMF protocol. We tested whether LD-MMF is associated with: i) lower rates of leukopenia and CMV, and ii) comparable rates/severity of acute cellular rejection (ACR) at 6-months after HT. <h3>Methods</h3> 108 pts who received HT between 6/16 to 8/20 were included. Pts were categorized based on LD- vs HD-MMF. ACR was defined according to ISHLT criteria. A total rejection score (TRS) was calculated as follows: 0R=0, 1R=1, 2R=2, 3R=3 by dividing summed scores by total number of biopsies during study period. Leukopenia = WBC<4.0x10⁹/L. Between-group differences in freedom from ACR, leukopenia and CMV at 6-months were evaluated by KM method. Adjusted Hazard Ratios (HRs) were calculated from Cox proportional models. <h3>Results</h3> Baseline characteristics of HD- (n=71) vs LD-MMF (n=37) pts were similar including WBC and CMV match status; 80% vs 86% of pts were discharged at target doses. 59 ACR, 71 leukopenia and 10 CMV events occurred at 6-months. Freedom from first ACR, leukopenia and CMV in HD- vs L`D-MMF are shown in Fig 1a-c. Total ACR events in HD- vs LD- MMF group were 50/722 (6.9%) biopsies in 71 pts vs 9/272 (3.3%) biopsies in 37 pts. However, ACR events in HD-MMF group were less likely to be high grade (≥2R): 12% vs 55% (<i>p</i>=.002). TRS did not differ between groups: .075±.12 vs .05±.11, <i>p</i>=.08. After multivariable adjustments, HD-MMF was associated with higher risk of any ACR (HR=2.23, <i>p=</i>.043) and higher risk of leukopenia (HR=1.71 <i>p</i>=.049) (Fig 1d). <h3>Conclusion</h3> LD-MMF was associated with less leukopenia. However this came at the cost of more clinical significant ≥2R rejections. Further studies are warranted to address the long-term implications of these findings.

Mycophenolate mofetil enhances the effects of tacrolimus on the inhibitory function of regulatory T cells in patients after liver transplantation via PD-1 and TIGIT receptors

Objective Regulatory T cells (Tregs) induce immune tolerance in patients after organ transplantation. Various immunosuppressors can affect Tregs function through different mechanisms. PD-1 and TIGIT are important receptors on Tregs surface. Here, we investigated the effects of Tacrolimus and mycophenolate mofetil (MMF) on the inhibitory function of Tregs and explored the regulatory mechanism in patients after liver transplantation. Methods Thirty patients that underwent a liver transplant and 15 healthy people were enrolled. Fifteen patients received Tacrolimus only, and 15 received a combination of Tacrolimus and MMF. Tregs and effector T cells (Teffs) were isolated using magnetic beads and were mixed at different ratios of 0:1, 1:4, 1:2 and 1:1. An inhibition assay was performed by adding anti-PD-1 and anti-TIGIT when the mixture ratio was 1:1. The Tregs inhibition rate was determined and the levels of IFN-γ and TNF-α were measured. Results As the ratios of Tregs to Teffs in the mixture increased, the Tregs inhibition rate increased and the levels of IFN-γ and TNF-α decreased. At each mixture ratio, Tacrolimus + MMF group had the highest Tregs inhibition rate compared to Tacrolimus and control group. At the specific mixture ratio of 1:1, the addition of both anti- PD-1 and anti-TIGIT led to lower Tregs inhibition rate and higher IFN-γ and TNF-α levels in all three groups as opposed to the addition of each antibody separately. Additionally, both the decrease in the Tregs inhibition rate and the increase in the IFN-γ and TNF-α levels were the most for Tacrolimus + MMF group among all cases, either adding antibodies alone or mixed. Conclusion Tacrolimus and MMF enhanced the function of Tregs by synergistically affecting PD-1 and TIGIT in liver transplant patients.

A Prospective Study on Long-Term Clinical Outcomes of Patients With Lupus Nephritis Treated With an Intensified B-Cell Depletion Protocol Without Maintenance Therapy

BackgroundWe aimed to investigate the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT) without immunosuppressive maintenance regimen compared with standard of care in biopsy-proven lupus nephritis (LN).MethodsThirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m2 and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for > 3 years as a maintenance therapy.ResultsAt 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (P = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P < 0.01) or CYC group (7.5 ± 9.0 mg/d, P < 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36–120 months), 48.6 months (IQR 36–120 months), and 45.3 (IQR 36–120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups.ConclusionIn biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by >3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.

Sirolimus Adverse Event Profile in a Non-Clinical Trial Cohort of Heart Transplantation Patients.

BackgroundSirolimus has been used increasingly in heart transplantation for its ability to reduce acute rejection, prevent the progression of cardiac allograft vasculopathy (CAV), and preserve renal function. We sought to assess the adverse reactions associated with the use of sirolimus compared to mycophenolate mofetil (MMF).Material/MethodsWe retrospectively reviewed the charts of 221 adult heart transplant patients who received either sirolimus or MMF as part of their immunosuppression from June 1, 2001 to April 1, 2005. Patients were assigned to 2 groups based upon immunosuppression use. The prevalence and types of complications were recorded in each group.ResultsSirolimus was received by 109 patients and 112 patients received MMF during the study period. Seventy-seven patients (71%) in the sirolimus group experienced adverse reactions compared to 45 patients (40%) in the MMF group (P<0.01). Compared to MMF, the use of sirolimus was associated with a higher prevalence of elevated triglyceride levels, lower-extremity edema, and oral ulcerations. Sirolimus was discontinued due to adverse reactions in 22% of patients, whereas no patients in the MMF group experienced adverse effects requiring drug discontinuation.ConclusionsCompared to MMF, sirolimus use is associated with a higher prevalence of adverse reactions requiring drug discontinuation, but most patients were able to stay on therapy despite adverse effects.