Mycophenolate Mofetil Treatment Research Articles

#2682 Evaluation of clinical, pathological findings and treatment outcomes of patients diagnosed with lupus nephritis: a single center experience

Abstract Background and Aim Renal involvement of systemic lupus erythematosus (SLE) is known as lupus nephritis (LN). The prognosis of lupus patients with LN is worse than those without kidney involvement. Renal survival can be improved in patients with lupus nephritis with appropriate and timely treatment. The aim of our study is to compare the clinical and pathological findings of patients diagnosed with LN in our clinic by renal biopsy, the results of the treatment applied in our center, and renal survival with the literature. Method The local ethical committee approved the study design (date: 04/10/2021; reference number: 121/07) and all procedures were conducted in accordance with the Declaration of Helsinki. Forty-four patients diagnosed with lupus nephritis between January 2012 and January 2021 in the Nephrology Department of Ankara Dıskapı Yıldırım Beyazıt Education and Research Hospital were enrolled in this study. Patient data were analyzed retrospectively. Exclusion criteria were as follows: 1) Patients under 18 years of age, 2) patients with follow-up of period less than 6 months and who did not attend regular follow-ups, 3) patients with connective tissue diseases other than SLE. Results The mean age of the study population was 36.0 ± 10.8, and the majority were female. All patients had proteinuria at diagnosis. Class IV LN was the most common (36.4%). Majority of the patients were in the proliferative LN group (65.9%). A significant difference was found between patients diagnosed with proliferative LN (n = 29) and non-proliferative LN (n = 15) in terms of high serum creatinine levels, low serum complement, presence of anti-dsDNA antibodies and active urinary sediment with proliferative LN (p = 0.021, p = 0.024, p = 0.008, p = 0.008). Treatment responses at 6 and 12 months are shown in Table 1. A significant difference was found between the patients who were in complete remission (n = 16) at 12 months and those who were not in remission (n = 27) in terms of low systolic blood pressure and the estimated glomerular filtration rate (eGFR) at the time of diagnosis (p = 0.008, p = 0.016). It was observed that most of the patients who were not in complete remission at 12 months were in the proliferative LN group (p = 0.024). There was no significant difference in the partial and complete remission rates at 6 and 12 months between the group receiving steroids + cyclophosphamide (n = 14) and the group receiving steroid + mycophenolate mofetil (MMF) (n = 15) in the initial treatment of proliferative LN (p>0.05). In the group taking MMF treatment (n = 15) had a shorter time to reach complete remission than the group taking cyclophosphamide treatment, and it was statistically significant (Table 2) (p = 0.048). It was found that end-stage renal disease (ESRD) developed in 9% of the patients and 2 patients died during followed up period. Recurrence was detected in 8 patients, and it was observed that more than half of the patients with relapse could not achieve complete remission at 12 months. Patients with relapse had higher systolic blood pressure and serum total cholesterol level at the time of diagnosis compared to patients without recurrence (p = 0.013, p = 0.045). In addition, patients with relapse were found to have a higher level of proteinuria at the time of diagnosis (p = 0.036). Conclusion Lupus nephritis remains an important source of morbidity and mortality for SLE patients. SLE patients should be regularly examined for renal involvement. About 10-20% of patients diagnosed with lupus nephritis develop ESRD. Early diagnosis of LN and initiating appropriate treatment when diagnosed without delay is important for renal and patient survival. Although there were some different results, most of the statistically significant data in our study were found to be compatible with the existing literature. However, these data need to be confirmed by studies with high patient participation.

Rituximab retention rate in systemic sclerosis: a long term real-life multicenter study.

to report real-life data on rituximab retention-rate as indicator of safety and efficacy in a multicentric national cohort of systemic sclerosis patients. SSc patients treated with rituximab and followed for at least 36 months were included, clinically characterized, and longitudinally monitored. A competing risk analysis with sub-Hazard Ratio(sHR) definition was performed to explore the clinical variables linked to specific cause of rituximab discontinuation. One-hundred-fifty-two SSc-patients (mean age 47.3 ± 12.3 years; females 79.6%; diffuse disease 77.6%; anti-topoisomerase-I positivity 63.2%) were evaluated over a median(IQR) time of 3.3(1.7-5.0) years. The primary indication for rituximab were interstitial lung disease (ILD)(38.8%), worsening skin fibrosis(36.8%), and arthritis(13.8%); 138 patients(90.8%) received more than one rituximab course. The 5-years rituximab retention rate was 59.9%(44.6-64.7%). Clinical response was the most common reason for rituximab discontinuation[5.7(3.7-8.4) per 100 patient-year] and was associated with a shorter disease duration[sHR 0.8(0.7-0.9)], anti-topoisomerase-I negativity[sHR 0.4(0.2-0.9)], previous digital ulcers[sHR 2.6(1.1-6.2] and no history of arthritis[sHR 0.3 (0.1-0.8)]. Treatment failure was the second cause of rituximab discontinuation[3.7(2.2-6.0) per 100 patient-year] and was associated with anti-centromere antibody positivity[sHR 2.8(1.1-7.4)] and anti-topoisomerase-I negativity[sHR 0.2(0.1-0.6)]. Adverse events(AEs) were the less common cause of discontinuation[3.1(1.7-5.2) per 100 patient-year], associated with limited cutaneous subset[sHR 3.4(1.2-9.7)] and previous mycophenolate mofetil treatment[sHR 4.5(1.2-16.3)]. rituximab is a safe and effective treatment in SSc: clinical response emerged as the primary reason for rituximab discontinuation, and AEs had a limited impact on treatment persistence. The identification of specific disease features associated with a response to rituximab will be useful in the management of SSc-patients.

Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study.

Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients. This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive SLE over time was evaluated by Kaplan-Meier's analysis. MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates was correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 μg·h·mL - 1 at 6 and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 μg·h·mL - 1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 μg·h·mL - 1. The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 μg·h·mL - 1.

A Case of Pemrolizumab-Associated Severe Gastritis Treated with Mycophenolate Mofetil

Immune checkpoint inhibitors have become a frequently used treatment in oncology practice. Although it has approved indications in many types of cancer, phase studies are ongoing in many types of cancer. Side effects due to the increasing use of immune checkpoint inhibitors have begun to be seen frequently. Cases of colitis, pancreatitis and hepatitis due to immune check point inhibitors have been reported very frequently; However, the number of gastritis cases is limited. Here, we presented a case of severe gastritis due to pembrolizumab in a patient with cholangiocellular carcinoma. When side effects develop due to immune check point inhibitors, infliximab and mycophenolate mofetil (MMF) treatments are used in steroid-refractory patients. In our patient, MMF treatment was started due to possible infectious processes due to a recent attack of cholangitis and the inability to remove the stones in the common bile duct. Response to MMF treatment was obtained after 3 months. We would like to state that MMF treatment is an option in cases that develop due to immune check point inhibitors. MMF treatment was used in a case of severe gastritis due to pembrolizumab, as it did not respond to steroid treatments. The patient responded after MMF treatment. We planned to present this rare side effect of pembrolizumab and the treatment strategies we applied in the development of side effects.

Abstract 1789: Machine learning-based method to analyze metabolic fluxes of patient tumors

Abstract Personalized oncology must overcome the complex challenge of distinct cancer phenotypes in each patient, formed in part in response to unique metabolic crosstalk among cells in the tumor microenvironment which can be a determining factor in therapeutic response. Although isotope tracing sheds light on differences of metabolite enrichments in tumor and normal tissues, quantifying the metabolic fluxes in patients remains elusive. The conventional metabolic flux analysis tools are unable to estimate patient metabolic fluxes because we are limited to a single time point enrichment datapoint from each patient’s in-vivo measurement at isotopic non-steady state. We overcame this challenge by generating training data from the limited patient data and implementing a machine learning model to predict fluxes. To generate training data, we first simulated constrained random fluxes and enrichment patterns at different time points using patient circulating metabolites enrichment via an isotopic non-stationary metabolic flux analysis framework. Using this data, we trained a convolutional neural network to predict flux ratios. To validate our model, we compared predicted flux ratios to the experimental data from mouse models for two different treatments. Our recent findings from a glioblastoma (GBM) mouse model study using conventional metabolic flux analysis revealed higher de novo guanosine monophosphate (GMP) synthesis in GBM than normal cortex. These tumors can be sensitive to mycophenolate mofetil (MMF) which inhibits inosine monophosphate dehydrogenase, but only if the major source of GMP production is de novo synthesis and not salvage. Our machine learning model can discriminate between sources of GMP synthesis in patients, thus enabling prediction of potential responders. Furthermore, we previously showed that serine uptake is higher in GBM than normal cortex, and a serine- and glycine-restricted diet slows tumor growth in mice. While both circulating serine and microenvironment-derived serine could account for serine uptake in GBM, we hypothesized that the circulating serine dependence would better predict response to dietary serine depletion. Hence, we combined patient scRNA-seq and metabolomics data to feed our neural network framework to estimate microenvironmental and circulating serine uptake in six patients with brain cancer. Thus, we have shown that our model can identify patients who will benefit from MMF treatment or a serine- and glycine-restricted diet, enabling administration of highly effective personalized treatments for GBM patients. Citation Format: Baharan Meghdadi, Anjali Mittal, Andrew J. Scott, Sravya Palavalasa, Daniel R. Wahl, Deepak Nagrath. Machine learning-based method to analyze metabolic fluxes of patient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1789.

A GC-MS-based untargeted metabolomics approach for comprehensive metabolic profiling of mycophenolate mofetil-induced toxicity in mice.

Background: Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is widely used for maintenance immunosuppression in transplantation. The gastrointestinal toxicity of MMF has been widely uncovered. However, the comprehensive metabolic analysis of MMF-induced toxicity is lacking. This study is aimed to ascertain the metabolic changes after MMF administration in mice. Methods: A total of 700mg MMF was dissolved in 7mL dimethyl sulfoxide (DMSO), and then 0.5mL of mixture was diluted with 4.5mL of saline (100mg/kg). Mice in the treatment group (n = 9) were given MMF (0.1mL/10g) each day via intraperitoneal injection lasting for 2weeks, while those in the control group (n = 9) received the same amount of blank solvent (DMSO: saline = 1:9). Gas chromatography-mass spectrometry was utilized to identify the metabolic profiling in serum samples and multiple organ tissues of mice. The potential metabolites were identified using orthogonal partial least squares discrimination analysis. Meanwhile, we used the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (http://www.kegg.jp) to depict the metabolic pathways. The percentages of lymphocytes in spleens were assessed by multiparameter flow cytometry analysis. Results: Compared to the control group, we observed that MMF treatment induced differential expression of metabolites in the intestine, hippocampus, lung, liver, kidney, heart, serum, and cortex tissues. Subsequently, we demonstrated that multiple amino acids metabolism and fatty acids biosynthesis were disrupted following MMF treatment. Additionally, MMF challenge dramatically increased CD4+ T cell percentages but had no significant influences on other types of lymphocytes. Conclusion: MMF can affect the metabolism in various organs and serum in mice. These data may provide preliminary judgement for MMF-induced toxicity and understand the metabolic mechanism of MMF more comprehensively.

The effects of food on the pharmacokinetics of mycophenolate mofetil in healthy horses

AbstractAdditional immunomodulatory treatment is needed for the management of immune‐mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six‐day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single‐dose administration but may be significant in horses receiving long‐term MMF treatment.

Predictors of azathioprine and mycophenolate mofetil response in patients with neuromyelitis optica spectrum disorder: A cohort study

BackgroundRelapse rates of 47 % have been reported in patients with neuromyelitis optica (NMOSD) using Azathioprine (AZA) and mycophenolate mofetil (MMF). Prediction of non-responders could help determine which patients are most likely to benefit from newer monoclonal antibody treatments from the outset. ObjectivesTo identify predictors of AZA and MMF treatment response in NMOSD. MethodsMulticenter cohort study of NMOSD patients from Brazil and the United Kingdom, treated with AZA and MMF. An unsatisfactory response was defined as one severe or two non-severe attacks in a year. Cox regression was used to identify predictive factors of unsatisfactory response to AZA and MMF. Results103 NMOSD patients, mean age 38 years, 83% female, and 65% of Black ethnic group were included. An unsatisfactory IS response was observed in 42% of patients over 2.5 years (IQR 1.0–8.8) years. A severe preceding attack was more common in non-responders (31.1% x 76.7%, p = <0.001). In multivariable analysis, severe attack (RR 3.13; 95 % CI 1.37-7.18, p = 0.007) or higher annualized relapse rate (RR 4.84; 95 % CI 2.01-11.65, p = < 0.001) predicted an unsatisfactory response. Interestingly, Black NMOSD patients had a lower risk of poor response (RR 0.39, 95 % CI 0.17-0.85, p = 0.019). ConclusionSevere attack and a higher annualized relapse rate before AZA or MMF initiation were associated with an unsatisfactory IS response. In patients with these characteristics, treatment with higher-efficacy drugs should be considered from the outset.

P-82 Riedel's thyroiditis: three-year follow-up under steroid, rituximab and mycophenolate mofetil treatment

Abstract Introduction Riedel's thyroiditis (RT) is an uncommon thyroiditis characterized by fibrosis, macrophage, and eosinophil infiltration and is assumed to be the primary cause of autoimmunity in the pathogenesis. Invasion of the surrounding tissues, particularly the trachea, occurs. RT is also regarded as thyroid involvement in IgG4-related systemic illness. Because there is no conventional medical treatment protocol for RT, this paper aims to highlight the problems we had in diagnosing and our approach throughout therapy. Clinical Case In the last 1.5 years, a 44-year-old female patient on levothyroxine replacement diagnosed with hypothyroidism developed bilateral swelling in the eyes, double vision, drooping eyelids, shortness of breath, and feeling something lodged in the throat. A diffusely enlarged and stiff thyroid gland was palpated in her physical examination. Neck CT revealed a diffusely enlarged thyroid gland 7cm in diameter and constricted trachea. She did not have any constitutional symptoms. According to physical and radiologic exams, preliminary differential diagnoses were anaplastic thyroid carcinoma and IgG4-related thyroiditis. In laboratory tests, TSH: 4.5 mIU/L, st3-4: normal, Anti TPO: +++ TRAB: 0.15 U/L, ANA: Negative, IgG4: 0.52 g/L (0.03-2.01), ACE:21.39. Since the thyroid fine needle aspiration biopsy reported a hypocellular smear, a lacrimal gland biopsy was performed for systemic involvement of IgG4 related disorder's. Her dyspnea was becoming critical; therefore, she was administered 0.5 mg/kg steroid for two weeks before the scheduled bilateral total thyroidectomy, and a considerable decrease in dyspnea, swallowing sensations, and regression in compression findings were seen. Lacrimal biopsies demonstrated persistent inflammation with plasma cells and severe fibrosis, consistent with late-stage IgG4-related illness. Both thyroid lobes were enlarged in neck T1 and T2-weighted MRI images (right lobe was 34×25×68 mm, the left lobe was 35×26×69 mm), diffuse hypointensity was noted, contrast uptake decreased in the thyroid parenchyma following IVCM, and the data was determined to be compatible with RT. The thyroid gland grew markedly on PET-CT, narrowing the air column, with increased FDG absorption in a heterogeneous character (SUVmax: 4.9), and mild-moderate involvement in bilateral lacrimal and parotid glands.The decision was made to continue steroid treatment at 1 mg/kg for one month. Rituximab was given twice every six months while the steroid was lowered. Mycophenolate mofetil (MMF) (2×500 mg) was introduced as a maintenance immunosuppressive medication. The initial radiologic findings regressed in the control neck MRI and PET-CT in the first year. The MRI findings were also steady in the second and third years of MMF. Conclusion Immunosupression therapy with steroid, rituximab and MMF was effective in our RT patient for the long term without significant complications. Clinical and radiological responses similar to surgery can be obtained with immunosuppressive agents.Figure 1.PET-CT and MRI images at diagnosis and third year

A case of progressive multifocal leukoencephalopathy in a post-kidney transplant patient with improvement after discontinuation of immunosuppressive drugs and combination therapy with mefloquine and mirtazapine

BackgroundProgressive multifocal leukoencephalopathy is a rare disease, but the prognosis is very poor, especially in the immunosuppressed state with a non-HIV background, and there is no established treatment.Case presentationsA 49-year-old patient who had undergone a renal transplant and was receiving prednisolone and mycophenolate mofetil treatment was admitted for peritoneal dialysis initiation. While hospitalized, he experienced aphasia and other percutaneous symptoms. Magnetic resonance imaging of the brain revealed a subcortical demyelinating lesion. JC virus DNA was identified in cerebrospinal fluid, and he was diagnosed with progressive multifocal leukoencephalopathy. Immunosuppressant was ceased, and he was treated with mefloquine and mirtazapine. The patient subsequently underwent a head MRI scan, confirming lesion reduction, improved activities of daily life, and survival.ConclusionsProgressive multifocal leukoencephalopathy is commonly observed in patients with compromised immune systems, which was the case for this patient due to long-standing immunosuppressive medication usage and end-stage renal failure necessitating dialysis.

Integrative analysis of purine metabolites and gut microbiota in patients with neuromyelitis optica spectrum disorders after mycophenolate mofetil treatment

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD.MethodsA total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients.ResultsPurine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p < 0.05). Additionally, the richness and microbial diversity of gut microbiota was found to be similar between EG and LEG patients. However, LEG patients had increased presence of Clostridium and Synergistes but decreased abundance of the Coprococcus genus.ConclusionsThe PSP metabolites and composition of the gut microbiota were changed between patients with or without optimal clinical response after MMF treatment. This may help us to understand the pharmacodynamics of MMF in NMOSD.

Real-World Effectiveness of Belimumab in Patients with Active Lupus.

This study evaluated the real-world effectiveness of belimumab (BLM) in the treatment of systemic lupus erythematosus (SLE) patients with moderate to high disease activity. This retrospective cohort study enrolled 129 Japanese patients with moderate to high SLE disease activity who received BLM between January 2013 and March 2023. The clinical outcomes, including the flare-free survival, SLE Disease Activity Index 2000 (SLEDAI-2K) score, and prednisone-equivalent dose, in the BLM and mycophenolate mofetil (MMF) treatment groups were compared before and after treatment. Safety data for BLM were collected. Additionally, we compared the effectiveness of BLM and intravenous cyclophosphamide (IV-CY) treatment using the stabilized inverse probability of treatment weighting (IPTW) method based on the propensity scores. This observational study enrolled 129 patients with moderate/severe SLE: 48 patients received belimumab, 45 received IV-CY, and 36 received MMF and prednisolone for remission induction therapy. The median follow-up for the BLM group was 17.0 months. Among them, 19 received BLM plus MMF. BLM significantly reduced the mean SLEDAI-2K (from mean baseline to 52 weeks: 49.2% reduction from 12.8 to 6.5) and prednisone daily dose (from mean baseline to 52 weeks: 21.9% reduction from 12.8 to 10.0 mg/day). The flare-free survival at 52 weeks was not significantly different between the BLM and MMF groups. There was no significant difference in the flare-free survival rates or reduction rates of the SLEDAI-2K between the patients treated with BLM and those treated with BLM plus MMF. In the propensity score-matched comparative analyses, there was no significant difference in the flare-free survival rates or an estimated decline in the SLEDAI-2K scores between the patients with lupus treated with BLM and IV-CY. BLM may be a promising alternative treatment option for lupus patients with moderate or high disease activity who do not respond to conventional treatments.

Complement gene mutations in children with C3 glomerulopathy: do they affect the response to mycophenolate mofetil?

C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes. Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival. Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group. This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival.

Intrathecal injection of methotrexate and dexamethasone for vasculitis granuloma of the fourth ventricle: a case report and literature review.

Granulomatosis with polyangiitis (GPA) is a pauci-immune small vessel vasculitis characterised by neutrophil-mediated vasculitis and granuloma. The presence of intracranial parenchymal space-occupying lesions is rarely seen in GPA patients. In this manuscript, we report a case of GPA with granuloma of the fourth ventricle accompanied by obstructive hydrocephalus. Treatment with glucocorticoids (GCs) and multiple immunosuppressants cyclophosphamide (CYC), mycophenolate mofetil (MMF), and rituximab (RTX) showed poor efficacy in this case. After removal of the granuloma by craniotomy, GPA relapsed within 3months. Under the premise of GC and MMF treatment combined with intrathecal injection of dexamethasone (DXM) and methotrexate (MTX), the intracranial granuloma gradually shrank, and the patient's general condition was alleviated, showing that this is an effective treatment method. Key Points • To date, there are few reports of granulomatous vasculitis combined with granuloma of the fourth ventricle, and our case is the second. • In this case, multiple immunosuppressants and rituximab were ineffective treatments, and the intracranial granuloma was effectively controlled by intrathecal injection of dexamethasone (DXM) and methotrexate (MTX). • Based on this report, it can be suggested that intrathecal injection is effective in treating patients with GPA and central nervous system involvement, but large-scale sample studies are needed.

Nephroprotective Effects of Mycophenolate Mofetil and Glibenclamide on Streptozotocin-induced Diabetic Renal Injury in Rats: An Experimental Study.

Diabetic renal injury is a microvascular complication associated with inflammation and oxidative stress, culminating in renal dysfunction. Conventionally, it is treated with hypoglycemic agents to address metabolic perturbations. However, the way to mitigate immunological, inflammation, and oxidative stress have seldom been studied. Hence, in the present study, the nephroprotective role of immunosuppressive and anti-inflammatory drugs, mycophenolate mofetil (MMF) in combination with the oral hypoglycemic agent glibenclamide, on streptozotocin (STZ)- induced diabetic renal damage was studied. Bodyweight, fasting blood glucose, and glycosylated hemoglobin levels were altered in the diabetic rats. Furthermore, renal injury was indicated by abnormal levels of urinary protein and creatinine and serum markers of renal function in diabetic rats. Hyperglycemia-induced oxidative stress and inflammation were also observed in the diabetic rats. The combination of MMF and glibenclamide treatment significantly attenuated the abnormal effects of hyperglycemia, oxidative stress, and inflammation-induced renal injury in diabetic rats. Histopathological studies confirmed the nephroprotective role of MMF and glibenclamide by reversing renal injury in diabetic rats. The present study suggests that MMF and glibenclamide have a protective role in STZ-induced diabetic renal damage.

Evaluation of neutropenia secondary to mycophenolate mofetil associated with valganciclovir in liver transplant patients

ObjectiveImmunosuppressive drugs are necessary to avoid or reduce the risk of rejection of transplanted organs. The immunosuppression generated may result in these patients needing antibiotics and antivirals to be prescribed to them in conjunction with their immunosuppressants to avoid the risk of infection. This has generated an increase in neutropenia in patients treated with mycophenolate mofetil in combination with valganciclovir. The purpose of this study is to estimate the risk of neutropenia attributable to combination treatment of mycophenolate mofetil with valganciclovir in patients with a transplanted liver. MethodThis is a retrospective cohort study. It included patients who received a liver transplant between 2012 and 2017 and who were treated with mycophenolate mofetil or with a combination of mycophenolate mofetil and valganciclovir. Minimum follow-up was 100 days post-transplantation. Children under 16 years of age and patients who died during follow-up were excluded. Binary logistic regression analysis was used to determine the association of neutropenia with sex, age, diabetes, creatinine at baseline and at discharge, and concomitant treatment of mycophenolate mofetil with valganciclovir. Relative risk and 95% CI were calculated using logistic regression coefficients. Results144 patients were analyzed, 87 were treated with mycophenolate mofetil and 57 received mycophenolate mofetil and valganciclovir together. An overall risk of neutropenia of 37% [95% CI (29-45)] was observed. The risk was significantly higher in patients who received the combination of mycophenolate mofetil and valganciclovir (56%) than in those treated with mycophenolate mofetil alone (24%), p = 0.001. Binary-logistic-regression analysis revealed that concomitant use of mycophenolate mofetil with valganciclovir was associated with an increased risk of neutropenia: Relative risk = 4.97, 95% CI [2.25-11.00]. ConclusionsOur study shows that concomitant use of mycophenolate mofetil and valganciclovir increases the risk of neutropenia in patients with a transplanted liver.

Gaucher disease in a patient with membranoproliferative glomerulonephritis: case report

BackgroundGaucher disease (GD) is a rare autosomal recessive inherited, lysosomal storage disoder that involves liver, spleen, lung, bone, bone marrow even central nervous. However, GD associated membranoproliferative glomerulonephritis (MPGN) is seldom reported.Case presentationHere we described a case of 35-year-old man suffering from GD with hepatosplenomegaly, ascites, bone destruction, myelofibrosis and MPGN. Renal biopsy revealed MPGN and Gaucher cells presented in the glomeruli capillaries. β-glucosidase activity was 1.95nmol/1 h/mg and gene detection demonstrated that one homozygous pathogenic variant Leu483Pro in GBA. He received the treatment of oral prednisone and mycophenolate mofetil and his ascites and renal outcomes had been significantly improved.ConclusionsTherapy of prednisone and mycophenolate mofetil may be an optional choice for patients with Gaucher disease who have no opportunity to use enzyme treatment.

A Phase 0 Study Assessing the Intracranial Activity of a Metabolic Radiosensitizer in Patients with Glioblastoma

Efforts to overcome treatment resistance in glioblastoma (GBM) have been unsuccessful due to tumor heterogeneity and poor intracranial drug penetration. Targeting altered metabolism is a promising approach to improve GBM therapy despite this heterogeneity. Mycophenolate mofetil (MMF) is an inhibitor of purine synthesis that sensitizes GBM to radiation and temozolomide (TMZ) in vitro and in vivo, but its ability to cross the blood brain barrier and inhibit GBM metabolism in patients is unknown. NCT04477200 is a phase 0/1 dose escalation study of MMF combined with radiation and temozolomide in GBM. Here we report the phase 0 results of this study assessing the intracranial activity of MMF. Purine (GTP and IMP) and mycophenolic acid (MPA, the active metabolite of MMF) concentrations were determined using mass spectrometry in flash-frozen tumor (enhancing and non-enhancing) and normal cortex obtained from 8 patients with recurrent GBM who received MMF (500, 1000, 1500 and 2000 mg BID, N = 2 patients each dose level) for 1 week prior to re-resection and 5 control patients who did not receive MMF prior to re-resection. Plasma MPA concentration was similarly quantified to calculate the enhancing tumor, non-enhancing tumor and normal cortex to plasma MPA ratios. Patients who received MMF had a mean MPA concentration of 2.2 ± 0.7 µM in the enhancing tumor samples, 1.2 ± 0.5 µM in the non-enhancing tumor samples and 1.3 ± 0.5 µM in normal cortex. MPA concentration was negligible in control patients. This corresponded to tissue/plasma MPA ratios of 0.31, 0.17 and 0.10 for enhancing tumor, non-enhancing tumor and normal cortex, respectively. The GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. The GTP/IMP ratio was also decreased in cortex and non-enhancing tumor, though a paucity of control samples prevented statistical analysis. Twice daily MMF treatment yields intracranial drug concentrations above 1 µM and lowers the GTP/IMP ratio in GBMs, consistent with target engagement. As we have previously observed radiosensitization in vitro with MPA concentrations of 1 µM, these data suggest that MMF may achieve adequate CNS penetration for therapeutic benefit. The Phase 1 component of this study to determine the dose limiting toxicity and maximally tolerated dose of MMF when combined with reirradiation in recurrent GBM and radiation and TMZ in newly diagnosed GBM is ongoing.

Comparison of the effects of mycophenolate mofetil alone and with testosterone on sperm, sex hormones and antioxidant enzymes in male rats

Background: Mycophenolate mofetil (MMF) is an immunosuppressant drug which is used to inhibit organ transplant rejection and to treat autoimmune diseases. Theoretically, such medications have spermatotoxic and genotoxic effects. However, evidence on the effects of MMF on fertility is limited and controversial.This study evaluated the effects of MMF and testosterone on sperm, sex hormones and antioxidant enzymes in male rats. Materials and Methods: In this experimental study 24 adult male Naval Medical Research Institute (NMRI) mice randomly divided into 3 groups: 1- saline serum (control), 2- MMF and 3- MMF along with testosterone by subcutaneous injection, for 65 days. Change in body weight, sperm quality (concentration, motility and morphology), serum level of gonadotropin hormones, and testosterone, superoxide dismutase (SOD), glutathione (GSH), catalase, total antioxidant capacity (TAC) in serum and epididymis were evaluated. Findings: Both MMF treatment groups compared to control showed a decrease in body weight, number and motility of sperm, level of testosterone, antioxidant enzymes (SOD, GSH, and catalase) and TAC (P&lt;0.05), and increase of gonadotropin hormones and sperm morphology abnormality (P&lt;0.05). The adverse effects on sperm count and epididymis testosterone levels in the Mycophenolatemofetil +testosterone group was less than the Mycophenolate mofetil group (P&lt;0.05). Conclusion: This study showed that Mycophenolatemofetil has adverse effects on sperm count, gonadotropins , testosterone and antioxidant pathway enzymes, and the use of testosterone cannot reduce the adverse effects of MMF. The adverse effects of Mycophenolate mofetil may be due to a decrease in the level of antioxidants.

Engineering immunosuppressive drug-resistant armored (IDRA) SARS-CoV-2 T cells for cell therapy.

Solid organ transplant (SOT) recipients receive immunosuppressive drugs (ISDs) and are susceptible to developing severe COVID-19. Here, we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients (n = 136) treated with different ISDs. We demonstrate that a combination of a calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone (Pred) treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response. Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection. To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients, we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor (TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta, Delta, Gamma, and Omicron variants. This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.