Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.

Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris.

BACKGROUND: Rituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials. METHODS: In 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). RESULTS: Of 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. CONCLUSIONS: Rituximab 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.).

Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia.

BACKGROUND: Immune 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. METHODS: In 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. RESULTS: A 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. CONCLUSIONS: The 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.).

Inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C (rs11706052) and 12-month evolution of the graft function in renal transplant recipients on mycophenolate-based immunosuppression.

Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93-1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99-1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.

Efficacy and Adverse Reactions of Mycophenolate Mofetil Combined with Hormone in the Treatment of Idiopathic Membranous Nephropathy: A Meta-Analysis.

Background: The detection and prevalence of idiopathic membranous nephropathy in China are increasing yearly. However, the current treatment of idiopathic membranous nephropathy relies on empirical treatment regimens such as hormones and immunosuppressants, with unclear prognosis and easy recurrence. Methods: Eight databases were searched to obtain controlled trials on the effects of mycophenolate mofetil combined with hormones in the treatment of idiopathic membranous nephropathy. After literature quality evaluation, data analysis was performed using RevMan 5.3 software. Results: 12 studies were ultimately included in this meta-analysis. 12 studies reported that, compared with the control group, the effective rate (OR: 1.15; 95% CI: 1.06, 1.26; P < .001), 24hUP (SMD:-0.35; 95% CI: -0.47, -0.23; P < .001), Alb (SMD: 1.92; 95% CI: -0.51, 4.36; P = .122), Scr (SMD: 4.44; 95% CI: -10.26, 1.38; P = .135), TG (SMD: 0.51; 95% CI: 0.88, 0.15; P < .01) and adverse events (OR: 0.86; 95% CI: 0.67,1.11; P = .255) of the test group was significantly higher. Conclusion: The results of this study suggested that mycophenolate mofetil combined with hormone may be effective on patients with idiopathic membranous nephropathy, as evidenced by effective rate, 24hUP, Alb, Scr, TG, adverse events, and the above conclusions need to be verified by more high-quality studies.

High- and low-dose cyclophosphamide in Egyptian lupus nephritis patients: a multicenter retrospective analysis.

BACKGROUND: Lupus nephritis (LN) is a common serious presentation of systemic lupus erythematosus. Cyclophosphamide (CYC) and mycophenolate mofetil (MMF) are listed as the first-line drugs in induction therapy for LN. OBJECTIVE: This study aimed to compare high- and low-dose CYC in a cohort of Egyptian LN patients. PATIENTS AND METHODS: The data of 547 patients with class III/IV active LN who received CYC as induction therapy were retrospectively analyzed. Whereas 399 patients received 6­monthly 0.5-1 g/m2 CYC doses, 148 patients received six biweekly 500 mg CYC doses. Demographic data, laboratory test results, and disease activity index were recorded and compared at presentation and at 6, 12, 18, 24, and 48 months of follow-up. RESULTS: After 48 months, the proportion of patients maintaining normal creatinine levels was higher in the group receiving induction therapy with high-dose CYC (67.9%, 60.4%, p = 0.029), and these patients also had higher proteinuria remission at 36 (26.6%, 14.8%, p = 0.014) and 48 months (24.3%, 12.8%, p = 0.006). Comparison of patient outcomes according to both induction and maintenance therapy showed the best results in patients who received high-dose CYC and continued MMF as maintenance therapy. CONCLUSION: High- and low-dose CYC are comparable in early phases of treatment. However, after a longer duration of follow-up, high-dose CYC was associated with higher remission rates in the current cohort.

Relative efficacy and safety of calcineurin inhibitor, mycophenolate mofetil, and azathioprine as maintenance therapies for lupus nephritis: a network meta-analysis.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and azathioprine (AZA) as maintenance therapies for lupus nephritis. METHODS: Randomized controlled trials (RCTs) examining the efficacy and safety of CNI, MMF, and AZA as maintenance therapies in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine the direct and indirect evidence from RCTs. RESULTS: Ten RCTs comprising 884 patients were included in the study. Although the difference was not statistically significant, MMF showed a trend toward a lower relapse rate compared with AZA (odds ratio [OR] 0.72, 95% credible interval [CrI] 0.45-1.22). Similarly, tacrolimus showed a trend toward a lower relapse rate compared with AZA (OR 0.85, 95% CrI 0.34-2.00). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that MMF had the highest probability of being the best treatment based on the relapse rate, followed by CNI and AZA. The incidence of leukopenia in the MMF and CNI groups was significantly lower than that in the AZA group (OR 0.12, 95% CrI 0.04-0.34; OR 0.16, 95% CrI 0.04-0.50; respectively). Fewer patients with infections were observed in the MMF group than in the AZA group, although the difference was not statistically significant. The analysis of withdrawals due to adverse events showed a similar pattern. CONCLUSION: Lower relapse rates combined with a more favorable safety profile suggest that CNI and MMF are superior to AZA as maintenance treatments in lupus nephritis patients.

Pretransplant mycophenolate mofetil may be associated with reduced intrahepatic cholangiopathy in ABO-incompatible liver transplantation.

Intrahepatic cholangiopathy is a life-threatening sequela of ABO-incompatible liver transplantation. We analyzed the clinical impact of pretransplant administration of mycophenolate mofetil in reducing intrahepatic cholangiopathy in ABO-incompatible liver transplantation. Patients who underwent living donor liver transplantation between 2010 and April 2022 were included. Pretransplant mycophenolate mofetil was started in November 2020. A comparison between patients who experienced intrahepatic cholangiopathy and who did not among ABO-incompatible transplantation was performed. Recipients of ABO-incompatible transplantations were categorized based on donor surgery into open, laparoscopy without pretransplant mycophenolate mofetil, and laparoscopy with pretransplant mycophenolate mofetil groups. Cox analysis of intrahepatic cholangiopathy was performed. A total of 234 ABO-incompatible transplantations were included. Intrahepatic cholangiopathy occurred in 1.1% (n=1/94), 13.3% (n=12/90), and 2.0% (n=1/50) of patients who received an ABO-incompatible liver with open surgery, laparoscopic donor surgery without pretransplant mycophenolate mofetil and laparoscopic donor surgery with pretransplant mycophenolate mofetil. ( p = 0.001) Multivariable analysis showed that transplantations involving a donor who underwent a laparoscopic hepatectomy and a recipient who did not receive pretransplant mycophenolate mofetil were associated with a higher risk of intrahepatic cholangiopathy (HR=13.449, CI=1.710-105.800, p = 0.02) compared with transplantations from donors who underwent open surgery. Transplantations involving a donor who underwent laparoscopic donor surgery and a recipient who received pretransplant mycophenolate mofetil resulted in no increased risk compared with transplantations from donors who underwent open surgery. (HR=5.307, CI=0.315-89.366, p = 0.25) Laparoscopic donor hepatectomy was a risk factor for intrahepatic cholangiopathy in ABO-incompatible liver transplantation, while pretransplant mycophenolate mofetil was related to risk reduction of intrahepatic cholangiopathy.

Risk Factors for Fractures in Renal Transplantation: A Population-Based Cohort Study.

INTRODUCTION: Kidney transplant recipients are at an increased risk of fractures, and targeted preventive strategies are needed. Therefore, in this retrospective cohort study, we investigated a large population-based cohort to identify the transplant recipient-specific risk factors for fractures in Taiwanese kidney transplant recipients. METHODS: We conducted a retrospective cohort study using the National Health Insurance Research Database. Patients who underwent renal transplantation between 2003 and 2015 were identified and followed until December 31, 2015, to observe the development of fractures. Variables associated with the development of post-transplant fractures were identified by calculating hazard ratios in a Cox regression model. RESULTS: 5,309 renal transplant recipients were identified, of whom 553 (10.4%) were diagnosed with post-transplant fractures. Independent predictors of post-transplant fractures included an age at transplant ≥65 years (p < 0.001), female sex (p < 0.001), fractures within 3 years prior to transplantation (p < 0.001), and diabetes mellitus (p < 0.001). In addition, daily prednisolone doses >2.9­5.3 mg/day (p < 0.001), >5.3­8.7 mg/day (p < 0.001), and >8.7 mg/day (p < 0.001) were also independent predictors of post-transplant fractures. Conversely, the use of peritoneal dialysis before renal transplantation (p = 0.021), hypertension (p = 0.005), and the use of tacrolimus (p < 0.001), azathioprine (p = 0.006), mycophenolate mofetil/mycophenolic acid (p = 0.002), mTOR inhibitors (p = 0.004), and calcium supplements (p = 0.009) were inversely correlated with post-transplant fractures. CONCLUSION: We recommend minimizing daily glucocorticoids as early and as far as possible in conjunction with immunosuppressive regimens such as tacrolimus, azathioprine, mycophenolate mofetil/mycophenolic acid, mTOR inhibitors, and calcium supplements, especially in older female recipients and in recipients with diabetes and a history of prior fractures.

Efficacy and safety of multi-target therapy in children with lupus nephritis.

BACKGROUND: To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN). METHODS: In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed. RESULTS: The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy. CONCLUSIONS: Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN. IMPACT: The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.

Gastroduodenal Ulcers in Liver Transplant Recipients under Immunosuppressive Therapy.

INTRODUCTION: The proportion of gastroduodenal ulcers caused by drugs is increasing. However, the risk of gastroduodenal ulcer from drugs other than nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin is unclear. An association between immunosuppressive drugs and gastroduodenal ulcers has been suggested. We aimed to identify the immunosuppressive drugs and clinical characteristics associated with gastroduodenal ulcers in post-liver transplant patients. METHODS: The study investigated 119 patients who underwent esophagogastroduodenoscopy after liver transplantation, and 2 patients were excluded. Clinical characteristics, medications, and endoscopic images were retrospectively reviewed. RESULTS: Among 117 post-living donor liver transplant recipients, gastroduodenal ulcers were found in 10 (9.2%) patients. The ulcer group had endoscopic gastritis more frequently (40%) compared with the non-ulcer group (10%). Logistic regression analysis revealed gastritis, NSAID use, and mycophenolate mofetil were risk factors in the post-liver transplant patients. Among 103 patients not on NSAIDs, 8 (7.8%) had peptic ulcer. The most common ulcer site and ulcer shape were the gastric antrum and a circular shape, respectively. All patients in the ulcer group were taking mycophenolate mofetil, which was the only immunosuppressive drug that showed a significant difference between the two groups. Five out of 8 ulcer patients (63%) were taking gastric acid suppressants, and gastroduodenal ulcers in post-liver transplant recipients were suggested to be refractory. CONCLUSION: Patients treated with immunosuppressive drugs after liver transplantation can develop gastroduodenal ulcers, even with gastric acid suppressant medication. Mycophenolate mofetil may increase the risk of gastroduodenal ulcers compared with other immunosuppressive drugs.

Immunogenicity and safety of SARS-CoV-2 mRNA vaccine in patients with nephrotic syndrome receiving immunosuppressive agents.

BACKGROUND: As there are no large-scale reports of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with nephrotic syndrome using immunosuppressive agents, we conducted the prospective study. METHODS: SARS-CoV-2 mRNA vaccines were administered to patients with nephrotic syndrome receiving immunosuppressive agents. The titers of SARS-CoV-2 spike protein receptor-binding domain antibodies were measured before and after vaccination. We evaluated factors associated with antibody titers after vaccination and analyzed adverse events. RESULTS: We enrolled 40 patients and evaluated vaccine immunogenicity in 35 of them. Seroconversion (> 0.8 U/mL) was achieved in all patients, and the median antibody titer was 598 U/mL (interquartile range, 89-1380 U/mL). Patients using mycophenolate mofetil (MMF) showed lower antibody titers than those who were not (median: 272 U/mL vs. 2660 U/mL, p = 0.0002), and serum immunoglobulin G (IgG) levels showed a weak linear relationship with antibody titers (R2 = 0.16). No breakthrough infections were noted. Three patients (7.5%) suffered from a relapse of nephrotic syndrome (2 and 3 days, respectively, after the first dose and 8 days after the second dose), two of whom had a history of relapse within 6 months before the vaccination. CONCLUSIONS: The SARS-CoV-2 mRNA vaccine was immunogenic in patients with nephrotic syndrome using immunosuppressive agents, although the use of MMF and low levels of serum IgG were associated with lower antibody titers after vaccination. Patients with high disease activity may experience a relapse of nephrotic syndrome after vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mycophenolate mofetil-associated collagenous ileitis in a kidney transplant recipient: A case report.

We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3 years earlier was admitted to our department for severe diarrhea and rapid weight loss. Infection studies were negative, and tumors were ruled out, so drug-induced factors were suspected. He had been taking mycophenolate mofetil for immunosuppression, which was then suspended, and he had a rapid resolution of diarrhea. Pathological findings of gastrointestinal endoscopy biopsy showed the presence of thickened collagen bands in the subepithelium of the terminal ileum. This is the first report of collagenous ileitis caused by mycophenolate mofetil in a patient with a kidney transplantation, adding another reversible cause to this rare condition. It is important for clinicians to recognize and treat it promptly.

Retrospective evaluation of prognosis and survival with various immunosuppressants in 82 dogs diagnosed with meningoencephalitis of unknown etiology (2010-2021).

BACKGROUND: Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. RESULTS: The overall survival time was 769 days (range 14-2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126-2163 days), mycophenolate mofetil 865 days (range 39-2191 days), cyclosporin 441 days (range 11-2176 days), cytosine arabinoside 754 days (range 6-1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23-1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. CONCLUSIONS: The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.

Study about evaluation of efficacy of methotrexate in localized scleroderma using ultrasonography.

BACKGROUND: The treatment and curative effect evaluation of localized scleroderma (LS) still perplexes many clinical workers. PURPOSE: To investigate the efficiacy of methotrexate in the treatment of LS by the evaluation of ultrasonography. METHODS: A prospective study enrolled 10 patients treated with MTX for at least 6 months was conducted. Treatment outcome was evaluated by a clinical score and 15-MHz ultrasonography. Safety assessment included the monitoring of adverse drug reactions and clinical laboratory examinations. RESULTS: Eight of the 10 patients achieved clinical remission only with MTX. One patient was relieved after MTX combined with corticosteroids, while another one does not improve after the treatment of mycophenolate mofetil and corticosteroids. The effective rate of MTX is 80%. Nine patients were significantly improved with a decrease of the Localized Scleroderma Cutaneous Assessment Tool (the mean score of the LoSCAT cutaneous activity dropped from 5.2 to 1.0, p < 0.001, the mean score of the LS cutaneous damage dropped from 4.3 to 2.3, p = 0.002). The average difference of thickness between skin lesions and normal skin evaluated by ultrasonography decreased from 0.13 cm to 0.04 cm (p = 0.009) in eight patients. No serious adverse reactions occurred. CONCLUSION: Methotrexate is a safe and effective treatment for patients with LS. Ultrasonography can be considered as an efficient assessment tool for evaluation LS.

Mycophenolate mofetil may be an alternative for maintenance therapy of Behçet syndrome uveitis: a single-center retrospective analysis.

Experience with mycophenolate in uveitis due to Behçet syndrome (BS) is limited. Twelve patients with panuveitis or posterior uveitis who were started mycophenolate were included. Data on demographic characteristics, therapies, ocular attacks, and adverse events were extracted from patient charts. Seven patients with BS uveitis were prescribed mycophenolate for remission induction, of which 6 were refractory/intolerant to conventional immunosuppressives. Mycophenolate was combined with anti-TNFs in 3 patients, resulting in no further ocular attacks. Mycophenolate had to be stopped in the fourth patient due to adverse events. The remaining 3 patients continued to have ocular attacks and were switched to other agents without any drop in visual acuity. Among the 5 patients who were prescribed mycophenolate for maintenance, 2 were relapse free, but 3 experienced ocular attacks. One patient had an exacerbation of mucocutaneous lesions, and 2 experienced adverse events. Mycophenolate monotherapy may not be adequate for remission induction of refractory BS uveitis, but it can be a safe and effective alternative when combined with a biologic agent. It may also be an option for maintenance therapy.

Diarrhea after kidney transplantation: A study of risk factors and outcomes.

Background: Diarrhea in kidney transplant recipients (KTRs) can be associated with significant morbidity. Material and Methods: We evaluated 198 KTRs for a history of diarrhea post-kidney transplant at a tertiary care center in western India over 1 year. A protocol-based evaluation of diarrhea was done with respect to clinical features, diagnostic evaluation, associated acute allograft dysfunction, and its impact on long-term allograft function. Primary outcomes of interest were: chronic allograft injury (CAI) and the need for mycophenolate mofetil (MMF) withdrawal. We also assessed the effect of MMF withdrawal on the risk of the development of CAI. Results: Eighty-five of 198 (42.5%) recipients experienced diarrhea and a total of 140 diarrheal episodes were evaluated. The mean age of these 85 recipients was 38 ± 12 years and 72 (84.7%) were males. 73 of 85 recipients were on MMF at the time of diarrhea and in 35 (48%) of them MMF withdrawal was needed for chronic and persistent symptoms. Diarrhea was attributed to infective etiologies in 90 of 140 (64.2%) cases. Among the microbiologically confirmed infective diarrheal episodes, giardia and cryptosporidium were the common pathogens in 11/28 (39%) and 6/28 (21.4%) episodes respectively. One hundred and twenty-eight episodes out of 140 (91.4%) episodes were complicated by acute allograft dysfunction. Forty-one of 85 recipients (48.2%) developed chronic allograft injury and 12 (14.1%) developed allograft rejection (acute and/or chronic). Probability of chronic allograft injury was higher in those with MMF withdrawal. Conclusion: Diarrhea post-kidney transplant adversely affects graft function, especially after MMF withdrawal.

Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors.

Patients with lymphangioleiomyomatosis (LAM) and lung transplantations are treated with multiple drugs, such as tacrolimus, mycophenolate mofetil, prednisolone, and itraconazole, for long-term suppression of rejection response and prevention of infection. Additional drugs are required when lung transplant recipients develop graft complications. Therefore, managing polypharmacy is critical because of drug-drug interactions caused by various factors, including drug-metabolizing enzymes such as cytochrome P450 3A (CYP3A). The patient was a 48-year-old woman (height 144.9 cm and weight 38.4 kg) who underwent lung transplantation for LAM. Mycophenolate mofetil, tacrolimus (target blood concentration, 4.0-8.0 ng/mL), and prednisolone were administered for immunosuppression, and itraconazole and clarithromycin were administered to manage graft infection. The patient developed unilateral lymphedema, predominantly in the left leg; therefore, sirolimus was initiated with a target blood concentration of 3.0-5.0 ng/mL. In addition to 1.0 mg/day of sirolimus, tacrolimus (0.3 mg/day), itraconazole (100 mg/day), and clarithromycin (800 mg/day) were added. Blood sirolimus concentrations ranged from 18.8 to 36.9 ng/mL on days 6 to 9; thus, treatment with sirolimus was stopped because of over-target blood concentrations. Blood concentrations of sirolimus and tacrolimus were successfully managed without adverse events using therapeutic drug monitoring (TDM) and azole anti-fungal substitution of azithromycin instead of clarithromycin although sirolimus concentration was relatively lower compared to the target range. Thereby, frequent TDM, management of polypharmacy that influences CYP3A activity, and possibly CYP3A genotyping should be appropriately conducted for personalized medicine.