Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

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.

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

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.

Oral mycophenolate mofetil as a stabilizing treatment for progressive non-segmental vitiligo: results from a prospective, randomized, investigator-blinded pilot study.

Dexamethasone oral mini-pulse (OMP) is commonly used to halt progression of non-segmental vitiligo (NSV). There is an unmet need for non-phototherapy, non-corticosteroid therapeutic options for stabilizing actively spreading NSV. To assess the efficacy of oral mycophenolate mofetil in stabilizing active NSV in comparison to OMP. In this prospective, randomized, investigator-blinded study, 50 patients of active vitiligo [baseline vitiligo disease activity (VIDA) score 4] were randomized into two groups in 1:1 ratio. Group A received oral dexamethasone (2.5 mg on two successive days a week) and group B received mycophenolate mofetil (up to 2 g) for 180 days with a treatment-free follow-up period of 90 days. Assessment was done using VIDA, number of new lesions in past 30 days, and Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in past 30 days. Twenty-five patients received OMP (group A, 11 males, 14 females), and 25 received mycophenolate (group B, 12 males, 13 females). In both groups, Kruskal-Wallis revealed a significant trend for reduction in VIDA and the number of new lesions in last 30 days, over the treatment and follow-up duration when compared to baseline (p < 0.001). The first significant reduction in VIDA was noticed on 90th day in groups A and B (p < 0.001). In both groups, VIDA reduced significantly at the 180th day compared to baseline (p < 0.001, WMP), only to increase significantly at the 270th day (p < 0.001, WMP). VIDA in group B was marginally higher at 270 days than group A (p 0.03; Mann-Whitney). Eighteen and 17 patients achieved VIDA 2 + on the 180th day in groups A and B, respectively. The mean number of new lesions in last 30 days reduced significantly in both groups at the 180th day (p < 0.001) and 270th day [p < 0.001; Wilcoxon matched pairs (WMP)] when compared to baseline; but increased significantly at the 270th day compared to the 180th day (p 0.006 WMP). Twenty patients in group A and 18 patients in group B had arrest of the disease activity with treatment. Mean duration to arrest disease progression was 47.2 ± 12.1 days in group A, and 52.5 ± 9.3 days in group B; p 0.21. The difference between VASI at baseline and VASI at the 180 and 270th days was non-significant in both groups (p 0.18 WMP). Five patients in each group failed the respective treatments. Acne (n = 3), weight gain (n = 3), headache, insomnia and menstrual irregularity (n = 1 each) were the important adverse effects noted with dexamethasone pulse; whereas nausea (n = 6) and diarrhea (n = 4) were the commonest adverse effects noted with mycophenolate. Two patients in group B discontinued treatment because of leucopenia (n = 1) and transaminitis (n = 1) that resolved after the discontinuation of mycophenolate. Both OMP and mycophenolate mofetil halt actively spreading vitiligo, and have distinct adverse effect profiles. These should be offered in progressive vitiligo, especially in circumstances precluding the use of phototherapy. Relapse occurred significantly earlier with mycophenolate, and relapse rate was higher (though non-significant) than dexamethasone OMP. The repigmentation potential is minimal for both therapies. This study was approved by Institute Ethics Committee, and retrospectively registered with clinical trial registry of India (CTRI/2018/02/011,664).

Evaluation of the Effectiveness and Tolerability of Mycophenolate Mofetil and Mycophenolic Acid for the Treatment of Morphea.

Importance: First-line systemic therapy for morphea includes methotrexate with or without systemic corticosteroids. When this regimen is ineffective, not tolerated, or contraindicated, a trial of mycophenolate mofetil (MMF) or mycophenolic acid (MPA)-referred to herein as mycophenolate-is recommended; however, evidence to support this recommendation remains weak. Objective: To evaluate the effectiveness and tolerability of mycophenolate for the treatment of morphea. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 1999, to December 31, 2018, among 77 patients with morphea from 8 institutions who were treated with mycophenolate. Main Outcomes and Measures: The primary outcome was morphea disease activity, severity, and response at 0, 3 to 6, and 9 to 12 months of mycophenolate treatment. A secondary outcome was whether mycophenolate was a well-tolerated treatment of morphea. Results: There were 61 female patients (79%) and 16 male patients (21%) in the study, with a median age at disease onset of 36 years (interquartile range, 16-53 years) and median diagnostic delay of 8 months (interquartile range, 4-14 months). Generalized morphea (37 [48%]), pansclerotic morphea (12 [16%]), and linear morphea of the trunk and/or extremities (9 [12%]) were the most common subtypes of morphea identified. Forty-one patients (53%) had an associated functional impairment, and 49 patients (64%) had severe disease. Twelve patients received initial treatment with mycophenolate as monotherapy or combination therapy and 65 patients received mycophenolate after prior treatment was ineffective (50 of 65 [77%]) or poorly tolerated (21 of 65 [32%]). Treatments prior to mycophenolate included methotrexate (48 of 65 [74%]), systemic corticosteroids (42 of 65 [65%]), hydroxychloroquine (20 of 65 [31%]), and/or phototherapy (14 of 65 [22%]). After 3 to 6 months of mycophenolate treatment, 66 of 73 patients had stable (n = 22) or improved (n = 44) disease. After 9 to 12 months of treatment, 47 of 54 patients had stable (n = 14) or improved (n = 33) disease. Twenty-seven patients (35%) achieved disease remission at completion of the study. Treatments received in conjunction with mycophenolate were frequent. Mycophenolate was well tolerated. Gastrointestinal adverse effects were the most common (24 [31%]); cytopenia (3 [4%]) and infection (2 [3%]) occurred less frequently. Conclusions and Relevance: This study suggests that mycophenolate is a well-tolerated and beneficial treatment of recalcitrant, severe morphea.

Mycophenolate Mofetil in Severe Atopic Dermatitis: A Review.

Atopic Dermatitis (AD) is a chronic inflammatory skin disease that is a significant cause of morbidity, quality-of-life impairment and health-care costs. Although many patients can be treated satisfactorily with topical medications and phototherapy, a smaller subset requires more aggressive systemic therapies. Multiple studies have shown promise for the use of mycophenolate mofetil (MMF) to treat refractory AD. This report summarizes the evidence for use of MMF in the treatment of recalcitrant AD for both children and adults. Familiarity with these studies on the benefits and risks of MMF will enable the clinician and patient to select the most appropriate therapy.

J Drugs Dermatol. 2016;15(6):715-718.

Recent clinical trials in lupus nephritis.

Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil.

From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.

BACKGROUND: Many studies have identified cardiovascular risk factors in patients with psoriasis. Some psoriasis therapies may increase cardiovascular disease (CVD) and others may decrease CVD. OBJECTIVE: We reviewed the literature to define the impact of common psoriasis therapies on cardiovascular measures and outcomes. RESULTS: Phototherapy has no major cardiovascular impact and may reduce levels of proinflammatory cytokines. Acitretin increases serum lipids and triglycerides, but has not been shown to increase cardiovascular risk. Cyclosporine A increases blood pressure, serum triglycerides, and total cholesterol. Methotrexate is associated with a decreased risk of CVD morbidity and mortality. Among the biologics, data for tumor necrosis factor inhibitors suggest an overall reduction in cardiovascular events. Most data on short-term ustekinumab use suggest no effect on major adverse cardiovascular events, however some authorities remain concerned. Nevertheless, ustekinumab use over a 4-year period shows a decrease in major adverse cardiovascular events when compared both with the general US population and with psoriatics in Great Britain. LIMITATIONS: Most studies lack the power and randomization of large clinical trials and long-term follow-up periods. In addition, the increased risk of CVD associated with psoriasis itself is a confounding factor. CONCLUSION: Some therapies for moderate to severe psoriasis, including methotrexate and tumor necrosis factor inhibitors, may reduce cardiovascular events in psoriatic patients. Ustekinumab appears to be neutral but there may be a long-term benefit. Appropriate patient counseling and selection and clinical follow-up are necessary to maximize safety with these agents. Further long-term study is necessary to quantify the benefits and risks associated with biologic therapies.

Late, severe, noninfectious diarrhea after renal transplantation: high-risk factors, therapy, and prognosis.

OBJECTIVE: Late severe noninfectious diarrhea in renal transplant recipients can lead to malnutrition and even graft loss. The purpose of this study was to evaluate risk factors associated with this condition and summarize therapy for these patients. METHODS: For more than 36 months we observed a cohort of 541 recipients who underwent kidney transplantation from January 2001 to June 2007. They were provided a calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF). The four group includes a continuous cyclosporine (CsA); a preconversion to tacrolimus and a postconversion group as well as a continuous tacrolimus group. The rate of severe late noninfectious diarrhea was compared among the four groups. Risk factors were analyzed between the diarrhea and nondiarrhea cohorts. Clinical characteristics, efficacy, and safety were observed after modifying the immunosuppressive protocol for late severe noninfectious diarrhea recipients. RESULTS: Twenty-eight recipients presented with late sever noninfectious diarrhea. No patients displayed chronic diarrhea in the CsA (n = 145) or preconversion group (n = 95). The rate of diarrhea was 7.31% in the postconversion and 7.35% in the tacrolimus group. Using multivariate Cox proportional hazards analysis, factors associated with an increased risk of noninfectious diarrhea were cytochrome P450(CYP)3A5 *3/*3 type, chronic renal allograft dysfunction, and patient ingestion of Tripterygium wilfordii Hook F. All diarrheal recipients experienced weight loss, hypoalbuminia, and an increased serum creatinine. All affected patients underwent adjustment of the immunosuppressive regimen to achieve remission. Renal allograft survival in recipients with diarrhea was worse than that in nondiarrheal recipients receiving tacrolimus combined with MMF. CONCLUSION: Tacrolimus with MMF increased the risk of late severe noninfectious diarrhea among renal transplant recipients compared with hosts treats with CsA plus MMF. The CYP3A5 *3/*3 type, chronic renal allograft dysfunction, and T. wilfordii supplementation were high-risk factors for late diarrhea. Prompt adjustment of immunosuppression was an effective, feasible therapy for these patients.

Effect of mycophenolate mofetil on hematological side effects incidence in renal transplant recipients.

Mycophenolate mofetil (MMF), an immunosuppressant administered after solid organ transplantation, is generally well tolerated; however, it frequently causes hematological toxicity. In this study, we aimed to assess the relation between the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA] and 7-O-MPA glucuronide [MPAG]) and the adverse effects on the hematopoietic system in renal transplant recipients. The four-h pharmacokinetic profiles of MPA and MPAG were determined using the HPLC method for MMF-treated patients (n = 61) among 106 renal transplant recipients (during the late post-transplant period) participating in the study. Anemia was more frequently observed in the study group compared with the control group (30.7% vs. 20.0%) and although the difference was insignificant, plasma iron concentrations were significantly higher in patients treated with MMF (32.9 ± 9.4 µmol/L vs. 28.7 ± 9.4 µmol/L; p = 0.032). Iron supplementation was more frequently applied to patients with anemia (48.2%) compared with patients with hemoglobin within the norm (20.3%; p = 0.005). As all MPAG pharmacokinetic parameters correlated negatively with hemoglobin and hematocrit, and MPAG pharmacokinetic parameters were higher in patients with anemia, MPAG may be the predicting factor of MMF side effects. In renal transplant recipients, especially with deteriorated renal function, extensive iron supplementation may be ineffective as anemia was associated with declined renal function and was not caused by low iron concentration.

Treatment of mucous membrane pemphigoid with mycophenolate mofetil.

PURPOSE: To evaluate the clinical outcomes of mycophenolate mofetil (MMF) treatment of mucous membrane pemphigoid (MMP). METHODS: This is a retrospective analysis of consecutive patients with clinical MMP seen in the Ocular Surface Disease Clinic at the Wills Eye Institute, between January 1, 2004, and December 31, 2010, treated with MMF. The main outcomes measured were control of inflammation and discontinuation of MMF. RESULTS: A total of 23 MMP patients taking MMF were identified. The median age of the MMF-treated patients was 77.0 years. Eleven of the 23 patients (47.8%) had biopsy-proven MMP. All patients were at least Foster grading system stage 2, with most stage 3 or 4. Eight patients (34.8%) failed previous treatments with dapsone, methotrexate, prednisone, azathioprine, cyclophosphamide, or 6-mercaptopurine. The average duration of MMF treatment was 23.32 ± 33.17 months (range 1-124.83 months, median 7.4 months). Of the 23 patients with MMP, control of inflammation was achieved with MMF within 3 months for 56.5% [95% confidence interval (CI) 54.5-59.6], within 6 months for 69.6% (95% CI 65.2-76.6), and within 12 months for 82.6% (95% CI 75.3-92.4) of the patients. Nineteen patients (82.4%) achieved control of inflammation, with 16 of the 19 (84.2%) achieving control of inflammation with MMF as monotherapy. Fifteen patients were treated with MMF as initial therapy. Twenty-one percent of patients (5 of 23) were taken off MMF for failure of inflammatory control (4) or an allergic reaction (1). CONCLUSIONS: Treatment of MMP with MMF in this uncontrolled case series resulted in control of inflammation in the majority of patients with minimal side effects. Our data support consideration of MMF as an initial treatment option for active ocular MMP.

Malignancy concerns with psoriasis treatments using phototherapy, methotrexate, cyclosporin, and biologics: facts and controversies.

Cancer is one of the several comorbidities that have been linked with psoriasis. Not surprisingly, tumors associated with well-documented risk factors for the dermatosis, such as smoking and obesity, have been found with increased incidence in psoriatic patients. They include lung, kidney, and colon cancers. For unknown reasons, the risk of lymphoma is also increased in psoriatic patients. Despite several difficulties with documenting risks, some systemic treatments for psoriasis have been linked with an increased risk of selected cancers. The best-documented association is nonmelanoma skin cancer with psoralen plus ultraviolet A therapy and cyclosporin. More recently, an increased risk of cancer has been a concern with newly introduced biologic agents. The documentation of such a purported increased risk requires long-term follow-up of treated patients.

Combination of everolimus and tacrolimus in kidney transplant patients with intolerance to mycophenolate mofetil/mycophenolic acid.

OBJECTIVE: Most immunosuppressive protocols in de novo renal transplantation include tacrolimus in combination with mycophenolate mofetil/mycophenolic acid (MMF/MPA) and prednisone. A variable percentage of patients show intolerance to MMF/MPA needing a reduction, interruption, or suspension of the drug, thereby exposing the patient to a greater risk of a rejection episode. The association of everolimus and tacrolimus may prove to be an alternative option in such cases. The aim of this study was to present our clinical experience, evaluating the incidence of graft rejection. PATIENTS AND METHODS: We performed a descriptive study of 19 kidney transplant patients from 2001-2008 who were treated with tacrolimus, MMF/MPA, and prednisone and displayed gastrointestinal or hematological adverse events to MMF/MPA, which were addressed with everolimus. We analyzed parameters up to 2 years after the change. RESULTS: The doses and levels of everolimus were increased progressively. At the same time, we decreased the doses and levels of tacrolimus. Renal function remained stable during the period and there was no case of a rejection episode during the 2 years. Only 5 patients (26%) showed side effects which were attributable to everolimus; 36% of patients required starting and/or increasing the erythropoietin dose, 15% required iron supplements, 15% required diuretics, and 31% began or increased treatment with statins. CONCLUSION: Our experience suggested that a combination of tacrolimus and everolimus may be a safe, effective alternative for kidney transplant patients who show intolerance to MMF/MPA.

Treatments for psoriasis and the risk of malignancy.

BACKGROUND: There are multiple therapeutic options for the treatment of moderate to severe psoriasis. The process of choosing among potential treatment options requires both the physician and the patient to weigh the benefits of individual modalities against their potential risks. Traditional systemic therapies for psoriasis, including methotrexate (MTX) and cyclosporine (CsA), have a well-documented array of toxicities, particularly end-organ toxicities. Over the past several years, the use of biologic therapies for the treatment of moderate to severe psoriasis has been a major clinical and research focus. With the advent of these novel immunosuppressive therapies, one of the central safety issues surrounding these agents is their potential to increase the risk of malignancy. OBJECTIVE: Our objective was to review the risk of malignancy associated with therapies for moderate to severe psoriasis, including phototherapy, traditional systemic therapies, and biologic therapies. We reviewed the existing body of literature in order to define the known incidence of malignancy associated with psoralen and ultraviolet A (PUVA), narrowband and broadband ultraviolet B (UVB), MTX, CsA, mycophenolate mofetil (MMF), and biologic therapies, including alefacept, efalizumab, infliximab, etanercept, adalimumab, and ustekinumab. RESULTS: PUVA, when given long term, is associated with increased risks of cutaneous squamous cell carcinoma and malignant melanoma. Reviews of studies on UVB, both narrowband and broadband, do not indicate any increased risk of nonmelanoma skin cancer or melanoma. The traditional systemic psoriasis therapies-MTX, CsA, and MMF-may be associated with an increased risk of lymphoproliferative disorders during treatment, demonstrated in clinical trials in patients with rheumatoid arthritis and documented in case reports concerning psoriasis patients. The risk of malignancy with biologic therapy is still unclear. However, the majority of studies examining this carcinogenic risk suggest that tumor necrosis factor-alpha inhibitors may cause a slightly increased risk of cancer, including nonmelanoma skin cancer and hematologic malignancies. LIMITATIONS: The majority of studies cited in this review lack the power and randomization of large clinical trials, as well as the long-term follow-up periods which would further substantiate the hypothetical link between these antipsoriatic treatment regimens and the potential for malignancy. Because of the substantial lack of clinical data, the majority of studies evaluated focus on the treatment of patients with rheumatoid arthritis, which is a systemic inflammatory disorder comparable to psoriasis. Additionally, the increased risk of malignancy associated with psoriasis itself is a confounding factor. CONCLUSION: Many of the therapies for moderate to severe psoriasis, including PUVA, traditional systemic therapies, and some biologic therapies, may increase the risk of malignancy. Appropriate patient counseling and selection, as well as clinical follow-up, are necessary to maximize safety with these agents. Further long-term study is necessary to more precisely quantify the risks associated with biologic therapies.

Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium.

BACKGROUND: Anemia is a known adverse effect of sirolimus (SRL) therapy. Sirolimus may contribute to anemia by a direct antiproliferative effect or by increasing inflammation, worsening kidney function, or decreasing iron utilization. After observing the need for high dose exogenous erythropoietin dosage in some patients on SRL, we hypothesized that SRL therapy may influence anemia by inducing a state of erythropoietin resistance. METHODS: Twenty-five stable renal transplant patients on maintenance tacrolimus and SRL therapy were enrolled in a prospective trial with conversion from SRL to enteric coated mycophenolate sodium. Measurement of plasma erythropoietin and red cell indices were performed pre- and postconversion. RESULTS: Renal function remained unchanged after conversion. Serum hemoglobin (Hb) increased in 18/21 (86%) of patients after conversion. Endogenous erythropoietin level decreased from a median of 28.3 (11.5-374) to 16.6 (3.1-78.8) mIU/mL, (P<0.001); and the erythropoietin:Hb ratio dropped from 2.7 (0.7-34.3) to 1.2 (0.2-6.7), (P<0.001); indicating less erythropoietin resistance after conversion. Mean corpuscular volume increased after conversion, but transferrin saturation and ferritin did not change. Conversion was complicated by posttransplant erythrocytosis in two patients. DISCUSSION: Conversion from SRL to enteric coated mycophenolate sodium led to an increase in Hb and a decrease in erythropoietin resistance in stable kidney transplant recipients. Increase in Hb seemed to be independent of renal functional changes or changes in iron sequestration.

Effect of the antioxidant idebenone on adverse events under mycophenolate mofetil therapy in a rat model.

BACKGROUND: Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects. METHODS: Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically. RESULTS: High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group. CONCLUSION: Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS.

[Revision of the recommendations of the Commission on Pharmacotherapy of the German Society for Rheumatology. Comment on the use of mycophenolic acid for systemic lupus erythematosus]. / Neufassung der Empfehlungen der Kommission Pharmakotherapie der DGRh. Stellungnahme zum Einsatz von Mycophenolsäure bei SLE.

According to the NIH scheme, the "evidence based medicine" standard in the treatment of severe proliferative lupus-nephritis is cyclophosphamide in combination with steroids. Undesired effects, therapy resistance, and deficient long-term effects underscore the necessity for the development of alternative therapies for the treatment of organ involvement. Mycophenolate mofetil (MMF) possesses the potential to decisively improve the therapeutic possibilities for systemic lupus erythematosus (SLE). On the basis of the available data, MMF represents an alternative to the current standard therapies for severe lupus-nephritises and shows less toxicity. MMF is also effective in patients with other manifestations refractory to conventional therapy. Questions remain unanswered on the optimal dosage and possible reduction in cases of remission. In addition, the duration of maintenance therapy is unclear. Therefore, large, prospective, randomized clinical studies in the treatment of lupus-nephritis with a sufficiently long follow-up phase are underway.

Mycophenolate mofetil therapy for moderate to severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that can be refractory to topical and systemic corticosteroids, phototherapy, topical immunomodulators and systemic immunosuppressive drugs. Recent studies have shown promise for the use of mycophenolate mofetil (MMF) to treat recalcitrant AD. AIM: To assess the effectiveness and adverse effects of MMF used for moderate to severe AD in a university outpatient dermatology clinic. METHODS: A retrospective chart review of 20 patient charts was conducted for patient age, gender, duration of disease, prior therapies, concomitant therapy, clinical response and adverse side-effects. RESULTS: Of the 20 patients, 17 improved within 4 weeks of starting MMF therapy. Ten patients had disease remission and were subsequently able to discontinue MMF. Seven attained satisfactory control of their AD using MMF as maintenance therapy. Overall, MMF was well tolerated, with mild headaches, gastrointestinal complaints and fatigue as the commonest side-effects. During therapy, herpes zoster developed in four patients, Staphylococcus aureus cutaneous infections in two, and herpes simplex in one. One patient discontinued MMF because of insufficient control of pruritus. CONCLUSION: MMF can be rapidly effective and well tolerated in patients with moderate to severe AD resistant to conventional therapies. The limitations of this retrospective study include no control group and a lack of a standardized scoring index to assess improvement, and the concomitant use of adjuvant therapies makes the contribution of MMF alone difficult to assess. Larger controlled studies are needed.

Establishment of an animal model with side effects induced by mycophenolate mofetil and pharmacohistological analysis of them.

UNLABELLED: Mycophenolate mofetil (MMF) is used for immunosuppression after organ transplantation, but gastrointestinal side effects including diarrhea are sometimes observed with this drug. We sought to construct on animal model of diarrhea with MMF in rodents. MATERIALS AND METHODS: BALB/Cj mice, weighing 25 g received 500 mg /kg of MMF, 60 mg/kg of levofloxacin (LVFX), 1000 mg/kg of Hangeshashin-to (HST), which is traditional Kampo medicine. This cocktail was administered orally to MMF, LVFX, HST, MMF+LVFX, and MMF+LVFX+HST groups for 21 days. We measured the water content fecal collected on days 1, 4, 8, 11, 14, 18, and 21. Feces on day 21 were cultured for identification of fecal flora. Mice were sacrificed on day 21, with blood samples collected to measure mycophenolic acid (MPA) concentrations by HPLC. Jejunum, cecum, and colon were taken for histological evaluation. RESULTS: Significant weight loss of mice and increased fecal water content of were observed in MMF and MMF+LVFX but not in MMF+LVFX+HST groups. Serum MPA levels didn't differ in MMF-administered groups. Inflammatory changes in intestinal villi were observed in the cecum in MMF and MMF+LVFX groups. A change in fecal flora was observed in LVFX-administered groups. CONCLUSION: Diarrhea induced by MMF in a rodent model produced inflammatory changes in the cecum. LVFX seemed to change the activity of beta-glucuronidase in the fecal flora. HST suppressed fecal softening induced by MMF in this animal model.