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Virulence Dec 2024Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even...
Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.
Topics: Humans; Oseltamivir; Antiviral Agents; Influenza, Human; Influenza A Virus, H1N1 Subtype; Immunosuppressive Agents; Influenza A virus; Orthomyxoviridae Infections; Virus Replication; RNA, Messenger; Protein Stability
PubMed: 38170681
DOI: 10.1080/21505594.2023.2301242 -
PloS One 2024Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with... (Observational Study)
Observational Study
Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with mycophenolate or mechanistic target of rapamycin (mTORi) with or without corticosteroids. An Italian retrospective multicentre observational study was conducted to investigate the risk-benefit profile of different immunosuppressive regimens. We identified all subjects who underwent kidney transplant between 2009 and 2019, using healthcare claims data. Patients on cyclosporine and tacrolimus-based therapies were matched 1:1 based on propensity score, and effectiveness and safety outcomes were compared using Cox models (HR; 95%CI). Analyses were also conducted comparing mTORi versus mycophenolate among tacrolimus-treated patients. Patients treated with cyclosporine had a higher risk of rejection or graft loss (HR:1.69; 95%CI:1.16-2.46) and a higher incidence of severe infections (1.25;1.00-1.55), but a lower risk of diabetes (0.66;0.47-0.91) compared to those treated with tacrolimus. Among tacrolimus users, mTORi showed non-inferiority to MMF in terms of mortality (1.01;0.68-1.62), reject/graft loss (0.61;0.36-1.04) and severe infections (0.76;0.56-1.03). In a real-life setting, tacrolimus-based immunosuppressive therapy appeared to be superior to cyclosporine in reducing rejection and severe infections, albeit with an associated increased risk of diabetes. The combination of tacrolimus and mTORi may represent a valid alternative to the combination with mycophenolate, although further studies are needed to confirm this finding.
Topics: Humans; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tacrolimus
PubMed: 38165971
DOI: 10.1371/journal.pone.0295205 -
Middle East African Journal of... 2022The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases.
PURPOSE
The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases.
METHODS
For this retrospective study, patients who were treated with systemic MMF for ocular surface inflammatory diseases between March 2020 and March 2022 were evaluated. Apart from demographic data, examination notes including MMF treatment indication and systemic side effect interrogation and routine laboratory examinations during drug treatment were extracted from the patient records. Detailed staging scores were performed according to the diagnosis including Foster and Mondino for ocular mucous membrane pemphigoid (MMP) and limbal stem cell deficiency scoring for limbal transplantation. For thorough evaluation, anterior segment pictures were used.
RESULTS
Fourteen patients were enrolled to the study, with a mean age of 58 ± 12. MMP (6, 42.8%) and limbal allograft transplantation (6, 42.8%) constituted the main indications for the MMF treatment, followed by keratitis-ichthyosis-deafness (KID) syndrome (1, 7.2%) and Mooren's ulcer (1, 7.2%). Five of six patients with MMP regressed according to both staging systems. Only one remained stable which was evaluated as Stage 3. Furthermore, while all limbal transplant groups (6) stabilized and showed regression according to the individualized limbal stem cell deficiency staging system with no rejection during follow-up. Furthermore, patients with Mooren's ulcer and KID syndrome showed control of the inflammation and stabilization after MMF treatment. No significant systemic side effects apart from constipation and nausea (3) were observed in patients whose routine laboratory tests were stable throughout the follow-up.
CONCLUSION
MMF has the potential to be a valuable and safe systemic agent of first choice in the control of ocular surface inflammatory disorders, especially when topical treatment is not effective. With such studies, it is predicted that MMF may reach wider usage areas with the increase in its effectiveness and safety in its use for ocular surface inflammatory pathologies.
Topics: Humans; Middle Aged; Aged; Mycophenolic Acid; Immunosuppressive Agents; Retrospective Studies; Limbal Stem Cell Deficiency; Ophthalmologists; Ulcer; Eye Diseases; Graft Rejection
PubMed: 38162558
DOI: 10.4103/meajo.meajo_109_23 -
The Journal of International Medical... Jan 2024Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease, which has been seen in patients with systemic lupus erythematosus (SLE). Its main... (Review)
Review
Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease, which has been seen in patients with systemic lupus erythematosus (SLE). Its main manifestations are seizure, headache and other neurological symptoms. While the condition is reversible, if not treated in time, there can be risks of cerebral haemorrhage. We report here the case of a young patient with SLE who developed PRES after receiving the immunosuppressant, mycophenolate mofetil. Neurological symptoms, signs, or changes in a patient's condition that cannot be explained by lupus, should alert physicians to the possibility of the drug causing PRES, and prompt discontinuation should ensue.
Topics: Humans; Mycophenolic Acid; Posterior Leukoencephalopathy Syndrome; Lupus Erythematosus, Systemic; Seizures; Headache
PubMed: 38156668
DOI: 10.1177/03000605231218620 -
Saudi Journal of Kidney Diseases and... Mar 2023The data available on immunoglobulin A (IgA) deposition disease indicate an inherited predisposition to the disease with autoimmune triggering. Hence, we prospectively...
The Beneficial Effect of Three-month Induction Therapy with High-dose Prednisone and Mycophenolate Mofetil Followed by Maintenance Therapy in Acute Non-crescentic Nephritis Associated with Immunoglobulin A Deposition Disease in Adults.
The data available on immunoglobulin A (IgA) deposition disease indicate an inherited predisposition to the disease with autoimmune triggering. Hence, we prospectively evaluated the role of a new autoimmune regimen in the treatment of severe nephrotic or nephritic flares associated with noncrescentic nephritis in adult patients. Thirty-six patients were included, and the regimen consisted of an initial 3-month induction phase of prednisone and mycophenolate mofetil (MMF), followed by a maintenance phase of MMF alone for 21 months. Complete remission (CR) (normalization of creatinine clearance [CrCl] and a decrease in protein output to <500 mg/day) was achieved in 29 of 36 patients, and a partial response (no further decline in CrCl and a decrease in proteinuria to <50%) was seen in seven patients. CrCl was maintained in patients with CR but was mildly reduced in partially responsive ones. Our study showed the short- and longterm safety and efficacy of this autoimmune regimen directed toward the autoimmune triggering factors in severe forms of noncrescentic IgA nephritis.
Topics: Adult; Humans; Prednisone; Mycophenolic Acid; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Treatment Outcome; Drug Therapy, Combination; Remission Induction; Immunoglobulin A
PubMed: 38146726
DOI: 10.4103/1319-2442.391895 -
Saudi Journal of Kidney Diseases and... Mar 2023Acquired perforating dermatosis (APD) is an adult skin disease characterized by an umbilicated papulonodular rash with transepidermal elimination of dermal components...
Acquired perforating dermatosis (APD) is an adult skin disease characterized by an umbilicated papulonodular rash with transepidermal elimination of dermal components such as collagen and/or elastin. It is frequently associated with multiple medications and diseases such as diabetes and chronic renal failure. It is a disabling disease with severe pruritus in 83.3% of cases and generalized ulcerating lesions that are associated with infections and scarring. Nearly 10% of renal patients are affected. Supportive measurements of disease activity and previous medications failed to halt its natural progression. In our study, we documented significant improvements in the severity of the disease as measured by the eczema area and severity index (EASI), in 32 patients with the renal disease through the use of mycophenolate mofetil (MMF), with EASI decreasing from 31 [interquartile range (IQR) = 4] to 3 (IQR = 4) by the 3rd month. Moreover, such changes persisted for up to 2 years despite a decrease in the dose of MMF to half after 1 year. In conclusion, our study showed that MMF is a safe and effective immunosuppressive drug for short- and intermediate-term therapy of severe APD and confirmed its autoimmune etiology.
Topics: Adult; Humans; Mycophenolic Acid; Skin Diseases; Skin; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Immunosuppressive Agents
PubMed: 38146723
DOI: 10.4103/1319-2442.391892 -
Vaccines Nov 2023To review the data on the immunogenicity of COVID-19 vaccines, administered by different strategies, in solid organ transplant recipients (SOTRs). : COVID-19 booster... (Review)
Review
To review the data on the immunogenicity of COVID-19 vaccines, administered by different strategies, in solid organ transplant recipients (SOTRs). : COVID-19 booster vaccines were given to SOTRs as a widespread practice in many transplant centers, mostly as the third and/or fourth dose in an extended vaccine series, with a significantly improved humoral response compared with the initial two-dose scheme. However, one-third of SOTRs remained unresponsive, despite these boosters. : Vaccination with standard dosing remains the most feasible strategy for attaining protection against COVID-19. Additional booster doses and temporarily holding or reducing mycophenolate mofetil/mycophenolic acid may provide immunogenicity to vaccines, according to recent studies demonstrating some efficacy with these measures. Preexposure prophylaxis with monoclonal antibodies showed benefit in immunocompromised patients but is no longer recommended by the National Institutes of Health (NIH) due to diminished efficacy against Omicron and recent variants. Screening for the presence and titers of SARS-CoV-2-specific antibodies in SOTRs is not recommended in most clinical settings. T cell-based techniques are needed to evaluate vaccine efficacy and risk of infection. As SARS-CoV-2 continues to evolve, new vaccines based on conservative protein component/complexes of the COVID virus, in addition to its spike protein, are warranted to offer prolonged protection.
PubMed: 38140160
DOI: 10.3390/vaccines11121755 -
Pharmaceutics Dec 2023Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However,...
Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m, 1.0 m, 1.5 m) and dosing (400 mg/m, 600 mg/m, 900 mg/m twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on V/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.
PubMed: 38140082
DOI: 10.3390/pharmaceutics15122741 -
Journal of Personalized Medicine Dec 2023Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With... (Review)
Review
Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor-recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. : Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.
PubMed: 38138933
DOI: 10.3390/jpm13121706 -
Children (Basel, Switzerland) Nov 2023An infection with SARS-CoV-2 can trigger a systemic disorder by pathological autoimmune processes. A certain type of this dysregulation is known as Multisystemic...
"Multisystem Inflammatory Syndrome in Children"-Like Disease after COVID-19 Vaccination (MIS-V) with Potential Significance of Functional Active Autoantibodies Targeting G-Protein-Coupled Receptors (GPCR-fAAb) for Pathophysiology and Therapy.
BACKGROUND
An infection with SARS-CoV-2 can trigger a systemic disorder by pathological autoimmune processes. A certain type of this dysregulation is known as Multisystemic inflammatory syndrome in children (MIS-C). However, similar symptoms may occur and have been described as Multisystemic inflammatory syndrome after SARS-CoV-2 Vaccination (MIS-V) following vaccination against SARS-CoV-2. We report the case of a 12-year-old boy who was identified with MIS-C symptoms without previous SARS-CoV-2 infection after receiving two doses of the Pfizer-BioNTech COVID-19 vaccine approximately one month prior to the onset of symptoms. He showed polyserositis, severe gastrointestinal symptoms and, consequently, a manifestation of a multiorgan failure. IgG antibodies against spike proteins of SARS-CoV-2 were detected, indicating a successful vaccination, while SARS-CoV-2 Nucleocapsid protein antibodies and SARS-CoV-2 PCR were not detected. Several functional, active autoantibodies against G-protein-coupled receptors (GPCR-fAAb), previously associated with Long COVID disease, were detected in a cardiomyocyte bioassay. Immunosuppression with steroids was initiated. Due to side effects, treatment with steroids and later interleukin 1 receptor antagonists had to be terminated. Instead, immunoadsorption was performed and continued with tacrolimus and mycophenolic acid therapy, leading to improvement and discharge after 79 days. GPCR-fAAb decreased during therapy and remained negative after clinical curing and under continued immunosuppressive therapy with tacrolimus and mycophenolic acid. Follow-up of the patient showed him in good condition after one year.
CONCLUSIONS
Infection with SARS-CoV-2 shows a broad and severe variety of symptoms, partly due to autoimmune dysregulation, which, in some instances, can lead to multiorgan failure. Despite its rarity, post-vaccine MIS-C-like disease may develop into a serious condition triggered by autoimmune dysregulation. The evidence of circulating GPCR-fAAb and their disappearance after therapy suggests a link of GPCR-fAAb to the clinical manifestations. Thus, we hypothesize a potential role of GPCR-fAAb in pathophysiology and their potential importance for the therapy of MIS-C or MIS-V. However, this observation needs further investigation to prove a causative correlation.
PubMed: 38136038
DOI: 10.3390/children10121836