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Bilateral Aggressive Mooren Ulcer in the Setting of Bilateral Pterygia and Pregnancy: A Unique Case.Cornea Jun 2024To report an unusual case of bilateral aggressive Mooren ulcer that occurred in the setting of bilateral pterygia and showed a relentless course during pregnancy.
PURPOSE
To report an unusual case of bilateral aggressive Mooren ulcer that occurred in the setting of bilateral pterygia and showed a relentless course during pregnancy.
METHODS
A 39-year-old woman of Black African ethnicity, 36-week pregnant, presented to the eye casualty with bilateral nasal corneal ulcer and associated melt around preexisting pterygia. A detailed workup including microbial evaluation, culture and sensitivity, polymerase chain reaction for herpes simplex virus, varicella zoster virus, and cytomegalovirus, inflammatory blood profile, autoimmune markers, and human leucocyte antigen (HLA) screening was undertaken. Treatment was initiated in a stepwise approach.
RESULTS
Infections and systemic autoimmune and rheumatologic conditions were ruled out. A diagnosis of bilateral Mooren ulcer was made by exclusion. The peripheral blood was positive for HLA DQ2. As the condition seemed refractory to medical management (topical steroids and intravenous pulse methylprednisolone followed by oral prednisolone and topical cyclosporine), urgent bilateral conjunctival resection with multilayered amniotic membrane transplantation was performed to reduce the inflammatory stimulus and keratolysis. Stabilization of the condition warranted the need for systemic immunosuppressive agents. Using a multidisciplinary approach, in liaison with Obstetricians and Rheumatologists, the patient was planned for an earlier elective Cesarean section and commencement of oral mycophenolate mofetil postpartum, which aided in successful control of the disease.
CONCLUSIONS
Mooren ulcer could follow an aggressive course during pregnancy, especially in the setting of preexisting pterygium. The complex hormonal and immunological changes during pregnancy and the delivery of inflammatory mediators directly onto the cornea by pterygium could contribute to the severity. A well-planned, stepwise, and multidisciplinary management is pivotal for the treatment of this condition.
PubMed: 38900823
DOI: 10.1097/ICO.0000000000003591 -
Journal of Virology Jun 2024Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of...
Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like and ) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.
PubMed: 38899900
DOI: 10.1128/jvi.00846-24 -
Kidney International Reports Jun 2024
The Conversion From Mycophenolic Acid to Mammalian Target of Rapamycin Inhibitor Reduces the Incidence of Cytomegalovirus Replication in Belatacept-Treated Kidney-Transplant Recipients.
PubMed: 38899171
DOI: 10.1016/j.ekir.2024.02.1433 -
Journal of Clinical Medicine May 2024Pediatric uveitis has a low incidence. It is very diverse in its presentation and is often the first sign of a severe systemic disease. The pediatric population poses a... (Review)
Review
Pediatric uveitis has a low incidence. It is very diverse in its presentation and is often the first sign of a severe systemic disease. The pediatric population poses a special therapeutic and diagnostic challenge due to the potentially adverse effects of therapeutic agents on the young body and difficult cooperation with the patient during the examination, as well as the increased risk of complications that can lead to severe disability. The most commonly diagnosed type of uveitis is non-infectious, with first-line therapy consisting of systemic corticosteroids followed by disease-modifying drugs (methotrexate (MTX), mycophenolate mofetil (MMF), and cyclosporin A (CsA)). In severe, refractory cases, biologic therapy is used. The authors reviewed the current literature on the etiology, diagnostic tools, and treatment of uveitis in the pediatric population covering the years 2018-2023, presenting current methods of modern diagnosis and treatment. The reason for writing this article was the need to update the knowledge on uveitis, driven by the increasing prevalence of autoimmune uveitis in the pediatric population. This trend presents significant challenges in diagnosing and treating the disease, as well as managing its complications. Correctly identifying the pathogenetic factor of uveitis can facilitate the diagnosis of the systemic disease underlying the ocular infection and enable the timely implementation of systemic treatment. Furthermore, the emergence of new diagnostic methods necessitates a revision and update of ophthalmic knowledge, essential for both ophthalmologists and other specialists involved in the treatment of uveitis.
PubMed: 38892808
DOI: 10.3390/jcm13113097 -
International Journal of Molecular... May 2024IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA...
IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.
Topics: Humans; Telomerase; Glioblastoma; Cell Line, Tumor; IMP Dehydrogenase; Drug Synergism; Gene Expression Regulation, Neoplastic; Antineoplastic Agents; Brain Neoplasms; Apoptosis
PubMed: 38892179
DOI: 10.3390/ijms25115992 -
Advances in Rheumatology (London,... Jun 2024To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
OBJECTIVE
To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
METHODS
Two methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.
RESULTS
All SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.
CONCLUSION
This consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.
Topics: Lupus Nephritis; Humans; Immunosuppressive Agents; Brazil; Societies, Medical; Creatinine; Proteinuria; Mycophenolic Acid; Antibodies, Monoclonal, Humanized; Rheumatology; Rituximab; Biopsy; Cyclophosphamide; Leflunomide; Glucocorticoids; Hydroxychloroquine; Azathioprine; Remission Induction; Cyclosporine; Evidence-Based Medicine; Consensus; Disease Progression; Kidney Failure, Chronic; Randomized Controlled Trials as Topic
PubMed: 38890752
DOI: 10.1186/s42358-024-00386-8 -
Journal of Hepatology Jun 2024
PubMed: 38885882
DOI: 10.1016/j.jhep.2024.06.012 -
Pharmacogenomics May 2024This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The... (Review)
Review
This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5'-diphospho-glucuronosyltransferase ( and ) and transmembrane transporters ( and ) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including , , and have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.
PubMed: 38884938
DOI: 10.1080/14622416.2024.2344430 -
Transplantation Direct Jul 2024Mycophenolate dose reduction (MDR) is associated with acute rejection and transplant failure in kidney transplant recipients (KTRs). The optimal dose to prevent...
BACKGROUND
Mycophenolate dose reduction (MDR) is associated with acute rejection and transplant failure in kidney transplant recipients (KTRs). The optimal dose to prevent rejection and reduce complications remains poorly defined in tacrolimus-based regimens.
METHODS
We assessed adult KTRs from 2005 to 2017 initiated on mycophenolate mofetil 2 g/d, tacrolimus, and prednisolone from the Australia and New Zealand Dialysis and Transplant Registry. KTRs with rejection within the first 30 d posttransplant were excluded. The primary outcome was time to first rejection between 30 d and 2 y posttransplant. Mycophenolate dose was modeled as a time-varying covariate using Cox proportional hazards regression. Secondary outcomes included assessment of early MDR to <1.5 g/d within the first 6 mo posttransplant and subsequent patient and death-censored graft survival.
RESULTS
In the primary analysis, 3590 KTRs were included. Compared with mycophenolate dose of ≥2 g/d, both 1.0-<1.5 and <1 g/d were associated with an increased risk of rejection during the 2 y posttransplant (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.29-2.16; < 0.001 and HR 2.06; 95% CI, 1.36-3.13; = 0.001, respectively) but not 1.5-<2 g/d (HR 1.20; 95% CI, 0.94-1.53; = 0.14). Early MDR to <1.5 g/d occurred in 45.3% of KTRs and was an independent risk factor for death-censored graft failure (HR 1.32; 95% CI, 1.05-1.66; = 0.016) but not death (HR 1.18; 95% CI, 0.97-1.44; = 0.10), during a median follow-up of 5.0 (interquartile range, 2.6-8.5) y.
CONCLUSIONS
Early MDR was a risk factor for subsequent rejection and graft failure in KTRs receiving contemporary tacrolimus-based regimens.
PubMed: 38881745
DOI: 10.1097/TXD.0000000000001659 -
The Journal of the Association of... Jun 2024The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile.... (Randomized Controlled Trial)
Randomized Controlled Trial
Mycophenolate Mofetil with Steroid, a Reasonable Alternative to Current First-line Therapy, for Idiopathic Membranous Nephropathy in Resource-constrained Settings: A Randomized, Open-label Study.
BACKGROUND
The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile. Though mycophenolate mofetil (MMF) + steroid (S) is not recommended by Kidney Disease Improving Global Outcomes guidelines, it can be used as an alternative to mPR due to higher tolerability and steroid-sparing effect. Thus, we compared the safety and effectiveness of MMF + S and mPR regimens in patients with IMN.
METHODS
This randomized, open-label study enrolled patients with adult-onset nephrotic syndrome (NS) and biopsy-proven IMN. Forty-two patients were allocated to MMF + S group (MMF 1 gm twice daily + oral prednisolone 0.5 mg/kg/day; = 21) and mPR group [methylprednisolone (1 gm intravenous) for 3 days followed by alternating monthly cycles of oral prednisolone (0.5 mg/kg/day) for the next 27 days and cyclophosphamide (2 mg/kg/day) for 6 months; = 21]. The primary outcome measure was change in urinary protein creatinine ratio (UPCR).
RESULTS
At 6 months, both groups demonstrated a significant increase in serum albumin levels and estimated glomerular filtration rate (eGFR) (both -values <0.0001) as well as a decrease in 24-hour proteinuria (MMF + S group: -value = 0.003, and mPR group: -value <0.0001) and UPCR (both -values <0.0001). However, the groups did not differ in any of these parameters at any of the monthly follow-up visits. Moreover, the groups did not differ significantly in terms of the composite remission rates (61.91% for MMF + S group and 71.43% for mPR group).
CONCLUSION
MMF + S and mPR had comparable tolerability and effectiveness, with MMF-associated advantage of reduced steroid exposure.
Topics: Humans; Glomerulonephritis, Membranous; Mycophenolic Acid; Male; Female; Adult; Immunosuppressive Agents; Drug Therapy, Combination; Prednisolone; Middle Aged; Glucocorticoids; Cyclophosphamide; Methylprednisolone; Treatment Outcome
PubMed: 38881128
DOI: 10.59556/japi.72.0558