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Annals of Clinical and Translational... Apr 2024We aim to characterize the sociodemographic and clinical factors associated with loss of jobs, income, and work hours in people with neuromyelitis optica spectrum...
BACKGROUND AND OBJECTIVES
We aim to characterize the sociodemographic and clinical factors associated with loss of jobs, income, and work hours in people with neuromyelitis optica spectrum disorder (NMOSD) in the United States.
METHODS
A REDCap-based survey was administered to working-age NMOSD patients (18-70 years old) querying demographic information, symptoms, immunosuppression, work hours, income, and caregiver work (11/2022-07/2023). Regression models were developed using MATLAB.
RESULTS
Of 127 participants (97 female; 55% AQP4-antibody, 19% MOG antibody; 69% Caucasian, 7% Hispanic), with an average diagnosis age of 38.7 years, average disease duration of 6.4 years, mean 3.1 attacks, and 94% of whom were treated with immune system-directed therapy (53% rituximab, 8% satralizumab, 7% eculizumab, 6% mycophenolate mofetil, 4% inebilizumab, 2% azathioprine, 10% IVIg, 10% other), 56% lost a job due to NMOSD. Employment decreased 12% (80% pre- to 68% post-diagnosis). Thirty-six percent of participants said they no longer worked outside the home. Significant predictors for post-NMOSD diagnosis employment status included younger age, lower pain level, no walking aids, and having a job prediagnosis. Sixty-eight percent of those employed prediagnosis reduced their work hours, dropping an average of 18.4 h per month since being diagnosed (±10.1 h). Average annual income grew slowly at $1998 during the average 6.4 years of disease duration (14% of the value predicted by the U.S. Bureau of Labor Statistics). Sixty percent of participants had a regular unpaid caregiver; 34% of caregivers changed their work hours or job to help manage NMOSD.
DISCUSSION
We provide a structured analysis of the impact of NMOSD on employment, work hours, and income in the United States, demonstrating its major effect on the livelihoods of patients and their caregivers.
Topics: Humans; Female; United States; Adolescent; Young Adult; Adult; Middle Aged; Aged; Neuromyelitis Optica; Rituximab; Mycophenolic Acid; Immunoglobulins, Intravenous
PubMed: 38374778
DOI: 10.1002/acn3.52021 -
Journal of Medical Case Reports Feb 2024Scleredema adultorum of Buschke is a rare disease characterized by firm and non-pitting edema of the skin. The condition is rare with unknown etiology. Diagnosis is made...
BACKGROUND
Scleredema adultorum of Buschke is a rare disease characterized by firm and non-pitting edema of the skin. The condition is rare with unknown etiology. Diagnosis is made on the basis of clinical findings and skin biopsy.
CASE PRESENTATION
Here, we describe a 14-year-old Iranian girl presenting with non-pitting edema and woody thickening of the skin that progressed within a month. She was evaluated for possible underlying malignancy or connective tissue disorders, which were excluded by multiple laboratory workups. She underwent a skin biopsy which confirmed the diagnosis of scleredema, and she was successfully treated with intravenous immunoglobulin and mycophenolate mofetil.
CONCLUSION
While scleredema adultorum of Buschke is a rare disease with no definite treatment, our effort through this report was to highlight the possible benefits of treatment by intravenous immunoglobulin and mycophenolate mofetil.
Topics: Female; Humans; Adolescent; Scleredema Adultorum; Immunoglobulins, Intravenous; Mycophenolic Acid; Iran; Rare Diseases; Edema
PubMed: 38350929
DOI: 10.1186/s13256-024-04427-0 -
Food Chemistry Jun 2024This work provided an accurate analytical method to perform a multitarget analysis of a variety of antimicrobials (AMs) including sulfonamides, tetracyclines,...
This work provided an accurate analytical method to perform a multitarget analysis of a variety of antimicrobials (AMs) including sulfonamides, tetracyclines, macrolides, fluoroquinolones and quinolones, one imidazole and one nitroimidazole, one triazole, one diaminopyridine and one derivative of Penicillium stoloniferum in vegetables. The analysis is performed using liquid-chromatography coupled to a low-resolution triple quadrupole mass spectrometer (UHPLC-MS/MS) to detect the target analytesor coupled to a high-resolution q-Orbitrap (HRMS) to monitor the formed transformation products (TPs). Both instruments were compared in terms of limits of quantification and matrix effect at the detection. The method was applied to determine the presence of AMs in organic and non-organic vegetables, where sulfadiazine and mycophenolic acid were detected. On the other hand, the transference of four AMs (trimethoprim, sulfamethazine, enrofloxacin, and chlortetracycline) from soils to lettuces was evaluated through controlled uptake experiments. The choice of AMs was based on the classification into different families, and on the fact that those AM families are the most frequently detected in the environment. In this case, each of the AMs with which the soils were contaminated were found in the exposed lettuces. Moreover, in both studies, specific TPs of the AMs were identified, posing the necessity of assessing their effects in relation to food and human safety.
Topics: Humans; Tandem Mass Spectrometry; Vegetables; Chromatography, Liquid; Anti-Bacterial Agents; Soil; Chromatography, High Pressure Liquid
PubMed: 38340504
DOI: 10.1016/j.foodchem.2024.138643 -
Medicine Feb 2024While some systemic lupus erythematosus (SLE) patients may experience varying degrees of liver function abnormalities, only a small portion of these cases have clinical...
RATIONALE
While some systemic lupus erythematosus (SLE) patients may experience varying degrees of liver function abnormalities, only a small portion of these cases have clinical significance, and the majority of patients typically exhibit low levels of serum bilirubin. However, in this article, we present a case of a middle-aged female patient with SLE who exhibited persistent skin jaundice as her initial symptom, offering a fresh perspective on diagnosing and treating patients who exhibit unexplained liver dysfunction and SLE combined with liver injury.
PATIENT CONCERNS
A 45-year-old woman was initially admitted to the hospital due to yellowing of the skin and sclera, and her symptoms did not improve significantly during treatment. The results were abnormal after relevant immunological tests.
DIAGNOSES
Persistent non-conjugated bilirubin elevation due to lupus hepatitis.
INTERVENTIONS
The use of methylprednisolone sodium succinate (40 mg/Qd) and mycophenolate mofetil (0.75 g/d) suppressed immunity, polyolefin choline (20 mL/d) and glutathione (0.6 g/Qd) improved liver function, and nutritional support therapy.
OUTCOMES
After 2 weeks of treatment, a significant decrease in the yellow skin and sclera of the patient was observed.
LESSONS
Most clinicians overlook that liver function abnormalities are the main manifestation of SLE, resulting in many patients not receiving timely treatment. This study highlights the importance that SLE is also a cause of abnormal liver function.
Topics: Humans; Middle Aged; Female; Lupus Erythematosus, Systemic; Liver Diseases; Mycophenolic Acid; Methylprednisolone Hemisuccinate; Bilirubin
PubMed: 38335395
DOI: 10.1097/MD.0000000000036999 -
Frontiers in Medicine 2024Following kidney transplantation, lifelong immunosuppressive therapy is essential to prevent graft rejection. On the downside, immunosuppression increases the risk of...
Following kidney transplantation, lifelong immunosuppressive therapy is essential to prevent graft rejection. On the downside, immunosuppression increases the risk of severe infections, a major cause of death among kidney transplant recipients (KTRs). To improve post-transplant outcomes, adequate immunosuppressive therapy is therefore a challenging but vital aspect of clinical practice. Torque teno virus load (TTVL) was shown to reflect immune competence in KTRs, with low TTVL linked to an elevated risk for rejections and high TTVL associated with infections in the first year post-transplantation. Yet, little is known about the dynamics of TTVL after the first year following transplantation and how TTVL changes with respect to short-term modifications in immunosuppressive therapy. Therefore, we quantified TTVL in 106 KTRs with 108 clinically indicated biopsies, including 65 biopsies performed >12 months post-transplantation, and correlated TTVL to histopathology. In addition, TTVL was quantified at 7, 30, and 90 days post-biopsy to evaluate how TTVL was affected by changes in immunosuppression resulting from interventions based on histopathological reporting. TTVL was highest in patients biopsied between 1 and 12 months post-transplantation (N = 23, median 2.98 × 10 c/mL) compared with those biopsied within 30 days (N = 20, median 7.35 × 10 c/mL) and > 1 year post-transplantation (N = 65, median 1.41 × 10 c/mL; < 0.001 for both). Patients with BK virus-associated nephropathy (BKVAN) had significantly higher TTVL than patients with rejection ( < 0.01) or other pathologies ( < 0.001). When converted from mycophenolic acid to a mTOR inhibitor following the diagnosis of BKVAN, TTVL decreased significantly between biopsy and 30 and 90 days post-biopsy ( < 0.01 for both). In KTR with high-dose corticosteroid pulse therapy for rejection, TTVL increased significantly between biopsy and 30 and 90 days post-biopsy ( < 0.05 and < 0.01, respectively). Of note, no significant changes were seen in TTVL within 7 days of changes in immunosuppressive therapy. Additionally, TTVL varied considerably with time since transplantation and among individuals, with a significant influence of age and BMI on TTVL ( < 0.05 for all). In conclusion, our findings indicate that TTVL reflects changes in immunosuppressive therapy, even in the later stages of post-transplantation. To guide immunosuppressive therapy based on TTVL, one should consider inter- and intraindividual variations, as well as potential confounding factors.
PubMed: 38327708
DOI: 10.3389/fmed.2024.1337367 -
Journal of Translational Medicine Feb 2024Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood....
Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer.
BACKGROUND
Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC.
METHODS
An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro.
RESULTS
Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP.
CONCLUSIONS
IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.
Topics: Humans; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; IMP Dehydrogenase; Oxaliplatin; Oxidoreductases; Wnt Signaling Pathway
PubMed: 38310229
DOI: 10.1186/s12967-024-04934-0 -
The British Journal of Dermatology Mar 2024The direct antitumour effects of mTOR inhibitors against cutaneous squamous cell carcinoma (SCC) have prompted a paradigm shift towards using sirolimus for allograft...
The direct antitumour effects of mTOR inhibitors against cutaneous squamous cell carcinoma (SCC) have prompted a paradigm shift towards using sirolimus for allograft rejection prophylaxis in patients with high-risk SCC who have had a solid organ transplant (SOT). Patients who have had an SOT are at higher risk for Merkel cell carcinoma (MCC), yet there is little evidence concerning potential antitumour effects of immunosuppressive drugs against MCC. Screening seven immunosuppressive drugs in six MCC cell lines revealed that mycophenolate mofetil (MMF) had strong antitumour activity (surpassing mTOR inhibitors) and higher potency in MCC vs. other cancer types. MMF also inhibited MCC tumour growth in mice. Our preclinical findings strongly suggest the utility of MMF in patients with MCC who require immunosuppression.
Topics: Humans; Mycophenolic Acid; Carcinoma, Merkel Cell; Immunosuppressive Agents; Graft Rejection; Skin Neoplasms
PubMed: 38266271
DOI: 10.1093/bjd/ljae018 -
Trials Jan 2024Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the...
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.
Topics: Humans; Tacrolimus; Hepatitis, Autoimmune; Quality of Life; Retrospective Studies; Treatment Outcome; Immunosuppressive Agents; Mycophenolic Acid; Enzyme Inhibitors; Liver Cirrhosis; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 38233878
DOI: 10.1186/s13063-023-07832-w -
Journal For Immunotherapy of Cancer Jan 2024Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can...
Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.
Topics: Humans; Abatacept; Adrenal Cortex Hormones; Colitis; Hepatitis; Immunoglobulins, Intravenous; Infliximab; Mycophenolic Acid; Myocarditis; Neoplasms; Nitriles; Pneumonia; Pyrazoles; Pyrimidines
PubMed: 38233099
DOI: 10.1136/jitc-2023-007409 -
Lupus Science & Medicine Jan 2024Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment.
METHODS
A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics.
RESULTS
A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C) of MPA showed a strong association with renal response, evidenced by C values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events.
CONCLUSION
This meta-analysis emphasised the meaningful correlation between MPA AUC and C with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.
Topics: Humans; Drug Monitoring; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid
PubMed: 38233072
DOI: 10.1136/lupus-2023-001093