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Advances in Rheumatology (London,... May 2024This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares,...
BACKGROUND
This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data.
METHODS
The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes.
RESULTS
Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual.
CONCLUSIONS
This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.
Topics: Humans; Lupus Erythematosus, Systemic; Female; Immunosuppressive Agents; Hydroxychloroquine; Male; Glucocorticoids; Adult; Azathioprine; Prednisolone; Standard of Care; Methotrexate; Antimalarials; Cohort Studies; Middle Aged; Mycophenolic Acid; Leflunomide; Calcineurin Inhibitors; Logistic Models; Propensity Score; Severity of Illness Index; Tacrolimus; Symptom Flare Up; Treatment Outcome; Antirheumatic Agents
PubMed: 38720354
DOI: 10.1186/s42358-024-00366-y -
Clinical Pharmacology and Therapeutics May 2024On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other...
On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m with titration up to a maximum of 900 mg/m twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m up to a maximum of 900 mg/m b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors.
PubMed: 38695530
DOI: 10.1002/cpt.3288 -
Nature Communications Apr 2024The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft...
Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma.
The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.
Topics: Heart Transplantation; Humans; Male; Graft Rejection; Carcinoma, Squamous Cell; MTOR Inhibitors; Biological Products; Skin Neoplasms; Middle Aged; Everolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Herpesvirus 1, Human
PubMed: 38693123
DOI: 10.1038/s41467-024-47965-3 -
World Journal of Hepatology Apr 2024malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to...
BACKGROUND
malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients.
AIM
To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.
METHODS
A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1 January 2002 to 11 August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.
RESULTS
A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.
CONCLUSION
The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.
PubMed: 38689747
DOI: 10.4254/wjh.v16.i4.650 -
Journal of Medical Case Reports May 2024Mycophenolate mofetil (MMF) is an immunosuppressive drug that is frequently prescribed to patients with rheumatological diseases. MMF's side effects include abdominal... (Review)
Review
BACKGROUND
Mycophenolate mofetil (MMF) is an immunosuppressive drug that is frequently prescribed to patients with rheumatological diseases. MMF's side effects include abdominal discomfort, nausea, vomiting, and other gastro-intestinal side effects, which typically appear in the first few months of treatment. However, late-onset diarrhea does not rule out the presence of MMF-induced colitis, which can be misdiagnosed since it is linked to a broad range of histopathological characteristics, including alterations that resemble inflammatory bowel disease, graft-versus-host disease, and ischemia. The differences in treatment response may be explained by the complexity of the histopathologic characteristics.
CASE PRESENTATION
Here we present a case of a 29-year-old Arabian female with lupus nephritis who started on MMF as induction therapy. In two months, the patient was presented to the Emergency Department with diarrhea and manifestations of severe dehydration. Infectious diseases and adverse drug events were suspected, so the patient was admitted for further workup, and MMF was stopped. The patient was diagnosed with MMF-induced colitis based on colonoscopy and histological findings. Fourteen days after stopping MMF, she was within her baseline.
CONCLUSION
The purpose of this paper is to report a case of early-onset MMF-induced colitis in a patient with lupus nephritis who had started MMF as induction therapy. A review of the available literature on this uncommon immunosuppressive effect is also presented.
Topics: Adult; Female; Humans; Colitis; Colonoscopy; Diarrhea; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid
PubMed: 38689344
DOI: 10.1186/s13256-024-04539-7 -
BMC Pediatrics Apr 2024X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are...
BACKGROUND
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are at an increased risk of developing autoimmune diseases. However, renal involvement are rare in cases of XLA.
CASE PRESENTATION
In this report, we discussed a specific case involving a 6-year-old boy with XLA who experienced recurrent upper respiratory tract infections since the age of one. He presented with symptoms of hematuria and proteinuria, and renal pathology confirmed the presence of immunoglobulin (Ig) A nephropathy. Treatment comprised glucocorticoids, mycophenolate mofetil, and intermittent intravenous immunoglobulin replacement therapy. Consequently, there was a remission of proteinuria and a partial improvement in hematuria.
CONCLUSIONS
In this study, we describe the first case of IgA nephropathy associated with XLA. This is an interesting phenotype found in XLA, and it provides valuable insights into the process of autoimmunity and the regulation of immune function in individuals with XLA. Based on our findings, we recommend the evaluation of immunoglobulin levels in patients diagnosed with IgA nephropathy.
Topics: Humans; Agammaglobulinemia; Male; Glomerulonephritis, IGA; Genetic Diseases, X-Linked; Child; Immunoglobulins, Intravenous; Glucocorticoids; Mycophenolic Acid; Immunosuppressive Agents
PubMed: 38689221
DOI: 10.1186/s12887-024-04746-7 -
Polymers Apr 2024The obtention of amorphous solid dispersions (ASDs) of mycophenolic acid (MPA) in poly(ε-caprolactone) (PCL) is reported in this paper. An improvement in the...
The obtention of amorphous solid dispersions (ASDs) of mycophenolic acid (MPA) in poly(ε-caprolactone) (PCL) is reported in this paper. An improvement in the bioavailability of the drug is possible thanks to the favorable specific interactions occurring in this system. Differential scanning calorimetry (DSC) was used to investigate the miscibility of PCL/MPA blends, measuring glass transition temperature (T) and analyzing melting point depression to obtain a negative interaction parameter, which indicates the development of favorable inter-association interactions. Fourier transform infrared spectroscopy (FTIR) was used to analyze the specific interaction occurring in the blends. Drug release measurements showed that at least 70% of the drug was released by the third day in vitro in all compositions. Finally, preliminary in vitro cell culture experiments showed a decreased number of cancerous cells over the scaffolds containing MPA, presumably arising from the anti-cancer activity attributable to MPA.
PubMed: 38675007
DOI: 10.3390/polym16081088 -
Pathogens (Basel, Switzerland) Mar 2024The objective of this paper was to assess the airborne mold contamination, secondary metabolite profiles, and cytotoxicity of the dominant fungal species isolated from...
OBJECTIVE
The objective of this paper was to assess the airborne mold contamination, secondary metabolite profiles, and cytotoxicity of the dominant fungal species isolated from the air in selected rooms at a Zoological Garden.
MATERIALS AND METHODS
Fungal concentrations were measured with MAS-100 air samplers. The collected airborne fungi were identified using a combination of morphological and molecular methods. The cytotoxicity of 84 strains belonging to two and genera was determined using the quantitative colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium salt) assay. The mycotoxins were detected using high-performance liquid chromatography (HPLC) with a mass spectrometry detector.
RESULTS
The ITS gene was amplified and sequenced to identify the 132 species. For mycotoxicological and cytotoxicity analyses, 52 isolates and 32 representatives were selected. Cytotoxicity was confirmed in 97.6% of cases analyzed. Using the LC-MS/MS method, 42 out of 84 strains produced at least one of the following toxins: ochratoxin A, ochratoxin B, patulin, gliotoxin, roquefortine C, griseofulvin, sterigmatocystin, fumonisin B2, moniliformin, and mycophenolic acid.
CONCLUSIONS
Analytical methods for assessing the presence of mycotoxins in fungal isolates collected directly from the air have proven to be an effective tool. Our research provides new information on the occurrence of potentially toxin-producing molds within a zoo.
PubMed: 38668249
DOI: 10.3390/pathogens13040294 -
Transplantation May 2024
Comparative Study
Topics: Humans; Everolimus; Immunosuppressive Agents; Tacrolimus; Mycophenolic Acid; Sirolimus; Kidney Transplantation; Graft Rejection; Treatment Outcome; Middle Aged; Female; Time Factors; Male; Drug Therapy, Combination; Adult
PubMed: 38659117
DOI: 10.1097/TP.0000000000004941 -
Transplant International : Official... 2024Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to...
Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.
Topics: Humans; Immunosuppressive Agents; Cytomegalovirus Infections; T-Lymphocytes; Cytomegalovirus; Tacrolimus; Mycophenolic Acid; Sirolimus; Everolimus; Lymphocyte Activation; Prednisolone; Organ Transplantation; Cell Proliferation
PubMed: 38655204
DOI: 10.3389/ti.2024.12720