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Frontiers in Immunology 2023Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.
METHODS
We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.
RESULTS
Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).
DISCUSSION
This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.
Topics: Humans; Adult; Immunosuppressive Agents; Lupus Nephritis; Network Meta-Analysis; Treatment Outcome; Cyclophosphamide; Tacrolimus; Azathioprine; Mycophenolic Acid; Glucocorticoids; Bone Marrow Diseases; Kidney Failure, Chronic; Recurrence; Herpes Zoster; Neoplasms
PubMed: 37901212
DOI: 10.3389/fimmu.2023.1232244 -
Biomedicines Sep 2023The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence... (Review)
Review
The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence supporting the hypothesis that gut microorganisms may contribute to this variability by affecting cIMD pharmacokinetics, efficacy or tolerability. The evidence that these drugs affect the composition of intestinal microbiota was also reviewed. The PubMed and Scopus databases were searched using specific keywords without limits of species (human or animal) or time from publication. One thousand and fifty five published papers were retrieved in the initial database search. After screening, 50 papers were selected to be reviewed. Potential effects on cIMD pharmacokinetics, efficacy or tolerability were observed in 17/20 papers evaluating this issue, in particular with tacrolimus, cyclosporine, mycophenolic acid and corticosteroids, whereas evidence was missing for everolimus and sirolimus. Only one of the papers investigating the effect of cIMDs on the gut microbiota reported negative results while all the others showed significant changes in the relative abundance of specific intestinal bacteria. However, no unique pattern of microbiota modification was observed across the different studies. In conclusion, the available evidence supports the hypothesis that intestinal microbiota could contribute to the variability in the response to some cIMDs, whereas data are still missing for others.
PubMed: 37761003
DOI: 10.3390/biomedicines11092562 -
Seminars in Arthritis and Rheumatism Dec 2023Invasive fungal infections (IFIs) are life-threatening opportunistic infections in patients with connective tissue disease CTD) that cause significant morbidity and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Invasive fungal infections (IFIs) are life-threatening opportunistic infections in patients with connective tissue disease CTD) that cause significant morbidity and mortality. We attempted to determine the potential risk factors associated with IFIs in CTD.
METHODS
We systematically searched PubMed, Embase, and the Cochrane Library databases for relevant articles published from the database inception to February 1, 2023.
RESULTS
Twenty-six studies were included in this systematic review and meta-analysis. Risk factors identified for IFIs were diabetes (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.00 to 2.64), pulmonary diseases (OR 3.43; 95% CI 2.49 to 4.73), interstitial lung disease (ILD; OR, 4.06; 95% CI, 2.22 to 7.41), renal disease (OR, 4.41; 95% CI, 1.84 to 10.59), glucocorticoid (GC) use (OR, 4.15; 95% CI, 2.74 to 6.28), especially moderate to high-dose GC, azathioprine (AZA) use (OR, 1.50; 95% CI, 1.12 to 2.01), calcineurin inhibitor (CNI) use (OR, 2.49; 95% CI, 1.59 to 3.91), mycophenolate mofetil (MMF) use (OR, 2.83; 95% CI, 1.59 to 5.03), cyclophosphamide (CYC) use (OR, 3.35; 95% CI, 2.47 to 4.54), biologics use (OR, 3.43; 95% CI, 2.36 to 4.98), and lymphopenia (OR, 4.26; 95% CI, 2.08 to 8.73). Hydroxychloroquine (HCQ) use reduced risk of IFIs (OR, 0.67; 95% CI, 0.54 to 0.84). Furthermore, 17 of the 26 studies only reported risk factors for Pneumocystis jiroveci pneumonia (PJP) in patients with CTD. Pulmonary disease; ILD; and the use of GC, CNIs, CYC, methotrexate (MTX), MMF and biologics, and lymphopenia increased the risk of PJP, whereas the use of HCQ reduced its risk.
CONCLUSION
Diabetes, pulmonary disease, ILD, renal disease, use of GC (especially at moderate to high dose) and immunosuppressive drugs, and lymphopenia were found to be associated with significant risk for IFIs (especially PJP) in patients with CTD. Furthermore, the use of HCQ may reduce the risk of IFIs in patients with CTD.
Topics: Humans; Connective Tissue Diseases; Cyclophosphamide; Lung Diseases, Interstitial; Mycophenolic Acid; Glucocorticoids; Risk Factors; Diabetes Mellitus; Lymphopenia; Biological Products; Invasive Fungal Infections
PubMed: 37633041
DOI: 10.1016/j.semarthrit.2023.152257 -
Annals of the American Thoracic Society Jan 2024The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic... (Meta-Analysis)
Meta-Analysis
The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with mycophenolate. A literature search was conducted across the MEDLINE, EMBASE, and CENTRAL databases through June 2022 for studies using mycophenolate to treat patients with SSc-ILD. Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group method was used to assess the quality of evidence. The literature review resulted in seven studies fitting the inclusion criteria. The systematic review and meta-analyses revealed changes in forced vital capacity % predicted (mean difference [MD], 5.4%; 95% confidence interval [95% CI]: 3.3%, 7.5%), diffusing capacity of the lung for carbon monoxide % predicted (MD, 4.64%; 95% CI: 0.54%, 8.74%), and breathlessness score (MD, 1.99; 95% CI: 0.36, 3.62) favored mycophenolate over placebo. The risk of anemia (relative risk [RR], 2.3; 95% CI: 1.2, 71.4) was higher with mycophenolate. There were no significant differences between mycophenolate and cyclophosphamide, except risk of premature discontinuation (RR, 0.6; 95% CI: 0.4, 0.9), and leukopenia (RR, 0.1; 95% CI: 0.05, 0.4) favored mycophenolate. The quality of evidence was moderate to very low per GRADE. Mycophenolate use in patients with SSc-ILD is associated with statistically significant improvements in disease progression and quality-of-life measures compared with placebo. There were no differences in mortality, disease progression, or quality of life compared with cyclophosphamide, but there were fewer adverse events. The quality of evidence is very low.
Topics: Humans; Quality of Life; Lung Diseases, Interstitial; Mycophenolic Acid; Scleroderma, Systemic; Immunosuppressive Agents; Cyclophosphamide; Lung; Disease Progression
PubMed: 37027538
DOI: 10.1513/AnnalsATS.202301-054OC -
Polish Archives of Internal Medicine Sep 2023Although it is well established that 2 doses of COVID‑19 vaccines are associated with reduced immune responses in liver transplant recipients (LTRs), studies regarding... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Although it is well established that 2 doses of COVID‑19 vaccines are associated with reduced immune responses in liver transplant recipients (LTRs), studies regarding their immunogenicity and tolerability after a booster dose are limited.
OBJECTIVES
We aimed to review the available literature data regarding antibody responses and safety of the third dose of COVID‑19 vaccines in LTRs.
METHODS
We searched PubMed and Google Scholar for eligible studies. The primary outcome was to compare the rates of seroconversion after the second and third dose of COVID‑19 vaccine in LTRs. This meta‑analysis was performed using a generalized linear mixed model and the Clopper and Pearson method was employed to calculate the 2‑sided CIs.
RESULTS
Six prospective studies involving 596 LTRs met the inclusion criteria. The pooled rate of antibody response before the third dose was 71% (95% CI, 56%-83%; heterogeneity, I2 = 90%; P <0.001), while after the third dose it was 94% (95% CI, 91%-96%; heterogeneity, I2 = 17%; P = 0.31). There was no difference in antibody responses after the third dose in relation to the use of calcineurin inhibitors (P = 0.44) or mammalian target of rapamycin inhibitors (P = 0.33), while the pooled rate of antibody responses in the patients on mycophenolate mofetil (MMF) was 88% (95% CI, 83%-92%; heterogeneity, I2 = 0%; P = 0.57). It was significantly lower (P <0.001), as compared with those on MMF‑free immunosuppression (pooled rate, 97%; 95% CI, 95%-98%; heterogeneity, I2 = 30%; P = 0.22). No safety concerns were reported for the booster dose.
CONCLUSIONS
Our meta‑analysis demonstrated that the third dose of COVID‑19 vaccines induced adequate humoral and cellular immune responses in LTRs, while MMF remained a negative predictor of immunologic responses.
Topics: Humans; COVID-19 Vaccines; Seroconversion; COVID-19; Liver Transplantation; Prospective Studies; Mycophenolic Acid
PubMed: 36876925
DOI: 10.20452/pamw.16455 -
Journal of the American Pharmacists... 2023Although generic ciclosporin-A (CsA) and tacrolimus (TAC) have been used for the prophylaxis of organ rejection in transplant patients for decades, evidence in their... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Although generic ciclosporin-A (CsA) and tacrolimus (TAC) have been used for the prophylaxis of organ rejection in transplant patients for decades, evidence in their safety profile compared to reference listed drugs (RLDs) in real-world transplant patients remains limited.
OBJECTIVES
To compare safety outcomes of generic CsA and TAC with the reference-listed drugs in solid organ transplant patients.
METHODS
We systematically searched MEDLINE, International Pharmaceutical Abstracts, PsycINFO, and Cumulative Index of Nursing and Allied Health Literature from inception until March 15, 2022, to select randomized and observational studies comparing safety profiles of generic versus brand CsA and TAC in de novo and/or stable solid organ transplant patients. Primary safety outcomes were changes in serum creatinine (Scr) and glomerular filtration rate (GFR). Secondary outcomes included incidences of infection, hypertension, diabetes, other serious adverse events (AEs), hospitalization, and death. Mean difference (MD) and relative risk (RR) with 95% confidence intervals (CIs) were calculated using random-effects meta-analyses.
RESULTS
Of 2612 publications identified, 32 studies met inclusion criteria. Seventeen studies had a moderate risk of bias. Scr was statistically significantly lower in patients using generic CsA compared to brand at 1 month (MD = -0.07; 95% CI: -0.11, -0.04), while there were no statistically significant differences at 4 months, 6 months, and 12 months. No differences were detected in Scr (MD = -0.04; 95% CI: -0.13, 0.04) and estimated GFR (MD = -2.06; 95% CI: -8.89, 4.77) between patients using generic and brand TAC at 6 months. No statistically significant differences between generic CsA and TAC with their RLDs were observed for secondary outcomes.
CONCLUSION
Findings support similarity in safety outcomes between generic and brand CsA and TAC in real-world solid organ transplant patients.
Topics: Humans; Calcineurin Inhibitors; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus; Cyclosporine; Organ Transplantation
PubMed: 36863965
DOI: 10.1016/j.japh.2023.02.006 -
Clinical and Experimental Vaccine... Jan 2023This systematic and meta-analysis aims to evaluate humoral and cellular responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine among... (Review)
Review
Seroconversion rates in kidney transplant recipients following SARS-CoV-2 vaccination and its association with immunosuppressive agents: a systematic review and meta-analysis.
This systematic and meta-analysis aims to evaluate humoral and cellular responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine among kidney transplant recipients (KTRs). We conducted a systematic literature search across databases to evaluate seroconversion and cellular response rates in KTRs receiving SARS-CoV-2 vaccines. We extracted studies that assessed seroconversion rates described as the presence of antibody positivity in KTRs following SARS-CoV-2 vaccination published up to January 23rd, 2022. We also performed meta-regression based on immunosuppression therapy used. A total of 44 studies involving 5,892 KTRs were included in this meta-analysis. The overall seroconversion rate following complete dose of vaccines was 39.2% (95% confidence interval [CI], 33.3%-45.3%) and cellular response rate was 41.6% (95% CI, 30.0%-53.6%). Meta-regression revealed that low antibody response rate was significantly associated with the high prevalence of mycophenolate mofetil/mycophenolic acid (p=0.04), belatacept (p=0.02), and anti-CD25 induction therapy uses (p=0.04). Conversely, tacrolimus use was associated with higher antibody response (p=0.01). This meta-analysis suggests that postvaccination seroconversion and cellular response rates in KTRs are still low. And seroconversion rate was correlated with the type of immunosuppressive agent and induction therapy used. Additional doses of the SARS-CoV-2 vaccine for this population using a different type of vaccine are considered.
PubMed: 36844682
DOI: 10.7774/cevr.2023.12.1.13 -
Therapeutic Drug Monitoring Aug 2023Volumetric absorptive microsampling (VAMS) is an emerging technique that may support multisample collection to enhance therapeutic drug monitoring in solid organ...
BACKGROUND
Volumetric absorptive microsampling (VAMS) is an emerging technique that may support multisample collection to enhance therapeutic drug monitoring in solid organ transplantation. This review aimed to assess whether tacrolimus and mycophenolic acid can be reliably assayed using VAMS and to identify knowledge gaps by providing granularity to existing analytical methods and clinical applications.
METHODS
A systematic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed, Embase, and Scopus databases were accessed for records from January 2014 to April 2022 to identify scientific reports on the clinical validation of VAMS for monitoring tacrolimus and mycophenolic acid concentrations. Data on the study population, sample sources, analytical methods, and comparison results were compiled.
RESULTS
Data from 12 studies were collected, including 9 studies pertaining to tacrolimus and 3 studies on the concurrent analysis of tacrolimus and mycophenolic acid. An additional 14 studies that provided information relevant to the secondary objectives (analytical validation and clinical application) were also included. The results of the clinical validation studies generally met the method agreement requirements described by regulatory agencies, but in many cases, it was essential to apply correction factors.
CONCLUSIONSS
Current evidence suggests that the existing analytical methods that use VAMS require additional optimization steps for the analysis of tacrolimus and mycophenolic acid. The recommendations put forth in this review can help guide future studies in achieving the goal of improving the care of transplant recipients by simplifying multisample collection for the dose optimization of these drugs.
Topics: Humans; Tacrolimus; Mycophenolic Acid; Drug Monitoring; Tandem Mass Spectrometry; Organ Transplantation; Blood Specimen Collection; Dried Blood Spot Testing
PubMed: 36728554
DOI: 10.1097/FTD.0000000000001066 -
Zeitschrift Fur Rheumatologie Nov 2023The purpose of this study was to compare the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) as induction therapy and low-dose tacrolimus as treatment... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The purpose of this study was to compare the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) as induction therapy and low-dose tacrolimus as treatment for lupus nephritis (LN).
METHODS
Meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety of tacrolimus and MMF as induction therapy for LN. We systematically reviewed RCTs and prospective cohort studies with a tacrolimus dose of 3 mg daily and performed a meta-analysis of the efficacy and safety of tacrolimus as an induction treatment for LN in comparison to MMF.
RESULTS
The inclusion criteria were satisfied by eight studies (five RCTs and three prospective cohort studies) with a total of 408 individuals (289 for tacrolimus vs. MMF and 119 for low-dose tacrolimus). Tacrolimus and MMF had similar complete remission rates (odds ratio [OR] 1.028; 95% confidence interval [CI] 0.589-1.796; p = 0.922). The partial remission rate did not differ between the tacrolimus and MMF groups (OR 1.400; 95% CI 0.741-2.646; p = 0.300). Tacrolimus and MMF showed no differences in proteinuria, serum albumin, serum creatinine, creatinine clearance, renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), or extra-renal SLEDAI. The incidence of infection, severe infection, leukopenia, and hyperglycemia did not differ between the tacrolimus and MMF groups. However, herpes zoster infection was significantly less common in the tacrolimus group (OR 0.137; 95% CI 0.034-0.546; p = 0.005), whereas serum creatinine elevation was significantly higher in the tacrolimus group than in the MMF group (OR 8.148; 95% CI 1.369-48.50; p = 0.021). At 3 mg/d, tacrolimus was shown to be safe, well tolerated, and offered therapeutic benefits in all investigations.
CONCLUSION
Tacrolimus was comparable to MMF in terms of effectiveness and safety as an induction therapy for LN, with the exception of a reduced risk of herpes zoster infection and a rise in serum creatinine. In individuals with LN, 3 mg/d tacrolimus was proven to be efficacious and safe.
Topics: Humans; Tacrolimus; Lupus Nephritis; Mycophenolic Acid; Immunosuppressive Agents; Cyclophosphamide; Creatinine; Treatment Outcome; Herpes Zoster
PubMed: 36607421
DOI: 10.1007/s00393-022-01313-2 -
Transplant Infectious Disease : An... Feb 2023Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs)....
BACKGROUND
Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs). The burden of L/N is poorly quantified systematically. This systematic literature review aimed to summarize the incidence of, risk factors for, and clinical and economic outcomes associated with L/N post-KT.
METHODS
We systematically searched MEDLINE, Embase, and the Cochrane Library (from database inception-June 14, 2021) and conferences (past 3 years) to identify observational studies examining epidemiology, risk factors, or outcomes associated with L/N among adult KTRs.
RESULTS
Of 2081 records, 82 studies met inclusion criteria. Seventy-three studies reported the epidemiology of L/N post-KT. Pooled incidence of neutropenia, defined as absolute neutrophil counts (ANC) <1000/μl, ranged from 13% to 48% within 1-year post-transplant; ANC <500/μl ranged from 15% to 20%. Leukopenia, defined as white blood cell counts <3500/μl, was 19% to 83%. Eleven studies reported independent risk factors associated with L/N post-KT. D+/R- cytomegalovirus status, mycophenolic acid (MPA), and tacrolimus use were the most consistent risk factors across studies. Fourteen studies reported L/N-associated clinical outcomes. We noted a trend toward a positive association between neutropenia and acute rejection/opportunistic infections. Mixed findings were noted on the association between L/N and graft failure or mortality. Dosage modifications of valganciclovir, MPA, cotrimoxazole, and anti-thymoglobulin and the need for granulocyte colony-stimulating factor (G-CSF) use were common with L/N.
CONCLUSION
Findings suggest post-transplant L/N were common and associated with frequent modifications of immunosuppressive agents, requiring G-CSF use, and rejection or opportunistic infections. Findings highlight the need for interventions to reduce risk of L/N post-KT.
Topics: Humans; Adult; Kidney Transplantation; Neutropenia; Leukopenia; Valganciclovir; Immunosuppressive Agents; Granulocyte Colony-Stimulating Factor; Mycophenolic Acid; Anemia; Opportunistic Infections; Transplant Recipients; Graft Rejection
PubMed: 36508475
DOI: 10.1111/tid.14000