Do rheumatic diseases, long-term glucocorticoids, and immunosuppressant treatment, and vaccination impact the COVID-19 severity? Insight from a retrospective cohort study.

OBJECTIVES: The impact of rheumatic diseases, long-term medication, and vaccination on COVID-19 severity remain insufficiently understood, hindering effective patient management. This study aims to investigate factors influencing COVID-19 severity in Chinese rheumatic patients and to provide real-world evidence for patient care. METHODS: We conducted a retrospective observational study consisting of two cohorts, followed by a nested case-control analysis. The outpatient cohort included non-severe COVID-19 patients, while the inpatient cohort included consecutive severe COVID-19 inpatients. Additionally, rheumatic patients from both cohorts were included for the nested case-control study. Clinical information was obtained from electronic medical records and surveys. RESULTS: A total of 749 outpatients and 167 inpatients were enrolled. In the outpatient cohort, rheumatic diseases were identified as a risk factor for the severity of dyspnea (No rheumatic disease: OR = 0.577, 95% CI = 0.396-0.841, p = .004), but not for mortality, length of hospitalization, or hospitalization costs in the inpatient cohort. Long-term glucocorticoids use was identified as an independent risk factor for severity of dyspnea in rheumatic patients (OR = 1.814, 95% CI = 1.235-2.663, p = .002), while vaccination and immunosuppressant treatment showed no association. Vaccination was identified as a protective factor against hospitalization due to COVID-19 in patients with rheumatic diseases (OR = 0.031, 95% CI = 0.007-0.136, p < .001), whereas long-term glucocorticoids and immunosuppressant treatment showed no association. CONCLUSIONS: Rheumatic diseases and long-term glucocorticoids use are significant risk factors for COVID-19 severity in the Chinese population, whereas emphasizing the protective effects of vaccines against COVID-19 severity is crucial. Additionally, the investigation provides preliminary support for the concept that long-term immunosuppressant therapy does not necessarily require additional prescription adjustments.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors.

This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

A Randomized Trial Comparing Imlifidase to Plasmapheresis in Kidney Transplant Recipients With Antibody-Mediated Rejection.

BACKGROUND: Antibody-mediated rejection (ABMR) poses a barrier to long-term graft survival and is one of the most challenging events after kidney transplantation. Removing donor specific antibodies (DSA) through therapeutic plasma exchange (PLEX) is a cornerstone of antibody depletion but has inconsistent effects. Imlifidase is a treatment currently utilized for desensitization with near-complete inactivation of DSA both in the intra- and extravascular space. METHODS: This was a 6-month, randomized, open-label, multicenter, multinational trial conducted at 14 transplant centers. Thirty patients were randomized to either imlifidase or PLEX treatment. The primary endpoint was reduction in DSA level during the 5 days following the start of treatment. RESULTS: Despite considerable heterogeneity in the trial population, DSA reduction as defined by the primary endpoint was 97% for imlifidase compared to 42% for PLEX. Additionally, imlifidase reduced DSA to noncomplement fixing levels, whereas PLEX failed to do so. After antibody rebound in the imlifidase arm (circa days 6-12), both arms had similar reductions in DSA. Five allograft losses occurred during the 6 months following the start of ABMR treatment-four within the imlifidase arm (18 patients treated) and one in the PLEX arm (10 patients treated). In terms of clinical efficacy, the Kaplan-Meier estimated graft survival was 78% for imlifidase and 89% for PLEX, with a slightly higher eGFR in the PLEX arm at the end of the trial. The observed adverse events in the trial were as expected, and there were no apparent differences between the arms. CONCLUSION: Imlifidase was safe and well-tolerated in the ABMR population. Despite meeting the primary endpoint of maximum DSA reduction compared to PLEX, the trial was unsuccessful in demonstrating a clinical benefit of imlifidase in this heterogenous ABMR population. TRIAL REGISTRATION: EudraCT number: 2018-000022-66, 2020-004777-49; ClinicalTrials.gov identifier: NCT03897205, NCT04711850.

Therapeutic drug monitoring of mycophenolic acid and azole antifungals on two distinct LC-MS/MS instruments.

Background: As an active metabolite of a commonly prescribed immunosuppressant, mycophenolic acid (MPA) levels are often monitored to prevent organ rejection following a transplant. Triazoles are often prescribed for treatment of invasive fungal infections in immunocompromised patients. Due to the variability in individual pharmacokinetics and drug-drug interactions, therapeutic drug monitoring is recommended for triazole antifungals. A multiplex LC-MS/MS assay has been developed that can quantify both MPA and triazole drugs in serum. Methods: A sample preparation procedure was established to spike in internal standard compounds and precipitate proteins. Reversed-phase chromatographic separation was performed on a C18 column with an analysis time of five minutes per sample. The mass spectrometer was operated in multiple reaction monitoring mode. The method was validated on two HPLC systems interfaced with either a Triple Quad 6500 or an API 4000 instrument. Results: The multiplex assay was linear over a wide dynamic range with analyte measurable ranges of 0.4-48 µg/mL for MPA, 0.1-12 µg/mL for posaconazole, and 0.2-24 µg/mL for voriconazole, itraconazole, hydroxyitraconazole, and isavuconazole. The between-day and intraday imprecisions were less than 10 %. Limits of detection were below 0.04 ug/mL with limits of quantitation below 0.2 µg/mL. Method comparison studies against the current in-house method met acceptance criteria. The instrument comparison study demonstrated a strong correlation between data collected from the two systems. Conclusion: A robust multiplex LC-MS/MS assay was developed and validated for monitoring MPA and triazoles drug levels in a clinical laboratory. The assay performance on two distinct instruments was acceptable and comparable.

Topical Tacrolimus in Anterior Segment Disorders in Ophthalmology: A Review.

The purpose of this study is to emphasize topical tacrolimus's role in treating anterior segment diseases in ophthalmology. The present study analyzed research papers and publications from international databases, including Pubmed, MedLine, Google Scholar, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Scopus to highlight the significance and advantages of topical application of tacrolimus and its efficacy in treating allergic eye disorders, immune-mediated diseases, and other ocular surface disorders. Tacrolimus and cyclosporine are the two most commonly used topical immunosuppressants in ophthalmology. Tacrolimus is a selective calcineurin inhibitor administered for the prevention and treatment of allograft rejection in solid organ transplant recipients and has a similar mechanism of action to cyclosporine. Management of immune-mediated inflammatory anterior segment requires intense immunosuppression and studies have shown that tacrolimus is ten to hundred times more effective than cyclosporine. Abbreviations: IL-2 = interleukin-2, FDA = Food and Drug Administration Agency, GvHD = graft versus host disease, (Ig)E = immunoglobulin E, SAC = seasonal conjunctivitis, PAC = perennial allergic conjunctivitis, VKC = vernal keratoconjunctivitis, AKC = allergic keratoconjunctivitis, GPC = giant papillary conjunctivitis, PKC = phyctenular keratoconjunctivitis, DED = dry eye disease, TBUT = tear break up time.

Efficacy of Prednisone Avoidance in Patients With Liver Transplant Using the U.S. Food and Drug Administration Adverse Event Reporting System.

Background Immunosuppressants are administered in various combinations to prevent immune-induced transplant rejection in patients with liver transplant, as each immunosuppressant acts on different cellular sites. However, the use of multiple immunosuppressants also increases the risk for adverse events. Therefore, it is desirable to reduce the types of immunosuppressants administered without increasing the incidence of transplant rejection. The effectiveness of prednisone avoidance has been suggested, although this was not based on statistical significance in many instances. To definitively establish the effectiveness of prednisone avoidance, a statistically significant difference from a prednisone-use group should be demonstrated. Additionally, the effectiveness of prednisone avoidance might vary depending on the combination of other immunosuppressants administered. It has therefore been considered necessary to investigate, for various immunosuppressant combinations, the administration patterns in which prednisone avoidance is effective. Objectives This study aimed to investigate the effectiveness of prednisone avoidance in patients with liver transplant and discuss the results based on statistically significant differences. Methods Data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) were obtained. In studying immunosuppressant combinations, it was essential to control for confounding. Thus, the immunosuppressant combinations, excluding prednisone, were kept the same in the two groups being compared (prednisone-use and prednisone-avoidance groups). The large sample from FAERS allowed for those various immunosuppressant combinations to be compared. Comparisons of transplant rejection in the prednisone-use and prednisone-avoidance groups used the reporting odds ratio (ROR) and the adjusted ROR (aROR), which controlled for differences in patient background. Results With the prednisone-use groups being set as the reference, ROR and aROR were calculated for the prednisone-avoidance groups. Various immunosuppressant combinations were evaluated, and in four patterns - (1) the combination of prednisone and tacrolimus, (2) the combination of prednisone, cyclosporine, and tacrolimus, (3) the combination of prednisone, tacrolimus, and basiliximab, and (4) the combination of prednisone and everolimus) - both the ROR and the aROR for transplant rejection in the prednisone-avoidance group were significantly <1.000. Conclusions This study identified effective immunosuppressant combinations for prednisone avoidance that were not associated with increased transplant rejection. The evidence supporting the effectiveness of prednisone avoidance is strengthened when combined with results from previous studies.

Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits.

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 perforin and FasL) 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.

Mucocutaneous Ulcers Unmasking Severe Systemic Methotrexate Toxicity - A Case-Series and Review of Literature.

Background: Methotrexate is a widely used immunosuppressant with good efficacy and cost-effectiveness. However, one of the drawbacks of methotrexate has been toxicity due to accidental overdose. During the COVID pandemic, there was an alarming increase in the number of patients with methotrexate toxicity which prompted us to do this study. Objective: To evaluate the clinical features and contributing factors in patients presenting with methotrexate toxicity. Materials and Methods: A detailed evaluation of the clinical features, laboratory indices, contributing factors, and outcomes of the patients presenting with methotrexate toxicity was analyzed. Results: A total of 19 cases were seen during the study period. All of the patients had oral mucositis and several developed cutaneous ulcerations. Laboratory abnormalities included cytopenia, transaminitis, and renal impairment. While sixteen patients recovered successfully, three people died as a result of delays in medical assistance. In addition to comorbidities, pandemic-induced restrictions played a major role in patients accidentally overdosing with methotrexate. Conclusion: This study highlights the fact that even low-dose methotrexate taken incorrectly can result in a lethal outcome, which is preventable.

Improved Health Outcomes in Patients with Systemic Lupus Erythematosus Following Early Belimumab Initiation Without Prior Immunosuppressant Use: A Real-World Descriptive Study.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) have variable treatment pathways, including antimalarials, glucocorticoids, immunosuppressants, and/or biologics. This study describes differences in clinical outcomes when initiating belimumab (BEL) before and after immunosuppressant use. METHODS: This real-world, retrospective cohort study (GSK Study 217536) used de-identified administrative claims data from January 2015 to December 2022 in the Komodo Health Database. Adults with moderate/severe SLE initiating BEL (index date) were identified from January 2017 to May 2022, allowing a ≥ 24-month baseline period. Patients were stratified into those initiating BEL before immunosuppressant use (no immunosuppressant use within 24 months before index) and those initiating BEL after immunosuppressant use (one immunosuppressant used within 24 months before index). Oral glucocorticoid (OGC) use, SLE flares, new organ damage, and all-cause healthcare resource utilization (HCRU) were analyzed descriptively over a 24-month follow-up. RESULTS: Baseline SLE severity was similar for patients initiating BEL before (n = 2295) versus after (n = 4114) immunosuppressant use (moderate, 83.1% vs 79.0%; severe, 16.8% vs 21.0%). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates and OGC use. Post-index, patients initiating BEL before versus after immunosuppressant use discontinued their OGC sooner (moderate baseline SLE, 4.5 vs 8.9 months; severe baseline SLE, 6.2 vs 11.6 months). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates per person-year at all time points (especially severe flare rates in patients with severe baseline SLE, 0.70 vs 1.48 through 24 months post-index). Median time to new organ damage occurrence was longer in patients initiating BEL before versus after immunosuppressant use (moderate baseline SLE, 32.1 vs 26.7 months; severe baseline SLE, 22.7 vs 21.6 months). All-cause HCRU was similar between cohorts. CONCLUSIONS: These results suggest that patients initiating BEL before versus after immunosuppressant use had more favorable outcomes.

Influence of genetic polymorphisms on pharmacokinetics and treatment response of mycophenolic acid: a scoping 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 (UGT1A9, UGT1A8 and UGT2B7) and transmembrane transporters (ABCC2, SLCO1B1, SLCO1B3 and ABCB1) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including UGT1A9, UGT2B7, IMPDH1 and IMPDH2 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.

[Box: see text].

Successful treatment of fulminant and recurrent lymphocytic myocarditis with calcineurin inhibitors.

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

Diagnostic Dilemma of a Complex Case of Cerebral Vasculitis: A Rare Probable Drug-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Large Vessel Involvement.

A case of a 43-year-old male with a history of Graves' disease treated with propylthiouracil was investigated for vasculitis and lymphoproliferative disease. However, his clinical picture was complicated by recurrent episodes of neurological symptoms resembling stroke syndrome, which widened the breadth of the diagnostic workup. Extensive investigations, including imaging and biopsies, excluded other possibilities. The patient was treated as probable cerebral vasculitis after identifying new narrowing in the left middle cerebral artery and was treated with pulsed intravenous methylprednisolone, followed by high-dose oral prednisolone and cyclophosphamide. Repeated brain imaging showed further narrowing of the large vessels, which reaffirmed the likelihood of vasculitis necessitating continuation of induction therapy with further maintenance treatment, which led to stabilization of neurological burden and symptom recovery. This case elucidates complexities in reaching the diagnosis of drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which can present heterogeneously and mimic other clinical entities such as stroke.

Chemical constituents from the twigs with leaves of Tetradium trichotomum.

Twelve compounds, comprising of four new ones, 6ß,7α-limondiol (1) and ethyl 19-hydroxyisoobacunoate diosphenol (2), N-benzoyl 3-prenyltyramine (9) and 9-O-methyl integrifoliodiol (12), were isolated from the twigs with leaves of Tetradium trichotomum. The structures were elucidated by analysis of MS, NMR, and single-crystal X-ray diffraction. Compounds 1, 6, 8, 9 and 12 exhibited immunosuppressive activities in vitro against the proliferation of ConA-induced T lymphocytes and LPS-induced B cells.

Management of immunosuppressive therapy after functional renal graft failure: Results of a practice survey of French-speaking nephrologists / Gestion du traitement immunosuppresseur après arrêt fonctionnel du greffon rénal : résultats d'une enquête de pratique parmi les néphrologues francophones.

The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation Commission of the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) conducted a survey on the management of immunosuppressants (IS) after KTF among nephrologists at transplant centres and general nephrologists in France, Switzerland and Belgium between March and June 2023. We analysed 232 replies from 58 nephrologists at transplant centres and 174 general nephrologists, aged 43.6 (+10.6) years. In the first three months following KTF, nephrologists reported discontinuing antimetabolite, calcineurin inhibitor (CNI) and corticosteroid treatment in 83%, 39.9% and 25.8% of cases respectively. Conversely, some nephrologists reported that they were continuing to use CNI (14%) and corticosteroids (19.1%) on a long-term basis. The patient's comorbidities associated with the discontinuation of IS treatment are cancer and opportunistic infections as KT's complications and presence of diabetes mellitus at KTF, whereas humoral rejection encourages the IS to be maintained. Transplantectomy is proposed by nephrologists most often for graft intolerance syndrome (86.5%), more rarely to discontinue IS (17.6%) or in the absence of plans of new transplantation (9.3%). In multivariate analyses, the presence of a protocol in the centre facilitated the management of IS by the general nephrologists. The management of IS after AFG by French-speaking nephrologists is heterogeneous. Specific prospective studies are needed to establish new best practice recommendations, based on more robust evidence, which could encourage better adherence by nephrologists.

La prise en charge des patients avec un arrêt fonctionnel du greffon rénal (AFG) reste un processus complexe avec de multiples intervenants. Un groupe de travail de la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a conduit une enquête sur la gestion des traitements immunosuppresseurs (IS) après AFG parmi les néphrologues de centres de transplantation et néphrologues généraux en France, Suisse et Belgique francophone entre mars et juin 2023. Nous avons pu analyser 232 réponses de néphrologues (centres de transplantation N = 58 et généraux N = 174) âgés de 43,6 (± 10,6) ans. Dans les 3 premiers mois suivant l'AFG, les néphrologues déclarent interrompre le traitement par antimétabolites (83 %), inhibiteurs de la calcineurine (ICN) (39,9 %) et corticoïdes (25,8 %). À l'inverse, certains déclarent maintenir les ICN (14 %) et les corticoïdes (19,1 %) au long cours en cas de projet de nouvelle transplantation rénale (TR). La survenue de cancer pendant la TR, d'infections opportunistes dans la dernière année de TR ou à l'initiation de la dialyse, et la présence d'un diabète lors de l'AFG sont associées avec l'arrêt du traitement IS alors que la perte du greffon par rejet humoral incite à le maintenir. En analyse multivariée, la présence d'un protocole dans le centre facilite la gestion des IS par les néphrologues généraux. Enfin, la transplantectomie est proposée par les néphrologues le plus souvent pour un syndrome d'intolérance du greffon (86,5 %), plus rarement pour interrompre les IS (17,6 %) ou en l'absence de projet de nouvelle TR (9,3 %). La gestion des IS après l'AFG par les néphrologues francophones est hétérogène. Des études prospectives spécifiques sont nécessaires afin de formuler de nouvelles recommandations de bonnes pratiques, reposant sur des données probantes plus robustes, qui pourraient encourager une meilleure adhésion par les néphrologues.

Low-dose immune tolerance induction for severe hemophilia A inhibitor patients: Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL.

Importance: It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS40 regimen). Objective: To compare the efficacy of the LD-ITI-IS200 regimen with that of the LD-ITI-IS40 regimen for SHA patients with high-titer inhibitors. Methods: A prospective cohort study on patients receiving LD-ITI-IS200 compared to those receiving LD-ITI-IS40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS200 regimen and ≥40 BU/mL in the LD-ITI-IS40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected. Results: We enrolled 30 patients on LD-ITI-IS200 and 64 patients on LD-ITI-IS40, with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS200 regimen compared to the LD-ITI-IS40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS200 vs. LD-ITI-IS40) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS200 than for LD-ITI-IS40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS200 regimen) and 28 IS-using (on LD-ITI-IS40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months). Interpretation: In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL.

Management of immunosuppressive therapy after functional renal graft failure: results of a practice survey of French-speaking nephrologists / Gestion du traitement immunosuppresseur après arrêt fonctionnel du greffon rénal : résultats d'une enquête de pratique parmi les néphrologues francophones.

The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation Commission of the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) conducted a survey on the management of immunosuppressants (IS) after KTF among nephrologists at transplant centres and general nephrologists in France, Switzerland and Belgium between March and June 2023. We analysed 232 replies from 58 nephrologists at transplant centres and 174 general nephrologists, aged 43.6 (+10.6) years. In the first three months following KTF, nephrologists reported discontinuing antimetabolite, calcineurin inhibitor (CNI) and corticosteroid treatment in 83%, 39.9% and 25.8% of cases respectively. Conversely, some nephrologists reported that they were continuing to use CNI (14%) and corticosteroids (19.1%) on a long-term basis. The patient's comorbidities associated with the discontinuation of IS treatment are cancer and opportunistic infections as KT's complications and presence of diabetes mellitus at KTF, whereas humoral rejection encourages the IS to be maintained. Transplantectomy is proposed by nephrologists most often for graft intolerance syndrome (86.5%), more rarely to discontinue IS (17.6%) or in the absence of plans of new transplantation (9.3%). In multivariate analyses, the presence of a protocol in the centre facilitated the management of IS by the general nephrologists. The management of IS after AFG by French-speaking nephrologists is heterogeneous. Specific prospective studies are needed to establish new best practice recommendations, based on more robust evidence, which could encourage better adherence by nephrologists.

La prise en charge des patients avec un arrêt fonctionnel du greffon rénal (AFG) reste un processus complexe avec de multiples intervenants. Un groupe de travail de la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a conduit une enquête sur la gestion des traitements immunosuppresseurs (IS) après AFG parmi les néphrologues de centres de transplantation et néphrologues généraux en France, Suisse et Belgique francophone entre mars et juin 2023. Nous avons pu analyser 232 réponses de néphrologues (centres de transplantation N = 58 et généraux N = 174) âgés de 43,6 (± 10,6) ans. Dans les 3 premiers mois suivant l'AFG, les néphrologues déclarent interrompre le traitement par antimétabolites (83 %), inhibiteurs de la calcineurine (ICN) (39,9 %) et corticoïdes (25,8 %). À l'inverse, certains déclarent maintenir les ICN (14 %) et les corticoïdes (19,1 %) au long cours en cas de projet de nouvelle transplantation rénale (TR). La survenue de cancer pendant la TR, d'infections opportunistes dans la dernière année de TR ou à l'initiation de la dialyse, et la présence d'un diabète lors de l'AFG sont associées avec l'arrêt du traitement IS alors que la perte du greffon par rejet humoral incite à le maintenir. En analyse multivariée, la présence d'un protocole dans le centre facilite la gestion des IS par les néphrologues généraux. Enfin, la transplantectomie est proposée par les néphrologues le plus souvent pour un syndrome d'intolérance du greffon (86,5 %), plus rarement pour interrompre les IS (17,6 %) ou en l'absence de projet de nouvelle TR (9,3 %). La gestion des IS après l'AFG par les néphrologues francophones est hétérogène. Des études prospectives spécifiques sont nécessaires afin de formuler de nouvelles recommandations de bonnes pratiques, reposant sur des données probantes plus robustes, qui pourraient encourager une meilleure adhésion par les néphrologues.

Faecal Short-Chain, Long-Chain, and Branched-Chain Fatty Acids as Markers of Different Chronic Inflammatory Enteropathies in Dogs.

Chronic inflammatory enteropathies (CIEs) are classified based on treatment trials, and new methods are being sought for earlier differentiation and characterization. Giardia infection (GIA) is one of the first differential diagnoses and may be present in CIE-affected dogs. The aim of this study was to evaluate the faecal characteristics and faecal fatty acid profile (short, medium, long, and branched-chain fatty acids) in dogs with food-responsive enteropathy (FRE), immunosuppressant-responsive enteropathy (IRE), and dogs infected with Giardia compared to healthy control (HC) animals as a potential non-invasive indicator of intestinal health that helps in the differentiation of CIEs. The C16:1n-7 percentage (p = 0.0001) and C16:1n-7/C16:0 ratio (p = 0.0001) served to differentiate between HC, FRE, and IRE. IRE dogs presented lower levels of short-chain fatty acids (∑SCFAs) (p = 0.0008) and acetic acid (C2) (p = 0.0007) compared to the other three groups and lower propionic acid (C3) (p = 0.0022) compared to HCs. IRE and GIA presented higher faecal fat content (p = 0.0080) and ratio of iso/anteiso branched-chain fatty acids (BCFAs) compared to HC and FRE. Correlations between some fatty acids and desaturation indices with the canine inflammatory bowel disease activity index and faecal characteristics were observed, suggesting that these compounds could play an important role in the pathogenesis of these diseases.

Mizoribine Promotes Molecular Chaperone HSP60/HSP10 Complex Formation.

It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis. The molecular chaperone HSP60 alone induces inflammatory cytokine IL-6 and the co-chaperone HSP10 alone inhibits IL-6 induction. HSP60 and HSP10 form a complex in the presence of ATP. We analyzed the effects of Mizoribine, which is structurally similar to ATP, on the structure and physiological functions of HSP60-HSP10 using Native/PAGE and transmission electron microscopy. At low concentrations of Mizoribine, no complex formation of HSP60-HSP10 was observed, nor was the expression of IL-6 affected. On the other hand, high concentrations of Mizoribine promoted HSP60-HSP10 complex formation and consequently suppressed IL-6 expression. Here, we propose a novel mechanism of immunosuppressive action of Mizoribine.

Efficacy and safety of carrimycin in ten patients with severe pneumonia following solid organ transplantation.

BACKGROUND: The number of patients undergoing solid organ transplantation has increased annually. However, infections in solid organ transplant recipients can have a severe effect on patient survival owing to the continued use of immunosuppressants. Carrimycin is a novel macrolide antibiotic produced by genetically engineered streptomyces spiramyceticus harboring a 4''-O-isovaleryltransferase gene (ist) from streptomyces thermotoleran. Carrimycin has good antibacterial and antiviral effects. However, no relevant studies have been conducted on the efficacy and safety of carrimycin in patients with severe pneumonia (SP) after solid organ transplantation. AIM: To explore the efficacy and safety of carrimycin in patients with SP after solid organ transplantation to provide a medication reference for clinical treatment. METHODS: In March 2022, ten patients with SP following solid-organ transplantation were treated at our hospital between January 2021 and March 2022. When the condition was critical and difficult to control with other drugs, carrimycin was administered. These ten patients' clinical features and treatment protocols were retrospectively analyzed, and the efficacy and safety of carrimycin for treating SP following solid organ transplantation were evaluated. RESULTS: All ten patients were included in the analysis. Regarding etiological agent detection, there were three cases of fungal pneumonia, two cases of bacterial pneumonia, two cases of Pneumocystis pneumonia, and three cases of mixed infections. After treatment with carrimycin, the disease in seven patients significantly improved, the course of the disease was significantly shortened, fever was quickly controlled, chest computed tomography was significantly improved, and oxygenation was significantly improved. Finally, the patients were discharged after curing. One patient died of acute respiratory distress syndrome, and two patients discontinued treatment. CONCLUSION: Carrimycin is a safe and effective treatment modality for SP following solid organ transplantation. Carrimycin may have antibacterial and antiviral effects in patients with SP following solid organ transplantation.

Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.