Immunosuppressive Doses Research Articles

Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.

Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.

A review of heart transplant immunosuppressants and nonmelanoma skin cancer.

Heart transplant recipients experience high rates of skin cancer, likely due to greater length or dosage of immunosuppression. We review the impact of immunosuppressive medications on development of nonmelanoma skin cancer (NMSC) in heart transplant recipients. The authors searched keywords "heart transplant" and "nonmelanoma skin cancer" on PubMed in October 2022 for eligible articles available in English. Articles were selected for inclusion based on relevance to heart transplantation and NMSC. If any cited articles within included articles were related to our search they were also included. Of the 29 identified articles, 18 met the inclusion criteria with a total of 11,699 patients. Two studies found that tacrolimus and azathioprine increased the risk of NMSC. Five studies demonstrated that tacrolimus, everolimus, sirolimus, azathioprine and mycophenolate mofetil decreased the risk of NMSC. Three studies described that cyclosporine, tacrolimus, everolimus, sirolimus, azathioprine, mycophenolate mofetil and prednisone had no significant association with the development in NMSC. Two studies did not specify the correlation between immunosuppressant use and NMSC development. Ten studies did not discuss the association of immunosuppressants use with the development of NMSC. Our review highlights the commonly used immunosuppressive drugs that can impact the development of NMSC in heart transplant recipients. A management strategy in immunosuppression-associated skin cancers may ultimately involve adjusting the immunosuppressive regimen. This review serves as a summary of the most commonly used immunosuppressive drugs in heart transplant patients and their tumorigenic mechanisms to guide recommendations for dermatologic follow-up in heart transplant recipients.

Long-term mepolizumab treatment reduces relapse rates in super-responders with eosinophilic granulomatosis with polyangiitis

BackgroundThe mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown.MethodsSeventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a “super-responder group” (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a “responder group” (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined.ResultsBlood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment.ConclusionMepolizumab treatment of super-responders sustainably reduced the relapse rate.

Ultraviolet exposure regulates skin metabolome based on the microbiome

Skin metabolites (< 1500 Da) play a critical role in barrier function, hydration, immune response, microbial invasion, and allergen penetration. We aimed to understand the global metabolic profile changes of the skin in relation to the microbiome and UV exposure and exposed germ-free (devoid of microbiome), disinfected mice (partially devoid of skin microbiome) and control mice with intact microbiome to immunosuppressive doses of UVB radiation. Targeted and untargeted lipidome and metabolome profiling was performed with skin tissue by high-resolution mass spectrometry. UV differentially regulated various metabolites such as alanine, choline, glycine, glutamine, and histidine in germ-free mice compared to control mice. Membrane lipid species such as phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin were also affected by UV in a microbiome-dependent manner. These results shed light on the dynamics and interactions between the skin metabolome, microbiome, and UV exposure and open new avenues for the development of metabolite- or lipid-based applications to maintain skin health.

Treatment of Central Nervous System Post-Transplant Lymphoproliferative Disorder in Immunocompromised Patients with Pancreas Transplant– Between the Rock and a Hard Place (P2-13.002)

<h3>Objective:</h3> To describe the clinical presentation and management of two patients who developed pancreatic transplant rejection during treatment of post-transplant CNS lymphoma (PT-CNSL). <h3>Background:</h3> PT-CNSL is a rare neoplasm developing after immunosuppressive therapy following solid-organ transplantation. Treatment involves reducing immunosuppression, which risks graft rejection. In pancreas transplant recipients, this is associated with increased mortality rates with limited therapeutic alternatives. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Description:</h3> <h3>Case 1:</h3> a 43-year-old female status post pancreas-kidney transplant was diagnosed with PT-CNSL in 2022, initially managed by withholding tacrolimus and initiating rituximab therapy at 375 mg/m2 IV (starting weekly for 3 months, then monthly). The lymphoma regressed with treatment until the patient experienced pancreatic graft rejection (lipase peak 1,124 U/L). This was treated by adding on low-dose tacrolimus which resulted in an improvement in graft rejection and allowed ongoing therapy with rituximab, yielding a complete response of the PT-CNSL. <h3>Case 2:</h3> A 55-year-old female status post pancreas-kidney transplant in 2010, was diagnosed with PT-CNSL in 2021. Treatment involved discontinuation of mycophenolate and tacrolimus and initiation of rituximab at 375 mg/m2 IV (starting weekly for six months, then monthly). Although the lymphoma regressed, the patient experienced acute epigastric pain with a lipase peak of 2,715 U/L with CT of the abdomen illustrating acute pancreatitis. Due to concern for transplant rejection, low-dose tacrolimus was initiated along with rituximab, resulting in resolution of elevated lipase. Continued serial neuroimaging studies demonstrated a complete response. <h3>Conclusions:</h3> PT-CNSL increases morbidity and mortality in pancreas transplant patients with limited treatment options. Treatment should balance maintaining CNS response with careful re-initiation of immunosuppression in the setting of graft rejection; however, there is limited knowledge regarding ideal doses of immunosuppression. We demonstrate that low-dose tacrolimus to prevent graft rejection was safe and effective in treating two patients with PT-CNSL, highlighting the need for further investigation into optimal management strategies. <b>Disclosure:</b> Mrs. Haque has nothing to disclose. Prof. ORLANDO has nothing to disclose. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cancer Expert Now. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SDP Oncology. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Agios. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Incysus . Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ONO Pharma. Glenn Lesser has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. The institution of Glenn Lesser has received research support from Denovo Biopharma. The institution of Glenn Lesser has received research support from Oblato . The institution of Glenn Lesser has received research support from Novocure. The institution of Glenn Lesser has received research support from GBM Agile - GCAR. Dr. Strowd has received personal compensation for serving as an employee of Kaplan. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris Medical, Inc. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Strowd has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Strowd has received research support from Southeastern Brain Tumor Foundation. The institution of Dr. Strowd has received research support from Jazz Pharmaceuticals. The institution of Dr. Strowd has received research support from National Institutes of Health. The institution of Dr. Strowd has received research support from Alpha Omega Alpha. The institution of Dr. Strowd has received research support from American Board of Psychiatry and Neurology. Dr. Strowd has received publishing royalties from a publication relating to health care. Dr. Strowd has received publishing royalties from a publication relating to health care.

Immunosuppression Protocols in Intestinal and Multivisceral Transplantation—A Literature Review

Intestinal transplantation (IT) and multivisceral transplantation (MVT) are curative therapies for patients with intestinal failure and severe complications associated with total parenteral nutrition. High levels of immunosuppression are required to prevent acute cellular rejection (ACR) from the bowel. Studies regarding pre-treatment, induction, and post-transplant therapy have improved graft acceptance, reducing immunosuppression doses and infectious complications. However, the low rate of IT and MVT and the small number of specialized centers have resulted in a limited number of evidence-based immunosuppression protocols. We reviewed immunosuppression in IT and MVT to draw useful conclusions regarding the best protocol strategies for the induction, maintenance, and management of ACR. A review was performed using the PubMed database. Articles on immunosuppression protocols in IT and MVT that addressed graft rejection, infection, or survival, published between 2006 and 2022, were selected. A total of 690 articles were selected. Two researchers applied the inclusion and exclusion criteria and selected 14 articles independently. For induction, thymoglobulin, alemtuzumab, and basiliximab are the most frequently used immunosuppressants for induction. Classic maintenance therapy consists of a combination of corticosteroids and tacrolimus. Methylprednisolone with an increased tacrolimus dose is used most frequently to manage ACR. Depending on the receptor response, such as thymoglobulin, infliximab, adalimumab, or bortezomib, other immunosuppressants should be considered. There have been great advances in IT and TMV immunosuppression. We conclude that the gold standard immunosuppressive protocol is triple therapy, comprising induction with thymoglobulin, maintenance with steroids for a few months, and tacrolimus and mycophenolate therapy. Innovative approaches for treating intestinal rejection episodes with more appropriate drugs, such as infliximab, adalimumab, or bortezomib, are necessary.

Update on cryptogenic organizing pneumonia.

Cryptogenic organizing pneumonia (COP) is a form of idiopathic interstitial pneumonia that results from the pulmonary reaction to various unidentified injuries. Secondary organizing pneumonia is diagnosed when the triggering factor has been identified; it is mainly caused by infections, toxic substance exposure, drugs, connective tissue diseases, malignancies, autoimmune diseases, bone marrow, or organ transplantation, and radiotherapy. There has been an increase in the number of reports of drug-induced organizing pneumonia (OP). New biological therapies, interferon, monoclonal antibodies, anti-interleukin antibodies, and PD1/PDL-1 inhibitors may induce this specific pulmonary reaction. The classical form of COP is usually subacute and does not manifest as severe disease. Patients maintain sufficient respiratory function, and treatment with steroids is usually effective. Several specific forms of OP (e.g., the cicatricial variant or acute fibrinous type) have distinct clinical and histological features, require higher doses of immunosuppressive drugs, and have a worse prognosis. In the era of administering steroid-sparing therapies for the treatment of interstitial lung diseases, connective tissue dases, and other conditions, it is important to emphasize this type of therapy for patients with COP.

Hypoglycemia with insulin in post-transplant diabetes mellitus

IntroductionTo prevent hypoglycemic episodes, the management of insulin therapy against post-transplant diabetes mellitus (PTDM) is important. We compared glargine (long-acting insulin) versus NPH isophane (intermediate-acting insulin) as an armamentarium against PTDM. Indeed, the study evaluated PTDM patients with hypoglycemic episodes treated with isophane or glargine. Material and methodsWe evaluated a total number of 231 living-donor renal transplant recipients with PTDM of age ≥ 18 years admitted to the hospital between January 2017 and September 2021. However, patients taking hypoglycemic agents before transplantation were excluded from this study. Out of 231 patients, 52 (22.15%) suffered from PTDM out of whom 26 were treated with glargine or isophane. ResultsAfter applying exclusion criteria, out of 52 PTDM patients 23 were included in the study: 13 PTDM patients were treated with glargine, whereas 10 PTDM patients with isophane. Our analysis revealed 12 episodes of hypoglycemia in glargine-treated PTDM patients compared to 3 in isophane-treated PTDM patients (p = 0.056). Clinically, 9 out of 15 hypoglycemic episodes were nocturnal (60%). Furthermore, no other risk factors were observed in our study population. Detailed analysis showed that both groups had equivalent doses of immunosuppressants and oral hypoglycemic agents. The odds ratio for hypoglycemia in the group treated with isophane compared to that treated with glargine was 0.224 (95% CI, 0.032–1.559). Glargine users recorded significantly lower blood sugar levels before lunch, dinner and at bedtime with p-values of 0.001, 0.009 and 0.001 respectively. A better hemoglobin A1c (HbA1c) level was seen in the glargine vs. isophane group (6.98 ± 0.52 vs. 7.45 ± 0.49, p-value 0.03). ConclusionThe study shows better blood sugar control with long-acting insulin analog, glargine, than with intermediate-actin analog, isophane. Overall, a higher number of hypoglycemic episodes was nocturnal. Long term safety of long-acting insulin analogs needs to be further studied.

Therapeutic drug monitoring and dosage adjustments of immunosuppressive drugs when combined with nirmatrelvir/ritonavir in patients with COVID-19.

Nirmatrelvir/ritonavir (Paxlovid®) consists of a peptidomimetic inhibitor (Nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (Ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Co-administration of nirmatrelvir/ritonavir with immunosuppressant drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. While a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here we provide some general recommendations for therapeutic drug monitoring (TDM) of ISDs and dosing recommendations when co-administered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day-1, while cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

Do the drug doses of conventional synthetic DMARDs used for the treatment of biologic/targeted-synthetic DMARDs naive rheumatoid arthritis patients affect QuantiFERON-TB Gold Plus test results?

We aimed to obtain the effects of immunosuppressive doses on the QuantiFERON-TB Gold Plus (QFT-Plus) test results in Rheumatoid Arthritis (RA) patients. Besides this, the impact of the TB2 tube in QFT-Plus test was also investigated. This study included RA patients registered to HURBIO and were screened via QFT-Plus test for latent tuberculosis between January 2018 and March 2021, before the initiation of treatment of biologic/targeted-synthetic disease modifying anti-rheumatismal drugs (b/ts-DMARDs). Patients using methotrexate ≥ 10mg or leflunomide (any dose) or steroids (≥ 7.5mg prednisolone) at the time of QFT-Plus test were classified as the "high dose" group and the rest of the patients constituted the "low dose" group. The study included 534 RA patients; 353 [66.1%] in the high-dose group and 181 [33.9%] in the low-dose group. While QFT-Plus test was positive in 10.5% (37/353) patients in the high-dose group, it was positive in 20.4% (37/181) patients in the low-dose group (p < 0.001). The percentage of QFT-Plus indeterminate results were similar (around 2%) in both groups. The contribution of the TB2 tube to QFT-Plus test positivity was 6.89%. During a median (inter-quartile range) follow-up period of 23 (7-38) months under treatment of b/ts-DMARDs, latent TB reactivation was not observed. Primer active tuberculosis disease developed in two patients. Positive test results of Interferon-Gamma Release Assays (IGRAs) could decrease as immunosuppressive treatment doses increase in patients with RA and addition of the TB2 tube could increase test sensitivity.

ОСОБЕННОСТИ ТЕЧЕНИЯ КОРОНАВИРУСНОЙ ИНФЕКЦИИ У РЕЦИПИЕНТА ПОЧЕЧНОГО ТРАНСПЛАНТАТА

The new coronavirus infection poses a particular threat to patients receiving immunosuppressive therapy, including those with a history of organ transplantation. The article provides a clinical observation of coronavirus infection in a kidney transplant recipient. Patient M., 61 years old, was admitted to the infectious diseases department of the Kursk City Clinical Hospital No. 4 with complaints of high fever, cough, shortness of breath, severe weakness, loss of appetite. When examining a swab from the nose and throat by PCR for SARS-Cov-2 RNA, a positive result was obtained. Based on the clinical picture, computed tomography of the lungs, positive PCR result for SARS-Cov-2 RNA, the diagnosis was made: Coronavirus infection Covid-19 confirmed, moderate form. Bilateral polysegmental pneumonia of moderate severity. RF - 0-I degree (CT-1). Bilateral nephrosclerosis. Condition after kidney transplant (2006). On the fifth day, the patient's condition worsened, which was combined with the progression of lung damage according to CT of the chest to 45% (CT-2), the appearance of signs of acute respiratory distress syndrome. Taking into account the severity of the patient's condition, a consultation was held with a transplantologist and a decision was made to correct immunosuppressive therapy with temporary withdrawal of cyclosporine. Over the next two days, the patient's condition remained stably grave. Subsequently, against the background of complex therapy, including glucocorticosteroids, antibacterial drugs, monoclonal antibodies to the interleukin-6 receptor, positive dynamics was noted in the form of a decrease in shortness of breath, cough, normalization of body temperature, and an increase in SpO2 up to 95%. This was combined with the restoration of disturbed laboratory parameters and the positive dynamics of the inflammatory process in the lungs according to CT scans. The treatment of kidney transplant recipients with Covid-19 has a number of features due to a pronounced suppression of the immune system against the background of immunosuppressive therapy and, as a result, the development of a severe infection, often with impaired graft function. At the same time, despite the severity of the course of the infectious process, the complete abolition of immunosuppressive therapy is not carried out, but its correction is carried out in the form of the exclusion of one of the drugs and a decrease in the dose of other immunosuppressants. Coronavirus infection in patients with a history of organ transplantation justifies the need for timely hospitalization and correction of immunosuppressive therapy to prevent a severe course of the disease and adverse outcomes.

Expansion and characterization of regulatory T cell populations from Korean kidney transplant recipients.

The development of immunosuppressants has enabled remarkable progress in kidney transplantation (KT). However, current immunosuppressants cannot induce immune tolerance, and their nonspecific immunosuppressive effects result in many adverse effects. Regulatory T cells (Tregs) play crucial roles in controlling all specific immune responses. This study evaluated the distribution of Tregs and their effects on kidney allograft function in Korean KT recipients. We enrolled 113 KT recipients with stable graft function. The differentiation and expansion of Tregs were examined by flow cytometry to compare the Tregs subpopulations. Among the 113 patients, 73 (64.6%) were males, and the mean follow-up period from KT to Tregs collection was 147.5 + 111.3 months. Patients receiving lower doses of cyclosporine had higher proportions of Tregs than those with higher doses of cyclosporine (36.3 + 21.6 vs 17.0 + 12.7, P = .010, respectively). Patients taking cyclosporine tended to have higher Tregs numbers than those taking tacrolimus (94.7 + 158.1 vs 49.3 + 69.4, P = .095, respectively). However, no significant association was observed between Tregs and allograft dysfunction in the cox proportional hazard model. Tregs counts may be associated with the type and dose of immunosuppressants. However, no significant relationship was found between Tregs and kidney allograft function in stable KT recipients.

Leprosy-like reaction occurred during the treatment of a cutaneous Mycobacterium haemophilum infection: A case report

Rationale: Mycobacterium haemophilum is a rare pathogen, belongs to the slowly-growing nontuberculous mycobacterium family, and shares a close evolutionary relationship with Mycobacterium leprae. It is a fastidious organism that requires special media(iron or hemin supplementation)and conditions (incubation at 30–32°C) for growth, which differs from most other pathogenic mycobacteria. Patient concerns: A 43-year-old Asian male presented to our outpatient department due to the appearance of multiple infiltrative erythematous nodules and ulcerations on the extremities for more than 2 months. Diagnoses: Acid-fast bacteria were detected in the specimen and sequencing for hsp65 and 16S rRNA genes of the pathogen extracted from the biopsy tissue identified as M haemophilum. The diagnosis of cutaneous M haemophilum infection was established. Interventions: The patient received a 3-drug regimen (oral clarithromycin 1.0 g/d, rifampicin 0.6 g/d, and moxifloxacin 1.0 g/d) and local hot compression therapy, the dose of immunosuppressant was reduced. Outcomes: The lesions gradually improved after 6 months of continuous antibiotic therapy. There is no recurrence of erythema papules and nodules. Lessons: This case shows that the patient’s condition may be exacerbated immediately after the initiation of anti-nontuberculous mycobacterium therapy, which is analogous to the leprosy reaction. A high degree of clinical suspicion for the underlying disease is critical to avoid unnecessary interruption of treatment.

Prednisolone prescribing practices for dogs in Australia.

Although prednisolone is a routinely prescribed medication in dogs, there is a lack of information regarding prednisolone prescribing practices by veterinarians. This study aims to describe characteristics of dogs receiving prednisolone, disease processes treated, doses prescribed as well as to identify factors influencing the dose rate in Australia. The VetCompass Australia database was queried to identify dogs prescribed prednisolone between 1 July 2016 to 31 July 2018 (inclusive). A random sample of 2,000 dogs from this population were selected. Dog demographic data, prednisolone dose and indication for prescription were collated. Indicated dose for the condition treated was compared to prescribed dose. Multivariable linear regression was used to identify patient-level characteristics associated with prescribed prednisolone dose. A large and small breed dog cohort, treated for the same disease process, were compared for differences in dosing. Median age of dogs was 73 (range 2 to 247) months and median body weight was 17 (range 1.56 to 90) kg. Median prescribed prednisolone dose was 0.8 mg/kg/day, with most dogs receiving an anti-inflammatory dose (0.3-1 mg/kg/day, 58%). Prednisolone prescriptions were predominantly for diseases of the integument (n = 1645, 82%) followed by unknown indication and respiratory disease. A total of 152 dogs (8%) were prescribed immunosuppressive doses of prednisolone for conditions where an anti-inflammatory dose would be recommended. Increases in bodyweight were associated with lower doses on mg/kg scale but higher doses on a mg/m2 scale (p < 0.001). Overall, prednisolone was primarily used as an anti-inflammatory in this population, with some inappropriate use of immunosuppressive doses. Increasing bodyweight was associated with a small reduction in dose in mg/kg, suggesting that clinicians are adjusting prednisolone dose rates based on dog bodyweight.

Mycophenolate Mofetil Dose Adjustment in Pediatric Kidney Transplant Recipients.

The Immunosuppressant Bayesian Dose Adjustment web site aids clinicians and pharmacologists involved in the care of transplant recipients; it proposes dose adjustments based on the estimated area under the concentration-time curve (AUCs). Three concentrations (T 20 min , T 1 h , and T 3 h ) are sufficient to estimate mycophenolic acid (MPA) AUC 0-12 h in pediatric kidney transplant recipients. This study investigates mycophenolate mofetil (MMF) doses and MPA AUC values in pediatric kidney transplant recipients, and target exposure attainment when the proposed doses were followed, through a large-scale analysis of the data set collated since the inception of the Immunosuppressant Bayesian Dose Adjustment web site. In this study, 4051 MMF dose adjustment requests, corresponding to 1051 patients aged 0-18 years, were retrospectively analyzed. AUC calculations were performed in the back office of the Immunosuppressant Bayesian Dose Adjustment using published Bayesian and population pharmacokinetic models. The first AUC request was posted >12 months posttransplantation for 41% of patients. Overall, only 50% had the first MPA AUC 0-12 h within the recommended 30-60 mg.h/L range. When the proposed dose was not followed, the proportion of patients with an AUC in the therapeutic range for MMF with cyclosporine or tacrolimus at the subsequent request was lower (40% and 45%, respectively) than when it was followed (58% and 60%, respectively): P = 0.08 and 0.006, respectively. Furthermore, 3 months posttransplantation, the dispersion of AUC values was often lower at the second visit when the proposed doses were followed, namely, P = 0.03, 0.003, and 0.07 in the 4 months-1 year, and beyond 1 year with <6-month or >6-month periods between both visits, respectively. Owing to extreme interindividual variability in MPA exposure, MMF dose adjustment is necessary; it is efficient at reducing such variability when based on MPA AUC.

Reinforcement Learning for Clinical Applications.

Reinforcement Learning for Clinical Applications.

Low-dose interleukin-2 promotes immune regulation in face transplantation: A pilot study

Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.

Fingerprick Microsampling Methods Can Replace Venepuncture for Simultaneous Therapeutic Drug Monitoring of Tacrolimus, Mycophenolic Acid, and Prednisolone Concentrations in Adult Kidney Transplant Patients.

Kidney transplant patients undergo repeated and frequent venepunctures during allograft management. Microsampling methods that use a fingerprick draw of capillary blood, such as dried blood spots (DBS) and volumetric absorptive microsamplers (VAMS), have the potential to reduce the burden and volume of blood loss with venepuncture. This study aimed to examine microsampling approaches for the simultaneous measurement of tacrolimus, mycophenolic acid, mycophenolic acid glucuronide (MPAG), and prednisolone drug concentrations compared with standard venepuncture in adult kidney transplant patients. DBS and VAMS were simultaneously collected with venepuncture samples from 40 adult kidney transplant patients immediately before and 2 hours after immunosuppressant dosing. Method comparison was performed using Passing-Bablok regression, and bias was assessed using Bland-Altman analysis. Drug concentrations measured through microsampling and venepuncture were also compared by estimating the median prediction error (MPE) and median absolute percentage prediction error (MAPE). Passing-Bablok regression showed a systematic difference between tacrolimus DBS and venepuncture [slope of 1.06 (1.01-1.13)] and between tacrolimus VAMS and venepuncture [slope of 1.08 (1.03-1.13)]. Tacrolimus values were adjusted for this difference, and the corrected values showed no systematic differences. Moreover, no systematic differences were observed when comparing DBS or VAMS with venepuncture for mycophenolic acid and prednisolone. Tacrolimus (corrected), mycophenolic acid, and prednisolone microsampling values met the MPE and MAPE predefined acceptability limits of <15% when compared with the corresponding venepuncture values. DBS and VAMS, collected in a controlled environment, simultaneously measured multiple immunosuppressants. This study demonstrates that accurate results of multiple immunosuppressant concentrations can be generated through the microsampling approach, with a preference for VAMS over DBS.

Lupus low disease activity state attainment in the phase 3 TULIP trials of anifrolumab in active systemic lupus erythematosus

ObjectivesIn patients with systemic lupus erythematosus (SLE), lupus low disease activity state (LLDAS) attainment is associated with improved outcomes. We investigated LLDAS attainment in anifrolumab-treated patients.MethodsWe performed post hoc analysis...

Acute thyrotoxicosis-like graft-versus-host disease after cord blood transplantation

Reports of thyrotoxicosis and hypothyroidism occurring immediately after allogeneic stem cell transplantation are limited, and the detailed mechanisms remain unclear. Here, we present the case of a man in his 20s with thyrotoxicosis and hypothyroidism that occurred early after cord blood transplantation (CBT), with histopathology suggesting an immune reaction in the thyroid gland. The patient had acute myeloid leukemia and underwent a second CBT procedure. The patient developed thyrotoxicosis on day 43. The patient’s condition initially improved with increasing immunosuppressive drug doses; however, he later developed hypothyroidism and required thyroid hormone replacement therapy. Since conventional subacute thyroiditis, Graves’ disease, and Hashimoto’s thyroiditis were excluded due to the lack of histological evidence and autoantibodies, acute graft-versus-host disease (GVHD) was considered the main cause of thyroiditis. The possibility of even minor post-transplant thyroid function abnormalities is more common than expected and further studies are required.