Calcineurin Inhibitors Research Articles

The Favorable impact of everolimus on Chronic lung allograft dysfunction in lung transplant recipients

Standard immunosuppressive therapy for lung transplant recipients combines a calcineurin inhibitor, an antimetabolite, and corticosteroids. In an observational, retrospective, monocentric study, we sought to compare the development of chronic lung allograft dysfunction (CLAD) between 37 patients who received this standard therapy (triple-therapy group) and 59 patients who received the mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to the standard therapy (quadruple-therapy group). In the quadruple-therapy group, the time elapsed from transplantation to everolimus introduction (median [25th-75th percentile]) was 12 [7–25] months. In 46/59 cases, the indication for everolimus introduction was renal function sparing. Median follow-up durations were 36 [20–62] months and 84 [52–123] months in the triple-therapy and quadruple-therapy groups, respectively (p = 0.004). The incidence of CLAD was lower in patients receiving everolimus than in those who did not with an adjusted odds ratio of 0.303 [0.118–0.775]. In addition, the median time from transplantation to CLAD was longer in patients receiving quadruple therapy comprising everolimus than in those who did not (63 [30–92] vs. 29 [12–44] months; p = 0.025). This suggests that the addition of everolimus to a standard triple could result in a lower incidence of CLAD in lung transplant recipients.

Autoimmune hepatitis: Towards a personalized treatment

Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.

Association of Ruxolitinib Cream Initiation With Continued Reduction in Use of Other Topical Treatments, Oral Corticosteroids, and Biologics for Atopic Dermatitis

The objective of this analysis was to examine the impact of ruxolitinib cream on the use of other treatments for atopic dermatitis (AD). This study used claims data from the Healthcare Integrated Research Database (HIRD®) to identify new users of ruxolitinib cream from October 1, 2021, to March 31, 2022. The index date was the date of the first claim for ruxolitinib cream. The baseline period was the 6-month period before the index date, and the follow-up period was 12 months after the index date, which was divided into months 1–6 and months 7–12. Use of other topical and systemic therapies for AD were descriptively analyzed. Among 556 ruxolitinib cream users with follow-up data, the mean number of ruxolitinib cream fills in the overall 12-month follow-up period was 2.1 (SD, 1.77; range, 1–12). The mean (SD) patient age was 40.3 (17.32) years. In months 1–6 and 7–12, 39.9% and 37.4% of patients were treated with ruxolitinib cream monotherapy, respectively; 72.5% and 73.9% of patients did not receive a new class of AD treatment during the respective follow-up periods. Topical corticosteroid use in patients was reduced from 53.4% at baseline to 31.3% in months 1–6 and 26.6% in months 7–12. Topical calcineurin inhibitor use decreased from 14.9% at baseline to 5.2% in months 1–6 and 5.0% in months 7–12. Similarly, topical phosphodiesterase 4 inhibitor use decreased from 6.7% at baseline to 3.4% in months 1–6 and 1.6% in months 7–12. The mean cumulative prednisone-equivalent dose was also reduced from 83.9 mg during the baseline period to 58.0 mg for months 1–6 and 47.3 mg for months 7–12. For patients who did not receive AD biologic therapy during the baseline period (n=431), 92.3% in months 1–6 and 91.4% in months 7–12 continued to remain off AD biologic therapy. Among patients who received AD biologics at baseline (n=125), 16.0% did not receive them in months 1–6 and 26.4% did not receive them in months 7–12. In conclusion, following initiation of ruxolitinib cream, there was a continued reduction in use of other topical therapies and oral corticosteroids for AD. Most biologic-naive patients (>90%) avoided biologics in the 12 months following ruxolitinib cream initiation. Approximately 1 in 4 patients who had biologic treatment during baseline did not continue biologic use in months 7–12. This 12-month analysis confirms earlier 6-month findings that indicated treatment with ruxolitinib cream may reduce the use of other topical therapies, oral corticosteroids, and biologics in patients with AD. (Funding, Incyte Corporation)

Immediate hypersensitivity reactions to parenteral cyclosporine in patients with thalassemia major undergoing hematopoietic stem cell transplantation: a case report and review of the literature.

Allogeneic hematopoietic stem cell transplantation is a definitive cure for eligible patients with thalassemia major, and calcineurin inhibitors are essential for preventing graft-versus-host disease. Although invaluable, there are few reports of life-threatening hypersensitivity reactions associated with calcineurin inhibitors. These reactions are generally rare but seem to be more prevalent among patients with thalassemia. Herein, we retrospectively report four cases of patients with thalassemia major who developed hypersensitivity reactions to parenteral cyclosporine. The cases include one 19-year-old Caucasian female and three Caucasian males, aged 17, 10, and 20years, respectively. The patients exhibited symptoms of varying severity, necessitating different management strategies. The reactions occurred either immediately or within a few minutes after the onset of cyclosporine infusion and were often worsened by rechallenge. In all cases, cyclosporine was eventually replaced with tacrolimus or sirolimus. A comprehensive literature review was conducted to investigate the basis of severe immunoglobulin E-mediated hypersensitivity reactions to calcineurin inhibitors in patients with thalassemia major undergoing hematopoietic stem cell transplantation. Several immunogenic factors may potentially increase the susceptibility of these patients to hypersensitivity reactions to Cremophor-containing medications. While severe reactions to calcineurin inhibitors remain rare, clinicians should be aware of the potential for serious adverse events in patients with thalassemia.

The association between serum complement 4 and relapse of primary membranous nephropathy: a multicenter retrospective cohort study

BackgroundRelapse after initial remission reduces renal survival in patients with primary membranous nephropathy (PMN). In this study, we aim to identify risk factors of relapse in PMN and construct a model to identify patients at high risk of relapse early.MethodsWe conducted a multi-center retrospective study using the China Renal Data System database, which includes data from 24 urban academic centers across China. A prediction model based on the Cox proportional hazards model was derived in the derivation group and validated in the validation group.Result515 patients with biopsy-proven PMN achieving initial remission were enrolled. 32.62% of patients subsequently relapsed during a median of 6.08 months. Lower serum albumin (Alb) (per 1 g/L decrease, hazard ratio [HR] =1.48, 95% confidence interval [CI] 1.29–1.78, p < 0.001), lower estimated glomerular filtration rate (eGFR) (per 10 mL/min/1.73m2 decrease, HR =1.14, 95% CI 0.97–1.49, p < 0.001), higher serum complement 4 (C4) (per 0.1 g/L increase, HR =1.89, 95% CI 1.32–3.22, p = 0.012), partial remission (PR) (HR =2.28, 95%CI 1.74–4.04, p < 0.001), and treatment with calcineurin inhibitors (CINs) (HR =1.33, 95%CI 1.04–1.64, p < 0.001) at the time of remission were risk factors for relapse. C-statistic, time-dependent areas under the receiver operating characteristic curve, and calibration plots confirmed that the model had excellent discrimination and calibration in predicting PMN relapse. The anti-phospholipase A2 receptor antibody (aPLA2Rab) titers and pathologic features did not substantially improve the model.ConclusionOur study confirms the well-known low Alb and eGFR, PR, and treatment of CNIs at the time of remission as risk factors for PMN relapse, but aPLA2Rab and pathologic features may not predict relapse. In addition, it is the first study to show serum C4 is associated with PMN relapse. We suggest that complement-targeted therapies may be a potential therapy to prevent PMN relapse.

An Immune-Independent Mode of Action of Tacrolimus in Promoting Human Extravillous Trophoblast Migration Involves Intracellular Calcium Release and F-Actin Cytoskeletal Reorganization

We have previously reported that the calcineurin inhibitor macrolide immunosuppressant Tacrolimus (TAC, FK506) can promote the migration and invasion of the human-derived extravillous trophoblast cells conducive to preventing implantation failure in immune-complicated gestations manifesting recurrent implantation failure. Although the exact mode of action of TAC in promoting implantation has yet to be elucidated, the integral association of its binding protein FKBP12 with the inositol triphosphate receptor (IP3R) regulated intracellular calcium [Ca2+]i channels in the endoplasmic reticulum (ER), suggesting that TAC can mediate its action through ER release of [Ca2+]i. Using the immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo, our data indicated that TAC can increase [Ca2+]I, as measured by fluorescent live-cell imaging using Fluo-4. Concomitantly, the treatment of HTR8/SVneo with TAC resulted in a major dynamic reorganization in the actin cytoskeleton, favoring a predominant distribution of cortical F-actin networks in these trophoblasts. Notably, the findings that TAC was unable to recover [Ca2+]i in the presence of the IP3R inhibitor 2-APB indicate that this receptor may play a crucial role in the mechanism of action of TAC. Taken together, our results suggest that TAC has the potential to influence trophoblast migration through downstream [Ca2+]i-mediated intracellular events and mechanisms involved in trophoblast migration, such as F-actin redistribution. Further research into the mono-therapeutic use of TAC in promoting trophoblast growth and differentiation in clinical settings of assisted reproduction is warranted.

New and old topical treatments for psoriasis

Patiens with psoriasis and mild to moderate skin disease can be treated with topical agents. This review finds that the most effective topical treatment is calcipotriol and betamethasone combination formulations. Pure topical corticosteroids continue to have a role in the treatment of psoriasis, as they are available in many strengths and formulations that facilitate ease of use. In addition, the price is often lower than for the combination formulations. Topical calcineurin inhibitors can treat facial and intertriginous psoriasis to reduce the risk of skin atrophy.

Studying the association between single nucleotide polymorphisms of metabolizing enzymes and the therapeutic serum levels of calcineurin inhibitors in Egyptian liver transplant patients

BackgroundMany clinical variables might impact the pharmacokinetics of calcineurin inhibitors (CIs). Different alleles of cytochromes P450 (CYP)3A4/5 and drug transporter P-glycoprotein are the main variables. Other variables include relocated type, treatment duration after transplantation, age, sex, dietary consumption, medications used and renal or hepatic impairment. Tacrolimus and cyclosporine are two main CIs extensively used in organ transplantation. Both drugs are metabolized by CYP3A4 and CYP3A5 isoforms, and single-nucleotide polymorphisms in these genes have been displayed to influence CIs pharmacokinetics. Another important gene is the pregnane X receptor (PXR), which manages the statement of a variety of genes including CYP3A4 genes. PXR has a clinical significance in CIs metabolism. The liver is the essential site for CIs metabolism. A decreased clearance with a prolonged CIs half-life was occurred in patients with impaired liver compared with patients with normal liver function. The presence of different genetic and clinical factors that may affect calcineurin inhibitors trough levels will consequently affect their immunosuppressant effect after liver transplantation.PurposeThis study aims to determine the effect of different genetic polymorphisms in CYP3A4 1B rs2740574 and PXR A7635G rs6785049 and other clinical factors that may affect calcineurin inhibitors pharmacokinetics after liver transplantation.ResultsThe presence of T allele in CYP3A4 gene was associated with elevated DATLs with P values of 0.00, 0.00, 0.007 and 0.00 after tacrolimus doses 4, 30, 60 and 90, respectively. Regarding PXR gene, the presence of G allele was associated with elevated DATLs in cyclosporine. About 432 correlations were tested in both drugs. In CYP3A4 genotype CC, male sex was associated with elevated DATLs interpreted by strong positive correlations and statistically significant difference in all DATLs, except DATL 60 (P value 0.374). No strong association was found between low hemoglobin levels and DATLs in almost all the follow-up periods. There were many positive relations between increased total and direct bilirubin and increased DATLs.ConclusionsStudying the various genetics and clinical factors that may affect calcineurin inhibitors serum concentrations is very essential for successful treatment plans after organ transplantation. These different factors may interact with each other and these complicated interactions may complicate the patient’s conditions post-transplantation. Considering all these complicated interactions is very crucial in monitoring treatment plans, especially in the presence of other comorbidities or chronic diseases. More studies with large number of patients should be conducted to explore more consequences of these interacting variables of treatment plans of these patients and all studied parameters in this study should be considered while monitoring patients after transplantation.

Structure-guided design and synthesis of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi.

Invasive fungal infections cause significant mortality worldwide, and current antifungal treatments are often ineffective, toxic, or face growing resistance. This research identifies calcineurin (CaN), a critical protein for fungal survival, as a potential target for developing new antifungal drugs. Although existing CaN inhibitors such as FK506 (tacrolimus) and FK520 (ascomycin) possess antifungal properties, their immunosuppressive effects limit their clinical utility. By studying the structure of human and fungal FKBP12-FK506 or FK520 complexes with CaN, we have designed and synthesized modified FK520 derivatives with strong antifungal activity and reduced immunosuppressive effects. These new derivatives are expected to have significantly improved therapeutic profiles, offering hope for more effective and safer antifungal treatments.

IgA Vasculitis (Henoch-Schönlein Purpura): An Update on Treatment.

Objective: IgA vasculitis (IgAV), previously named as Henoch-Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10-30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therapy. Methods: A narrative literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing the main aspects of glucocorticoids and conventional disease-modifying drugs used in the management of IgAV, this review focuses on the latest information reported regarding biologics and potential future therapies. Results: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. Colchicine, dapsone, and methotrexate can be useful for controlling minor manifestations. Several immunomodulatory agents, such as cyclosporine A, tacrolimus, and mycophenolate mofetil, have shown favorable results as glucocorticoid-sparing agents. Leflunomide has shown promising results but requires further study. The use of rituximab has demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease in children and adults with IgAV. Immunoglobulins and plasma exchange therapy can also be useful in difficult and life-threatening situations. Other potential therapies with encouraging results include TRF-budesonide, B-cell-directed therapy, B-cell-depleting agents, sodium-glucose cotransporter-2 inhibitors, endothelin receptor antagonists, and complement pathway inhibitors. Conclusions: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. The role of various immunomodulatory therapies, such as calcineurin inhibitors and mycophenolate mofetil, remains promising, while rituximab reduces the long-term side effects of glucocorticoids and can help achieve disease remission. Other potential therapies with encouraging results require further research.

Anogenital psoriasis - clinical picture and therapy

Psoriasis presenting with anogenital lesions is an important medical and social problem that is not sufficiently covered in the literature. The genitals and perianal area are involved in severe plaque and inverse psoriasis. Occasionally, the disease can be localized only in the anogenital zone. Diagnosis of psoriasis with localization on the genitals and/or perianal area is difficult, which is associated with the anatomical and physiological characteristics of the affected area. The manifestations of psoriasis become exudative, infiltration of papules and plaques is expressed little, the borders of rashes lose clarity, peeling on the skin is expressed weakly, in the depth of the folds due to maceration and friction is absent. Subjectively significant localization of the process, its prolonged course, pruritus lead to significant violations of the quality of life of patients and serve as prerequisites for the formation of anxiety-depressive disorders and sexual dysfunction Diagnosis and treatment of anogenital psoriasis presents significant challenges. Clinical guidelines tend to emphasize external therapy with topical corticosteroids and calcineurin inhibitors; in recent years, the efficacy of genetically engineered biological agents, including interleukin-17 inhibitors and phosphodiesterase-4 inhibitors, has been considered. The presented review systematizes information about anogenital psoriasis, peculiarities of its epidemiology, clinical picture, diagnosis and approaches to therapy.

Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

Donor-specific Immune Senescence as a Candidate Biomarker of Operational Tolerance Following Liver Transplantation in Adults: Results of a Prospective, Multicenter Cohort Study

Immunosuppression can be withdrawn from selected liver transplant recipients, although robust clinical predictors of tolerance remain elusive. The Immune Tolerance Network ITN056ST study (OPTIMAL) assessed clinical outcomes and mechanistic correlates of phased immunosuppression withdrawal (ISW) in non-autoimmune, non-viral adult liver transplant recipients. Enrolled subjects were ≥3 years post-transplant with minimal/absent inflammation or fibrosis on a screening liver biopsy. The primary endpoint was operational tolerance at 52 weeks following complete ISW. Of 61 subjects who initiated ISW, 34 failed during ISW and 10 restarted immunosuppression due to clinically manifest acute rejection. Of the 17 subjects remaining off immunosuppression at 1 year, 10 were ultimately deemed tolerant by biopsy. There were no cases of chronic rejection or graft loss. The majority of subjects (78.6%), including those who experienced rejection, ended the study on same or less calcineurin inhibitor than at baseline. 28.3% developed de novo DSA during ISW, which persisted in 11.3%. A minority (16.4%) of histologically and clinically stable long-term adult liver transplant recipients can successfully discontinue and remain off immunosuppression. Increased frequency of donor-specific T cell senescence, C4d deposition and higher density of immune synapses on the screening liver biopsy emerged as potential candidate biomarkers for operational tolerance. NCT02533180.

ARCADIA trials: Can nemolizumab be a valid alternative to the therapies currently available?

ARCADIA 1 and ARCADIA 2 were two randomized, placebo-controlled phase 3 trials showing the effectiveness of nemolizumab with concomitant use of low-to-medium potency topical corticosteroids, and/or with or without topical calcineurin inhibitors, in adults and adolescents with moderate-to-severe atopic dermatitis. Coprimary endpoints were met in the nemolizumab plus background therapy groups in both trials, with significant differences versus placebo.

Cyclosporine's immunosuppressive effects, entwined toxicity, and clinical modulations of an organ transplant drug.

The discovery and use of cyclosporine since its inception into the clinics in the '70s and up have played a crucial role in the advancement of transplant therapy and containment of immune-based rejections. The drug had improved rates of acute rejections, and supported early graft survival. However, the long-term survival of renal allografts is still less prevalent, and an in-depth analysis and reported findings led us to believe that there is a chronic irreversible component to the drug that is tackled through its metabolites, and causes toxicity, which led to new therapies, including monoclonal antibody based medications. A recap of the immunosuppressive effects and entwined toxicity of the drug, now relegated to solid transplants, overviews the past protocols used to minimize and avoid, or use in combination with this calcineurin inhibitor class drug with other drugs. The current review circumvents the cyclosporine's mechanism of action, pathophysiology, cytochrome roles, and other factors associated with acute and chronic toxicity. It also attempts to find conclusive strategies reported in recent studies to avoid its toxic side effects and develop a safe-use strategy for the drug. Gastrointestinal decontamination, supporting the airway, monitoring for signs of respiratory insufficiency, monitoring for severe reactions such as seizures, administration of oxygen, and avoiding the administration of drugs that increase the blood levels of cyclosporine are beneficial interventions when encountering cyclosporine toxicity cases. The constrained therapeutic outcome has also led to redesign, and combine formulation to review the pharmacokinetics of the drug.

Evaluating the risk of cardiovascular events associated with different immunosuppression treatments for glomerular diseases.

Patients with glomerular disease are at high risk of cardiovascular disease but the contribution of immunosuppression to this risk is unclear. In this retrospective cohort study of 1912 patients (comprised of 759 with IgA nephropathy, 540 with focal segmental glomerulosclerosis, 387 with membranous nephropathy and 226 with minimal change disease) from British Columbia, Canada, we evaluated the association between exposure to specific immunosuppressive medications and a composite outcome including coronary artery, cerebrovascular and peripheral arterial events. Survival models were adjusted for baseline cardiovascular risk factors, type of glomerular disease, estimated glomerular filtration rate (eGFR) and proteinuria over time. During a median follow-up of 6.8 years, 212 patients (11.1%) experienced the primary outcome. Corticosteroid exposure was not significantly associated with the primary outcome after adjusting for cardiovascular risk factors. In fully adjusted models, cumulative calcineurin inhibitor exposure at modest (150-300 defined daily doses [DDD]) and higher (300 or more DDD) doses were associated with a 2-fold higher risk of cardiovascular events (hazard ratio 2.98, 95% confidence interval 1.27-6.95) and (2.78, 1.32-5.84), respectively. A peak daily dose of antimetabolite (azathioprine, mycophenolate mofetil and mycophenolate sodium) of 0.5 or more DDD was associated with higher risk of cardiovascular events after adjustment for baseline risk factors and type of glomerular disease, but not after adjusting for time-varying eGFR and proteinuria (1.70, 0.91-3.20). Each 10 grams of cumulative cyclophosphamide exposure was associated with a 1.5-fold higher risk of cardiovascular events in a fully adjusted model (1.46, 1.22-1.75) Thus, our findings suggest that immunosuppressive therapies used in the treatment of glomerular disease may have different cardiovascular risk profiles, which should be considered when deciding on immunosuppression for individual patients and as a safety endpoint in future clinical trials.

Association of gut microbiota with allograft injury in kidney transplant recipients: a comparative profiling through 16S metagenomics and quantitative PCR.

Introduction. The existence of a mutual relationship between gut microbiota and immune homeostasis highlights its importance in the context of kidney transplantation.Gap statement. The translational utility of gut microbiota as a biomarker for allograft injury has not been assessed before.Aim. In this study, we aimed to characterize the gut microbial diversity in kidney transplant recipients and investigate the alterations in the gut microbial composition in association with allograft injury such as histopathological graft rejection and calcineurin inhibitor toxicity. In addition, we compared the gut microbial quantitation using 16S metagenomics and quantitative PCR (qPCR) to assess its translational utility.Methodology. In this prospective longitudinal cohort study, we enrolled 38 kidney transplant recipients and collected serial faecal specimens (n=114), once before the induction therapy, and twice after transplant, during the first and third month. We characterized the gut microbial composition through 16S rRNA sequencing and qPCR from the DNA isolates of the samples. The recipients were clinically followed up for a median of 600 days post-transplant. Histopathological evidence of allograft rejection and calcineurin inhibitor toxicity were used for the correlational analysis with gut microbial diversity.Results. Significant differences in the gut microbial diversity were observed between the pre- and post-transplant samples. Pre-transplant gut microbiota revealed a higher relative abundance of phylum Bacteroidetes in the allograft rejection group, and a higher relative abundance of phylum Firmicutes was observed in the histopathological features of calcineurin inhibitor toxicity (hCNI toxicity) group. We found a high concordance between 16S metagenomics and qPCR outputs for assessing the gut microbial diversity. Furthermore, the receiver operating characteristic curve analysis has also proven that the pre-transplant levels of gut microbial dysbiosis, as a potential predictive biomarker for allograft injury.Conclusion. Our pilot study found a strong statistical association of gut microbial dysbiosis with kidney allograft injury, highlighting the potential of gut microbiota as a predictive biomarker and that qPCR serves as a more reliable and economic tool for assessing dysbiosis paving the way for its translational utility.

Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.

Management of Generalized Vitiligo in Adolescent with Tofacitinib: Clinical Case

Background. Vitiligo is a depigmenting skin disease characterized by selective loss of melanocytes leading to development of typical white spots. There are various theories on vitiligo etiology: genetic, autoimmune, neurogenic, autoinflammatory, oxidative stress theory, and many others. Generally accepted dominant role is given to the concept of its autoimmune nature. Vitiligo management traditionally includes different methods of phototherapy, topical and systemic glucocorticoids (GC), and calcineurin inhibitors. Recently, Janus kinase inhibitors (JAK) have shown its efficacy in treatment of vitiligo. Clinical case description. 13-year-old male adolescent has complaints of hypopigmentation areas on the skin of face, trunk and limbs that appeared after active solar insolation during summer vacation. Dermatologist has determined a diagnosis of vitiligo according to clinical picture. Topical GC of the 3rd activity class were used for treatment, as well as course of local narrow-band medium-wave photodynamic therapy (311 nm, No. 30) with no significant effect. The patient was admitted to the dermatology department of Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery where therapy with JAK inhibitor, tofacitinib, was initiated due to inefficacy of previous treatment and the generalized form of the disease. Conclusion. Management of vitiligo with JAK inhibitors, in particular tofacitinib, is a promising method and it can lead to significant clinical effect with safety profile comparable to conventional therapies for this pathology.

Pimecrolimus Efficacy and Safety in Management of Children with Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. Early management of AD is crucial for preventing the development of atopic disease such as asthma, allergic rhinitis, etc. Topical glucocorticoids (TGCs) are used as first-line therapy, however, their long-term use poses the risk for patient's health. Despite the rapid clinical response at skin process aggravation, long-term use of TGCs in first-line therapy is associated with various adverse events, including: skin atrophy, hypothalamic-pituitaryadrenal axis suppression, telangiectasis, etc. All together it limits the long-term TGCs use, especially in management of pediatric patients and using such drugs in sensitive regions such as face and intertriginous areas. Due to these limitations TGCs should only be used for a short period of time. Thus, limitations in both treatment duration and number of drugs make TGCs non-optimal for long-term AD treatment. Pimecrolimus (1% cream) is a topical calcineurin inhibitor that is indicated for the treatment of mild to moderate AD. Pimecrolimus does not cause any significant side effects compared to TGCs and it is well tolerated for long-term administration.