Combination Of Tacrolimus Research Articles

Excimer Light versus Combination of Tacrolimus and Excimer Light in the Treatment of Alopecia Areata

Background. Alopecia areata (AA) is a nonscarring alopecia that can affect any hairy area of the body. Excimer light at 308 nm with immunosuppressive effects is recommended as a promising management method for AA. Objectives. To assess the efficacy and safety of excimer light at 308 nm alone versus a combination of tacrolimus 0.1% and excimer light in the treatment of alopecia areata. Methods. Forty patients with AA of the scalp were divided into two groups, group A was treated with an excimer lamp twice per week for three months, and group B was treated with a combination of tacrolimus 0.1% and an excimer light. The efficacy of the treatment was evaluated by the SALT score and serum T‐regulatory cells at the baseline, after 3 months from the baseline, and after 6 months from the beginning of treatment. Results. In group (A), the median SALT decreased from the baseline (13.15) to (6.15) 3 months after the baseline and further decreased after 6 months of follow‐up to (3.3). While in group (B), the median SALT score was decreased from the baseline (11.15) to (0.5) after 6 months from the beginning of treatment. After 3 months, there was improvement in Treg function in both groups A and B (4.98 ± 1.02, 5.50 ± 0.84), respectively. There was a significantly higher improvement in group B (85.19 ± 8.55) than group A (70.05 ± 9.95). Dermoscopic findings reveal decreased signs of activity in group B more than group A. Conclusion. The combination of excimer light and tacrolimus is more effective than excimer light alone in treatment of AA.

Efficacy and safety of 308-nm Excimer lamp combined with Tacrolimus 0.1% ointment vs Tacrolimus 0.1% ointment as monotherapy in treating children with limited vitiligo: a randomized controlled trial

Objective This study aims to assess the efficacy and safety of combining the 308-nm Excimer lamp with Tacrolimus 0.1% ointment, compared to Tacrolimus 0.1% ointment monotherapy, for treating pediatric vitiligo involving less than 10% of the body surface area. Methods Fifty pediatric patients with vitiligo were randomly assigned to two groups. Group A received Tacrolimus 0.1% ointment twice daily and Excimer light at 308-nm twice weekly, while Group B received Tacrolimus 0.1% ointment alone, administered twice daily. Repigmentation percentages were evaluated after 30, 90, and 180 days using the rule of nine. Results Group A exhibited a significant improvement in repigmentation, increasing from 10% after one month to 65% after six months. In contrast, Group B observed an increase from 10% to 30% over the same timeframe. The efficacy of the treatment was significantly higher in Group A at both the 3-month and 6-month follow-up points (p-value < .001). Moreover, Group A achieved notably higher repigmentation rates in the face, trunk, and lower limbs. Conclusion The combination of Tacrolimus and the 308-nm excimer lamp yielded superior repigmentation results compared to Tacrolimus monotherapy in pediatric vitiligo patients. This combined approach may offer an effective new treatment protocol for pediatric vitiligo.

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression.

Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.

TBI-Containing with T-Cell Replete Full Haplotype Mismatched Hematopoietic Stem Cell Transplantation in Adult Patients with De Novo Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the 2nd most frequent developing hematologic malignancy with deep heterogeneity, but unfortunately the majority of patients relapse even after allogeneic hematopoietic stem cell transplantation (HSCT) in complete remission (CR). We have developed allogeneic HSCT from familial mismatched/haploidentical donors (FMT) in adult patients with a single disease entity of AML lacking of both HLA-identical siblings and well-matched unrelated donors (WMUD) from the mid 1990s. Previously, several pilot studies of FMT performed with various total body irradiation (TBI)-based conditioning regimens (2~12 gray) with or without post-transplant cyclophosphamide (PT-Cy) as a graft-versus-host disease (GvHD) prophylaxis were reported. Here, we demonstrate about the encouraging outcomes of FMT using unmanipulated peripheral blood donor stem cells (PBSCs) and de-escalated dose of TBI (4~8 gray) containing conditioning regimen without T-cell depletion manner. Although PT-Cy as a specific GvHD prophylaxis regimen is increasingly used for both adult and pediatric FMT, our group investigated the clinical outcomes in adult patients with de novo AML who received full haplotype mismatched HSCT after TBI containing preparation regimen consisted of fractionated TBI (total 4 gray for elderly and 8 gray for &amp;lt;60 years old), fludarabine (150 mg/m 2/day), busulfex (6.4mg/kg/day), and anti-thymocyte globulin (ATG). For GvHD prophylaxis, rabbit ATG (thymoglobulin, Genzyme, 1.25mg/kg/day for 4 days at D-4 to D-1) and a combination of tacrolimus and short-term methotrexate was used. G-CSF mobilized unmanipulated PBSCs were used with a median CD34+ dose of 6.5 x 10 6/kg (1~25.6). From 2008 to the end of 2022, total 429 adult patients were enrolled, and data demonstrated that our trial of intermediate-dose of ATG and reduced toxicity of TBI-containing conditioning regimen to reduce graft-failure even for high levels of donor-specific antibody titer, early transplant-related mortality, critical cytomegalovirus (CMV) disease, and emerging post-transplant lymphoproliferative disease with rapid immune recovery has shown very successful outcomes. Briefly, the median absolute neutrophil count recovery was 12 days (10~26) and the platelet of 14 days (5~38). There was no either primary or secondary graft-failures at all. With a median follow-up of 36.5 months (2~242) for survivors, overall survival rate (OS) and relapse-free survival (RFS) for patients in any CR (n=338) and relapse/refractory status (n=91) were 62.9% vs. 34.3% and 59.5% vs. 32.2%, respectively. Although there was no significant difference in the subgroup analysis, de novo and young aged patients in any CR showed the best OS 73% (Figure 1). Cumulative incidences of acute GvHD and chronic GvHD were 66% (59-73), 70% (63-76), respectively. The incidences of moderate to severe acute GvHD and chronic GvHD were 16.1%, 30.5%, respectively. By univariate and multivariate analyses, patient's age &amp;lt;54 (p=0.043), pre-HSCT CR1 (p &amp;lt;0.001), absence of mod to severe chronic GvHD (p &amp;lt;0.001), and use of post-transplant iron-chelating agent (p=0.001) were the statistically significant in the study. The GvHD-free and relapse-free survival rate in CR1 was 62.4% for younger patients (age &amp;lt;54) and 47.9% for older patients (p=ns). The non-relapse mortality rate was 27.2% for all enrolled patients and 16% for CR patients. The rapidity of immune recovery was also compared with our old control cohort when we performed T-cell depletion using the CliniMACS system, and it showed a significant reconstitution of CD4+ cells (&amp;gt;300/ul) at 3 months post-FMT compared to the much delayed T-cell depleted FMT. Of note, CMV DNAemia was relatively higher (76.9%) than reported in other studies, likely due to the use of ATG and the endemic region of our country. Therefore, we suggest that the strategic reduction of fractionated TBI 4~8 gray-based conditioning with unmanipulated PBSCs graft without PT-Cy seems feasible with favorable outcomes for adult patients with de novo AML undergoing FMT in CR, especially even in a certain subgroup of elderly patients with AML.

Humanized Anti-CD25 Monoclonal Antibody Replacing MTX for Graft-Versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplantation

Introduction Currently, a short course of methotrexate (MTX) remains the classical regimen for the prevention of graft-versus-host disease (GVHD) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Although MTX was widely applied for GVHD prophylaxis, it has been reported to be associated with significant toxicity and considerable side effects. We conducted a prospective, single-center, non-randomized controlled study to evaluate whether MTX can be safely removed from GVHD prophylaxis regimen after transplantation. Methods We prospectively reported and analyzed the data of 149 patients with hematologic malignancies who received haplo-HSCT from May 2022 to January 2023, and followed up until July 10, 2023. Patients were voluntarily enrolled in two groups according to different prevention programs of GVHD. A total of 82 patients were administrated with a combination of cyclosporine (CsA) or tacrolimus, mycophenolate mofetil (MMF), anti-human thymocyte immunoglobulin (ATG), MTX (15mg, +1d, 10mg, +3d, 10mg, +6d), and humanized anti-CD25 monoclonal antibody (Xenopax, 25mg, +0d, +4d) (single-dose anti-CD25 with MTX group). A total of 67 patients were given with CsA or tacrolimus, MMF, ATG and humanized anti-CD25 monoclonal antibody (Xenopax, 50mg, +0d, +4d) (double-dose anti-CD25 group). This study is registered with the Chinese Clinical Trial Registry (chictr.org.cn: ChiCTR2200060184). Results Compared with the single-dose anti-CD25 with MTX group, the median time to achieve neutrophil and platelet engraftment was shorten in double-dose anti-CD25 group (neutrophil: 9 days (7-20) vs 11 days (7-39), P=0.000; platelet: 9 days (7-30) vs 11 days (7-46), P=0.001). The incidence of total oral mucositis (OM) and grade 2-4 OM were significantly reduced in double-dose anti-CD25 group (total OM: 40.29% vs 63.41%, P=0.003; grade 2-4: 7.46% vs 32.05%, P=0.000). The median duration of OM was remarkably shorter in double-dose anti-CD25 group (5 days (2-18) vs 11 days (3-30), P=0.000). Lower cumulative incidence (CI) of grade II-IV aGVHD was observed in double-dose anti-CD25 group than in single-dose CD25 with MTX group (16.7 ± 4.6% vs 28.4 ± 5.0%, P=0.063). There was no statistical difference in two groups of the 100-day CI of grade III-IV aGVHD (6.1 ± 3.0% vs 13.6 ± 3.8%, P=0.123). Lower CI of cGVHD were occurred in double-dose anti-CD25 group (8.4 ± 4.1% vs 20.3 ± 5.1%, P=0.073). The CI of GVHD/relapse-free survival in double-dose anti-CD25 group was remarkably improved than that in single-dose CD25 with MTX group (73.9 ± 5.5% vs 55.6 ± 5.7%, P=0.044). No significant difference occurred in two groups of the overall CIs of CMV viremia, EBV viremia, overall survival, disease-free survival, relapse and treatment-related mortality. Conclusions Based on the efficacy and safety of the clinical trial results at our transplant center, replacing MTX with a single dose of humanized anti-CD25 monoclonal antibody is a promising GVHD prophylaxis for haplo-HSCT.

Impact of GAD65 and IA2 autoantibodies on islet allograft survival.

Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade's nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance. ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 - 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 - 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 - 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival.

Drug levels after sirolimus initiation and short-term outcomes in ambulatory heart transplantation recipients.

We evaluated the effect of relative changes in combined tacrolimus and sirolimus (drug) levels, following sirolimus initiation, on outcomes in ambulatory heart transplantation (HTx) recipients. We performed a retrospective analysis of HTx recipients who received tacrolimus, followed by sirolimus initiation, any time after HTx. We calculated the relative change in combined drug levels 1-month post-sirolimus initiation, relative to tacrolimus levels pre-initiation, and categorized patients into decreased (≥15% decrease), stable (<15% decrease to<15% increase), or increased (≥15% increase) groups. We compared, across the three groups, changes in post-initiation estimated glomerular filtration rate (eGFR) and left ventricular ejection fraction (LVEF) using one-way ANOVA and Šidák's post-hoc analysis, as well as the individual and composite outcomes of new donor specific antibodies (DSA), acute cellular rejection (ACR), and all-cause mortality using Fisher's exact test. Amongst 99 HTx recipients included, the median age was 53 years, time to sirolimus initiation was 1.5 years post-HTx, and pre-sirolimus eGFR was 52mL/min/1.73m2 . Nine patients had decreased, 15 stable, and 75 increased, relative combined drug levels. Relative change in eGFR was significantly higher in patients with decreased levels compared to patients with increased levels at 6 months post-initiation (P<.05), but this was not sustained at 12 months. There were no differences in LVEF change or in individual and composite risks for developing DSA, ACR, and all-cause mortality at 12 months across the groups. Post-sirolimus initiation, a relative decrease in combined drug levels, compared to increased levels, was associated with temporarily improved renal function.

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 &amp;lt;200 was the only risk factor (AUTC 14-28&amp;lt;200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 &amp;lt;200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 &amp;lt;200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 &amp;lt;200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

Long-Term Efficacy and Relapse in Lupus Nephritis Treated with Mycophenolate Mofetil and Tacrolimus Combination Therapy

Long-Term Efficacy and Relapse in Lupus Nephritis Treated with Mycophenolate Mofetil and Tacrolimus Combination Therapy

Efficacy and safety of immunosuppressive agents for adults with lupus nephritis: a systematic review and network meta-analysis.

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN. We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer. Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%). This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Interplay Between Inflammatory-immune and Interleukin-17 Signalings Plays a Cardinal Role on Liver Ischemia-reperfusion Injury-Synergic Effect of IL-17Ab, Tacrolimus and ADMSCs on Rescuing the Liver Damage.

This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1h)-reperfusion (72h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus. Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72h. The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001). Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy.

Comparative Study of Topical Latanoprost, Tacrolimus and Clobetasol Propionate in Combination with Microneedling and Narrow-Band Ultraviolet B in the Treatment of Non-Segmental Vitiligo

Abstract Background Vitiligo is a common skin disease in both sex. There are multiple options in the treatment of vitiligo but the response is unsatisfactory. In this comparative study we will study the effect of topical latanoprost, tacrolimus, clobetasol propionate in combination with microneedling and narrow-band ultraviolet B (NB-UVB) in the treatment of non-segmental vitiligo. Objective To evaluate and compare the efficacy and safety of topical latanoprost, tacrolimus, clobetasol propionate when combined with microneedling and NB-UVB in the treatment of nonsegmental vitiligo lesions. Patients and Methods This randomized self-controlled clinical trial included 30 vitiligo patients with at least 5 patches of stable vitiligo (150 patches), the patches were divided into five groups according to the treatment modality. The patients were recruited from the outpatient clinic of dermatology of Ain Shams University Hospital in the period from July 2019 to September 2020. Results Regarding safety of considered therapies, pain and erythema was reported with Microneedling + latanoprost and NB-UVB and Microneedling + topical tacrolimus and NB-UVB. Itching was associated with Microneedling + topical clobetasol propionate and NB-UVB while burning and dryness were associated with NB-UVB therapy. Conclusion Combination therapy in treatment of vitiligo showed higher efficiency compared to monotherapy. Microneedling + latanoprost and NB-UVB treatment combined therapy showed the maximal repigmentation in included patients followed by Microneedling + tacolimus and NB-UVB treatment. Monotherapy using NB-UVB showed minimal response when compared to other combination modalities.

CircFOXN2 alleviates glucocorticoid- and tacrolimus-induced dyslipidemia by reducing FASN mRNA stability by binding to PTBP1 during liver transplantation.

We aimed to examine impacts and functional mechanism of circular RNA forkhead box N2 (FOXN2) in tacrolimus (TAC)- and dexamethasone (Dex)-induced lipid metabolism disorders. RNA level and protein contents in TAC, Dex, or combined TAC- plus Dex-treated patients and Huh-7 cells were measured utilizing quantitative real-time (qRT)-PCR and western blotting assays measured the formation of lipid droplet. Total cholesterol (TC) and triglyceride (TG) levels were determined using corresponding commercial kits and Oil red O staining. RNA immunoprecipitation and RNA pull-down verified the binding relationship among circFOXN2, polypyrimidine tract binding protein 1 (PTBP1) and fatty acid synthase (FASN). Male C57BL/6 mice were used to establish a dyslipidemia mouse model to validate the discoveries at the cellular level. Dex treatment significantly promoted TAC-mediated increase of TC and TG in serum samples and Huh-7 cells. Moreover, circFOXN2 was reduced but FASN was elevated in TAC-treated Huh-7 cells, and these expression trends were markedly enhanced by Dex cotreatment. Overexpression of circFOXN2 could reverse the accumulation of TC and TG and the upregulation of FASN and sterol regulatory element binding transcription factor 2 (SREBP2) mediated by Dex and TAC cotreatment. Mechanistically, circFOXN2 reduced FASN mRNA stability by recruiting PTBP1. The protective roles of circFOXN2 overexpression on lipid metabolism disorders were weakened by FASN overexpression. In vivo finding also disclosed that circFOXN2 greatly alleviated the dysregulation of lipid metabolism triggered by TAC plus Dex. CircFOXN2 alleviated the dysregulation of lipid metabolism induced by the combination of TAC and Dex by modulating the PTBP1/FASN axis.NEW & NOTEWORTHY Collectively, our experiments revealed for the first time that circFOXN2 alleviated the Dex- and TAC-induced dysregulation of lipid metabolism by regulating the PTBP1/FASN axis. These findings suggested that circFOXN2 and FASN might be candidate targets for the treatment of Dex- and TAC-induced metabolic disorders.

Combination of Rituximab and Low-dose Tacrolimus in the Treatment of Refractory Membranous Nephropathy: A Retrospective Cohort Study

Conventional regimens for refractory idiopathic membranous nephropathy (IMN) still have limitations. Rituximab (RTX) has a good effect in the treatment of refractory IMN. However, whether RTX single or combined with immunosuppressive therapy is more effective and whether adverse events will increase are still inconclusive. To investigate the efficacy and safety of RTX combined with low-dose tacrolimus (TAC) versus RTX alone in the treatment of refractory IMN. A retrospective cohort study. We retrospectively studied 91 cases of refractory IMN diagnosed between January 2018 and June 2021, all of which immunosuppressive regimens had failed. Thirty-four patients received RTX combined with TAC (RTX + TAC group), and 57 patients were treated with RTX alone (RTX group). The RTX + TAC group was given RTX 1 g once every 2 weeks, two times, and TAC 0.03 mg/kg/day orally. In the RTX group, RTX was given at the same dosage as the RTX + TAC group. Clinical data were collected at 12 months of follow-up to compare the complete and partial remission rates and the incidence of adverse reactions between the two groups. The overall effectiveness rate of RTX + TAC in the treatment of refractory IMN was 87.14%, of which the partial and complete remission rates were 50.01% and 37.13%, respectively, and the median time to complete remission was 9 (interquartile range [IQR] 6.0, 12.0) months. The overall effectiveness rate of RTX was 65.87%, of which the partial and complete remission rates were 39.48% and 26.39%, respectively, and the median time to complete remission was 10.5 (IQR 6.0, 12.0) months. Adverse events occurred in 6 (17.65%) patients in the RTX + TAC group and in 11 (19.30%) in the RTX group (P = 0.473). Proteinuria and high titer of PLA2R are risk factors for non-remission. The complete and partial remission rates of RTX combined with low-dose TAC in the treatment of refractory IMN are higher than those of RTX alone, and no significant increase in adverse events was noted.

In vitro combination of antifungal drugs with tacrolimus (FK506) holds promise against clinical Candida species including Candida auris.

In vitro interactions between tacrolimus, a calcineurin inhibitor, and fluconazole, itraconazole, caspofungin, or anidulafungin were evaluated against Candida auris, C. albicans, C. parapsilosis, and C. glabrata (each five strains). Tacrolimus-itraconazole, tacrolimus-caspofungin, and tacrolimus-fluconazole combinations resulted in synergistic interactions against 95%, 90%, and 60% of Candida isolates, respectively. Contradictory, tacrolimus-anidulafungin resulted in only a 35% synergistic effect. A combination of tacrolimus and itraconazole was most potent with synergy against 100% of C. auris, C. parapsilosis, and C. glabrata isolates. Of note, no antagonistic interaction was found.

#6310 ANALYSIS OF THERAPEUTIC ATTITUDES TOWARDS BK VIRUS INFECTION IN RENAL TRANSPLANTATION: A RETROSPECTIVE COHORT STUDY

Abstract Background and Aims BK virus infection continues to be one of the most common clinical issues encountered by transplants providers, which can lead to BK virus nephropathy and, ultimately, graft loss. Despite its importance, there are still many uncertainties surrounding effective prevention and treatment strategies. The aim of this study is to evaluate the BK virus prevalence disease in a cohort of kidney transplant patients, examine consequences of immunosuppression regimens readjustments and assess the progression of viremia and viruria. Method This study analyzed a cohort of patients who received kidney transplants from January 2011 to January 2020 and had a minimum graft survival of three months. In accordance with our established protocol, viremia was measured on a quarterly basis during the first year after transplantation and annually thereafter. BK virus infection (BKVi) was defined as a plasma viral load, determined by real-time PCR, of 10,000 copies/ml or greater, or a viral load of 5,000 copies/ml or greater if accompanied by viruria of greater than 10 million copies/ml. Out of the 490 patients initially selected, 42 were excluded from the study due to inadequate data. Results The maximum levels of viremia during the course of the study were classified as follows: viremia ≥ 10,000 (N = 78; 17.4%), between 5,000-10,000 (N = 11; 2.4%), between 500-1,000 (N = 17; 3.8%) and undetectable (N = 342; 76.3%). The maximum levels of viruria were classified as: viruria ≥ 1 million (N = 98, 21.9%), between 999,999-100,000 (N = 15; 3.3%), between 99,999-10,000 (N = 20, 4.5%) and undetectable (N = 315; 70.3%). In the group diagnosed with BKVi, viremia ≥ 10,000 appeared at a median post-transplant time of 5.8 (2.9-11.7) months. The treatment approach involved replacing tacrolimus or mycophenolate with mTOR inhibitor, based on the patient's immunological risk. In some cases of high immunological risk or intolerance to mTOR inhibitor during the first month, treatment with tacrolimus and mycophenolate was continued. If the previous regimens were not effective, treatment with cyclosporine and mTOR inhibitor was initiated in some cases. The key results are summarized in the Table 1. Conclusion The combination of tacrolimus and mTOR inhibitor appears to be an effective option for BK virus infection, while the combination of mTOR inhibitor and mycophenolate has a high discontinuation rate, which can result in subsequent increase in viremia. In cases where there is no favorable response, the combination of cyclosporine and mTOR inhibitor can be effective. The changes in immunosuppression in patients with BKVi did not result in significant differences in renal function at one year or five years after transplantation, although the sample size is limited and more research is needed to confirm this. Keeping tacrolimus and mycophenolate may lead to a longer time until viremia becomes negative, which could have long-term implications for renal function.

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.

Combination of everolimus and low-dose tacrolimus controls histological liver allograft injury as sufficiently as high-dose tacrolimus.

The combination of everolimus (EVR) and low-dose tacrolimus (lowTAC) prevents T cell-mediated rejection of liver grafts as sufficiently as high-dose tacrolimus (highTAC) and mycophenolate, but is associated with a preserved kidney function within the first years after orthotopic liver transplantation (OLT). However, none of the available studies assessed the histological pattern of graft injury or fibrosis in surveillance biopsies (svLbx). All svLbx taken under at least one month of stable immunosuppression with either EVR (aim 3-8 ng/ml) combined with lowTAC (aim 3-5 ng/ml) or highTAC (aim 5-8 ng/ml) combined with mycophenolate (500-1500 mg/day) within the first three to four years after OLT at our center were included. Patients who were switched to EVR because of insufficient control of alloreactivity were excluded. Reasons for switches to EVR were mainly malignancies before or after OLT, or chronic kidney injury. We were able to include 20 svLbx with EVR/lowTAC and 49 with highTAC/mycophenolate. Both groups had similar liver enzymes and similar kidney function. The EVR/lowTAC group exhibited lower TAC trough levels at svLbx (4.4 vs. 6.6 ng/ml; p<.001) in comparison to highTAC/mycophenolate. Histological graft injury quantified by the rejection activity index and hepatitis activity index (Ishak), as well as fibrosis were not significantly different between the EVR/lowTAC and highTAC/mycophenolate groups. Likewise, subclinical TCMR, histological criteria justifying immunosuppression minimization, and steatosis had equal prevalence in both regimens. Immunosuppression was adjusted according to the svLbx findings. Immunosuppression regimens had similarly low rates of rejection after immunosuppression reduction, when relevant graft injury was absent in the biopsy. In conclusion, EVR/lowTAC seems to control alloreactivity and histological graft injury as sufficiently as highTAC/mycophenolate within the first 3-4 years after OLT.

Post-transplantation cyclophosphamide combined with tacrolimus and low-dose post-engraftment anti-thymoglobulin as GVHD prophylaxis for patients undergoing peripheral blood stem cell transplantation from haploidentical family donor: A single center analysis.

Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.

Physiologically-based pharmacokinetic modeling-guided rational combination of tacrolimus and voriconazole in patients with different CYP3A5 and CYP2C19 alleles

The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus.