Randomized controlled trial of sustained release tacrolimus vs twice daily tacrolimus in adult living donor liver transplantation.

BACKGROUND: To compare the safety and efficacy of once-daily tacrolimus (ODT) versus twice-daily tacrolimus (BDT) in adult live donor liver transplantation (LDLT). METHODS: In this open-labelled randomized trial, 174 adult patients undergoing LDLT were randomized into ODT or BDT, combined with basiliximab induction and mycophenolate mofetil (steroid-free regimen). Tacrolimus was started at a total dose of 1 mg and the trough level was aimed at 3-7 ng/ml. The primary endpoint was eGFR at 1,3- and 6 months post-transplant, using CKD- EPI equation. Secondary endpoints included biopsy-proven acute rejection (BPAR), metabolic complications, post-operative bilio-vascular complications and patient survival. RESULTS: There was no statistically significant difference in eGFR between the two groups at 6 months (ODT -96 ± 19, BDT -91 ± 21, p value-0.164). BPAR was comparable (18/84 in ODT, 19/88 in BDT, p value-0.981). For a similar dosage of tacrolimus, the median trough tacrolimus levels attained were significantly lower for ODT than BDT during the first-month post-transplant (p value-0.001). Metabolic complications due to immunosuppression, post-operative bilio-vascular complications and patient survival was similar between the two groups at 6 months. CONCLUSION: Once-daily tacrolimus has similar renal safety and efficacy as twice-daily tacrolimus when used in combination with basiliximab induction and mycophenolate in adult LDLT.

Efficacy and safety of tacrolimus versus mycophenolate mofetil as induction treatment and low-dose tacrolimus as treatment for lupus nephritis: a meta-analysis.

OBJECTIVE: The purpose of this study was to compare the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) as induction therapy and low-dose tacrolimus as treatment for lupus nephritis (LN). METHODS: Meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety of tacrolimus and MMF as induction therapy for LN. We systematically reviewed RCTs and prospective cohort studies with a tacrolimus dose of 3 mg daily and performed a meta-analysis of the efficacy and safety of tacrolimus as an induction treatment for LN in comparison to MMF. RESULTS: The inclusion criteria were satisfied by eight studies (five RCTs and three prospective cohort studies) with a total of 408 individuals (289 for tacrolimus vs. MMF and 119 for low-dose tacrolimus). Tacrolimus and MMF had similar complete remission rates (odds ratio [OR] 1.028; 95% confidence interval [CI] 0.589-1.796; p = 0.922). The partial remission rate did not differ between the tacrolimus and MMF groups (OR 1.400; 95% CI 0.741-2.646; p = 0.300). Tacrolimus and MMF showed no differences in proteinuria, serum albumin, serum creatinine, creatinine clearance, renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), or extra-renal SLEDAI. The incidence of infection, severe infection, leukopenia, and hyperglycemia did not differ between the tacrolimus and MMF groups. However, herpes zoster infection was significantly less common in the tacrolimus group (OR 0.137; 95% CI 0.034-0.546; p = 0.005), whereas serum creatinine elevation was significantly higher in the tacrolimus group than in the MMF group (OR 8.148; 95% CI 1.369-48.50; p = 0.021). At 3 mg/d, tacrolimus was shown to be safe, well tolerated, and offered therapeutic benefits in all investigations. CONCLUSION: Tacrolimus was comparable to MMF in terms of effectiveness and safety as an induction therapy for LN, with the exception of a reduced risk of herpes zoster infection and a rise in serum creatinine. In individuals with LN, 3 mg/d tacrolimus was proven to be efficacious and safe.

Effectiveness of tacrolimus concomitant with biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

OBJECTIVES: The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. METHODS: 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. RESULTS: Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. CONCLUSIONS: Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

BACKGROUND AND AIMS: To report 5-year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

First-line Combination Strategy Provides Favorable 5-year Outcomes for Patients with Lupus Nephritis: A Single-center Observational Study.

This observational study aimed to clarify the long-term results of the combination of mizoribine (MZB), tacrolimus (TAC) and prednisolone as first-line therapy for lupus nephritis (LN). This was our institution's standard therapy between 2009 and 2015, when we saw 36 patients with LN. When a patient thus treated achieved SLEDAI remission (= 0) and/or the prednisolone dose could be tapered to 5 mg/day, either MZB or TAC was stopped, and the other was continued for maintenance therapy. If treatment failure or relapse occurred, second-line therapy was introduced. At years 1 and 5, overall complete renal response and SLEDAI remission were 94% and 88%, and 50% and 62%, respectively. Excluding 2 cases lost to follow-up, medications after 5 years were as follows: 20 (59%) were stable on 1 drug (MZB or TAC), 11 (32%) required continuation of both drugs (MZB + TAC), and 3 (9%) required second-line therapy. The 5-year retention rate was 91% (non-secondline), with 0% of relapse in this group. Our first-line combination strategy showed high remission rates in the induction phase, and subsequent maintenance therapy demonstrated good outcomes for up to 5 years. Research that fine-tunes the order of therapeutic agents and institutes appropriate treatment goals may further improve long-term outcomes for patients with LN.

Efficacy of single dose dermatological 0.1% Tacrolimus Ointment in the treatment of vernal keratoconjunctivitis.

Objectives: To assess the safety of dermatological 0.1% tacrolimus ointment when used topically and its efficacy in the treatment of vernal keratoconvinctivtis. METHODS: The quasi-experimental, multi-centre study was conducted at the Gujranwala Medical College/District Headquarters Teaching Hospital, Gujranwala, and the Gomal Medial College/Mufti Mehmood Teaching Hospital, Dera Ismail Khan, Pakistan, from July 2019 to March 2020, and comprised patients of severe vernal keratoconvinctivtis. Symptoms and clinical signs were graded on a pre-devised scale. Patients were given small amount of tacrolimus 0.1% ointment applied to the inferior conjunctival fornix before going to bed. The duration of treatment was 3 months and the patients were followed up for up to 6 months. Data was analysed using SPSS 20. RESULTS: Of the 50 patients, 30(60%) were males and 20(40%) were females. The overall mean age was 10.64±3.199 years. Mean symptom score and clinical signs score gradually reduced on each follow-up (p<0.05). Mild recurrence was noted in 12(24%) patients who were managed with lubricants and anti-histamine topical drops. No complication was noted. CONCLUSIONS: Tacrolimus 0.1% was found to be effective and safe in the treatment of severe refractory vernal keratoconvinctivtis even when given once a day. Clinical Trial Registration: Chinese Clinical Trial Registry Id: ChiCTR2000031929 link: www.chictr.org.cn/hvshowproject.aspx?id=28053.

The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

Unmet medical needs in the treatment of atopic dermatitis in infants: An Expert consensus on safety and efficacy of pimecrolimus.

Atopic dermatitis (AD) is a common skin disease during infancy, which imposes a considerable burden on patients, their families, and the society, requiring effective treatment options that result in rapid and sustained symptom relief. Additionally, early treatment may prevent the development of atopic comorbidities by restoring the skin barrier. Currently, topical standard-of-care for AD in infants includes emollients and topical corticosteroids (TCS) to treat and reduce the risk of flares. However, only few have been approved for infants and long-term maintenance therapy with TCS is not indicated due to potential local and systemic side effects, including skin atrophy. Accordingly, the recently updated European guidelines for treatment of AD recommend topical calcineurin inhibitors (TCIs) for long-term use, treatment of sensitive skin areas, and for use in the pediatric population. Evidence on the use of TCIs for infants has almost been exclusively collected for pimecrolimus, with >4000 infants evaluated in clinical trials, consistently confirming that pimecrolimus is a safe and effective treatment for infants with AD. Nevertheless, its use is still restricted in most countries to children above the age of 2 years due to initial and mostly theoretical safety concerns. Based on a careful review of the available evidence of clinical trials, post-marketing surveillance, and epidemiological studies, an Expert Panel of European dermatologists and pediatric allergologists concluded that these safety concerns are no longer valid. Therefore, pimecrolimus offers a safe and effective alternative to TCS in infants aged 3 months and above, and labeling restrictions in this age group are no longer justified.

Invasive pulmonary aspergillosis associated with COVID-19 in a kidney transplant recipient.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 â†’ 3)-ß-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.

Topical therapy of atopic dermatitis with a focus on pimecrolimus.

Atopic dermatitis (AD) is a chronic and relapsing, inflammatory skin disease characterized by impaired skin barrier function and immune system dysregulation that results in dryness, skin microbiome dysbiosis and intense pruritus. It is highly heterogeneous, and its management is demanding. Patients with AD are at greater risk of comorbidities such as attention-deficit hyperactivity disorder as well as other atopic diseases. Early-onset AD cases typically improve or resolve in late childhood; however, it is proposed that the prevalence of persistent or adult-onset AD is higher than previously thought. Basic therapy consists of emollient application and trigger avoidance, and when insufficient, topical corticosteroids (TCS) are the first-line treatment. However, corticophobia/steroid aversion and TCS side-effects, particularly on sensitive skin areas, lead to low compliance and insufficient disease control. Several long- and short-term randomized controlled and daily practice studies have demonstrated that topical calcineurin inhibitors, such as pimecrolimus, have similar anti-inflammatory effects to low-to-medium strength TCS, reduce pruritus and improve the quality of life of patients. In addition, pimecrolimus does not cause skin atrophy, is steroid-sparing and has a good safety profile, with no evidence for an increased risk of malignancies or skin infections. In general, pimecrolimus cream is well-accepted and well-tolerated, encouraging patient adherence and leading to its use by many physicians as a preferred therapy for children and sensitive skin areas.

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis - A systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach. METHODS: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations. RESULTS: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day. CONCLUSION: Tacrolimus is effective with acceptable safety in the management of RA.

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review.

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. METHODS: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. RESULTS: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. CONCLUSIONS: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.

A comparative study of topical tacrolimus and topical triamcinolone acetonide in nodular scabies.

The aim of this study was to compare the efficacy and safety of 0.1% triamcinolone acetonide and 0.03% tacrolimus ointment for the treatment of nodular lesions of scabies. In this double-blind randomized controlled trial, 50 Indian men with postscabeitic persistent nodular lesions (labelled to have nodular scabies (NS)/postscabies prurigo (PSP)) over the external genitalia, were enrolled. They were randomized into two groups to receive either a mid-potency topical corticosteroid (TCS); triamcinolone acetonide 0.1% ointment twice daily, or topical calcineurin inhibitor (CNI); tacrolimus ointment 0.03% twice daily over the nodular lesions for 2 weeks. All patients were followed up on three visits: 1, 2, and 6 weeks, for assessment. Efficacy was evaluated by 5-point range investigator-assessed VAS, and a 4-point severity of pruritus scale (SPS) score. The mean VAS score was higher in triamcinolone group compared to tacrolimus group at both follow-ups, although statistically significant only at 2nd week visit. The fall in mean SPS at both follow-ups was also higher in the steroid group, but the difference was not statistically significant. While, the overall tolerance to either ointment was excellent, mild hypopigmentation, and epidermal atrophy were detected on dermoscopic evaluation of the treated areas at the 2nd week visit in a small subset of patients in the triamcinolone group. The frequency of relapse of lesions and/or pruritus after four weeks of the 2-week therapy was high in both the groups (higher in tarolimus group). Conclusively, although both treatment options provided safe and satisfactory short term improvement, the results from this study suggest an overall higher efficacy of a mid-potency TCS like triamcinolone 0.1% over topical CNI like tacrolimus 0.03%, in the short-term treatment of nodular lesions of NS/PSP. Topical CNIs may be considered for maintenance of effect, if prolonged therapy is warranted.

Pearls in Mitigating Application Pain of Topical Nonsteroidal Agents.

BACKGROUND: Topical steroid-sparing agents (SSA), such as tacrolimus, pimecrolimus, and crisaborole, represent an important therapeutic option in the treatment of inflammatory dermatoses such as atopic dermatitis. While these agents lack the common side effects associated with topical corticosteroids, they all share application site pain as an important adverse effect. SUMMARY: Based on the available evidence and our experience, we suggest the following 7 practical strategies for decreasing the pain associated with SSA use. (1) Use a topical corticosteroid for a few days to reduce inflammation before starting the SSA treatment. (2) Use SSAs strategically. (3) Apply moisturizer before applying SSAs. (4) Store moisturizers in the refrigerator. (5) Ask the patient to apply the SSA on a small test area before broader application. (6) Apply the SSA on dry rather than on damp skin. (7) Consider using aspirin when appropriate for the patient.

Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?

Introduced in 1995, mycophenolate mofetil (MMF) would become the most powerful antiproliferative agent in the field of organ transplantation, thereby supplanting azathioprine, the first antiproliferative agent introduced in the early 1960s. Its association with tacrolimus greatly improved kidney transplant (KT) prognosis by significantly reducing the incidence of posttransplant acute rejection. MMF is also reputed to be a safe medication, but the frequency of the gastrointestinal complications associated with it, even minor ones, has induced the marketing of a second molecule called enteric-coated mycophenolate sodium. This late form of mycophenolate was supposed to be better tolerated thanks to its pharmacokinetic properties but the studies did not show significant differences between the two molecules. Otherwise, the combination of MMF with tacrolimus has significantly increased the risk of infections, particularly viral, and of neoplasia. To reduce this risk and avoid any situation of under or overexposure while remaining effective, only a strict and long-term monitoring of MMF allows the maintenance of already established therapeutic targets within the predefined ranges. In KT, individualizing the prescription and targets of MMF according to immunologic risk, global immunosuppression, and posttransplant period, as for other immunosuppressants, is open to discussion and may be beneficial.

An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients.

This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.

Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta-analysis.

BACKGROUND: TCS (topical corticosteroids) are the first-line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, pimecrolimus and ciclosporin for OLP is still controversial. OBJECTIVES: To compare the efficacy and safety of TCI vs. TCS for OLP. METHODS: The authors searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and four Chinese databases from 1950 to May 2018. The randomized controlled trials comparing TCI and TCS for OLP reported at least one of the following outcomes: improvement of clinical signs and/or symptoms, relapse, blood levels of TCI and adverse events. RESULTS: Twenty-one trials involving 965 patients were included in the analysis. For the treatment of OLP (3-8 weeks), TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy. Tacrolimus-TCS resulted in similar outcomes, with relapse at 3 weeks to 6 months. Blood levels of TCI were usually undetectable. In addition, tacrolimus showed a statistically higher incidence of local adverse events than TCS for short-term treatment. A few systemic adverse events occurred in the tacrolimus and ciclosporin groups, but they were not serious. CONCLUSIONS: The evidence for tacrolimus (n = 12), pimecrolimus (n = 3) and ciclosporin (n = 6) demonstrated that treatment with TCI may be an alternative approach when OLP does not respond to the standard protocols. Tacrolimus 0·1% should be the first drug of choice when selecting TCI for short-term treatment in recalcitrant OLP. Further well-designed trials are warranted to evaluate the long-term efficacy and safety of TCI. What's already known about this topic? The main topical drug for oral lichen planus (OLP) is topical corticosteroids (TCS). Patients with OLP who are not responsive to TCS or are at risk of adverse events from TCS need other alternative drugs. Topical calcineurin inhibitors (TCI), including tacrolimus, pimecrolimus and ciclosporin, have become a hot topic in a variety of mucocutaneous immune-mediated diseases. What does this study add? TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy for the short-term treatment of OLP. The local adverse events of tacrolimus were higher than with TCS. A few systemic adverse events were reported with TCI, but they were all tolerable and not serious. The limited evidence for pimecrolimus (three trials) and ciclosporin (six trials) requires further studies to evaluate the short-term and long-term efficacy and safety of TCI compared with TCS.

Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS: We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS: The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION: This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

A case report: acute pancreatitis associated with tacrolimus in kidney transplantation.

BACKGROUND: Tacrolimus has been widely used for immunosuppressive therapy in solid organ transplantation (SOT) and allo-geneic stem cell transplantation (allo-SCT) over the past 2 decades. Pancreatitis caused by tacrolimus was rarely reported in kidney transplantation previously. CASE PRESENTATION: Here we presented a case of a 45-year-old male who underwent kidney transplantation and received immunosuppressive therapy of tacrolimus, on day + 67 after transplantation he developed acute pancreatitis with extremely high blood concentration of tacrolimus. We excluded other possible causes and speculated tacrolimus was the probable inducer of pancreatitis. After tacrolimus was discontinued and alternated with cyclosporine, he gradually recovered and was discharged home with no relapse. CONCLUSION: Tacrolimus can be a probable cause of pancreatitis after kidney transplantation. We recommended clinicians to be aware of the possibility of tacrolimus-induced pancreatitis during tacrolimus treatment.