Comparison of efficacy of continuous mycophenolate mofetil with sequential cyclophosphamide and tacrolimus as maintenance therapy for lupus nephritis.

OBJECTIVES: To evaluate the renal response to mycophenolate mofetil (MMF) as maintenance therapy for lupus nephritis (LN) in Japanese patients, we compared the efficacy of MMF and the sequential use of monthly intravenous cyclophosphamide (IVCY) followed by tacrolimus (TAC). METHODS: We examined 14 patients with LN who were treated with continuous MMF as induction and maintenance therapies (MMF group) and 10 patients with LN who received monthly IVCY as induction therapy followed by maintenance therapy with TAC (IVCY-TAC group). We assessed the therapeutic effects of each treatment regimen on renal manifestations and serological findings over a 36-month period after treatment initiation. RESULTS: Mean urine protein-to-creatinine ratios in the MMF and IVCY-TAC groups significantly decreased from 2.75 to 0.11 g/gCr and from 3.26 to 0.22 g/gCr, respectively. Significant improvements in serum immunological variables (serum complement C3 or C4 levels and the anti-double-stranded DNA antibody titer) and reductions in the SLE disease activity index and daily prednisolone dosages were observed in both groups during induction therapy and were maintained during maintenance therapy. Efficacy was similar between the MMF and IVCY-TAC groups. CONCLUSION: MMF has potential as an effective treatment for renal manifestations in Japanese patients throughout induction and maintenance therapies for LN, as an alternative to conventional IVCY-TAC therapy, and as a glucocorticoid-sparing agent.

Thiopurine naivety at tacrolimus induction is a predictor of long-term remission in patients with intractable ulcerative colitis who responded to tacrolimus.

BACKGROUND: The short-term efficacy of tacrolimus (Tac) for steroid-dependent and steroid-resistant refractory ulcerative colitis (UC) has been demonstrated; however, its long-term outcomes have not been well documented. Thus, this study aimed to clarify the long-term outcomes of patients who achieved Tac-induced remission and identify its predictors. METHODS: This study included patients with moderate-to-severe active UC who started receiving Tac at our hospital between July 2004 and December 2016. Short-term treatment response was assessed using the Lichtiger index 3 months after starting Tac, and responding patients were further followed up to assess long-term outcomes. The primary endpoint was the relapse-free survival after Tac-induced remission, and the secondary endpoint was the identification of factors associated with relapse after Tac-induced remission. RESULTS: The cumulative relapse-free survival rate at 10 years after Tac-induced remission was 33.2%. Multivariate analysis revealed that being thiopurine naïve at Tac induction was associated with the absence of relapse (hazard ratio: 0.45; 95% confidence interval: 0.22-0.92). CONCLUSIONS: Approximately one-third of patients who achieved Tac-induced remission maintained long-term remission. Being thiopurine naïve at Tac induction was a predictor of the absence of relapse.

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.

Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.

Update on the treatment of steroid-sensitive nephrotic syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) is a rare condition that develops primarily in preadolescent children after the age of 1 year. Since the 1950s, oral corticosteroids have been the mainstay of treatment of all children presenting with nephrotic syndrome, with most patients responding within 4 weeks to an oral course of prednisone (PDN). However, corticosteroids have important side effects and 60-80 % of patients relapse, developing frequently relapsing or steroid-dependent forms. For these reasons, many patients require second-line steroid-sparing immunosuppressive medications that have considerably improved relapse-free survival, while avoiding many PDN-related toxicities. Since most patients will eventually heal from their disease with a normal kidney function, the morbidity of SSNS is primarily related to side effects of drugs that are used to maintain prolonged remission. Therefore, treatment is essentially based on balancing the use of different drugs to achieve permanent remission with the lowest cumulative number of side effects. Treatment choice is based on the severity of SSNS, on patient age, and on drug tolerability. This review provides an update of currently available therapeutic strategies for SSNS.

Comparison of the Efficacy and Safety of Tacrolimus and Low-Dose Corticosteroid with High-Dose Corticosteroid for Minimal Change Nephrotic Syndrome in Adults.

BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study. METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation. RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences. CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.

Discussion on machine learning technology to predict tacrolimus blood concentration in patients with nephrotic syndrome and membranous nephropathy in real-world settings.

BACKGROUND: Given its narrow treatment window, high toxicity, adverse effects, and individual differences in its use, we collected and sorted data on tacrolimus use by real patients with kidney diseases. We then used machine learning technology to predict tacrolimus blood concentration in order to provide a basis for tacrolimus dose adjustment and ensure patient safety. METHODS: This study involved 913 hospitalized patients with nephrotic syndrome and membranous nephropathy treated with tacrolimus. We evaluated data related to patient demographics, laboratory tests, and combined medication. After data cleaning and feature engineering, six machine learning models were constructed, and the predictive performance of each model was evaluated via external verification. RESULTS: The XGBoost model outperformed other investigated models, with a prediction accuracy of 73.33%, F-beta of 91.24%, and AUC of 0.5531. CONCLUSIONS: Through this exploratory study, we could determine the ability of machine learning to predict TAC blood concentration. Although the results prove the predictive potential of machine learning to some extent, in-depth research is still needed to resolve the XGBoost model's bias towards positive class and thereby facilitate its use in real-world settings.

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.

Everolimus-facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2-year results from the subgroup analysis of the TRANSFORM study.

OBJECTIVE: We analyzed the efficacy and safety of an everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard-exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study. METHODS: In this 24-month, open-label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids. RESULTS: Of the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2 or treated biopsy-proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m2 , P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m2 , P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm. CONCLUSION: This subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819).

De novo tacrolimus extended-release tablets (LCPT) versus twice-daily tacrolimus in adult heart transplantation: Results of a single-center non-inferiority matched control trial.

Extended-release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release tacrolimus (IR-tacrolimus). We compared the efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. Twenty-five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non-inferiority analysis. LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 20% (90% CI: -40%, -.5%; non-inferiority P = .001). Tacrolimus trough levels peaked at 2-3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P = .03) with similar dose levels (LCPT vs. IR-tacrolimus: .08 vs. .09 mg/kg/day; P = .33). Cardiovascular-related readmissions were reduced by 62% (P = .046) in LCPT patients. The complication rate per transplant admission and all-cause readmission rate did not differ significantly. These results suggest that LCPT is non-inferior in efficacy to IR-tacrolimus with a similar safety profile and improved bioavailability in OHT.

Tacrolimus 0.03% ointment treatment in exfoliative cheilitis: A randomised controlled clinical trial and monitoring blood concentration.

BACKGROUND: Tacrolimus has been used to treat various inflammatory skin diseases, but its safety for topical application on the oral mucosa is unknown. Exfoliative cheilitis (EC) is a chronic inflammatory disorder of the lips characterised by repeated scaling; it is difficult to manage. The aim of this study was to assess the efficacy and safety of tacrolimus 0.03% ointment as a topical treatment in patients with EC. METHODS: In this randomised controlled clinical trial, 40 patients with EC were randomly assigned to receive either tacrolimus 0.03% ointment (experimental group, n = 20) or triamcinolone acetonide 0.1% cream (control group, n = 20) treatment for a 3-week period. Medication was administered in 3, 2 and 1 daily doses during the first, second and third weeks, respectively. The patients with complete healing were followed up for 3 months. The clinical outcomes were measured, including the scores regarding signs (scale, dryness, rhagades and swelling) and symptoms (rough, dry, pain, pruritus and burning sensation) at every visit. Blood concentrations of tacrolimus were assessed. RESULTS: After the 3-week treatment, healing rates of scale in the experimental and control groups were 65% and 10%, respectively (P = .018). Improvement in all signs and two symptoms (rough, pruritus) was much greater in the experimental group (P < .05). The 3-month recurrence rate was higher in the control group (P = .029). Tacrolimus blood concentrations were in the safe range (< 5 ng/mL). CONCLUSION: Topical tacrolimus 0.03% ointment has good short-term efficacy and safety for treating EC.

A comparative study on the use of fractional CO2 laser with tacrolimus or calcipotriol or narrow band ultraviolet-B in treatment of stable nonsegmental vitiligo.

Conventional methods of treatment for vitiligo are often unsatisfactory to the patients and time consuming, new treatment modalities are needed. This study was conducted to evaluate the efficacy and safety of fractional carbon dioxide (CO2 ) laser therapy followed by narrow band ultraviolet-B (NB-UVB) phototherapy, topical tacrolimus or topical calcipotriol on stable nonsegmental vitiligo. Thirty patients with stable nonsegmental vitiligo were evaluated. All patients were subjected to three sessions of fractional CO2 laser 1 month apart. Patients were divided into three groups (each group 10 patients). Group (A) treated with tacrolimus ointment twice daily for 3 months, group (B) treated with calcipotriol ointment twice daily for 3 months, and group (C) treated with NB-UVB twice weekly for 3 months. Outcomes were evaluated by calculating vitiligo area scoring index (VASI) score change, percentage of repigmentation, patient satisfaction, and adverse effects. There was a statistical significant decrease in VASI score after treatment in the three groups. The VASI change and % of regimentation was higher in group (C) treated by laser and NB-UVB and this was significantly higher than group (B) treated with laser and calcipotriol. Otherwise, there was no statistical significant difference between other treatment groups. In concluion, NB-UVB phototherapy, topical tacrolimus, or topical calcipotriol in combination with fractional CO2 laser could be used effectively and safely as an alternative modality for treatment of vitiligo. The combination of fractional CO2 laser and NB-UVB was found to be more effective.

Analysis of time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus is used to treat patients with lupus nephritis; however, its time course and dose effect on proteinuria in lupus nephritis patients remain unknown. The purpose of this study was to determine the time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients via model-based meta-analysis (MBMA). METHODS: PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov databases were systematically searched for information on the efficacy of tacrolimus against proteinuria in lupus nephritis patients. Useful data were extracted to build a model for the population studied using a non-linear mixed-effect model (NONMEM). This model was applied to simulate time course of tacrolimus on proteinuria using Monte Carlo simulations. RESULTS: Ten clinical studies that recruited 222 patients with lupus nephritis were included. Based on various diagnostic plots, we found that the established model described the observed data reasonably well. In addition, the typical Emax and ET50 of tacrolimus for 24-hour proteinuria in lupus nephritis patients were -5.88 g and 0.37 months, respectively. The baseline value of 24-hour proteinuria affected Emax . No significant dose-response relationship was observed in the range of tacrolimus concentration used in the present study (3-10 ng/mL), indicating that the effect of tacrolimus on proteinuria depends on effective concentration range and not the dose. However, the time course relationship was obvious; the efficacy of tacrolimus increased over time, reaching a plateau (80% Emax ) at approximately 1.48 months from the beginning of treatment. WHAT IS NEW AND CONCLUSION: When the concentration range of tacrolimus is maintained at 3-10 ng/mL, at least 1.48 months of treatment is required to achieve a better outcome with regard to proteinuria in lupus nephritis patients.

Occlusive treatment enhances efficacy of tacrolimus 0.1% in a pediatric patient with severe alopecia areata: Case report and literature review.

Tacrolimus is an immunomodulatory drug, available for topical and systemic treatment of several dermopathies that are characterized by immune dysregulation. In the case of alopecia areata, standard application has proven insufficient to yield satisfactory results. Herein, we present a 6-year-old patient with Down syndrome who was treated with topical tacrolimus 0.1% ointment under occlusion overnight with remarkable clinical improvement within 4 months.

Efficacy of topical non-steroidal immunomodulators in the treatment of oral lichen planus: a systematic review and meta-analysis.

OBJECTIVES: The aim of this systematic review was to assess the efficacy and safety of topical non-steroidal immunomodulators (TNSIs) for oral lichen planus (OLP) treatment. MATERIALS AND METHODS: A search strategy designed for this purpose retrieved 1156 references. After analysis of titles and abstracts, 75 studies were selected for full-text analysis. Only randomized controlled clinical trials were selected, resulting in 28 studies included for qualitative and quantitative analysis. RESULTS: The meta-analysis showed similar benefits in clinical response and symptom resolution between tacrolimus 0.1% and pimecrolimus 1% in comparison to topical steroids (TS). Pimecrolimus showed superior efficacy of clinical response but not for symptom resolution compared to placebo. Tacrolimus and pimecrolimus showed better performance preventing symptom relapse, while pimecrolimus also prevented clinical relapse better than TS. Cyclosporine was superior to placebo; however, TS showed better efficacy of clinical response. Thalidomide and retinoid were assessed in only one trial each, and both showed similar efficacy to TS. Rapamycin also presented similar clinical response to TS; however, the later showed greater reduction of symptoms. Mycophenolate mofetil 2% mucoadhesive was no better than placebo. No serious adverse effects have been reported. Cyclosporine showed a higher frequency and variety of adverse effects. CONCLUSIONS: Topical tacrolimus and pimecrolimus are safe and effective alternatives for OLP treatment. CLINICAL RELEVANCE: TS are usually the first choice for OLP treatment. Because some oral lesions may have a low response to treatment with TS, more topical therapeutic options, such as TNSIs, should be considered before systemic steroids are used.

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.

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation.

Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.