tacrolimus and Lupus-Nephritis

This study aimed to compare the effectiveness and safety of voclosporin + mycophenolate mofetil (MMF), tacrolimus + MMF, and monotherapy with MMF or cyclophosphamide as induction treatment for lupus nephritis.. The study included randomized controlled trials (RCTs) that evaluated the effectiveness and safety of voclosporin + MMF, tacrolimus + MMF, and monotherapy for induction treatment in patients with lupus nephritis. To incorporate direct and indirect evidence from RCTs, we used a Bayesian network meta-analysis.. Four RCTs, including 936 participants, met the inclusion criteria. Tacrolimus + MMF substantially increased the incidence of complete remission relative to that following monotherapy (odds ratio [OR] 2.85; 95% credible interval [CrI] 1.87-4.39). Tacrolimus + MMF was also more effective than voclosporin + MMF (OR 1.43; 95% CrI 0.80-2.57). Tacrolimus + MMF showed the greatest chance of being the optimal treatment for overall response (surface under the cumulative ranking curve [SUCRA] = 0.942), followed by voclosporin + MMF (SUCRA = 0.558) and monotherapy (SUCRA = 0.001). In terms of safety based on severe event rates, monotherapy had the greatest chance of being the safest treatment (SUCRA = 0.903), followed by voclosporin + MMF (SUCRA = 0.517) and tacrolimus + MMF (SUCRA = 0.081).. Tacrolimus + MMF and voclosporin + MMF were more effective than monotherapy, and tacrolimus + MMF was the most effective induction treatment for lupus nephritis patients. However, tacrolimus + MMF did pose a greater risk of serious adverse events than monotherapy.. ZIEL DER ARBEIT: Ziel der vorliegenden Studie war es, die Wirksamkeit und Sicherheit von Voclosporin + Mycophenolat-Mofetil (MMF) zum einen, Tacrolimus + MMF zum anderen und einer Monotherapie mit MMF oder Cyclophosphamid als Induktionstherapie bei Lupusnephritis zu vergleichen.. In die Studie wurden randomisierte kontrollierte Studien (RCT) einbezogen, in denen die Wirksamkeit und Sicherheit von Voclosporin + MMF, Tacrolimus + MMF und einer Monotherapie als Induktionstherapie bei Patienten mit Lupusnephritis verglichen wurde. Um direkte und indirekte Evidenz aus RCT zu erfassen, wurde eine Bayes-Netzwerk-Metaanalyse durchgeführt.. Von 4 RCT mit 936 Teilnehmern wurden die Einschlusskriterien erfüllt. Tacrolimus + MMF führten zu einer wesentlich erhöhten Inzidenz kompletter Remissionen im Verhältnis zur Situation nach Monotherapie (Odds Ratio [OR] 2,85; 95%-Glaubwürdigkeitsintervall, Credibility Interval [CrI] 1,87–4,39). Tacrolimus + MMF erwiesen sich auch als wirksamer denn Voclosporin + MMF (OR 1,43; 95%-CrI 0,80–2,57). Bei Tacrolimus + MMF bestand die höchste Wahrscheinlichkeit, die optimale Therapie in Bezug auf das Gesamtansprechen darzustellen (Oberfläche unter der kumulativen Ranking-Kurve [SUCRA] = 0,942), dann folgten Voclosporin + MMF (SUCRA = 0,558) und die Monotherapie (SUCRA = 0,001). In Hinsicht auf die Sicherheit, basierend auf der Rate schwerer unerwünschter Ereignisse, bestand die höchste Wahrscheinlichkeit, die sicherste Therapie darzustellen, für die Monotherapie (SUCRA = 0,903), dann folgten Voclosporin + MMF (SUCRA = 0,517) und Tacrolimus + MMF (SUCRA = 0,081).. Tacrolimus + MMF und Voclosporin + MMF waren wirksamer als die Monotherapie, und Tacrolimus + MMF erwies sich als die wirksamste Induktionstherapie bei Patienten mit Lupusnephritis. Allerdings war das Risiko schwerer unerwünschter Ereignisse unter Tacrolimus + MMF größer als unter Monotherapie.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Network Meta-Analysis; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus; Treatment Outcome

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).. 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.. 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.. 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.. ZIEL: Ziel der Studie war es, die Wirksamkeit und Sicherheit von Tacrolimus und Mycophenolat-Mofetil (MMF) als Induktionstherapie und von niedrigdosiertem Tacrolimus zur Behandlung der Lupusnephritis (LN) zu untersuchen.. Es wurde eine Metaanalyse randomisierter kontrollierter Studien (RCT) durchgeführt, um die Wirksamkeit und Sicherheit von Tacrolimus und Mycophenolat-Mofetil (MMF) als Induktionstherapie bei LN zu vergleichen. Dazu wurden RCT und prospektive Kohortenstudien mit einer täglichen Tacrolimusdosis von 3 mg systematisch überprüft und eine Metaanalyse der Wirksamkeit und Sicherheit von Tacrolimus als Induktionstherapie bei LN im Vergleich zu MMF durchgeführt.. Die Einschlusskriterien wurden von 8 Studien (5 RCT und 3 prospektive Kohortenstudien) mit insgesamt 408 Personen (289 für Tacrolimus vs. MMF und 119 für niedrigdosiertes Tacrolimus) erfüllt. Tacrolimus und MMF wiesen ähnliche komplette Remissionsraten auf (Odds Ratio [OR]: 1,028; 95%-Konfidenzintervall [95%-KCI]: 0,589–1,796; p = 0,922). Die partielle Remissionsrate unterschied sich nicht zwischen der Tacrolimus- und der MMF-Gruppe (OR: 1,400; 95%-KI: 0,741–2,646; p = 0,300). Bei Tacrolimus und MMF gab es keine Unterschiede in Bezug auf Proteinurie, Serumalbumin, Serumkreatinin, Kreatininclearance, den renalen Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) oder den extrarenalen SLEDAI. Auch die Inzidenz von Infektionen, schweren Infektionen, Leukopenien und Hyperglykämien unterschied sich nicht zwischen der Tacrolimus- und der MMF-Gruppe. Allerdings war eine Herpes-zoster-Infektion in der Tacrolimusgruppe signifikant weniger häufig (OR: 0,137; 95%-KI: 0,034–0,546; p = 0,005), während der Serumkreatininanstieg in der Tacrolimusgruppe signifikant höher war als in der MMF-Gruppe (OR: 8,148; 95%-KI: 1,369–48,50; p = 0,021). Bei Gabe von 3 mg/Tag erwies sich Tacrolimus als sicher und gut verträglich und bot in sämtlichen Untersuchungen therapeutische Vorteile.. Tacrolimus war in Bezug auf Wirksamkeit und Sicherheit als Induktionstherapie bei LN mit MMF vergleichbar, außer im Hinblick auf ein vermindertes Risiko für eine Herpes-zoster-Infektion und in Bezug auf einen Anstieg des Serumkreatinins. Bei Personen mit LN stellte sich Tacrolimus in der Dosis von 3 mg/Tag als wirksam und sicher heraus.

Topics: Creatinine; Cyclophosphamide; Herpes Zoster; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; Treatment Outcome

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.

Topics: Adult; Azathioprine; Bone Marrow Diseases; Cyclophosphamide; Glucocorticoids; Herpes Zoster; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Neoplasms; Network Meta-Analysis; Recurrence; Tacrolimus; Treatment Outcome

This study aimed to compare the efficacy and safety (infection events) between rituximab (RTX), tacrolimus (TAC), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) as induction therapies in lupus nephritis (LN).. Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched from inception up to December 9, 2021. Bayesian network meta-analysis was used to combine the direct and indirect evidence of different drugs for LN patients. The pooled relative effects were shown using odds ratios (ORs) and 95% credible intervals (CrIs).. Nineteen studies (1,566 patients) met the inclusion criteria and were selected in the present study. The network meta-analysis reported that no statistically significant differences were found in partial remission (PR) and infection among the four drugs. RTX showed a significantly higher complete remission (CR) than MMF (OR = 2.60, 95% CrI = 1.00-7.10) and seemed to be more effective than CYC (OR = 4.20, 95% CrI = 1.70-14.00). MMF had a better CR than CYC (OR = 1.60, 95% CrI = 1.00-3.20). TAC presented a better overall response than CYC (OR = 3.70, 95% CrI = 1.20-12.00). Regarding CR and overall response, the maximum surface under the cumulative ranking curve (SUCRA) values were 96.94% for RTX and 80.15% for TAC. The maximum SUCRA value of infection reaction was 74.98% for RTX and the minimum value was 30.17% for TAC, respectively.. RTX and TAC were the most effective drugs for induction remission in LN. Among the four drugs, TAC had the lowest probability of infection, and RTX showed the highest probability of experiencing an infection. This meta-analysis could not conclude about other adverse events.

Topics: Bayes Theorem; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Network Meta-Analysis; Rituximab; Tacrolimus; Treatment Outcome

There were limited data on randomized controlled trials (RCTs) evaluating the effectiveness and safety of tacrolimus (TAC), cyclosporin A (CSA), mycophenolate mofetil (MMF), cyclophosphamide (CYC), and corticosteroids as induction agents in membranous lupus nephritis, and they were inconclusive.. This study aimed to assess the relative efficacy and safety TAC, CSA, MMF, CYC, and corticosteroids as induction therapy for membranous lupus nephritis.. RCTs examining the efficacy and safety of TAC, CSA, MMF, CYC, and corticosteroids as induction therapy in patients with membranous lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs.. Five RCTs comprising 126 patients met the inclusion criteria. TAC and CSA showed a trend toward a higher overall response rate (complete remission plus partial remission) than MMF and CYC. Similarly, MMF and CYC showed a trend toward a higher overall response than corticosteroids. Ranking probability based on the surface under the cumulative ranking curve indicated that TAC had the highest probability of being the best treatment for achieving the overall response, followed by CSA, MMF, CYC, and corticosteroids. In terms of safety, corticosteroids showed the highest probability of decreasing the risk of infections, followed by CSA, CYC, MMF, and TAC.. TAC and CSA were the most efficacious induction treatments for patients with membranous lupus nephritis, and corticosteroids had the highest probability of decreasing the risk of infections.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Mycophenolic Acid; Network Meta-Analysis; Tacrolimus; Treatment Outcome

The safety of multitarget treatments is of concern. This study aimed to evaluate the effectiveness and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy.. This study included randomized controlled trials (RCTs) that evaluated the effectiveness and safety of multitarget therapies, such as voclosporin+mycophenolate mofetil (MMF), tacrolimus+MMF, or belimumab+standard of care in comparison with MMF or cyclophosphamide (CYC) monotherapy for induction treatment of lupus nephritis. We performed a meta-analysis of the efficacy and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy.. Six RCTs, including 1,437 participants, met the inclusion criteria. The complete remission rate was significantly higher in the multitarget therapy group than in the monotherapy group (odds ratio, 2.155; 95% CI, 1.695-2.739;. Multitarget therapy showed a higher complete remission rate than monotherapy; however, cases of infection and pneumonia were numerically more elevated in the multitarget therapy group than in the monotherapy group.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus; Treatment Outcome

The most frequently used immunosuppressive treatment in kidney transplant recipients is the combination therapy of a calcineurin inhibitor (CNI) and mycophenolate mofetil, with or without corticosteroids. Cyclosporine and tacrolimus are the 2 CNIs registered for this indication. Also, in the treatment of glomerular diseases, CNIs and mycophenolate are being used on a worldwide scale, either alone or as combined treatment. In January 2021, the US Food and Drug Administration approved voclosporin, a novel CNI, for the treatment of adult patients with active lupus nephritis. There is a clinically relevant drug-drug interaction between cyclosporine and mycophenolate. As a result of cyclosporine-induced inhibition of the enterohepatic recirculation of mycophenolate, the mycophenolic acid area under the curve is significantly lower (40%) in case of cyclosporine coadministration compared with cotreatment with either tacrolimus or voclosporin (or no CNI cotreatment). The aim of this mini review is to summarize this potential drug-drug interaction and explain how cyclosporine affects the pharmacokinetics of mycophenolate. The optimal dose of mycophenolate mofetil is likely to depend on the CNI with which it is coadministered. Furthermore, clinical implications are discussed, including the potential emergence of mycophenolic acid-related adverse effects after discontinuation of cyclosporine cotreatment.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

This study evaluated the relative efficacy and safety of tacrolimus, tacrolimus+mycophenolate mofetil (MMF), and cyclophosphamide (CYC) for lupus nephritis.. Randomized controlled trials (RCTs) were included to investigate the effectiveness and safety of tacrolimus, tacrolimus+MMF, and CYC as a lupus induction therapy. We performed a Bayesian network meta-analysis of the random effects to incorporate direct and indirect data from RCTs.. Four RCTs met the inclusion criteria, giving a sample size of 543 patients. Tacrolimus+MMF had a significantly higher overall response rate (complete plus partial remission) than CYC (OR 4.22, 95% credible interval (CrI) 11.02 - 29.23) and was more efficacious than tacrolimus (OR 2.02, 95% CrI 0.24 - 28.51). Tacrolimus had higher overall response than CYC (OR 2.14, 95% CrI 0.38 - 12.33). Ranking the treatments based on the surface under the cumulative ranking curve (SUCRA) suggested that tacrolimus+MMF was the best treatment by the overall response (SUCRA = 0.876), followed by tacrolimus (SUCRA = 0.533) and CYC (SUCRA = 0.091). Tacrolimus was the least likely to cause serious infections (-SUCRA = 0.758), followed by CYC (SUCRA = 0.398) and tacrolimus+MMF (SUCRA = 0.345).. Tacrolimus+MMF was the most effective induction treatment for patients with lupus nephritis, and tacrolimus was the least likely to cause severe infections.

Topics: Bayes Theorem; Cyclophosphamide; Humans; Immunosuppressive Agents; Infections; Lupus Nephritis; Mycophenolic Acid; Remission Induction; Tacrolimus; Treatment Outcome

Infection is an important concern in lupus nephritis treatment, but few studies have focused on this complication. Available data suggest marked variation in occurrence and outcome. This meta-analysis and review aims to provide an overview of infective complications, focusing on the risk factors and outcomes.. Original articles on lupus nephritis Class III/IV/V published in the period January 1980 to December 2016 were identified from the Pubmed/Medline electronic database. Meta-analysis of randomized controlled trials was performed to investigate total and serious infections at different phases of treatment and their associated factors. A descriptive review that included all studies was also performed, providing details on the types of infection, infection-related mortality, and potential impact of different eras on infection rates.. A total of 56 studies (32 randomized controlled trials) were included. The incidence rates of overall and serious infections were higher during the induction than maintenance phase of therapy, with serious infections occurring at 8.2-50 and 3.5 per 100 patient-years, respectively. Recent data, predominantly from Asia, suggested lower rates of overall infections with induction regimens that included tacrolimus compared with mycophenolate (risk ratio 0.50, 95% confidence interval 0.33-0.76, p = 0.001). Mycophenolate as induction treatment was associated with lower overall infection risks than cyclophosphamide in non-Asians (risk ratio 0.60, 95% confidence interval 0.48-0.75, p < 0.001). The rates of serious infections were 4.1-25% in Asian and 4.4-8.5% in non-Asian countries; with infection-related mortality rates of 0-6.7% in Asian, compared to 0-2.1% in non-Asian locations.. Infection remains a serious complication during treatment of lupus nephritis, but the reported rates and outcomes varied markedly. Mycophenolate was associated with lower infection risk than cyclophosphamide in non-Asians. Infection-related deaths appeared more common in Asian patients.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Infections; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Risk Factors; Tacrolimus

To avoid graft rejection during pregnancy, frequent monitoring of serum drug levels is recommended. Pregnancy induces hyperfiltration in transplanted kidneys, as in native kidneys; therefore, detection of rejection can be difficult when monitoring by serum creatinine. If rejection is suspected, ultrasonographguided graft biopsy can be done; once proven, it can be treated with pulse steroids, but data are scarce regarding other agents. Here, we present a 28-year-old pregnant female patient with resistant acute rejection but with successful pregnancy outcome. Our patient had end-stage kidney disease secondary to lupus nephropathy and underwent living-donor renal transplant in May 2013 after hemodialysis support for 1 year. She received thymoglobulin as induction therapy and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. She had normal renal graft function without proteinuria. After she received counseling, she became pregnant in February 2015. In June 2015, she presented with acute graft dysfunction with serum creatinine level of 365 μmol/L. Her abdominal ultrasonography showed mild hydronephrosis and viable fetus. She received empirical pulse steroids with partial response, and her graft biopsy showed acute T-cell-mediated rejection and negative C4d. Intravenous immunoglobulins and minipulse steroids were administered but without response. After gynecologic counseling and informed consent, she received 5 doses of thymoglobulin. She was dialysis dependent until premature vaginal labor, which resulted in birth of a viable 2-kg boy. We suggest that successful pregnancy outcomes could occur with close monitoring and daily dialysis in female kidney transplant patients with resistant rejection.

Topics: Acute Disease; Adult; Antilymphocyte Serum; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunity, Cellular; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Live Birth; Living Donors; Lupus Nephritis; Mycophenolic Acid; Prednisolone; Pregnancy; Pregnancy, Unplanned; Renal Dialysis; Risk Factors; T-Lymphocytes; Tacrolimus; Treatment Outcome

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that affects multiple organs and tissues. Lupus nephritis (LN) is a serious complication of SLE, which occurs at a high rate. Conventional treatment strategies of LN have been widely accepted by two concepts such as induction therapy and maintenance therapy. In LN induction therapy until recently, cyclophosphamide in combination with prednisone (PSL) has been the standard method of treatment for proliferative forms of LN. In the latest review, the combination of mycophenolate mofetil (MMF) is also considered a standard treatment option. Furthermore, a multi-target therapy with tacrolimus (Tac) added to PSL and MMF, with reference to a regimen after organ transplantation has also been reported. In LN maintenance therapy, although recent reports have demonstrated that MMF, azathioprine, and Tac in combination with PSL may prevent renal flares, there is no definite opinion in the period of use or the method of tapering. On the contrary, there are also concepts of two mechanisms of therapy for LN, such as a treatment based on the immunological mechanism as an autoimmune disease and a treatment based on the non-immunological mechanism as a chronic kidney disease. Nephrologists need to continue searching for the best-mix treatment regimen according to various clinical findings. We review the options available for the treatment of LN, and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE.

Topics: Antihypertensive Agents; Antirheumatic Agents; Cyclophosphamide; Drug Therapy, Combination; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Prednisone; Remission Induction; Rituximab; Tacrolimus

Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012.. Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens?. We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included.. Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE.. In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprec. In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

Topics: Adult; Azathioprine; Calcineurin; Child; Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Maintenance Chemotherapy; Male; Mycophenolic Acid; Randomized Controlled Trials as Topic; Recurrence; Tacrolimus

Background/aim: Multitarget therapy for lupus nephritis (LN) remains in its exploratory phrase and the recent evidence is insufficient. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF), tacrolimus (TAC), and steroids (multitarget therapy) versus intravenous cyclophosphamide (IVC) and steroids in induction treatment of LN. Materials and methods: We searched for randomized controlled trials of MMF plus TAC versus IVC in LN using PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the China Biology Medicine Database, and the China National Knowledge Infrastructure Database. We assessed the retrieved citations and selected studies according to predefined inclusion and exclusion criteria. Results: In total, we identified 8 trials including 801 patients. The metaanalysis revealed that overall multitarget therapy is more effective at inducing complete renal remission compared with IVC (RR: 1.94, 95% CI: 1.61-2.33; P < 0.00001). In terms of LN classification, multitarget therapy exhibited superiority compared with IVC for inducing complete remission of class IV LN (RR: 1.52, 95% CI: 1.10- 2.08; P = 0.01), class V LN (RR: 4.24, 95% CI: 1.30-13.88; P = 0.02), and class V+IV LN (RR: 2.29, 95% CI: 1.45-3.62; P = 0.0004); however, no superiority was noted for class III LN or class V+III LN. The rates of gastrointestinal symptoms, abnormal liver function, leukopenia, and irregular menstruation were significantly reduced in the multitarget therapy group compared with the IVC group for LN. Nevertheless, the multitarget therapy group more frequently exhibited new-onset hypertension compared with the IVC group. Conclusion: Multitarget therapy is more effective than IVC in the induction treatment of LN in Chinese patients and exhibits a better safety profile.

Topics: Administration, Intravenous; Adolescent; Adult; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Randomized Controlled Trials as Topic; Tacrolimus; Young Adult

This study aimed to assess the relative efficacy and safety of tacrolimus, mycophenolate mofetil (MMF), azathioprine (AZA), and cyclophosphamide (CYC) as maintenance therapy for lupus nephritis.. Randomized controlled trials (RCTs) examining the efficacy and safety of tacrolimus, MMF, AZA, and CYC for maintenance therapy in lupus nephritis patients were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs.. Five RCTs including 525 patients were included. Although the difference was not statistically significant, tacrolimus showed a trend toward a lower renal relapse rate than AZA or CYC. Similarly, MMF showed a trend toward a lower relapse rate than AZA or CYC. Renal relapse tended to be lower in the AZA group than in the CYC group. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tacrolimus had the highest probability of being the best treatment based on the renal relapse, followed by MMF, AZA, and CYC. Analysis of withdrawal due to adverse events showed the same pattern. The leukopenia incidence was significantly lower in the MMF group than in the AZA group. Similarly, it tended to be lower in the tacrolimus group than in the AZA group. Ranking probability based on SUCRA indicated that MMF had the highest probability of being the safest treatment based on leukopenia incidence, followed by tacrolimus and AZA.. Lower renal relapse rates combined with a more favorable safety profile suggest that tacrolimus and MMF are superior to AZA and CYC as maintenance treatments in these patients.

Topics: Azathioprine; Bayes Theorem; Cyclophosphamide; Humans; Long-Term Care; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

A 31-year-old woman with systemic lupus erythematosus and lupus nephritis was treated with prednisone and immunosuppressants. After her lupus nephritis symptoms worsened, both high-dose steroid and cyclophosphamide pulse therapy were administered. The patient developed an intestinal perforation, and laparoscopic Hartmann's surgery was performed on the sigmoid colon. Serum Cytomegalovirus (CMV) antigen C7HRP was detected, and the patient was diagnosed with CMV colitis and underwent a colon resection. Severe hematochezia continued despite ganciclovir administration, and the patient underwent laparoscopic total colectomy and partial ileostomy. CMV enteritis should be considered in patients treated with prednisone and immunosuppressants and those who have abdominal pain and hematochezia. Immunocompromised patients with intestinal perforation due to CMV enteritis have a poor prognosis. We report a case with along with the results of a literature review.

Topics: Adult; Antiviral Agents; Betamethasone; Colitis; Colon, Sigmoid; Cytomegalovirus; Cytomegalovirus Infections; Enteritis; Female; Ganciclovir; Gastrointestinal Hemorrhage; Humans; Immunocompromised Host; Immunosuppressive Agents; Intestinal Perforation; Lupus Nephritis; Prednisolone; Tacrolimus

There is growing interest in the role of tacrolimus as a potential therapeutic agent in SLE. This systematic review and meta-analysis evaluates the evidence for tacrolimus use in the management of lupus nephritis. Thirteen controlled studies were identified (9 suitable for inclusion), using Cochrane database, SCOPUS, Web of Science and OVID (MEDLINE and EMBASE). Data on complete and partial remission rates, proteinuria reduction and adverse events was extracted and analysed using RevMan software. The meta-analysis showed that overall tacrolimus is more effective at inducing complete renal remission than IVCYC (p=0.004), but there is no significant difference compared to MMF (p=0.87). Multi-target TAC+MMF therapy is more effective than IVCYC only when partial remission is included (p=0.0006). Frequency of key adverse effects seems comparable to other agents used in the management of lupus nephritis with fewer gastrointestinal side effects, leukopenia, menstrual disorders, infections and episodes of liver dysfunction reported, but more new onset hypertension and hyperglycaemia. Mortality was lower in the tacrolimus groups, but this was not statistically significant (p=0.15). Tacrolimus may be more effective at reducing proteinuria, but again this was not statistically significant. There are no controlled trials looking at use in pregnancy or juvenile patients, however case reports suggest potential efficacy and safety. In conclusion, in moderately severe lupus nephritis, there is some evidence supporting efficacy of tacrolimus or multi-target TAC+MMF over IVCYC, but no evidence supporting tacrolimus over MMF. Tacrolimus may be more effective at reducing proteinuria, having potential implications for long-term outcome. Key limitations of this study are the lack of long-term outcome data and the lack of high quality, large, blinded controlled trials in multi-ethnic groups.

Topics: Animals; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Remission Induction; Tacrolimus

To evaluate the efficacy and safety of the calcineurin inhibitors (CNIs) cyclosporine (CyA) and tacrolimus (TAC) in the induction and maintenance treatment of lupus nephritis (LN).. The Cochrane library, PubMed, Embase, and CENTRAL databases were searched and reviewed up to February 2015. Randomized controlled trials were analyzed using RevMan 5.2 software.. Ten randomized controlled trials were selected and included in this study according to our inclusion and exclusion criteria, and six were included in the meta-analysis. The analysis results indicated that, in induction treatment, no statistically significant difference was observed in the rates of complete remission (CR), partial remission (PR), or response between the CNIs and intravenous cyclophosphamide (ivCYC). However, the rates of adverse events such as infection (RR 0.65, P = 0.04), leukocytopenia (RR 0.32, P = 0.04), and menstruation disorder (RR 0.37, P = 0.01) following the use of the CNIs were remarkably lower than those after ivCYC. No differences in the CR, PR, infection, or leukocytopenia rates were observed between the CNIs and mycophenolate mofetil (MMF). In the maintenance treatment period, the relapse rate between the CNIs and azathioprine (AZA) was similar (RR 0.44, P = 0.27), while the leukocytopenia rate was lower with the CNIs (RR 0.26, P = 0.0005).. The efficacy of the CNIs CyA and TAC in induction therapy for lupus nephritis is comparable to ivCYC and MMF, and they are much safer than ivCYC. CNI treatment during the maintenance period was also as effective as AZA treatment, with a much lower risk of adverse effects. The CNIs CyA and TAC should be recommended for both induction and maintenance therapy of LN.

Topics: Azathioprine; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Randomized Controlled Trials as Topic; Tacrolimus

With advancement in our understanding of pathogenic mechanisms in systemic lupus erythematosus (SLE), there is tremendous enthusiasm in examining drugs, old and new, to improve outcomes. This review highlights recent trials' successes and impasses that have come to fore.. Among B-cell therapies, belimumab continues its run of successes with sustained safety and tolerability documented in a long-term extension as well as the likely approval of a subcutaneous formulation in the near future. With greater antibody-dependent cytotoxicity and less immunogenicity, there is hope for obinituzumab to succeed where its anti-CD 20 predecessors have failed. Drugs targeting type I interferons - sifalimumab and anifrolumab - have been efficacious albeit with an increase in incidence of Herpes zoster infections. There is also renewed interest in evaluating the efficacy of calcineurin inhibitors, specifically tacrolimus in the induction and maintenance of lupus nephritis. Introspection into clinical trial designs have highlighted the effects of entry criteria, end points, background medications and geographical differences on study outcomes.. There are at least 50 drugs and targets being evaluated in SLE. In addition to developing new drugs to treat lupus, future trials have to focus on more effective study designs to improve chances of trial success.

Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B-Lymphocytes; Clinical Trials as Topic; Cyclosporine; Herpes Zoster; Humans; Immunosuppressive Agents; Interferon Type I; Lupus Erythematosus, Systemic; Lupus Nephritis; Maintenance Chemotherapy; Peptide Fragments; Plasma Cells; Quinolones; Recombinant Fusion Proteins; Remission Induction; T-Lymphocytes; Tacrolimus; Treatment Outcome

To compare benefits and harms of lupus nephritis (LN) induction and maintenance treatments.. We performed a systematic review and Bayesian network metaanalyses of randomized controlled trials (RCT) of immunosuppressive drugs or corticosteroids (CS) in LN. OR and 95% credible intervals (CrI) were calculated.. There were 65 RCT that met inclusion and exclusion criteria. Significantly lower risk of endstage renal disease (ESRD; 17 studies) was seen with cyclophosphamide (CYC; OR 0.49, 95% CrI 0.25-0.92) or CYC + azathioprine (AZA; OR 0.18, 95% CrI 0.05-0.57) compared with standard-dose CS, and with high-dose (HD) CYC (OR 0.16, 95% CrI 0.03-0.61) or CYC + AZA (OR 0.10, 95% CrI 0.03-0.34) compared with HD CS. HD CS was associated with higher risk of ESRD compared with CYC (OR 3.59, 95% CrI 1.30-9.86), AZA (OR 2.93, 95% CrI 1.08-8.10), or mycophenolate mofetil (MMF; OR 7.05, 95% CrI 1.66-31.91). Compared with CS, a significantly higher proportion of patients had renal response (14 studies) when treated with CYC (OR 1.98, 95% CrI 1.13-3.52), MMF (OR 2.42, 95% CrI 1.27-4.74), or tacrolimus (TAC; OR 4.20, 95% CrI 1.29-13.68). No differences were noted for the risk of malignancy (15 studies). The risk of herpes zoster (17 studies) was as follows: OR (95% CrI) MMF versus CS 4.38 (1.02-23.87), CYC versus CS 6.64 (1.97-25.71), TAC versus CS 9.11 (1.13-70.99), and CYC + AZA versus CS 8.46 (1.99-43.61).. Renal benefits and the risk of herpes zoster were higher for immunosuppressive drugs versus CS. Data on relative and absolute differences are now available, which can be incorporated into patient-physician discussions related to systemic lupus erythematosus medication use.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Nephritis; Remission Induction; Tacrolimus; Treatment Outcome

Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.

Topics: Antimalarials; Azathioprine; Biological Products; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lupus Nephritis; Mycophenolic Acid; Ribonucleosides; Severity of Illness Index; Sirolimus; Tacrolimus

This study aimed to assess the relative efficacy and safety of tacrolimus, mycophenolate mofetil (MMF) and cyclophosphamide (CYC) as induction therapy for lupus nephritis.. Randomized controlled trials (RCTs) examining the efficacy and safety of tacrolimus, MMF and CYC for induction therapy in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs.. Nine RCTs including 972 patients met the inclusion criteria and pair-wise comparisons were performed, including 11 direct comparisons. Tacrolimus showed a significantly higher overall response rate (complete remission plus partial remission) than CYC (OR 2.35, 95% confidence interval (CI) 1.03-5.45), and was more efficacious than MMF (OR 1.60, 95% CI 0.70-3.57). MMF was superior to CYC in terms of overall response (OR 1.45, 95% CI 0.96-2.42). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tacrolimus had the highest probability of being the best treatment for achieving the overall response (SUCRA = 0.9321), followed by MMF (SUCRA = 0.5385) and CYC (SUCRA = 0.0294). In terms of safety, tacrolimus showed the highest probability of decreasing the risk of serious infections (SUCRA = 0.9253), followed by MMF (SUCRA = 0.4027) and CYC (SUCRA = 0.1720).. Tacrolimus was the most efficacious induction treatment for patients with lupus nephritis, and had the highest probability of decreasing the risk of serious infections. Higher remission rates combined with a more favorable safety profile suggest that MMF is superior to CYC as induction treatment in these patients.

Topics: Bayes Theorem; Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus; Treatment Outcome

Renal disease in systemic lupus erythematosus carries significant morbidity and mortality. Intensive immunosuppression to dampen kidney inflammation timely and maintenance therapy to prevent renal flares is necessary to reduce the long-term risk of renal failure. Mycophenolate mofetil (MMF) has emerged to be the first-line treatment of lupus nephritis for its better safety profile compared with cyclophosphamide. In controlled trials, MMF is non-inferior to cyclophosphamide for induction therapy but is superior to azathioprine as maintenance therapy. Although biologics have shown promise in refractory lupus nephritis, combining MMF with a number of novel biological agents does not enhance the therapeutic efficacy. Recently, low-dose combination of MMF and tacrolimus has been shown to be more efficacious than intravenous pulse cyclophosphamide in inducing remission of lupus nephritis in Chinese patients. Therapeutic monitoring of the serum mycophenolic acid level to enhance the efficacy of MMF in lupus nephritis is being explored.

Topics: Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Humans; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

Systemic lupus erythematosus (SLE) is a ripe area for drug development. There are great unmet needs, especially for those with lupus nephritis, in which good responses occur only in the minority of treated patients. An expanded understanding of immunopathogenesis of SLE coupled with the availability of sophisticated bioengineering technologies has resulted in the ability to supply the lupus community with the reagents needed to perform clinical trials. However, drug development in SLE has proven to be particularly challenging. Only one drug, belimumab, has been approved for patients with SLE through the traditional route of randomized controlled trials. The basis for our failures is unknown, but most assuredly relates to trial design issues, confounding by background medicines, and the multiplicity of active biologic pathways in this disease. Off-label use of failed trial drugs such as mycophenolate mofetil and rituximab paradoxically has become routine in many parts of the world. Despite the obstacles, there currently is unprecedented clinical trial activity in lupus nephritis, which most likely will lead to at least one drug approval in years to come.

Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Boron Compounds; Bortezomib; Clinical Trials as Topic; Drug Discovery; Glycine; Humans; Immunologic Factors; Immunosuppressive Agents; Infliximab; Isoxazoles; Leflunomide; Lupus Nephritis; Mycophenolic Acid; Off-Label Use; Oligonucleotides; Quinolones; Recombinant Fusion Proteins; Rituximab; Tacrolimus; Treatment Outcome

To evaluate and determine the most effective immunosuppressive therapy for the induction treatment of proliferative lupus nephritis (PLN) based on renal remission.. A systematic review of randomized controlled trials was conducted. The outcomes were renal remission at 6 months: (1) normalization of serum creatinine [(sCr), or within 15% of the normal range, i.e., sCr < 132 µmol/l - creatinine remission]; and (2) proteinuric remission (prU < 0.5 g/day/1.73m(2)). A Bayesian network metaanalysis was used.. The OR (95% credible interval) of inducing an sCr remission at 6 months was 1.70 (0.51, 6.87) for mycophenolate mofetil (MMF) versus cyclophosphamide (CYC); 2.16 (0.38, 13.36) for tacrolimus (Tac) versus CYC; and 1.25 (0.13, 10.51) for Tac versus MMF. For proteinuric remission the OR was 1.46 (0.81, 3.04) for MMF versus CYC; 1.96 (0.80, 5.11) for Tac versus CYC; and 1.34 (0.43, 3.90) for Tac versus MMF. The probability (95% credible interval) of inducing a creatinine remission at 6 months was Tac 56% (19%, 88%); MMF 51% (23%, 79%); and CYC 37% (28%, 47%). The probability of inducing a proteinuric remission was Tac 41% (23%, 63%); MMF 34% (23%, 50%); CYC 26% (20%, 32%); azathioprine 10% (1%, 55%); prednisone 11% (2%, 38%). None of the results were conclusive when examined in a sensitivity analysis.. There is currently insufficient evidence to determine which of these immunosuppressive agents is superior. The probability of renal remission is 50% or lower at 6 months.

Topics: Azathioprine; Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome

Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As a standard treatment regimen for remission induction of proliferative LN, intravenous cyclophosphamide (IVCYC) and corticosteroids has been widely accepted. However, cyclophosphamide (CYC) is associated with significant adverse effects. Tacrolimus, a T-cell-specific calcineurin inhibitor, shares similar immunosuppressive actions with cyclosporine. We performed a meta-analysis of randomized controlled trials (RCTs) to compare efficacy and safety between tacrolimus (oral administration and/or IV injection) and IVCYC in the induction treatment for LN. We identified 5 trials, including 225 patients. Meta-analysis showed that tacrolimus could significantly increase complete remission (RR 1.61, 95% CI, 1.17 to 2.23; P = 0.004), response rate (RR 1.25, 95% CI, 1.09 to 1.44; P = 0.001), serum albumin level (SMD 1.11, 95% CI, 0.17 to 2.06; P = 0.02) and anti-dsDNA negative conversion rate (RR 1.34, 95% CI, 1.01 to 1.78; P = 0.04), and decrease urine protein (SMD -0.52, 95% CI, -0.83 to -0.22; P = 0.0008), systemic lupus erythematosus disease activity index (SLE-DAI) (SMD -0.59, 95% CI, -1.00 to -0.19; P = 0.004) compared with that of IVCYC. The rates of gastrointestinal symptoms and irregular menstruation (or amenorrhea) were significantly lower in tacrolimus group than IVCYC group (RR 0.46, 95% CI, 0.22 to 0.93; P = 0.03 and RR 0.14, 95% CI, 0.04 to 0.50; P = 0.003). In conclusion, tacrolimus was found to be more effective and safer than IVCYC as an induction therapy for Chinese LN patients.

Topics: Adult; Complement C3; Cyclophosphamide; Female; Humans; Injections, Intravenous; Lupus Nephritis; Male; Proteinuria; Publication Bias; Randomized Controlled Trials as Topic; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome; Young Adult

Some day we will have powerful targeted therapies for autoimmune diseases. Remission will be induced efficiently. Side effects will be mere ripples. Unfortunately, that day is not imminent. Current therapies are powerful but with unintended targets and side effects that can be equivalent to a sea change. For SLE, the current competition to select the 'gold standard' immunosuppressant has come down to two regimens: intravenous cyclophosphamide (IVCY, standard NIH protocol or its variations) versus oral mycophenolate (MMF). Until recently, IVCY reigned as the gold standard, a title it achieved through a curious journey that did not involve rigorous head-to-head competition. Oral cyclophosphamide (POCY) has not been invited to the current competition to select the gold standard immunosuppressant despite the substantial evidence that POCY can perform at least as well as IVCY or mycophenolate, and compared to IVCY, is far less expensive, easier for the patient, and maybe more effective in African-Americans. Here, we state the case for POCY as therapy for severe autoimmune diseases. We suggest that if POCY is allowed to compete, it will not disappoint.

Topics: Autoimmune Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

The aim of this study was to assess the efficacy and safety of tacrolimus for the treatment of lupus nephritis (LN). A systematic review of clinical trials on tacrolimus in LN was conducted. Seven studies met the review inclusion criteria. Two studies were case-control studies, and five studies were open-label trials. One randomized controlled trial (RCT) found that tacrolimus significantly improved lupus nephritis disease activity index (LNDAI) as compared with a placebo, but no difference was observed between these two groups in terms of treatment-related adverse events. The other case-control study compared tacrolimus with standard protocols of oral cyclophosphamide or azathioprine for the treatment of membranous LN and found that efficacies were similar. All five open-label prospective studies concluded that tacrolimus is safe and effective as an induction and maintenance therapy for LN or for the treatment of LN with persistent proteinuria that failed to respond to prednisolone and immunosuppressants. In conclusion, this systematic review shows that tacrolimus may be effective as an induction and maintenance therapy for LN or as a treatment for LN with persistent proteinuria despite gold standard treatment. However, further RCTs are needed to compare tacrolimus with standard regimens for the treatment of LN.

Topics: Clinical Trials as Topic; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Severity of Illness Index; Tacrolimus; Treatment Outcome

To systematically evaluate the clinical effects of cyclosporine A (CsA) and tacrolimus, which are calcineurin inhibitors, on lupus nephritis.. In this study, the clinical trials on treatment of lupus nephritis with cyclosporine A and tacrolimus published until May 2010 were searched at www.guideline.gov, www.nice.org.uk, mdm.ca/cpgsnew/cpgs/index.asp, www.show.scot.nhs.uk, www.nzgg.org.nz, www.eguid elines.co.uk, www.gin.net, Cochrane library, EMBASE, MEDLINE, Wanfang database, Chinese Journal full-text Database, Chongqing Weipu Database by using the methods of Cochrane systematic review. At the same time the information from related journals, professional data and network were hand-searched. The homogeneous evaluation was performed by meta-analysis.Statistical analysis of clinical data was performed by using RevMan 4.2 software provided by the Cochrane Collaboration.. A total of 214 reports were found, while only 7 randomized controlled trials met the inclusion criteria, 4 of them were on the treatment with CsA (treatment group) and cyclosporine (CTX) group (control group), and 3 of them were the on treatment with FK506 (treatment group) and CTX group (control group). There were 148 reports in the treatment of CsA and CTX group, while 185 reports in the treatment of FK506 and CTX group. Both CsA and tacrolimus group could decrease daily urinary protein. Tacrolimus group was good at reducing daily urinary protein as compared with CTX group, and the difference was statistically significant (Z = 2.8, P = 0.005), but there was no significant difference between CsA and CTX groups (Z = 1.08, P = 0.28). Tacrolimus group was good at complete remission as compared with CTX group (Z = 3.64, P = 0.0003), partial remission was similar in both groups (Z = 0.53, P = 0.6), and tacrolimus group was good at total remission (Z = 2.2, P = 0.03). There was no significant difference between CsA and CTX group in side effect within a short period, while FK506 had less side-effect than CTX group.. Compared with the treatment with CTX, tacrolimus was good at reducing daily urinary protein. CsA and CTX were similar in reducing daily urinary protein in the treatment of lupus nephritis. Tacrolimus resulted in better total remission than CTX and had less side effect. CsA and CTX groups were similar in side effect. On the whole, calcineurin inhibitor could significantly decrease daily urinary protein, and tacrolimus was better in treatment and had less side-effect than CTX. However, large scale, multicenter, well-designed clinical trials should be adopted to further confirm the conclusions.

Topics: Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Humans; Lupus Nephritis; Tacrolimus

Topics: Antineoplastic Combined Chemotherapy Protocols; Azathioprine; Calcineurin Inhibitors; Drug Therapy, Combination; Fluorouracil; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Mitomycin; Prognosis; Ribonucleosides; Semustine; Tacrolimus

To consider the challenges in the management of lupus nephritis with respect to diagnosis and optimal therapy for induction and maintenance of response.. Despite several large clinical trials in lupus nephritis, no second line drug is licensed for use in induction of remission in lupus nephritis. An important issue is how remission and flare are defined and the role of repeat renal biopsies. On the background of negative trials with mycophenolate mofetil and rituximab, there are recent data demonstrating superiority of mycophenolate mofetil in certain subgroups. New data suggest a role for tacrolimus in the treatment of lupus nephritis. Additionally, dogma is being challenged by data showing very low and even no oral steroids can be used in mycophenolate mofetil and rituximab-based regimes.. Despite the negative outcome of recent trials there is growing evidence that there are increasing opportunities in patients with lupus nephritis to offer treatments tailored to the individual needs of the patient based not only on the class and severity of their nephritis but also on their ethnicity, their desire to have children and their predictors of outcome.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antirheumatic Agents; Biopsy; Drug Therapy, Combination; Humans; Immunologic Factors; Kidney; Lupus Nephritis; Mycophenolic Acid; Rituximab; Steroids; Tacrolimus

An immunosuppressive antimetabolite, mycophenolate mofetil (MMF), has been widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. A fixed dosing of MMF often causes bone marrow toxicity or cytomegalovirus antigenemia under the optimal dosing of calcineurin inhibitors. Pharmacokinetic characteristics of MMF and its relation to the degree of immune suppression have not been fully clarified in clinical practice. This review summarizes our achievements on pharmacokinetic disposition of mycophenolic acid (MPA) and inosine 5'-monophosphate dehydrogenase (IMPDH) activity in patients with kidney transplantation and with lupus nephritis. Contribution of enterohepatic recirculation to plasma disposition of MPA in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA pharmacokinetics in lupus nephritis was characterized by high MPA clearance most likely due to better renal function. In addition, concomitant metal cation decreased MPA concentration in patients receiving tacrolimus but not cyclosporine. This interaction may depend on amount of biliary-excreted MPA glucuronide. Renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated patients. Its ratio to creatinine clearance was much higher than unbound fraction of MPA in each calcineurin inhibitor treatment. These kinetic data revealed the presence of renal tubular secretion in the urinary excretion process. In multivariate analysis, the plasma disposition of MPA and its glucuronides affected IMPDH activity in erythrocytes. The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor.

Topics: Animals; Antimetabolites; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Glucuronides; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking.. To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China.. This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020.. Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone.. Complete or partial response rate at week 24 (prespecified).. A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs.. In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN.. ClinicalTrials.gov Identifier: NCT02457221.

Topics: Adult; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Tacrolimus; Treatment Outcome; Young Adult

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Mycophenolic Acid; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Mycophenolic Acid; Remission Induction; Tacrolimus; Treatment Outcome

To report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial.. Patients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis.. 150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis.. Long-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy.. NCT00371319.

Topics: Adult; Azathioprine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Symptom Flare Up; Tacrolimus; Time; Treatment Outcome

Here, we aimed to compare the clinical effects of mycophenolate mofetil combined with either tacrolimus or with cyclophosphamide on lupus nephritis (LN) and to analyze their influence on the expression of cystatin C and on transforming growth factor-1 (TGF-β1).. A total of 234 patients were randomly divided into two groups: group A, for mycophenolate mofetil combined with tacrolimus (n=117) and group B, for mycophenolate mofetil combined with cyclophosphamide (n=117). The enzyme-linked immunosorbent assay was adopted to detect the expression levels of serum TGF-β1 and cystatin C before and after treatment.. The total effectiveness rate in group A was much higher than that in group B. The times of effectiveness and effect validity in group A were much lower than those in group B. The expression levels of serum TGF-β1 and cystatin C decreased slightly after treatment in the two groups, and those of group A were much lower than those of group B.. The combination of mycophenolate mofetil and tacrolimus showed better clinical efficacy on LN and was safer than that of mycophenolate mofetil and cyclophosphamide. Moreover, the drug combination of mycophenolate mofetil and tacrolimus greatly reduced the expression levels of serum TGF-β1 and cystatin C.

Topics: Cyclophosphamide; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

Background Pulsed cyclophosphamide or mycophenolate mofetil for lupus nephritis has limited efficacy. We previously reported a case of mixed-class IV + V lupus nephritis successfully treated with cyclophosphamide and tacrolimus. This study assessed the efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for the treatment of lupus nephritis. Methods In a prospective, single-arm, open label pilot study, we recruited 15 patients aged 18-64 years with active lupus nephritis who met the American College of Rheumatology criteria for a diagnosis of systemic lupus erythematosus (1997). The treatment protocol was a starting dose of prednisolone of 0.6-1.0 mg/kg/day for 2 weeks and then tapered to a maintenance dose, intravenous cyclophosphamide (500 mg biweekly for 3 months) and tacrolimus (3.0 mg/day). Tacrolimus was continued as maintenance therapy. Complete remission was defined as a spot urine protein/creatinine ratio of < 0.5 g/gCr with no active urine casts and a serum creatinine level that was either normal or within 30% of a previously abnormal baseline level. We retrospectively compared results for the study patients with those of 18 historical controls conventionally treated with cyclophosphamide and prednisolone. Results At baseline, the mean patient age was 41.5 ± 14.6 years (male:female ratio 2:13), urine protein/creatinine ratio 3.9 ± 2.3 g/gCr and serum creatinine 84.6 ± 34.6 µmol/L. Lupus nephritis classifications included classes IV ( n = 8), III + V ( n = 1), IV + V ( n = 5) and unclassified ( n = 1). Eleven patients completed the treatment protocol and four withdrew. At 6 months, 12 of 15 (80.0%) had achieved complete remission using intention-to-treat analysis, significantly more than historical controls (seven of 18 patients, 38.9%). A transient increase in serum creatinine and gastric symptoms occurred in three cases. One patient withdrew due to cytomegalovirus antigenemia and severe diabetes, and one patient died of thrombotic microangiopathy. Conclusions Multitarget therapy with cyclophosphamide and tacrolimus can be a therapeutic option for lupus nephritis. Clinical trials registration Combination therapy of tacrolimus and intravenous cyclophosphamide for remission induction of lupus nephritis, UMIN: 000004893, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005830&language=E . Date of registration: 18 January 2011.

Topics: Administration, Intravenous; Adult; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Prospective Studies; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

We conducted a prospective multicenter, opened-label, parallel, randomized, controlled trial to compare tacrolimus (TAC) and mycophenolate mofetil (MMF) for induction and maintenance therapy in lupus nephritis (LN). Adult patients with biopsy-proven LN International Society of Nephrology/Renal Pathology Society classes III-V and active nephritis were to receive prednisolone (0.7-1.0 mg/kg/day for four weeks of run-in period and tapered) and randomly assigned to receive TAC (0.1 mg/kg/day) or MMF (1.5-2 g/day) as induction therapy for six months. All patients who had remission received azathioprine (AZA) 1-2 mg/kg/day as standard treatment in the maintenance phase. The primary outcome was Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) at six and 12 months, and the secondary outcomes included renal SLEDAI, non-renal SLEDAI, modified SLEDAI-2K, immunity SLEDAI, and disease activity remission. Eighty-four patients were randomized. One patient who was randomized to the TAC group withdrew from the study immediately after randomization. Therefore, 42 patients received MMF and 41 patients received TAC. Disease activity remission rate and time to disease activity remission were similar in both groups. Twelve patients (28.57%) in the MMF group and 10 patients (24.39%) in the TAC group achieved disease activity remission. For disease activity scores, both regimens significantly improved SLEDAI-2K during induction and maintenance therapy. Overall, SLEDAI-2K score in the MMF group decreased more compared with the TAC group. In the MMF group, mean SLEDAI-2K decreased from 11.6 ± 4.8 to 6.3 ± 3.9 after induction therapy and to 5.4 ± 4.4 after maintenance therapy. In the TAC group, mean SLEDAI-2K decreased from 9.0 ± 3.7 to 6.3 ± 5.1 after induction therapy and to 7.1 ± 5.4 after maintenance therapy. Renal SLEDAI and modified SLEDAI-2K showed a similar pattern with SLEDAI-2K. In non-renal SLEDAI and immunity SLEDAI, both regimens also resulted in decreased disease activity scores during the first two months. After that the scores were slightly increased. In the MMF group, the scores were still lower than baseline but in the TAC group were not. In conclusion, disease activity remission rate was similar in the MMF and TAC groups. For disease activity score as measured by SLEDAI-2K, TAC was comparable with MMF during induction but MMF was more effective on disease activity of active LN classes III and IV at 12 months, especially in the renal system.

Topics: Adult; Biopsy; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus; Thailand; Time Factors; Treatment Outcome; Young Adult

To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).. This is an open randomised controlled parallel group study.. Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.. 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).. TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.. Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Creatinine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Recurrence; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Topics: Adult; Aged; Drug Combinations; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Treatment Outcome

Treatment of lupus nephritis (LN) remains challenging.. To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN.. 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616).. 26 renal centers in China.. Adults (aged 18 to 65 years) with biopsy-proven LN.. Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy.. The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events.. After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]).. The study was limited to 24 weeks of follow-up.. Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN.. National Basic Research Program of China, National Key Technology R&D Program.

Topics: Adolescent; Adult; Aged; Biopsy; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisone; Prospective Studies; Remission Induction; Tacrolimus; Young Adult

Recent advances in the management of lupus nephritis (LN) have also contributed to a favorable outcome in patients with pediatric-onset LN. Nevertheless, we believe that a more effective and less toxic treatment is needed to attain optimal control of pediatric-onset LN.. Seven consecutive children with biopsy-proven LN (four with class III/IV and three with class V) received multitarget induction therapy consisting of mizoribine (MZR), tacrolimus (Tac), and prednisolone (PDN). They were prospectively evaluated at three, six, and 12 months, and at the latest observation point after a mean period of 32 months. Post-treatment renal biopsy was performed in two patients with class III/IV.. Despite gradually tapering the dose of concomitantly administered PDN, a significant improvement compared with baseline values was observed in the urinary, serological, and clinical assessment measures even at three months of treatment, and the favorable changes persisted throughout the treatment period in most of the study participants except for one. In two patients who underwent post-treatment renal biopsy, a marked histologic improvement was confirmed. No serious adverse events were observed.. Multitarget therapy may be an attractive option for the treatment of pediatric-onset LN. Further studies involving a larger number of patients are needed.

Topics: Adolescent; Child; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Male; Pilot Projects; Prednisolone; Prospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

Although the use of aggressive immunosuppression has improved both patient and renal survival of patients with lupus nephritis (LN), the optimal treatment of LN remains challenging. The objective of this study is to assess the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus compared with intravenous cyclophosphamide (IVC) as induction therapies for active lupus nephritis (ALN).. In this open-label, 24-week prospective study, 60 patients with biopsy-proven ALN (Classes III, IV, V or combination) were randomly assigned to receive MMF, tacrolimus or IVC in combination with corticosteroids. The remission of proteinuria, systemic lupus erythematosus disease active index and adverse events were compared.. The response rates at 24 weeks were 70% (14/20) in the MMF group, 75% (15/20) in the tacrolimus group and 60% (12/20) in the IVC group (P>0.05). The complete remission rates were also similar in the three groups (40, 45 and 30%, respectively; P>0.05). There were more cases of infection in the IVC group (8/20) and the MMF group (8/20) than the tacrolimus group (3/20) and more hyperglycemia in the tacrolimus group (5/20) than the other two groups (2 or 3/20), but the results were not statistically significant among the three groups. Proteinuria decreased and serum albumin increased more quickly in the patients treated with tacrolimus (P=0.0051 and P=0.048).. This pilot study suggests that both MMF and tacrolimus are possible alternatives to IVC as induction therapies for ALN in Chinese patients. Tacrolimus possibly results in a faster resolution of proteinuria and hypoalbuminemia. Further studies are necessary to determine the optimal dosage and duration of the therapies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoalbuminemia; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult

This pilot study compared mycophenolate mofetil (MMF) and tacrolimus (Tac) in the treatment of severe membranous lupus nephritis (MLN).. This was a 24 month prospective, randomized, open-label multi-centre exploratory study on Chinese patients with biopsy-proven pure Class V MLN with nephrotic syndrome. Patients were randomized to treatment with either MMF or Tac, both in combination with prednisolone and the efficacy and tolerability outcomes were examined.. Sixteen patients were included, seven in the MMF and nine in the Tac treatment arm. At 24 months the complete response, partial response and overall response rates were 57.1% vs. 11.1% (P = 0.049), 14.3% vs. 44.4% (P = 0.197) and 71.4% vs. 55.6% (P = 0.515) in the MMF and Tac groups, respectively. The two groups had similar reduction of proteinuria and longitudinal profiles of serum albumin and creatinine levels. Serum creatinine remained stable in both groups, except in two patients who had a transient increase associated with high Tac blood levels. Adverse events in the MMF group included herpes zoster in one patient and reversible leucopenia in another, while in the Tac group four patients had severe infections and one developed new onset diabetes. No relapse occurred during the study period.. Both MMF and Tac when combined with corticosteroids are effective treatment options for severe MLN.

Topics: Adult; Biomarkers; Biopsy; Chi-Square Distribution; China; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Nephrotic Syndrome; Pilot Projects; Prednisolone; Prospective Studies; Serum Albumin; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The optimal maintenance therapy for active diffuse lupus nephritis remains to be established. In this study, we explored the efficacy and safety of tacrolimus for maintaining remission of active lupus nephritis compared to that of azathioprine.. Seventy patients with biopsy-proven lupus nephritis who achieved remission were enrolled in nine nephrology centers in China from 2006 to 2008. Patients were randomized either to tacrolimus plus prednisone (n = 34) or azathioprine plus prednisone (n = 36) for six months. Tacrolimus was titrated to achieve a trough blood concentration of 4-6 ng/mL, and the dosage of azathioprine was 2 mg/kg/d. Prednisone was administered at a dose of 10 mg/d to both groups. The primary outcome was incidence of relapse. Response, clinical parameters and adverse effects were secondary endpoints.. After six months of therapy, two of the azathioprine-treated patients developed renal relapse compared to none of the tacrolimus-treated patients (p = 0.49; odds ratio, 1.06; 95% CI (0.98, 1.15)). Leucopenia (defined as < 2000 cells per cubic millimeter) was significantly more frequent in the azathioprine group than the tacrolimus group (47% vs. 9%, p < .001).. In conjunction with prednisone, maintenance therapy with tacrolimus and azathioprine has a similar low rate of renal relapse, and the tacrolimus regimen has a more favorable safety profile, with less leucopenia. However, since our study lacked sufficient power, longer follow-up is needed to draw final conclusions.

Topics: Adult; Azathioprine; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome

The optimal long-term treatment for lupus nephritis (LN) in pubertal patients remains to be determined. Tacrolimus (Tac) inhibits T cell activation, and is therefore expected to be effective in patients with LN. However, little has been published about the long-term efficacy and safety of Tac-based immunosuppressive treatment of young patients with LN in daily clinical practice.. Nineteen consecutive patients with biopsy-proven LN were recruited for an open-label, prospective, long-term Tac-based treatment regimen. Tac was administered once daily at a dose of 3 mg as induction- or reinduction-maintenance treatment. Four patients (21%) with new-onset LN received mizoribine at a dose of 150 mg once daily in addition to Tac. Treatment outcomes were defined by the European Consensus Lupus Activity Measurement (ECLAM) index, urinary protein/creatinine ratio (Up/cr), serum creatinine and serological lupus markers (complement C3, complement hemolytic activity, CH50, and anti-dsDNA antibody titer). Data on these parameters were collected prospectively. The median follow-up was 42 months.. Baseline characteristics of the patients were as follows: mean age, 18 years; Up/cr, 0.89 ± 1.17; serum C3, 68.1 ± 23.2 mg/dl (normal, 79-152 mg/dl); serum CH50, 26.4 ± 10.5 U/ml (normal, 23-46 U/ml); serum anti-dsDNA antibody titer, 69.3 ± 67.5 IU/ml (normal, <12.0 IU/ml); serum creatinine, 0.55 ± 0.18 mg/dl, and ECLAM index, 4.6 ± 1.9. Despite gradually tapering the dose of concomitantly administered prednisolone, a marked improvement compared with baseline values was observed in all outcome measures as early as 3 months after the initiation of treatment, and the favorable changes persisted throughout the treatment period in most of the patients. Sustained improvements in the outcome measures compared with the baseline values were confirmed after a mean of 42 months of treatment: ECLAM index, 1.1 ± 1.1; serum CH50, 36.0 ± 12.8 U/ml, anti-dsDNA antibody titer, 22.5 ± 26.5 IU/ml (all p < 0.01); Up/cr ratio, 0.35 ± 0.58, and serum C3 level, 79.7 ± 17.6 mg/dl (both p < 0.05). Serum creatinine level remained within the normal range in all the study participants. Complete response was achieved in 12 patients (63%), and a partial response was achieved in 5 patients (26%). The remaining 2 patients showed no response. No serious adverse effects were observed.. The data suggest that long-term, relatively low-dose Tac-based immunosuppressive treatment is beneficial and has low cytotoxicity, and therefore represents an attractive option for the treatment of young patients with LN in daily clinical practice. Further studies involving a larger number of patients are needed to confirm these results.

Topics: Adolescent; Child; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Japan; Longitudinal Studies; Lupus Nephritis; Male; Tacrolimus; Treatment Outcome

Intravenous cyclophosphamide with prednisone is an effective treatment for lupus nephritis, but with significant toxicities. We compared the efficacy and safety of tacrolimus versus intravenous cyclophosphamide as induction therapy.. Multicenter noninferiority randomized controlled trial.. 81 patients with biopsy-proven lupus nephritis from 9 nephrology centers in China from 2006-2008.. Prednisone and either tacrolimus (n = 42) or intravenous cyclophosphamide (n = 39) for 6 months. Tacrolimus was started at 0.05 mg/kg/d and titrated to achieve a trough blood concentration of 5-10 ng/mL. Intravenous cyclophosphamide was initiated at 750 mg/m² of body surface area, then adjusted to 500-1,000 mg/m² every 4 weeks for a total of 6 pulse treatments.. The primary outcome was complete remission (proteinuria with protein excretion <0.3 g/24 h, serum albumin ≥3.5 g/dL, normal urinary sediment, and normal or stable serum creatinine level) at 6 months. Response (complete or partial remission), clinical parameters, and adverse effects were secondary end points.. After the 6-month induction therapy, the tacrolimus group achieved higher cumulative probabilities of complete remission and response (52.4% vs 38.5% and 90.5% vs 82.1%, respectively) than the intravenous cyclophosphamide group, but differences were not statistically significant (log-rank test, P = 0.2 and P = 0.7, respectively). Proteinuria [corrected] was significantly decreased in tacrolimus- versus intravenous cyclophosphamide-treated patients after the first month of treatment, even with adjustment for baseline proteinuria (protein excretion, 1.76 vs 2.40 g/d; P = 0.02 for the log-transformed analysis). [corrected] After treatment, serum creatinine levels and estimated glomerular filtration rates were not significantly different between treatment groups. Adverse effects, such as leukopenia and gastrointestinal symptoms, were less frequent in the tacrolimus group.. Nonblinded, small sample size, and short duration of follow-up.. In conjunction with prednisone, induction therapy with tacrolimus is at least as efficacious as intravenous cyclophosphamide and prednisone in producing complete remission of lupus nephritis and has a more favorable safety profile.

Topics: Adult; Anti-Inflammatory Agents; China; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

We conducted an open-labeled, prospective study to determine the efficacy and safety of tacrolimus as an alternative therapeutic option for those patients with refractory lupus nephritis. The study population comprised one male and eight female patients with diffuse proliferative lupus nephritis. All patients had failed to respond to sufficient intravenous cyclophosphamide therapy with proteinuria of >or=1 g/day and active urinary sediments. Tacrolimus (0.1 mg/kg/day) was administered for 1 year with adjusting drug level (4-10 microg/l). The mean serum creatinine level and spot urine protein creatinine ratio (UPCR) at baseline were 1.39 mg/dl and 2.27, respectively. After the treatment, proteinuria reduced significantly from median UPCR value of 2.19 (range, 1.19-3.34) to 0.44 (range, 0.12-2.13) (p < 0.05). Seven (78%) of the nine patients showed a complete clinical response, which was defined as stabilization in the disease-activity markers and serum creatinine level with reduction of >or=50% in UPCR; two patients showed complete remission with UPCR <0.2. One patient showed treatment failure because of the disease progression. No serious adverse effects were observed during the study. This study demonstrates that tacrolimus can show a significant therapeutic response in cases that are refractory to the standard regimen for diffuse proliferative lupus nephritis.

Topics: Adult; Cyclophosphamide; Disease Progression; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Failure; Treatment Outcome

We evaluated the efficacy and safety of tacrolimus in patients receiving glucocorticoid therapy for lupus nephritis. Patients with persistent nephritis were randomized to receive 28 weeks of double-blind treatment with tacrolimus (3 mg/day) or placebo. The primary endpoint was the change in the lupus nephritis disease activity index (LNDAI) calculated from scores for daily urinary protein excretion, urinary red cells, serum creatinine, anti-double-stranded DNA antibody, and serum complement. Statistical analysis was performed using the full analysis set. The LNDAI was decreased by 32.9 +/- 31.0% (mean +/- SD) in the tacrolimus group (n = 28) and was increased by 2.3 +/- 38.2% in the placebo group (n = 35) at final evaluation. There was significant improvement in the tacrolimus group. Daily urinary protein excretion showed a significant decrease in the tacrolimus group (p < 0.001). The complement (C3) level showed a significant increase in the tacrolimus group (p = 0.001). Treatment-related adverse events occurred in 92.9% of the tacrolimus group and 80.0% of the placebo group, but the difference was not significant. In patients on glucocorticoid therapy for lupus nephritis, addition of tacrolimus to basal therapy achieved significant improvement compared with placebo. Tacrolimus may therefore be a useful alternative treatment for lupus nephritis.

Topics: Adolescent; Adult; Analysis of Variance; Complement C3; Creatinine; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Patient Selection; Severity of Illness Index; Statistics, Nonparametric; Tacrolimus; Treatment Outcome; Urinalysis

The purpose of this study was to examine whether tacrolimus is effective and safe, and to determine the optimal dose of tacrolimus for maintenance treatment in patients with lupus nephritis (LN).. A total of 17 adult patients (1 man and 16 women) with LN were enrolled. Tacrolimus was initiated at a dose of 3 mg/day which was administered once per day after the evening meal. Prospective data on renal response and serologic lupus activity were collected and followed for a year.. Mean age at baseline was 48.8 +/- 12.6 years (range 31-72 years). The mean urinary protein/creatinine ratio significantly decreased from 1.14 +/- 1.74 at baseline to 0.23 +/- 0.47 at 1 year (p < 0.05). Mean serum C3 significantly increased from 73.0 +/- 12.3 mg/dl at baseline to 84.7 +/- 12.2 mg/dl at 1 year (p < 0.01). Mean serum creatinine levels were unchanged after tacrolimus treatment. The mean blood concentration of tacrolimus was 3.9 +/- 2.1 ng/ml. There was no relationship between the incidence of adverse effects and blood tacrolimus level.. Our results suggest tacrolimus to be potentially effective and safe for maintenance treatment in patients with LN.

Topics: Adult; Aged; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Tacrolimus; Treatment Outcome

Studies on immunosuppressive treatment with tacrolimus (Tac) in subjects with lupus nephritis (LN) are limited. Here, we report our experience with Tac administered daily as a single-dose for maintenance therapy in young patients with pediatric-onset, long-standing LN.. Eleven consecutive patients with long-standing biopsy-proven LN were recruited for at least 6 months or longer (6 - 24 months) as part of an open-label trial for the single-daily-dose administration of Tac (3 mg/day, 0.04 - 0.075 mg/kg) without dose increases of concomitantly administered prednisolone (PDN). Tac treatment was started at the time of the most recent flare. Data on clinical parameters and serologic lupus activity were collected prospectively.. The baseline characteristics of the patients were as follows: mean age, 18 years; urinary protein/creatinine ratio (Up/cr), 0.74 +/- 1.49; serum C3 level, 69.5 +/- 26.5 mg/dl (normal 79 - 152 mg/dl); serum complement hemolytic activity (CH50), 23.0 +/- 8.9 U/ml (normal 23 - 46 U/ml); serum anti-dsDNA antibody titer, 58.9 +/- 54.2 IU/ml (normal < 12.0 IU/ml); serum creatinine, 0.54 +/- 0.13 mg/dl; and European Consensus Lupus Activity Measurement (ECLAM) index, 4.4 +/- 2.2. Despite the gradual tapering of the PDN dose, a marked improvement, compared with the baseline values was observed in the ECLAM index even at 1 month and in the serological parameters at 3 months after the start of treatment. These favorable results persisted until the end of the study. The Up/cre ratio gradually decreased and had dropped significantly at 24 months after the start of treatment. After a mean of 18 months of treatment, complete responses were achieved in 8 patients (73%) and a partial response was achieved in 2 patients. The remaining one patient showed no response. No serious adverse effects were observed.. These data suggest that low-dose Tac treatment, administered once daily, is an effective and safe method for managing selected young patients with pediatric-onset, long-standing LN. However, further studies involving a larger number of patients are needed to confirm these results.

Topics: Adolescent; Adult; Antibodies, Antinuclear; Biopsy; Complement C3; Complement Hemolytic Activity Assay; DNA; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.

Topics: Adult; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Prospective Studies; Tacrolimus; Treatment Outcome

The objective of the current work is to report the preliminary experience with tacrolimus (TL) administered as a single-dose daily for maintenance therapy of young patients with pediatric-onset, long-standing systemic lupus erythematosus (SLE). Six consecutive patients with long-standing SLE were recruited for a 6-month open-label trial of single-dose-daily administration of tacrolimus (3 mg/day) without dose up of concomitantly administered prednisolone (PDN). TL treatment was started at the time of the most recent flares. Data on the clinical and serologic lupus activity were collected prospectively. The baseline characteristics of the patients were: mean age, 20 years; urinary protein/creatinine ratio, 1.22 +/- 1.94; serum C3 level, 70.8 +/- 21.2 (normal, 79-152 mg/dL); serum complement hemolytic activity (CH50), 22.2 +/- 10.3 (normal, 23-46 U/mL); serum anti-dsDNA antibody titer, 60.4 +/- 71.7 IU/mL (normal, < 12.0 IU/mL); serum creatinine, 0.55 +/- 0.11 mg/dL; European Consensus Lupus Activity Measurement (ECLAM) index, 5.2 +/- 2.6. Despite the gradual tapering of the PDN dose, marked improvement as compared with the baseline values was observed in the ECLAM index examined at one and three months and serological parameters examined at three months after the start of treatment. After a 6-months' therapy, complete response was achieved in all of the patients (serum CH50 value, 27.7 +/- 8.3 U/mL; serum anti-dsDNA antibody titer, 28.4 +/- 27.9 U/mL and the ECLAM index, 1.2 +/- 1.2 (P < 0.05), respectively), except in one patient who showed WHO class V lupus nephritis. No serious adverse effects were observed. These data suggest that TL, even when administered as a single-daily dose, is effective and safe for selected young patients with pediatric-onset, long-standing SLE. However, further studies on a larger number of patients are needed to confirm these results.

Topics: Adolescent; Adult; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Pilot Projects; Tacrolimus; Treatment Outcome

Tacrolimus is a relatively new calcineurin inhibitor that has been increasingly used in transplant medicine. The objective of the current work is to report our preliminary experience with tacrolimus in the treatment of diffuse proliferative glomerulonephritis in systemic lupus erythematosus (SLE).. Nine consecutive patients who fulfilled the American College of Rheumatology criteria for SLE and with biopsy-proven diffuse proliferative glomerulonephritis were recruited for an open-labeled trial with prednisolone and oral tacrolimus (0.1 mg/kg/day for 2 months, followed by 0.06 mg/kg/day). Prospective data on renal response and serologic lupus activity were collected. The efficacy and safety of this regimen was reported.. Baseline characteristics of the patients were: mean age 33.3 +/- 12 years, women to men ratio 2:1, serum creatinine 94.2 +/- 46 micromol/L, daily proteinuria 4.56 +/- 2.4 g, seven (78%) patients were nephrotic, three (33%) were hypertensive, and four (44%) had elevated serum creatinine at the time of renal biopsy. At 6 months of therapy, complete and partial renal response was achieved in six (67%) and two (22%) patients, respectively. Significant improvement in proteinuria, hemoglobin, serum albumin, and C3 levels was observed in comparison with baseline values, starting at the second month. Tacrolimus was generally well tolerated, except for two patients who developed transient hyperglycemia. Infective complications, amenorrhea, hypertrichosis, gingivitis, new-onset hypertension, and significant increase in serum creatinine were not reported.. Tacrolimus is an effective option for induction treatment of SLE-diffuse proliferative glomerulonephritis. Further trials are necessary to determine the optimal dosage and duration of therapy, and its efficacy in comparison to standard regimens.

Topics: Adult; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Pilot Projects; Prednisolone; Prospective Studies; Severity of Illness Index; Tacrolimus

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Topics: Adult; Angiomyolipoma; Everolimus; Female; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Tacrolimus may be administered to pregnant women with lupus nephritis in Japan if considered therapeutically beneficial, but supporting data are limited. We assessed the safety and effectiveness of tacrolimus before, during, and after pregnancy in women with lupus nephritis receiving tacrolimus.. This was an ad hoc analysis of data from a post-marketing surveillance study of tacrolimus in patients with lupus nephritis in Japan. Pregnancy outcomes, nephritis status, and adverse events were assessed for up to 2 years postpartum.. Data were available for 23 births in 21 patients (two patients had two births each). Tacrolimus for lupus nephritis was continued during 11 births in nine patients (during and after pregnancy) and discontinued in 12 patients (when pregnancy was known or when approaching delivery). Renal function was generally maintained in patients who gave birth while receiving tacrolimus; however, there were cases of increased urine protein and decreased renal function over 2 years. There were no unexpected adverse events/safety concerns.. These data from clinical practice suggest that tacrolimus is a valid treatment option for lupus nephritis in fertile women in Japan and, with careful monitoring, pregnant women with lupus nephritis may continue their tacrolimus treatment.

Topics: Female; Humans; Immunosuppressive Agents; Japan; Kidney; Lupus Nephritis; Pregnancy; Pregnancy Outcome; Product Surveillance, Postmarketing; Tacrolimus

Topics: Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; Treatment Outcome

To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN).. In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed.. The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy.. Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN.. The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.

Topics: Child; Cyclophosphamide; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease characterised by autoantibodies targeting insulin receptors. TBIR is often complicated by systemic lupus erythematosus (SLE). We describe the case of a 59-year-old Japanese man with TBIR complicated with lupus nephritis (LN), who presented with nephrotic syndrome and severe hypoglycaemia. Treatment with prednisolone (PSL), mycophenolate mofetil (MMF), and tacrolimus (TAC) resulted in improved SLE activity and glucose intolerance with the reduction of anti-insulin receptor autoantibodies. To the best of our knowledge, this is the first reported case of TBIR complicated with LN that was successfully treated using multitarget therapy with PSL, MMF, and TAC.

Topics: Humans; Immunosuppressive Agents; Insulin Resistance; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

P-glycoprotein (P-gp)-mediated efflux of corticosteroids (CS) may contribute to treatment unresponsiveness in Lupus Nephritis (LN) patients. Tacrolimus is a P-gp inhibitor and hence, may overcome this resistance. We aimed to study the response to tacrolimus, along with the expression and function of P-gp on peripheral blood lymphocytes (PBL) in patients with refractory and relapsing proliferative Lupus Nephritis. We enrolled 12 refractory/relapsing LN patients and treated them with corticosteroids and tacrolimus for 6 months. Expression and function of P-gp on PBL was measured by flow cytometry (as relative fluorescence index, RFI and Rhodamine dye efflux assay) before and 3 months after tacrolimus therapy. Renal response was assessed according to ACR response criteria after 3 and 6 months of tacrolimus therapy. 8 out of 12 refractory/relapsing LN patients achieved renal response (5 partial response, PR and 3 complete responses, CR) as early as 3 months, and 11 patients achieved renal response (7 PR and 4 CR) at 6 months from start of tacrolimus therapy. Proteinuria decreased from median urine protein creatinine ratio (UPCR) of 2.80 (2.00-3.40) at baseline to 1.20 (0.66-1.73) at 3 months (p < 0.001) and to 0.80 (0.19-1.30) at 6 months (p < 0.01). There was significant decrease in P-gp expression [RFI, 3.33 (2.87-4.97) vs 2.03 (1.25-3.86), p < 0.05) and P-gp function (RFI, 55.7 (29.7-84.1) vs 26.8 (16.1-37.0), p < 0.01) after 3 months of tacrolimus therapy. Tacrolimus achieves renal response in refractory/relapsing proliferative LN patients which may be partly related to overcoming P-glycoprotein mediated treatment unresponsiveness.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Humans; Immunosuppressive Agents; Lupus Nephritis; Lymphocytes; Recurrence; Remission Induction; Tacrolimus; Treatment Outcome

Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options.. This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed.. Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients.. Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE.

Topics: Child; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.

Topics: Azathioprine; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Recurrence; Tacrolimus; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; Treatment Outcome

BACKGROUND Nephrotic syndrome caused by minimal mesangial lupus nephritis is considered rare. Nephrotic syndrome can be caused by minimal mesangial lupus nephritis with diffuse epithelial foot-process effacement and lupus podocytopathy. CASE REPORT A 23-year-old Japanese woman diagnosed with mixed connective tissue disease was admitted because of weight gain and generalized edema for 2 weeks prior to admission. She had butterfly-shaped erythema on her cheeks, proteinuria, leukocytopenia with lymphocytopenia, and hypoalbuminemia. She was positive for antinuclear antibodies, and specific autoantibodies were only positive for the ribonucleoprotein (RNP) antigen. She was diagnosed with systemic lupus erythematosus. Renal biopsy showed minor glomerular abnormalities, and immunofluorescence revealed peripheral deposits of IgM and complement C3c. Electron microscopy revealed diffuse podocyte foot-process effacement of >80% of the capillary loop surfaces, with only a few subendothelial deposits. Consequently, we diagnosed minimal mesangial lupus nephritis with lupus podocytopathy. On hospital day 4, we administered 1000 mg/day of methylprednisolone for 3 days, followed by prednisolone 50 mg/day, but proteinuria persisted. On day 12, we administered tacrolimus (3 mg/day). Proteinuria improved and then disappeared on day 17. Prednisolone was gradually tapered and stopped after 3 years, although tacrolimus 3 mg/day was continued. No flare-up was observed 4 years after admission. CONCLUSIONS Tacrolimus showed good efficacy in this case of minimal mesangial lupus nephritis with lupus podocytopathy. Prospective and randomized controlled trials should be conducted to demonstrate the efficacy of tacrolimus for this indication.

Topics: Adult; Female; Humans; Induction Chemotherapy; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Prospective Studies; Proteinuria; Tacrolimus; Young Adult

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.

Topics: Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Prednisolone; Recurrence; Tacrolimus; Treatment Outcome

Combination therapy with mycophenolate mofetil, tacrolimus and steroids are effective in achieving complete remission in lupus nephritis (LN). Combination therapy uniquely downregulated caspase-1 compared with monotherapies, which can cleave gasdermin D (GSDMD) and was recently identified as the pyroptosis executioner. We therefore investigated whether combination therapy enabled the suppression of caspase-1/GSDMD-mediated pyroptosis in LN.. Expression and activation of GSDMD were detected in kidney specimens of the human and mouse with LN using immunohistochemical staining and immunoblotting. Primary podocytes isolated from MRL/lpr mice were incubated with LPS+ATP, and pretreated with monotherapy or combination therapy. Inhibition of caspase-1/GSDMD-induced pyroptosis by combination therapy were assessed in MRL/lpr mice and human specimens. Pyroptosis was examined using a FAM caspase-1 kit and flow cytometry. The correlation between pyroptosis in peripheral blood and the systemic lupus erythematosus disease activity index (SLEDAI) was analyzed.. Kidney tissue specimens from LN patients and mice exhibited greatly increased expression levels and cleavage of GSDMD. In cultured podocytes, combination treatment significantly suppressed the activation of NLRP3 and caspase-1 and reduced GSDMD N-terminal levels. Combination therapy repressed disease progression through inhibition of caspase-1/GSDMD-mediated pyroptosis in both humans and MRL/lpr mice. Caspase-1/PI positive cell numbers in peripheral blood were positively correlated with SLE-DAI. LN patients with complete remission and partial remission had remarkably reduced caspase-1/PI positive cell numbers compared to baseline. Ac-FLTD-CMK, a GSDMD-derived inhibitor, prevented the development of LN.. Combination therapy suppressed caspase-1/GSDMD-mediated pyroptosis

Topics: Adolescent; Adult; Aged; Animals; Calcineurin Inhibitors; Caspase 1; Caspase Inhibitors; Cells, Cultured; Cohort Studies; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Lupus Nephritis; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Middle Aged; Mycophenolic Acid; Phosphate-Binding Proteins; Podocytes; Prednisone; Pyroptosis; Tacrolimus; Young Adult

Topics: Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Glomerulonephritis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting.. This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016.. Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation (. Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747).

Topics: Humans; Immunosuppressive Agents; Japan; Lupus Nephritis; Tacrolimus; Treatment Outcome

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus

Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Fas. Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone.. Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

Topics: Animals; Apoptosis; Chitosan; Female; Fibrosis; Gene Expression; Hydrophobic and Hydrophilic Interactions; Inflammation; Kidney; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Micelles; NF-kappa B; Signal Transduction; Tacrolimus

Coronavirus Disease 2019 (COVID-19) is currently a pandemic with a mortality rate of 1%-6% in the general population. However, the mortality rate seems to be significantly higher in elderly patients, especially those hospitalized with comorbidities, such as hypertension, diabetes, or coronary artery diseases. Because viral diseases may have atypical presentations in immunosuppressed patients, the course of the disease in the transplant patient population is unknown. Hence, the management of these patients with COVID-19 is an area of interest, and a unique approach is warranted. Here, we report the clinical features and our treatment approach for a kidney transplant patient with a diagnosis of COVID-19. We believe that screening protocols for SARS-Cov-2 should be re-evaluated in patients with solid-organ transplants.

Topics: Adult; Antiviral Agents; Betacoronavirus; Coronavirus Infections; Cough; COVID-19; COVID-19 Drug Treatment; Disease Management; Female; Fever; Glucocorticoids; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Oseltamivir; Pandemics; Pneumonia, Viral; Prednisone; SARS-CoV-2; Severity of Illness Index; Tacrolimus

The inhibition of mesangial cell proliferation has become an important therapy for the prevention of glomerular proliferation‑associated diseases. The combined application of immunosuppressants with multiple targets presents a novel direction in the treatment of kidney diseases. The present study was designed to explore the inhibitory effects of tacrolimus (TAC) combined with mycophenolate mofetil (MMF) on the proliferation of mesangial cells based on the cell cycle. In vitro, the levels of the proliferation index markers, Ki67 and cyclin D1, in human mesangial cells (HMCs) were determined by immunofluorescence staining and western blot analysis, respectively. In mice with lupus nephritis (LN), the proliferation of mesangial cells was determined using PAS and Masson's trichrome staining, while immunohistochemistry was used to detect Ki67 and western blot analysis was employed for the evaluation of cyclin D1 levels. The expression of platelet‑derived growth factor (PDGF), a proliferation‑associated protein, was estimated using immunohistochemistry and western blot analysis. In patients with LN, Ki67, cyclin D1 and PDGF expression was estimated by immunohistochemistry. The transforming growth factor‑β1/Smad pathway influenced by TAC and the p38 pathway influenced by MMF were also examined by western blot analysis. The results suggested that the combination of TAC and MMF at half the concentration based on the cell cycle was more effective than monotherapy in inhibiting mesangial cell proliferation in vitro and in vivo. TAC inhibited HMC proliferation by affecting the Smad2 signaling pathway. MMF inhibited HMC proliferation by affecting the p38 signaling pathway. Combined treatment with TAC and MMF significantly improved the clinical indexes of patients with LN without severe adverse effects. On the whole, the findings of the present study validate and reinforce the potential use of the combination of TAC and MMF for the treatment of mesangial proliferative diseases.

Topics: Animals; Cell Cycle; Cell Proliferation; Cyclin D1; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ki-67 Antigen; Lupus Nephritis; Mesangial Cells; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mycophenolic Acid; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Tacrolimus

We aimed to evaluate the efficacy of low-dose cyclosporine (CsA) or tacrolimus (Tac) in children with proliferative lupus nephritis (PLN) during maintenance therapy.. A low dose of CsA or Tac was added to 11 children who relapsed during mycophenolate mofetil (MMF) maintenance therapy. Renal remission was analyzed at 3 and 6 months, and at 1, 2, and 3 years after CsA/Tac addition. Adverse effects were recorded.. The clinical response rates were 81.9%, 100%, 90.0%, 100%, and 100% at 3 months, 6 months, 1 year, 2 years, and 3 years after CsA/Tac addition, respectively. Complete renal remission rates were 45.5%, 45.5%, 40.0%, 44.4%, and 71.4% at 3 months, 6 months, 1 year, 2 years, and 3 years after CsA/Tac addition, respectively. None of the patients had severe adverse events.. Low-dose CsA/Tac combined with MMF shows a promising effect in renal remission with acceptable safety in children with PLN. Therefore, this combination would be a good choice for children with lupus nephritis who relapse or have suboptimal MMF maintenance therapy.

Topics: Adolescent; Antibiotics, Antineoplastic; Child; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Male; Mycophenolic Acid; Recurrence; Remission Induction; Retrospective Studies; Tacrolimus

To assess the renal and non-renal efficacy of mycophenolate mofetil (MMF) in Japanese patients with systemic lupus erythematosus (SLE).. We conducted a retrospective study to assess the renal and non-renal efficacies of MMF in Japanese patients with systemic lupus erythematosus (SLE). We analyzed 14 patients with lupus nephritis (LN) who were given MMF, and 13 patients who received monthly intravenous cyclophosphamide (IVCY) as induction therapy, and a further 19 patients without LN who were treated with MMF, and 13 patients who took tacrolimus (TAC) to reduce glucocorticoid dosages. We assessed the therapeutic effects of each therapeutic regime on renal and non-renal disease manifestations over a six-month period after treatment initiation.. Median urine protein to creatinine ratios in the MMF and IVCY groups significantly decreased from 2.2 to 0.7 g/gCr and from 3.3 to 0.5 g/gCr, respectively. Significant improvements in serum immunological variables (serum complements C3 and C4 and the anti-double stranded DNA antibody) and reductions in the SLE disease activity index (SLEDAI) and daily prednisolone dosages were observed in each group with LN. MMF and TAC significantly improved SLEDAI and serum immunological variables and reduced daily prednisolone dosages in patients without LN.. The present results demonstrated that MMF might be an effective treatment for renal and non-renal manifestations in Japanese patients with SLE and has potential as a good therapeutic alternative and steroid-sparing agent.

Topics: Administration, Intravenous; Adult; Antibodies, Antinuclear; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Japan; Kidney Function Tests; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Long-term treatment programs with low toxicity represent a therapeutic challenge in lupus nephritis (LN). Although a therapeutic benefit of rituximab (RTX) has been reported in LN patients who have failed conventional treatment, the results are controversial. We aimed to assess the clinical efficacy and safety of RTX as a new immunosuppressive medicine in the treatment of LN with a meta-analysis.. Based on predetermined criteria, PubMed, Embase, and Cochrane Library were used to identify the eligible studies. Cochrane Review Manager version 5.3 was applied to pool the data extracted from individual investigations and provide summary effect estimates.. Twenty-four studies with 940 patients were analyzed. In case series trials with specific LN assessment, the complete remission (CR) rate at 12 months was 35.9% (95% CI: 24.2%-49.5%), and total remission (TR: CR plus partial remission) was 73.4% (95% CI: 66.0%-79.7%). In controlled trials, RTX was associated with a higher probability of TR (OR =2.02, 95% CI: 1.23-3.32,. RTX is a promising therapy for the treatment of LN due to significant clinical efficacy and a favorable safety profile. In future studies, larger study populations and longer-term time points may identify additional important patient-centered outcomes.

Topics: Humans; Immunosuppressive Agents; Lupus Nephritis; Meta-Analysis as Topic; Tacrolimus

The purpose of this study was to detect the efficacy and safety of tacrolimus (TAC) in induction therapy of patients with lupus nephritis.. Associated studies were extracted from the PubMed and the Cochrane Library on July 10, 2018, and applicable investigations were pooled and analyzed by meta-analysis. Data on complete remission (CR), total remission (TR; complete plus partial remission), proteinuria levels, urine erythrocyte number, albumin, glomerular filtration rate, negative rate of ds-DNA, C. In the therapeutic regimen of TAC + glucocorticoids (GC) vs cyclophosphamide (CYC) + GC, the results indicated that the TAC group had high values of CR, TR, albumin, and negative rate of ds-DNA, and low values of proteinuria levels and SLE-DAI when compared with those in CYC group (all. TAC is an effective and safe agent in induction therapy of patients with lupus nephritis.

Topics: Humans; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus

To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine.. A continuous survey was conducted between March 2010 and July 2015.. The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use.. The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Product Surveillance, Postmarketing; Ribonucleosides; Tacrolimus

A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.

Topics: Animals; Cytoskeleton; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Gene Expression Profiling; Gene Expression Regulation; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice, Inbred MRL lpr; Mycophenolic Acid; Podocytes; Prednisone; Signal Transduction; Tacrolimus; Transcriptome

Objectives Outcomes of systemic lupus erythematosus (SLE) have significantly improved over the years. However, when there is major organ involvement, the outcomes can still be unfavorable. Outcomes of multitarget therapy using mycophenolate mofetil (MMF) and tacrolimus in patients with SLE who were refractory to standard therapy were assessed. Methods We retrospectively reviewed the Hanyang BAE lupus cohort to identify patients with biopsy-confirmed lupus nephritis (classes III, IV, or V) who failed to either achieve complete response with standard induction therapy or those who had a lupus flare after achieving a complete response with conventional induction therapy and subsequently were switched to multitarget combination therapy with MMF and tacrolimus. Outcomes, including renal response, proteinuria, glomerular filtration rate, serum albumin, anti-dsDNA antibody level, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and complements, were assessed at six and 12 months. Results Twenty-nine patients, including 12 who failed to achieve a complete response at 12 months after initial conventional induction therapy and 17 with lupus flare after achieving a complete response at 12 months and treated with multitarget therapy, were included in the analysis. At six months, 53.9% of the patients showed a response, with 15.4% of patients showing a complete response and 38.5% of patients showing a partial response. At 12 months, 55.5% of patients exhibited a response (with complete and partial response in 25.9% and 29.6%, respectively). The dosage of steroids was significantly decreased at six months compared with baseline and was maintained at 12 months. Proteinuria, anti-double-stranded DNA antibody positivity, as well as C3 and C4 levels improved after treatment and persisted until 12 months, but were not significant. SLEDAI also improved. Outcomes were significantly better in patients who had a complete response but later had a flare, resulting in the use of multitarget therapy and achieving a subsequent complete response. Conclusions Multitarget therapy with MMF and tacrolimus can be a reasonable option in refractory lupus nephritis patients who failed to show adequate response to conventional induction therapy or who had flares during maintenance therapy. This treatment can help patients achieve a renal response and reduce the use of steroids.

Topics: Adolescent; Adult; Drug Resistance; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Recurrence; Remission Induction; Retrospective Studies; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Topics: Aged; Antiviral Agents; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Remission Induction; Ribavirin; Sofosbuvir; Tacrolimus

Topics: Adult; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Incidence; Induction Chemotherapy; Kidney; Lupus Nephritis; Male; Middle Aged; Prognosis; Remission Induction; Retrospective Studies; Tacrolimus

Despite the high efficacy of mycophenolate mofetil (MMF)/tacrolimus-based multitarget treatment, risks of infections are a matter of concern. In the present study, we clarified the potential of multitarget therapy using mizoribine opposed to MMF.. A total of 36 patients with biopsy-proven lupus nephritis were treated with mizoribine, tacrolimus, and glucocorticoids and then retrospectively evaluated. To determine the efficacy, proteinuria remission (≤ 0.2 g/day), complete remission (Liu et al. in Ann Intern Med 162:18-26, 2015) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) remission rates, and the prednisolone dose at months 6 and 12 were evaluated. The associations between serum mizoribine/tacrolimus levels and clinical parameters were investigated. To assess safety, adverse events were inspected.. All patients could continue the original treatment regimen without withdrawal or exacerbations through month 12. At month 6, the proteinuria remission, complete remission, SLEDAI remission rates, and prednisolone dose were 69, 53, 36%, and 12.1 mg/day, respectively, whereas the values at 12 months were 92, 67, 50%, and 8.8 mg/day, respectively. The treatment was efficacious for every histologic type of nephritis and non-renal manifestations of SLE. Excluding one patient who was hospitalized due to upper respiratory tract infection, serious infections, including pneumonia and cytomegalovirus disease, were not observed. Higher trough tacrolimus levels were associated with normalization of complement, whereas higher peak mizoribine levels with prevention of cytomegalovirus viremia.. Our results suggest that multitarget therapy using mizoribine opposed to MMF is highly safe and effective through 12 months. The therapy may enable faster dose reduction of concomitant glucocorticoids.

Topics: Adolescent; Adult; Aged; Cytomegalovirus Infections; Female; Humans; Lupus Nephritis; Male; Middle Aged; Ribonucleosides; Tacrolimus; Young Adult

Previously, we reported the short-term effects of tacrolimus in treating lupus nephritis (LN); however, long-term data are lacking. We conducted a retrospective study of 26 adult patients with LN. Tacrolimus was initiated at a dose of 3 mg/day after induction therapy. We retrospectively collected data on renal response; modified lupus nephritis disease activity index (m-LNDAI), including hematuria, proteinuria, complement 3, anti-double-stranded DNA antibody, and estimated glomerular filtration rate (eGFR); and prednisolone (PSL) dose. Three patients discontinued tacrolimus treatment because of related complications, including acute myeloblastic leukemia, tremor, or a general personal choice or a desire to become pregnant. We analyzed data from 23 patients who were treated with tacrolimus over a 5-year period. The mean urinary protein/creatinine ratio decreased from a baseline of 0.24 (min 0.00-max 4.20) to 0.00 (0.00-7.05) at 5 years (p = 0.0134), while eGFR levels remained unchanged throughout the 5 years. The mean m-LNDAI decreased from a baseline of 3.00 (0.00-12.0) to 2.00 (0.00-4.00) at 5 years (p = 0.0074). The mean PSL dose decreased from a baseline of 0.33 (0.00-0.75) mg/kg/day to 0.15 (0.15-0.33) at 5 years (p = 0.001). Our results suggest that tacrolimus is potentially effective for treating LN and that the current dosage was generally well tolerated for long-term maintenance treatment in our patients with LN.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Japan; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197-37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997-0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001-1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996-0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.

Topics: Adult; Creatinine; Cyclophosphamide; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Logistic Models; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Podocytes; Prednisolone; Prognosis; Proteinuria; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67;

Topics: Adolescent; Adult; Aged; Azathioprine; China; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recurrence; Tacrolimus; Treatment Outcome; Young Adult

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Proteinuria; Risk Factors; Tacrolimus

Topics: Adult; Clarithromycin; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Lupus Nephritis; Tacrolimus

Topics: Adult; Biopsy; Delayed Graft Function; Female; Humans; Hypophosphatemia; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Phosphates; Tacrolimus; Treatment Outcome

Topics: Cyclophosphamide; Drug Therapy, Combination; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Remission Induction; Tacrolimus

Topics: Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Tacrolimus

Topics: Azathioprine; Cyclophosphamide; Female; Glomerulonephritis; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Tacrolimus

Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0-6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7-12.0 weeks) in combination therapy (p = 0.076). Twenty-seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6-125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen.

Topics: Adolescent; Adult; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Isoxazoles; Kidney; Leflunomide; Lupus Nephritis; Male; Mycophenolic Acid; Nephrotic Syndrome; Podocytes; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

Several studies have reported that tacrolimus (TAC) significantly reduced proteinuria in lupus nephritis (LN) patients and mouse models. However, the mechanism for this effect remains undetermined. This study explored the mechanism of how TAC protects podocytes from injury to identify new targets for protecting renal function.. MRL/lpr mice were given TAC at a dosage of 0.1 mg/kg per day by intragastric administration for 8 weeks. Urine and blood samples were collected. Kidney sections (2 μm) were stained with hematoxylin-eosin (HE), periodic acid-Schiff base (PAS) and Masson's trichrome stain. Mouse podocyte cells (MPC5) were treated with TAC and/or TGF-β1 for 48 h. The mRNA levels and protein expression of synaptopodin and Wilms' tumor 1 (WT1) were determined by real-time PCR, Western blotting and/or immunofluorescence, respectively. Flow cytometry was used to detect cell apoptosis with annexin V. Podocyte foot processes were observed under transmission electron microscopy. IgG and C3 deposition were assessed with immunofluorescence assays and confocal microscopy.. Synaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine. TAC, however, reduced proteinuria, improved renal function, attenuated renal pathology, restored synaptopodin expression and preserved podocyte numbers. In MPC5 cells, TGF-β1 enhanced F-actin damage in podocytes and TAC stabilized it. TAC also decreased TGF-β1-induced podocyte apoptosis in vitro and inhibited foot process fusion in MRL/lpr mice. In addition, our results also showed TAC inhibited glomerular deposition of IgG and C3.. This study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis.

Topics: Animals; Apoptosis; Cell Line; Complement C3; Cytoprotection; Cytoskeleton; Drug Evaluation, Preclinical; Female; Immunoglobulin G; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice, Inbred MRL lpr; Microfilament Proteins; Podocytes; Protein Stability; Proteinuria; Tacrolimus

1. The purpose of the present study was to investigate the effect of tacrolimus concentration in blood 12 h after administration (C12h) on acute renal dysfunction in patients with lupus nephritis (LN) taking tacrolimus once daily. 2. Five of the 35 LN patients experienced tacrolimus-induced acute renal dysfunction. 3. The average annual C12h of tacrolimus was higher for patients with events of elevated serum creatinine level than for patients not experiencing these events [6.4 (5.6-8.8) versus 2.8 (2.2-4.6) ng/mL, respectively, p=0.001]. 4. The average annual tacrolimus C12h was higher for patients with CYP3A5*3/*3 (PM) than for patients with the CYP3A5*1 allele (EM) [4.6 (3.2-6.6) versus 2.5 (2.0-3.1) ng/mL, respectively, p=0.002]. 5. The area under the receiver operating characteristic was 0.887, which gave the best sensitivity (80.0%) and specificity (86.7%) at a tacrolimus C12h (average annual C12h or C12h at events) threshold of 5.2 ng/mL. 6. C12h measurements, CYP3A5 genotyping and dose adjustments of tacrolimus should be performed to prevent acute renal dysfunction in LN patients taking tacrolimus once daily.

Topics: Adolescent; Adult; Aged; Area Under Curve; Creatinine; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Lupus Nephritis; Male; Middle Aged; Polymorphism, Genetic; Tacrolimus; Young Adult

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Coloring Agents; Disease Progression; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Peroxidase; Proteinuria; Renal Insufficiency; Tacrolimus; Treatment Outcome

To examine the efficacy and safety of multi-target therapy using tacrolimus (TAC), mycophenolate mofetil (MMF) and a steroid as initial treatment for active lupus nephritis (LN).. We conducted a retrospective analysis of the data of 16 consecutive patients who received the multi-target therapy for active Classes III-V LN at our department. We also compared the outcomes of the multi-target therapy with those of TAC therapy (TAC + steroid), a study of which we had conducted previously in 13 patients with active LN (TAC group).. All the patients treated with multi-target therapy achieved complete remission (CR) (mean, 4.6 ± 3.8 months; range, 1-15 months). The clinical profiles of the patients of the multi-target group were similar to those of the TAC group at baseline, except for a significantly higher level of proteinuria (4.6 ± 2.8 vs. 2.5 ± 2.1 g/gCr, p = 0.033) in the former. The CR rate at 6 months was significantly higher in the multi-target group as compared with that in the TAC group (81% vs. 38%, p = 0.018). Two cases of serious adverse events were associated with cytomegalovirus infection in the multi-target group, namely gastric ulcer and pancytopenia, both of which were successfully treated by antiviral therapy.. Multi-target therapy was effective as initial treatment for active LN, with CR achieved early and in a high percentage of patients. Although this therapy was generally well tolerated, it is important to bear in mind the associated risk of cytomegalovirus infection.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

A 57-year old male patient was admitted to our hospital because of severe vomiting and abdominal pain with massive ascites. He had been diagnosed as mixed connective tissue disease in 1997 and lupus nephritis ISN III (A/C) + V in 2003. Treatment was started with intravenous steroid pulse therapy combined with an immunosuppressant resulting in improvement of his proteinuria and serological activity. In 2008, the disease activity flared and he was admitted to our hospital with nephrotic syndrome. Hemodialysis was unavoidable, despite treatment with intravenous steroid pulse therapy and plasma exchange. We continued to treat him with oral prednisolone and tacrolimus. However, for personal reasons, he terminated tacrolimus treatment and massive ascites remained because of insufficient hemodialysis. Since the end of 2011, he suffered repeated abdominal pain with ileus and encapsulating peritoneal sclerosis (EPS) was detected. In February 2013, he underwent synechotomy for EPS. Here, we present a rare case of EPS in a hemodialysis patient.

Topics: Ascites; Chronic Disease; Digestive System Surgical Procedures; Humans; Ileus; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mixed Connective Tissue Disease; Peritoneal Fibrosis; Prednisolone; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed

Lupus nephritis during pregnancy increases morbidity and mortality for mother and baby. Flares are difficult to treat as many therapeutic options are teratogenic or fetotoxic. Steroids alone may be unable to control disease activity and are associated with higher rates of preterm delivery, sepsis and gestational diabetes. Reports of using tacrolimus to treat lupus nephritis in pregnancy are limited. We describe the pregnancies of nine women in whom tacrolimus was successfully used to treat lupus nephritis flare (six patients) or maintain stable disease (three patients). Introduction or dose escalation of oral steroids was avoided in five of the patients who developed active disease and steroid dose was rapidly reduced in the sixth patient. All women with disease flare attained partial or complete remission after starting tacrolimus. None of the women on maintenance treatment developed active disease. We propose tacrolimus as an effective adjuvant or alternative therapy to steroids for treating lupus nephritis flare or maintaining stable disease during pregnancy.

Topics: Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Pregnancy; Pregnancy Complications; Tacrolimus; Treatment Outcome

Calcineurin inhibitors are effective immunosuppressants. They also reduce proteinuria in glomerular diseases but are potentially nephrotoxic. Short-term data suggest that tacrolimus (TAC) combined with corticosteroids is effective in LN, but long-term data are lacking. This study examined the long-term outcomes and tolerability of TAC for the treatment of LN.. We retrospectively reviewed 29 LN patients who received TAC treatment for 46.9 months (s.d. 37.9).. In 17 patients with class III/IV or V LN and persistent proteinuria >2 g/day despite induction immunosuppression, response rates after 12 and 24 months of add-on TAC treatment were 66.7% and 80.0%, respectively. In 10 patients with nephrotic syndrome due to class V LN who were given prednisolone and TAC as initial treatment, the response rate was 60.0% and 90.0% after 12 and 24 months, respectively. TAC facilitated steroid minimization in two patients with lupus podocytopathy. As a group, proteinuria decreased from 3.6 g/day (s.d. 2.6) to 1.0 (s.d. 1.1) (P < 0.05). Four patients developed end-stage renal failure, with 3-, 5- and 8-year renal survival rates of 93%, 83% and 83%, respectively. In the remaining patients, serum creatinine and estimated GFR remained stable after 36 months. One patient with pre-existing chronic renal failure developed TAC nephrotoxicity. Four renal flares occurred, all associated with low TAC blood levels. Six patients (20.1%) had deterioration of hypertension and one patient (3.4%) had new-onset diabetes mellitus. Six patients (20.1%) had infections that required hospitalization. Two deaths occurred: one due to pneumonia and one to breast cancer.. The results suggest efficacy of TAC in LN, especially in reducing proteinuria, and its role as a long-term maintenance agent warrants further investigation.

Topics: Adult; Creatinine; Drug Evaluation; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Prednisolone; Proteinuria; Retrospective Studies; Tacrolimus; Treatment Outcome

A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi-target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN.

Topics: Adolescent; Antihypertensive Agents; Biphenyl Compounds; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Infusions, Intravenous; Irbesartan; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Pulse Therapy, Drug; Recurrence; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tetrazoles

The objective of this paper is to evaluate the efficacy of combined mycophenolate mofetil (MMF) and tacrolimus (TAC) for lupus nephritis with suboptimal response to standard therapy.. Inclusion criteria for patients: (1) biopsy-confirmed active lupus nephritis; and (2) inadequate response to ≥ 2 immunosuppressive regimens. While prednisolone (≤ 10 mg/day) and angiotensin-converting enzyme inhibitors were continued, immunosuppressive agents were replaced by combined MMF (1 g/day) and TAC (4 mg/day). Patients were followed every 2 months for the clinical response and adverse events at 12 months.. Twenty-one patients were recruited (20 women; age 35.8 ± 9.2 years; systemic lupus erythematosus (SLE) duration 111 ± 51 months). The histological classes of lupus nephritis were: IV/III (33%), V+III/IV (33%) and pure V (33%). The creatinine clearance (CrCl), urine protein-to-creatinine ratio (uP/Cr) and serum albumin was 82.4 ± 33 ml/min (<90 ml/min in 57%), 3.27 ± 1.5 and 30.1 ± 5.9 g/l, respectively. Thirteen (62%) patients had active urinary sediments and 17 (81%) patients had active lupus serology. At 12 months, eight (38%) patients had very good response, one (5%) patient had good response and five (24%) patients had partial response. Significant improvement in uP/Cr, albumin, complement C3 and anti-dsDNA titer, and stabilization of CrCl was observed in the responders. Thirty-three adverse events were reported in 18 patients: major infection requiring hospitalization (6%), infection not requiring hospitalization (27%), herpes infection (9%), diarrhea (12%), cramps (9%), dyspepsia (6%), transient increase in serum Cr (6%), alopecia (4%), facial twitching (3%), tremor (3%) and diabetes mellitus (3%). None of these had led to protocol withdrawal.. Combined low-dose MMF and TAC is an option for lupus nephritis that fails to respond adequately to standard regimens, with two-thirds of patients improving after 12 months. Longer-term observation is needed to confirm its efficacy and safety.

Topics: Adult; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Serum Albumin; T-Lymphocytes; Tacrolimus

Standard treatment for class III, IV, and V lupus nephritis (LN) is a combination of oral corticosteroids and mycophenolate mofetil (MMF). There is an estimated failure rate of 16%. Several small studies have looked at the use of tacrolimus in class III, IV, and V LN, both as induction treatment and as maintenance in patients refractory to other treatments. The majority of these studies were conducted in Asian patients. We discuss a cohort of eight female patients of various ethnicities with biopsy proven LN. All patients were evaluated retrospectively. Six were started on tacrolimus after failing to respond to MMF and corticosteroids, and one was started on tacrolimus alone because treatment options were limited by pregnancy. Five were Caucasian, one African American, one Hispanic, and one Vietnamese. Mean tacrolimus dose was 3.3mg daily (range 2-5 mg) titrated to a mean level of 3-6 ng/dl (range 3-6.6 ng/dl) for a mean of duration of 16 months (range 2-54 months). Six patients experienced complete remission (proteinuria <0.33 g/day), and two patients had a partial remission (minimum of 50% reduction in baseline proteinuria). Albumin increased an average of 32%. Average C3/C4 levels were 64/15 mg/dL, respectively, prior to treatment, and 95/25 mg/dL following treatment. No treatment-limiting adverse effects were reported. Our case series supports the growing body of evidence that tacrolimus is an effective therapy in LN patients with refractory proteinuria. Further studies are required to establish the long-term safety and efficacy of tacrolimus.

Topics: Adult; Female; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Retrospective Studies; Tacrolimus; Young Adult

A 37-year-old female patient was admitted for evaluation of nephrotic proteinuria refractory to prednisolone and other immunosuppressants in 2004. On admission, urinary protein loss was 16 g/d. Anti-ds DNA antibody was positive and hypocomplementemia was detected. Renal biopsy revealed membranous lupus nephritis. Because 5 cyclophosphamide pulse therapies did not have an effect, tacrolimus was started at 3 mg daily. Proteinuria decreased to 4.8 g/d after 5 months and was < 0.1 g/d in 2009, but antids DNA antibody remained positive and hypocomplementemia persisted. Repeat renal biopsy revealed thinning of the glomerular capillary walls and disappearance of subepithelial electron-dense deposits. However, the subendothelial and mesangial deposits were unchanged. In this patient, proteinuria refractory to various immunosuppressants including cyclosporine A improved after administration of tacrolimus, and selective disappearance of subepithelial deposits was seen histologically. This is the first histological evidence that tacrolimus therapy may cause removal of subepithelial deposits, which are separated from the circulation by the glomerular basement membrane. This finding is supported by experimental data that tacrolimus selectively block the binding of FK-binding protein 12 to transient receptor potential-cation channel 6, resulting in normalization of affected podocytes.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus

Both itraconazole (ITCZ) and voriconazole (VCZ) are potent inhibitors of cytochrome P450 (CYP) 3A, and their effects have been reported to be equal. However, ITCZ is metabolized by CYP3A, whereas VCZ is mainly metabolized by CYP2C9 and CYP2C19 and only partially by CYP3A. We experienced the case of a patient who showed a 5-fold increase in trough levels of tacrolimus (FK) level after switching from ITCZ to VCZ. Our objective is to discuss the mechanism of the increase drug-drug interaction in terms of serum concentration of the azole drugs and patient pharmacogenomics.. A 53-year-old woman was treated with FK (1 mg/day) for lupus nephritis. Because fungal infection was suspected, she received ITCZ (100 mg/day). When ITCZ was replaced with VCZ (400 mg/day), the blood concentration of FK increased markedly from 6·1 to 34·2 ng/mL. During coadministration with FK, the levels of ITCZ and VCZ were 135·5 ng/mL and 5·5 μg/mL, respectively, with the VCZ level around 3-fold higher than the previously reported level (1·4-1·8 μg/mL). Her CYP genotypes were CYP2C19*1/*2, CYP3A4*1/*1 and CYP3A5*3/*3.. The patient was a CYP2C19 intermediate metabolizer (IM) and deficient in CYP3A5. The increase in plasma VCZ level appears to have been at least in part, associated with the CYP2C19 IM phenotype. One possible explanation for the marked increase in blood FK concentration was increased inhibition of CYP3A because of the impaired metabolism and subsequent increased plasma concentration of VCZ. This case shows that the severity of drug interactions may be influenced by metabolic gene polymorphism.

Topics: Antifungal Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Drug Interactions; Female; Genotype; Humans; Immunosuppressive Agents; Itraconazole; Lupus Nephritis; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.. We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.. All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.. This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

Topics: Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Middle Aged; Pilot Projects; Prednisolone; Proteinuria; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

Treatment of lupus nephritis (LN) with cyclophosphamide (CYC) is effective but retains a certain severe adverse effect. Tacrolimus (TAC) may be a suitable treatment for LN. Forty patients with diffuse proliferative or membranous LN were recruited for this non-randomized open-label study - 67.5% (27/40) had nephrotic proteinuria (>3.5 g/day) and 50.0% (20/40) had low estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73m(2)). We compared the efficacy and adverse effects of TAC (0.04-0.08 mg/kg/d)/prednisone for 12 months (TAC group, n = 20) with intravenous CYC (750 mg/m(2) per month)/prednisone for six months followed by azathioprine (Aza) (100 mg/day)/prednisone for six months (CYC group, n = 20). The TAC target concentration was 6-8 ng/mL or 4-6 ng/mL, respectively, when induction or maintenance therapy was required and 4.0 ng/mL for patient with renal insufficiency. In the TAC group, mean urinary protein excretion decreased significantly from 5.00 ± 1.91 g/day at baseline to 2.54 ± 1.68 g/day after two weeks of therapy (P < 0.001), compared with the CYC group (4.9 ± 19.4 g/day), P = 0.001, and 65.0% (13/20) achieved partial remission at one month, compared with the CYC group (0/20), P < 0.001. The incidence of complete remission (CR) was significantly higher in the TAC group than in the CYC group (55.0% vs.15.0% by five months, P = 0.008, and 75.0% vs.40.0% by 12 months, P = 0.025, respectively). The significant improvement in serum anti-dsDNA and systemic lupus erythematosus (SLE) disease activity index (DAI) was in the TAC group relative to the CYC group at 12 months (P = 0.031, P = 0.003, respectively). The eGFR improved in the TAC group from 59.90 ± 23.64 mL/min/1.73m(2) at baseline to 93.75 ± 28.52 mL/min/1.73m(2) after 12 months, P = 0.001. In the CYC group, two patients developed end-stage renal disease (ESRD), three patients experienced serious pneumonia, and one patient died. Our preliminary study showed TAC is a safe and effective treatment for LN with severe renal disease, and with less-severe adverse events compared with CYC followed Aza therapy. Further larger sample studies are needed to confirm our conclusion.

Topics: Adolescent; Adult; Cohort Studies; Cyclophosphamide; Female; Glomerular Filtration Rate; Humans; Lupus Nephritis; Male; Middle Aged; Prospective Studies; Tacrolimus

Topics: Azathioprine; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Tacrolimus

Proliferation signal inhibitors (PSI) have demonstrated efficacy in prevention and treatment in an animal model of lupus nephritis (LN) but there are no data regarding the use of PSI in human LN. We report here our experience of using PSI treatment in seven patients with severe proliferative lupus nephritis.. This is a retrospective study on patients with proliferative lupus nephritis who had received PSI treatment.. Seven patients were included. Two patients had concomitant membranous lupus nephropathy. The indications for PSI included mycophenolate mofetil intolerance (n = 4), history of malignancy (n = 2) and leucopoenia (n = 1). Five patients were given PSI when disease was active. Two had treatment discontinued because of acute cholecystitis and leucopoenia, respectively. In the other three patients combined steroid and PSI treatment as induction therapy led to improvements in serology, renal function and proteinuria. In two patients treated with PSI and low-dose steroid as maintenance immunosuppression, both maintained stable lupus serology, renal function and proteinuria over 18 months. Side-effects included dyslipidemia and oral ulcers.. Proliferation signal inhibitors warrants further investigation as an alternative immunosuppressive treatment in lupus nephritis.

Topics: Adrenal Cortex Hormones; Adult; Cell Proliferation; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Severity of Illness Index; Signal Transduction; Sirolimus; Tacrolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Adolescent; Drug Therapy, Combination; Female; Humans; Lupus Nephritis; Prednisolone; Ribonucleosides; Tacrolimus

The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Time Factors; Treatment Outcome

Systemic lupus erythematosus (SLE) is one of the common autoimmune disorders that affect women during their childbearing years. Disease activity frequently increases during pregnancy and the postpartum period, representing a challenge for both the patient and the treating physician(s). We report a case of successful management of lupus nephritis flare in the first trimester. The patient developed bilateral leg edema and nephrotic-range proteinuria of 5 g/day. She was treated with steroids and tacrolimus, which resulted in the induction of remission during pregnancy. The patient reached full-term with no maternal or fetal complications. This case indicates that tacrolimus, which is convenient to use and has limited adverse effects, may represent a potential safe and effective treatment option for SLE nephritis during pregnancy.

Topics: Adult; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Live Birth; Lupus Nephritis; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Tacrolimus; Term Birth

After the completion of a double-blind placebo-controlled trial, tacrolimus (TAC) was approved for the treatment of lupus nephritis (LN) in Japan. However, the approved maximal dose, 3 mg/day, is almost half the dose used for induction therapy outside Japan. In this study, we retrospectively evaluated the efficacy and safety of low-dose TAC (≤3 mg/day) for induction therapy in 13 adult patients (2 men and 11 women) with active LN. Eight patients were treated for LN flares. Twelve patients underwent renal biopsies: 8 with class IV, 2 with class III + V, 1 with class IV + V, and 1 with class V renal histology, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. The mean initial doses of prednisone and TAC were 34.6 ± 14.5 and 2.7 ± 0.6 mg/day, respectively. All the patients achieved a complete remission (CR) at 7.7 ± 6.7 months (mean ± SD) after the last administration of TAC, except for 2 patients who discontinued TAC treatment; 1 because of worsening systemic lupus erythematosus and 1 because of hypertension. Two patients experienced a flare-up after achieving CR. The mean blood TAC concentration 12 h after the last administration (C12) was significantly lower among the patients with flare-ups than among those with a sustained CR (1.5 ± 1.5 vs. 5.1 ± 1.9 ng/mL, P = 0.034). These data showed that low-dose TAC was effective for induction therapy in patients with active LN, although a lower TAC concentration may be associated with a poor outcome.

Topics: Adrenal Cortex Hormones; Adult; Angiotensin II Type 1 Receptor Blockers; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus

The pharmacokinetics of orally administered tacrolimus were examined in six female lupus nephritis patients (mean age 43 years, range 24-55 years). Tacrolimus (3 mg) was administered after supper, and blood tacrolimus concentrations were measured just prior to dosing and 1, 2, 4, 6, 8, 12 and 24 h after administration. The maximum blood concentration (C(max)) was observed 4-8 h (mean: 6.7 h) after administration. The mean C(max) and area under the tacrolimus concentrationti-me curve (AUC(0-24 h)) were 12.7 ng/ml and 163.1 ng x h/ml, respectively. Although there was a weak correlation between AUC(0-24 h) values and tacrolimus concentrations 2, 4, and 6 h after administration, concentrations at 12 h and 24 h were highly correlated with AUC(0-24 h) values, suggesting that the trough concentration (C(24 h)) and C(12 h) are valid markers for therapeutic tacrolimus monitoring. Enzyme-linked immunoabsorbent assay (ELISA) and microparticle enzyme immunoassay (MEIA) measurements of blood tacrolimus concentrations were similar. We recommend that monitoring should be carried out by C(12 h) in lupus nephritis outpatients.

Topics: Administration, Oral; Adult; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus; Time Factors; Young Adult

A 43-year-old Japanese woman with systemic lupus erythematosus (SLE) developed rapidly progressive renal failure and nephritic syndrome with a high titer of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). Methylprednisolone pulse therapy did not suppress the progression of renal failure. Intravenous cyclophosphamide pulse therapy and administration of azathioprine was abandoned due to adverse effects. Tacrolimus was employed as an alternative immunosuppressive therapy and was well tolerated, effectively preventing renal failure. Oral prednisolone dosage was successfully tapered without recurrence, along with decreasing titer of MPO-ANCA. Renal biopsy showed diffuse proliferative lupus nephritis (International Society of Nephrology/Renal Pathology Society class IV-G A/C) with crescent formation. These findings indicate that in addition to lupus nephritis, which usually results from deposition of circulating or locally formed immune complexes, MPO-ANCA may be involved in the pathogenesis of crescentic glomerulonephritis. Furthermore, we propose that tacrolimus is an effective immunosuppressant for MPO-ANCA-related renal crisis in diffuse proliferative lupus nephritis.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Peroxidase; Tacrolimus; Treatment Outcome

Since most lupus nephritis patients have an incomplete response to mycophenolate mofetil, combination regimens may improve outcomes. Tacrolimus (FK506) has shown some benefit in lupus nephritis in small trials, and combined with mycophenolate mofetil is standard immunosuppression in transplant patients. We investigate the addition of FK506 to mycophenolate mofetil, in patients who were mycophenolate mofetil failures. All patients were part of a prospective cohort, but evaluated retrospectively. Seven lupus nephritis patients (mean age 27.1, 100% female, 42% Caucasian and 42% African American) were evaluated. Three patients had combined ISN class III and V, two ISN class IV, one ISN class V and II and one ISN class IV and V. Six were taking an ACE-inhibitor or angiotensin receptor blocker, 6 hydroxychloroquine and 5 prednisone (mean dose 11.5 mg; range 0-30 mg). Mean mycophenolate mofetil dose at time of tacrolimus addition was 2.8 g (range 2-3 g). Mean tacrolimus dose was 3.4 mg (range 2-8 mg) titrated to a mean level of 4.67 ng/dl (range 2.2-11.8 ng/dl) for a mean of duration of 16 months (range 2-54 months). Two patients continued both therapies, while five discontinued therapy. One patient achieved a complete renal remission, while three achieved partial remission with 82.9%, 77.1%, 55.3% reductions in proteinuria. Toxicity limited the use of combination therapy: diabetic ketoacidosis (one patient), pneumonia (two) and muscle pain (two). These data suggest that adding tacrolimus in patients refractory to mycophenolate mofetil might have some benefit, although complete responses were rare. Unfortunately, tacrolimus toxicity appeared to be prevalent in these systemic lupus erythematosus patients, limiting its long term use.

Topics: Adult; Cohort Studies; Drug Resistance; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Prospective Studies; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Failure; Treatment Outcome; Young Adult

Although mycophenolate mofetil (MMF) is being increasingly used to manage lupus nephritis (LN), long-term experience is limited. Despite treatment, a significant proportion of patients will be refractory to this regime.. We report, in this observational study, our long-term experience treating 70 patients with biopsy-proven LN, with MMF as continuous induction-maintenance therapy, who were followed up prospectively over a 5-year period. As rescue therapy for MMF-resistant cases, tacrolimus (0.075 mg/kg/day) was added. The study primary end point was complete response (CR). Secondary end points included partial response (PR), treatment failure, relapse and side effects. Predictor factors associated to renal outcome were analysed by Cox regression analysis.. Thirty-six MMF-treated patients (51%) remained in CR, and 23 (33%) failed treatment at last follow-up. Time to treatment failure was associated with persistent hypoalbuminaemia (hazard ratio (HR) = 0.87; 95%CI, 0.81-0.95; P = 0.001), higher proteinuria (HR = 1.29; 95%CI, 1.03-1.62; P = 0.030) and fewer early responses (HR 0.28; 95%CI, 0.10-0.77; P = 0.014). Renal relapse occurred in 24 (34%) patients. Time to flare was associated with persistent anti-dsDNA titres (HR = 1.001; 95%CI, 1.001-1.003; P = 0.005) and younger age at inclusion (HR = 0.36; 95%CI, 0.14-0.90; P = 0.029). Tacrolimus was added to 17 (24%) patients. A significant reduction of proteinuria was already observed at 3 months (P = 0.002). After 2 years follow-up, 12 (70%) of them achieved clinical response (six CR and six PR). Conclusions. MMF is an effective treatment for LN. Combination therapy with tacrolimus is an effective and safe alternative for MMF-resistant patients.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Longitudinal Studies; Lupus Nephritis; Male; Mycophenolic Acid; Prospective Studies; Regression Analysis; Tacrolimus; Treatment Outcome

The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE.. We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months.. Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group.. A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Topics: Adult; Case-Control Studies; Chi-Square Distribution; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prednisolone; Recurrence; Tacrolimus; Treatment Outcome

Topics: Drug Therapy, Combination; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus; Treatment Outcome

A 55-year-old woman developed bilateral leg edema in June 2006. Since the edema tended to worsen, she visited our hospital on November 11. Laboratory tests showed a serum albumin level of 2.5 g/dl with 3+ proteinuria, and suggested nephrotic syndrome, which led to her hospitalization on November 14. The findings of discoid erythema, an antinuclear antibody titer of 1: 640, anti-ds DNA antibody titer of 16.8 IU/ml, and ISN/RPS class III (A/C)+V lupus nephritis on kidney biopsy led to the diagnosis of systemic lupus erythematosus. Treatment with prednisolone at 1 mg/kg/day was initiated. Despite an increase in complement levels and decreases in anti-ds DNA antibody titers and immune complexes, proteinuria persisted; therefore, the patient was concomitantly given 125 mg/day of azathioprine, which was discontinued because of the poor improvement of proteinuria and development of myelosuppression, and replaced by 3 mg/day of tacrolimus (Tac), with a consequent marked improvement in proteinuria. We report a patient with refractory proteinuria due to class III/V lupus nephritis who achieved a Tac-induced complete remission.

Topics: Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Middle Aged; Tacrolimus

Persistent proteinuria in patients with quiescent lupus can result from membranous lupus nephritis and/or glomerular scarring following previous flares. This pilot study examined the effects of tacrolimus over two years in six patients with membranous/inactive lupus nephritis and persistent proteinuria despite angiotensin inhibition/blockade. Tacrolimus treatment reduced proteinuria and increased serum albumin (time effect, P = 0.047 and 0.032 respectively). Compared with baseline levels, proteinuria improved by more than 50% in five patients (83.3%) and hypoalbuminaemia was corrected in four patients. The efficacy was most prominent in four patients with biopsy-proven membranous lupus nephritis, whose protienuria improved by over 80%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment, despite non-excessive blood levels. These data suggest that tacrolimus is an effective treatment for proteinuria due to membranous lupus nephritis, but should probably be reserved for patients who are refractory to other non-nephrotoxic treatments, in view of the potential risk of subclinical nephrotoxicity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Antinuclear; Autoantigens; Blood Glucose; Blood Pressure; Complement C3; Creatinine; DNA; Drug Evaluation; Drug Resistance; Female; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Diseases; Lipids; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Proteinuria; Retrospective Studies; Serum Albumin; Tacrolimus; Treatment Outcome

A 22-year-old woman hospitalized for polyarthralgia was diagnosed with systemic lupus erythematosus (SLE). She was treated with prednisolone, and her clinical manifestations improved. However, she was re-admitted for renal biopsy because of persistent hypocomplementemia and development of proteinuria. The biopsy revealed segmental spike formation of basement membrane and subepithelial immune complex deposition, and membranous lupus nephritis (class V) was diagnosed. When tacrolimus was added to prednisolone, the serum complement titer quickly improved and proteinuria disappeared after about 11 months. Nevertheless, when tacrolimus was replaced examination showed cyclosporine due to gastrointestinal symptoms, she complained about arthralgia. Examination showed drop in the serum complement titer and recurrence of proteinuria. Renal biopsy at the time of recurrence showed increased subepithelial immune complex deposition in the capillary loops as compared to the first biopsy, a high degree of thickening of the basement membrane, and segmental circumferential interposition in some of the glomeruli. Membranous lupus nephritis (classes V + III) was diagnosed. By changing to tacrolimus and higher doses of steroids, the serum complement titer improved and proteinuria disappeared. This case indicates that tacrolimus can be an effective therapeutic agent for membranous lupus nephritis.

Topics: Adult; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus; Treatment Outcome

To investigate the significance of the calcineurin (CaN) activation in active lupus nephritis patient.. Peripheral blood mononuclear cells (PBMCs) were separated from twenty-one active LN patients and 12 healthy controls. Phosphatase activity of CaN was determined using the CaN assay kit by measuring the content of released PO4. Reverse transcription-PCR was used to detect the expression of CD40L mRNA. Flow cytometry analysis was used to detect the expression of CD40L in LN PBMC.. (1) Increased activation of CaN in spontaneous cultured PBMC in active LN group was found as compared with control group (46.08 +/- 5.58 vs 8.81 +/- 3.61, P < 0.01). In stimulated by PMA/Ionomycin , activity of CaN in active LN group was also higher than that of control (69.34 +/- 12.59 vs 37.12 +/- 11.57, P < 0.01). (2) Relative content of CD40L in PBMC in active LN groups increased significantly as compared with the control groups under spontaneous and PMA/Ionomycin-induced culture, respectively (P < 0.01). (3) FK506 reduced significantly production of CD40L in spontaneous and PMA/Ionomycin-induced PBMC of LN.. Elevated activation of CaN in active LN may participate in regulation overexpression of CD40L in PBMC of LN. Through inhibiting CaN activity, FK506 may prevent abnormal activation of CD40-CD40L costimulatory pathway in lupus nephritis.

Topics: Adolescent; Adult; Calcineurin; Case-Control Studies; CD40 Ligand; Cells, Cultured; Female; Humans; Leukocytes, Mononuclear; Lupus Nephritis; Male; Middle Aged; Tacrolimus; Young Adult

There is only limited experience in patients with systemic lupus erythematosus (SLE) with drugs that have developed for immunosuppression after organ transplantation, namely calcineurin inhibitors (CI). The aim of this study is to determine the effect of these drugs on disease activity after kidney transplant in patients affected by SLE.. Between January 1990 to March 2003, 13 patients with end- stage renal disease secondary to SLE received 14 kidney transplants. The outcome variables assessed include graft and patient survival as well as clinical and serological lupus activity.. All received CI-based immunosuppression (cyclosporine or tacrolimus). Actuarial patient and graft survivals at 5 yr were 100 and 93%, respectively. Recurrence of clinical or serological disease was never detected.. To date, only anecdotal experience with CI in the treatment of SLE has been reported. The favorable response observed in our patients suggests that CI at low-doses are effective in preventing SLE-reactivation. Further studies focused on calcineurin inhibitor treatment in SLE patients who fail to respond to standard medical management should be conducted.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Secondary Prevention; Severity of Illness Index; Tacrolimus

The T-helper 1/T-helper 2 (Th1/Th2) cell balance was examined in 6-month-old New Zealand black/white F1 (B/WF1) mice treated with an immunosuppressive agent, FK506. The survival rate of mice treated with 10 mg/kg/day of FK506 was 7/8, while that of those treated with 2.5 mg/kg/day was 5/8, and 4/8 after treatment for 8 weeks with placebo. Proteinuria, which was already positive in all mice before the treatment, in the seven of eight mice treated with 10 mg/kg/day remained mildly positive (< or = 1+), while seven of eight mice treated with 2.5 mg/kg/day and six of eight mice treated with the placebo showed severe proteinuria (> or = 2+). Pathological changes in the kidneys of mice treated with 10 mg/kg/day of FK506 were less severe than in mice treated with the placebo or 2.5 mg/kg/day of FK506. Expression of mRNA was unchanged for all cytokines determined in the groups treated with 2.5 mg/kg/day of FK506 or placebo. In contrast, expression of mRNA for interleukin (IL)-2, and interferon (IFN)-gamma was suppressed, while that for IL-4 and IL-10 was not suppressed in the group treated with 10 mg/kg of FK506. The serum levels of IgG-class anti-DNA antibodies, which had been elevated before the treatment, were suppressed--especially in the IgG2a subclass--and the deposition of IgG2a and IgG2b in the glomeruli was reduced in the group treated with 10 mg/kg/day of FK506 compared with the other groups. These findings suggest that an improvement in the lupus nephritis of 6-month-old B/WF1 mice induced by FK506 might be associated with a predominant inhibition of Th1 cytokine.

Topics: Animals; Antibodies, Antinuclear; Base Sequence; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Lupus Nephritis; Lymphocyte Count; Male; Mice; Mice, Inbred NZB; Molecular Sequence Data; Probability; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Survival Rate; Tacrolimus; Th1 Cells

To explore the expression of IL-18 in patients with active lupus nephritis(LN) and the inhibitory effects of immunosupressive agents FK506, cyclosporin A (CsA) and dexamethasone(DEX).. Peripheral blood samples were collected from 16 LN patients and 10 health volunteers and cultured with or without PHA/LPS, PHA/LPS+FK506, PHA/LPS+CsA and PHA/LPS+DEX for 24 hours. The IL-18 level in cultured supernatants and the IL-18 mRNA expression in cultured whole blood cells were detected by ELISA and semi-quantitative RT-PCR respectively, and the inhibitory effects of FK506, CsA and DEX on IL-18 expression were investigated.. The expression levels of IL-18 mRNA and its protein in whole blood cell cultures from LN patients were higher than those in normal control group (P<0.01) either spontaneously or after stimulation with LPS/PHA. FK506, CsA and DEX suppressed significantly the expressions of IL-18 mRNA and its protein (P<0.001) in LPS/PHA-stimulated whole blood cell from LN patients. The inhibitory effects of FK506, CsA and DEX on the IL-18 protein expression in LN patients were stronger than that in normal control group (P<0.01 or P<0.05).. IL-18 may play an important role in the pathogenesis of LN and inhibition of IL-18 production may be an useful way to treat LN.

Topics: Adolescent; Adult; Cells, Cultured; Cyclosporine; Dexamethasone; Female; Humans; Immunosuppressive Agents; Interleukin-18; Lupus Nephritis; Male; RNA, Messenger; Tacrolimus

Topics: Adult; Ceftriaxone; Epilepsies, Myoclonic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Postoperative Complications; Risk Assessment; Tacrolimus; Tomography, X-Ray Computed; Transplantation Immunology; Treatment Outcome

The development of thrombotic microangiopathy (TMA) associated with the use of cyclosporine has been well documented. Treatments have included discontinuation or reduction of cyclosporine dose with or without concurrent plasma exchange, plasma infusion, anticoagulation, and intravenous immunoglobulin G infusion. However, for recipients of organ transplantation, removing the inciting agent is not without the attendant risk of precipitating acute rejection and graft loss. The last decade has seen the emergence of tacrolimus as a potent immunosuppressive agent with mechanisms of action virtually identical to those of cyclosporine. As a result, switching to tacrolimus has been reported to be a viable therapeutic option in the setting of cyclosporine-induced TMA. With the more widespread application of tacrolimus in organ transplantation, tacrolimus-associated TMA has also been recognized. However, literature regarding the incidence of the recurrence of TMA in patients exposed sequentially to cyclosporine and tacrolimus is limited. We report a case of a living donor renal transplant recipient who developed cyclosporine-induced TMA that responded to the withdrawal of cyclosporine in conjunction with plasmapheresis and fresh frozen plasma replacement therapy. Introduction of tacrolimus as an alternative immunosuppressive agent resulted in the recurrence of TMA and the subsequent loss of the renal allograft. Patients who are switched from cyclosporine to tacrolimus or vice versa should be closely monitored for the signs and symptoms of recurrent TMA.

Topics: Adult; Colon; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Microcirculation; Tacrolimus; Thrombosis

FKBP52 (FKBP59, FKBP4) is a "macro" immunophilin that, although sharing high structural and functional homologies in its amino-terminal domain with FKBP12 (FKBP1), does not have immunosuppressant activity when complexed with FK506, unlike FKBP12. To investigate the physiological function of FKBP52, we used the yeast two-hybrid system as an approach to find its potential protein partners and, from that, its cellular role. This methodology, which already has allowed us to find the FK506-binding protein (FKBP)-associated protein FAP48, also led to the detection of another FKBP-associated protein. Determination of the sequence of this protein permitted its identification as phytanoyl-CoA alpha-hydroxylase (PAHX), a peroxisomal enzyme that so far was unknown as an FKBP-associated protein. Inactivation of this enzyme is responsible for Refsum disease in humans. The protein also corresponds to the mouse protein LN1, which could be involved in the progress of lupus nephritis. We show here that PAHX has the physical capacity to interact with the FKBP12-like domain of FKBP52, but not with FKBP12, suggesting that it is a particular and specific target of FKBP52. Whereas the binding of calcineurin to FKBP12 is potentiated by FK506, the specific association of PAHX and FKBP52 is maintained in the presence of FK506. This observation suggests that PAHX is a serious candidate for studying the cellular signaling pathway(s) involving FKBP52 in the presence of immunosuppressant drugs.

Topics: Animals; Base Sequence; Cloning, Molecular; DNA Primers; Gene Library; Humans; Immunophilins; Jurkat Cells; Lupus Nephritis; Mice; Microbodies; Mixed Function Oxygenases; Molecular Sequence Data; Polymerase Chain Reaction; Recombinant Fusion Proteins; Recombinant Proteins; Refsum Disease; Saccharomyces cerevisiae; Tacrolimus; Tacrolimus Binding Proteins

We evaluated the effect of the novel immunosuppressive agent, FK506, which is known to inhibit T cell immunity, on the development of lupus nephritis in MRL/MpJ-lpr/lpr (MRL/l) mice. FK506 was administered subcutaneously (1 mg/kg body weight) from 12 to 20 weeks of age in 13 MRL/l mice with spontaneous lupus nephritis. Nine animals receiving no treatment were used as the control. FK506 significantly reduced the development of proteinuria, lowered the level of BUN, and suppressed the elevation of serum anti-dsDNA antibodies. Histopathological study showed that FK506 significantly inhibited the progression of glomerular hypercellularity and crescent formation. Glomerular deposition of C3 was significantly reduced in the FK506-treated mice compared to the nontreated controls. These findings suggest that FK506 may protect against progression of lupus nephritis in MRL/l mice, an animal model of systemic lupus erythematosus.

Topics: Animals; Blood Urea Nitrogen; Female; Fluorescent Antibody Technique; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred Strains; Organ Size; Proteinuria; Spleen; Tacrolimus

A newly developed immunosuppressive drug, FK506 (Fujisawa, Japan) is known to inhibit T-cell immunity. We have evaluated the action of this compound in MRL/lpr mice which develop a severe autoimmune disease. Eight-week-old female MRL/lpr of mice were treated subcutaneously with 2 mg/kg (high dose), 0.8 mg/kg (medium dose), 0.2 mg/kg (low dose) or solvent only (control) six times per week. Survival times of the mice were prolonged in the medium and the high dose treatment groups. The lymph node swelling was dramatically prevented with the high dose treatment. The increasing footpad swelling seemed to be also suppressed with the treatment. FACS analyses of the spleen cells revealed that FK506 reduced the percentage of double negative T cells (Thy-1.2+, Lyt-2-, L3T4-). Serological studies showed that anti-ssDNA and anti-dsDNA activities were significantly reduced by the high dose treatment, which is different from recent findings with Cyclosporine A. The high dose treatment also suppressed the total amount of IgG, even though the IgG concentration was rather increased by the medium dose treatment. Decreased proteinuria as well as pathological evaluations of the kidneys and lungs indicated that there were marked ameliorations in these organs with the treatment. These results suggest that FK506 could be potentially used for the treatment of autoimmune diseases.

Topics: Animals; Anti-Bacterial Agents; Arthritis; Autoimmune Diseases; Female; Immunoglobulin G; Immunosuppressive Agents; Lupus Nephritis; Lymphatic Diseases; Mice; Mice, Mutant Strains; Pulmonary Fibrosis; T-Lymphocytes; Tacrolimus

A novel immunosuppressive compound extracted from the fermentation broth of Streptomyces tsukubaensis belongs to the macrolide family. We gave this drug (FK-506) to MRL/lpr and NZB X NZW F1 (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE), to investigate its effect on the course of the disease. This drug showed potential to prolong the lifespan, to reduce proteinuria, and to prevent the progression of nephropathy. Appreciable differences in the levels of anti-dsDNA antibodies between treated and control animals were nil.

Topics: Animals; Autoantibodies; DNA; Immunoglobulin G; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Proteinuria; Pyridines; Spleen; Tacrolimus