Long-term data on tacrolimus treatment in lupus nephritis

Yap, Desmond Y H; Maggie, K M; Mok, Maggie M Y; Kwan, Lorraine P Y; Chan, Gcf; Chan, Tak Mao

doi:10.1093/rheumatology/keu265

Cited by 49 publications

(39 citation statements)

References 23 publications

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“…Cyclophosphamide was reserved for patients with severe crescentic features in the kidney biopsy. Calcineurin inhibitors (CNI) were used as second-line treatment in patients who could not tolerate MMF, or as add-on therapy in patients who showed persistent significant proteinuria ( > 2g/D) despite standard therapy for 6 months [37]. Sirolimus was used in patients who could not tolerate standard immunosuppressants or who had a history of malignancy.…”

Section: Methodsmentioning

confidence: 99%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

Yap¹,

Tang²,

Chan³

et al. 2018

Oncotarget

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Our pilot short-term data suggested efficacy of sirolimus treatment in lupus nephritis (LN) patients, but its long-term data remains limited. We retrospectively reviewed 16 Class III/IV/V LN patients who have received prednisolone and sirolimus either as initial or maintenance treatment. Sixteen patients received sirolimus treatment (9 due to intolerance to standard immunosuppressants and 7 due to a history of malignancy) for 45.3 ± 36.5 months. In five patients sirolimus and prednisolone was given as induction for active nephritis, and they showed improvements in proteinuria (2.8 ± 1.9 g/day at baseline, 0.1 ± 0.1 g/day after 36 months, p = 0.011), anti-dsDNA (107.7 ± 91.9 IU/mL and 37.0 ± 55.4 IU/mL respectively, p = 0.178) and C3 (54.8 ± 26.1 mg/dL and 86.3 ± 18.6 mg/dL respectively, p = 0.081). Eleven patients received sirolimus and low-dose prednisolone as long-term maintenance, and they showed continued improvement in C3 (90.4 ± 18.1 mg/dL and 117.7±25.1 mg/dL at commencement and after 36 months respectively, p = 0.025) and stable renal function (eGFR 58.6 ± 25.8 ml/min and 63.0 ± 29.6 mL/min respectively, p = 0.239) and proteinuria (0.8 ± 0.7 g/day and 0.7 ± 0.7 g/day respectively, p = 0.252). Renal flare occurred in one patient and another patient with Stage 4 chronic kidney disease when sirolimus was started developed endstage renal failure after 27 months. Sirolimus was discontinued in five patients, in four cases related to drug sideeffects. Deterioration of dyslipidaemia occurred in four patients, but was adequately controlled with statin therapy. The preliminary evidence suggests that sirolimus may serve as an alternative treatment for LN who do not tolerate standard treatment or had history of malignancy, and with acceptable long-term safety profile.

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Section: Methodsmentioning

confidence: 99%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

Yap¹,

Tang²,

Chan³

et al. 2018

Oncotarget

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“…Notwithstanding these limitations, it is generally agreed that patients with low levels of proteinuria, stable kidney function, low serological activity, no evidence or risk of concomitant severe proliferative features based on clinical judgment and an adequate renal biopsy should be managed with blood pressure control and renin-angiotensin pathway blockade, while patients with nephrotic and/or increasing proteinuria despite conservative management warrant an escalation of immunosuppressive therapy to aim for induction of proteinuria response [38,47]. The latter should be a combination of corticosteroids and any one of the following, CYC, AZA, MPA or a calcineurin inhibitor, and the efficacy of these treatment regimens has been observed in Asian patients [34,48,49,50]. …”

Section: Current Immunosuppressive Treatments For Ln: An Asian Perspementioning

confidence: 99%

“…Therefore, the safety of TAC, especially when given as long-term treatment, in patients with pre-established chronic kidney damage remains to be investigated. We have reported our data on the efficacy of TAC when used as add-on therapy, guided by therapeutic drug level monitoring, in patients with LN who showed persistent significant proteinuria despite treatment with other immunosuppressive agents, and in patients given long-term TAC therapy the renal survival rate at 3, 5 and 8 years was 93, 83 and 83%, respectively [50]. Mok et al [59] reported the outcomes of patients with class III/IV/V LN given corticosteroids and TAC as induction therapy followed by low-dose corticosteroids and AZA maintenance, and the complete remission rate at 6 months was comparable to that for patients treated with corticosteroids and MMF for induction followed by AZA during maintenance (59 vs. 62%; p = 0.71).…”

Section: Emerging Treatments In Asia and Concluding Remarksmentioning

confidence: 99%

“…It should be noted that in this study TAC was given at a standard dose according to body weight, and the dose was reduced when there was a rise in serum creatinine level, without conventional therapeutic drug level monitoring. Although our data showed stable renal function after 46.9 ± 37.9 months of follow-up when the TAC trough blood level was maintained within the range of 4-6 ng/l, the issue of chronic nephrotoxicity of TAC and other calcineurin inhibitors remains a concern with long-term treatment especially in patients with chronic renal impairment due to prior renal scarring [50]. …”

Section: Emerging Treatments In Asia and Concluding Remarksmentioning

confidence: 99%

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Lupus Nephritis in Asia: Clinical Features and Management

Yap

Chan²

2015

Kidney Dis

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Background: Lupus nephritis (LN) is a common and severe organ involvement manifesting itself in systemic lupus erythematosus (SLE). There is a considerable difference in prevalence, severity, treatment response and outcomes between Asian LN patients and LN patients from other racial backgrounds. Summary: Asian SLE patients have a higher prevalence of LN than Caucasian SLE patients and often present with a more severe disease. Increasing data from genetic studies, accompanied by progress in high-throughput genotyping, have advanced our knowledge about genetic predispositions that might partly contribute to the clinical variations observed. Corticosteroids combined with either cyclophosphamide (CYC) or mycophenolic acid (MPA) is the current standard-of-care induction regimen for severe LN irrespective of race or ethnicity. However, the preference for MPA or CYC, and possibly the optimum dose for MPA, is influenced by the patient's origin. Also, there is an insufficient evidence base for reduced-dose intravenous CYC in Asian patients. Health economics and access to prompt diagnosis and treatment are still challenging issues in some Asian regions. The former represents a significant obstacle limiting the access of patients to MPA despite the proven efficacy of the drug as an induction agent and its superiority over azathioprine (AZA) in preventing disease flares when used for long-term maintenance immunosuppression. Calcineurin inhibitors such as tacrolimus deserve further investigation in view of their additional effect on podocytes by reducing proteinuria and the promising data from Asian patients. Despite considerable advances in the clinical management of LN over the past few decades with resultant improvements in patients' outcomes, there are still knowledge gaps and unmet clinical needs. Asia has made substantial contributions to the evidence base that guides clinical management and continues to offer invaluable opportunities for research pursuits. Key Messages: Treatment responses and clinical outcomes in Asian patients with LN compare favorably with patients from other parts of the world. The prevention and treatment of infective complications remain significant challenges in managing LN in Asia. Facts from East and West: (1) The prevalence of SLE is lower among Caucasians than other ethnicities. A higher prevalence is observed among Asians and African Americans, while the highest prevalence is found in Caribbean people. The prevalence of LN in Asian SLE patients is much higher than in Caucasians as well. However, the 10-year renal outcome and renal survival rate appear to be better in Asians. (2) Polymorphisms of genes involved in the immune response, such as Fcγ receptor, integrin alpha M, TNF superfamily 4, myotubularin-related protein 3 and many others, might be partly responsible for the differences in prevalence between the different ethnic groups. European ancestry was shown to be associated with a decrease in the risk of LN even after adjustment for genes most associated with renal disease. (3) Access...

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“…Tacrolimus, a macrolide antibiotic that also inhibits calcineurin, was found to be more effective and safer than intravenous cyclophosphamide in induction treatment for Asians with proliferative or membranous lupus nephritis [25], [26]. Longterm tacrolimus treatment was also well tolerated and effective, especially in regards to reducing proteinuria, in a series of 29 Asian patients with lupus nephritis, but larger prospective studies including other racial groups are warranted [27]. A topical formulation of the calcineurin inhibitor pimecrolimus was comparable to betamethasone 0.1 % cream in a double-blind randomized controlled trial of facial discoid lupus [28].…”

Section: Surface and Intracellular Signaling In Sle T Cellsmentioning

confidence: 99%