In the initial treatment of "lupus nephritis", tacrolimus can replace cyclophosphamide!

*For medical professionals to read and refer to the first large-sample RCT study published by Chinese experts! In March 2022, Academician Liu Zhihong from the Eastern Theater General Hospital and Liu Zhangsuo's team from the First Affiliated Hospital of Zhengzhou University published a large multi-center clinical study on JAMA Network Open to evaluate whether tacrolimus can be used as an alternative to cyclophosphamide.
Initial Treatment of lupus nephritis (LN)
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 Picture: The study was published on JAMA Network Open.
"Medical Rheumatism Immunity Channel" specially invited the first work of the study - Professor Zheng Zhaohui, Department of Rheumatology and Immunology, The First Affiliated Hospital of Zhengzhou University to share this research and bring clinical value to readers.
dry goods
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Swipe up on the study abstract to read Objectives: Intravenous cyclophosphamide (IVCY) in the treatment of LN may cause serious adverse effects
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Tacrolimus may be an alternative to the initial treatment of LN; however, large-scale, randomized clinical studies on tacrolimus are lacking
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The aim of this study was to evaluate the efficacy and safety of tacrolimus and IVCY as initial LN therapy in Chinese patients
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 Methods: This randomized (1:1), open-label, parallel-controlled, non-inferiority phase III clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus (SLE) combined with III, Patients with type IV, V, III+V or IV+V LN
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Inclusion criteria included body mass index 18.
5-27 kg/m2, 24-hour urine protein ≥1.
5 g, and serum creatinine ≤260 μmol/L
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In the end, 314 people were randomly assigned
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The first patient was enrolled on March 10, 2015, and the study ended on September 13, 2018
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The follow-up period was 24 weeks
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The data analysis time was from December 2019 to March 2020
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 Interventions: Oral tacrolimus (target plasma concentration, 4-10ng/ml) or IVCY for 24 weeks in the background of prednisone
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 Primary endpoint: Complete or partial response rate at week 24
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 RESULTS: A total of 314 patients were randomized, and 299 patients (95.
2%) received treatment [157 (52.
5%) in the tacrolimus group; 142 (47.
5%) in the IVCY group]
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Tacrolimus was found to be non-inferior to IVCY in response to LN at week 24
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The complete or partial response rate was 83.
0% (117/141) in the tacrolimus group and 75.
0% (93/124) in the IVCY group
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At week 24, the LSM change in SLEDAI score was -8.
6 and -6.
4 in the tacrolimus and IVCY groups, respectively
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Changes in other immune parameters and renal function were similar between the two groups
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Serious adverse events (TEAEs) were reported in 29 patients (18.
5%) in the tacrolimus group and 35 patients (24.
6%) in the IVCY group
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The most common serious study drug-related TEAE was infection (8.
9% vs 16.
2%)
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Seven patients in each group withdrew due to AEs
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 Conclusions and relevance: In this study, oral tacrolimus appeared to be non-inferior to IVCY for initial treatment of active LN, and its safety profile was superior to IVCY
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As an initial treatment for LN, tacrolimus may be an alternative to IVCY
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There is a lot of room for the treatment of LN.
The medical community: LN is a common cause of death in SLE.
About 70% of patients will develop end-stage renal disease.
The current basic drugs for treatment are glucocorticoids and cytotoxic drugs.
What is the current status of LN treatment in my country? how? Professor Zheng Zhaohui: LN is the most common secondary glomerular disease in China
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The main goals of LN treatment are to reduce urinary protein, protect the kidneys, prevent the deterioration of renal function, and improve the prognosis of patients
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LN therapy consists of two phases, the first is induction therapy; the second is maintenance therapy
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In induction therapy, a very important treatment method is hormone combined with immunosuppressive agents
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The most commonly used immunosuppressants are cyclophosphamide and mycophenolate mofetil
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However, the side effects of cyclophosphamide include ovarian toxicity, bone marrow suppression, infection, etc.
In particular, ovarian toxicity is irreversible
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Therefore, the exploration of alternative drugs for cyclophosphamide is an urgent clinical problem
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The maintenance treatment period is mainly maintained by mycophenolate mofetil and azathioprine for a long time, usually 3 to 5 years
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In addition, for some refractory LN, there are some new drugs to explore, such as biological agents
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In general, there is still a lot of room for improvement in the current treatment of LN, which still needs to be explored continuously
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 Conduct large-scale clinical trials to supplement international research gaps Q medical community: On March 31, 2022, you published an article in JAMA Network Open on the efficacy and safety of tacrolimus combined with IVCY in the initial treatment of Chinese patients with LN of RCT study, could you please briefly describe the background of the study and what makes it unique? Professor Zheng Zhaohui: As mentioned above, the treatment of LN is mainly hormones and cytotoxic drugs
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Due to the many side effects of cyclophosphamide, it is necessary to explore alternative methods for the treatment of LN, and tacrolimus is one of the important options
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Mechanistically, tacrolimus can inhibit the activation of T cells, reduce the production of autoantibodies, and reduce the deposition of immune complexes in the glomerulus, thereby protecting the kidneys for a long time
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In addition, tacrolimus also has certain protective effects on podocytes, including stabilizing the actin cytoskeleton and inhibiting podocyte apoptosis
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 At present, there is not a lot of evidence-based medicine on the question of "whether tacrolimus can be used as initial treatment of LN"
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In a placebo-controlled phase III study conducted in Japan, a significant reduction in LN disease activity index was observed in patients treated with tacrolimus for more than 28 weeks
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We would also like to know more about the efficacy and safety of tacrolimus compared to cyclophosphamide for initial treatment
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It is reported that we are the first large-scale randomized clinical trial to evaluate the safety and efficacy of tacrolimus and IVCY in patients with LN
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 This study is a randomized, multicenter, open-label, parallel, non-inferiority large-scale clinical study
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A total of 314 LN patients were included, including types III, IV, V, III+V and IV+V LNs
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They were then assigned 1:1 to tacrolimus and cyclophosphamide for 24 weeks
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Both groups received intravenous methylprednisolone pulse therapy (0.
5g/d, 3 days), then changed to oral prednisone [at 0.
8mg/kg/d (maximum dose 45mg/d)], Continue for 4 weeks; then gradually reduce the dose by 5 mg/d to 20 mg/d every 2 weeks; then reduce the dose by 2.
5 mg/d every 2 weeks to a maintenance dose of 10 mg/d
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With this study, we can assess whether tacrolimus can replace cyclophosphamide as an initial treatment for LN
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 Multiple indicators and multiple perspectives confirm that the efficacy of tacrolimus is superior to that of cyclophosphamide Q: The study found that the remission rate (83%) of tacrolimus in the treatment of LN was not inferior to that of cyclophosphamide (75%).
What do you think about this? In addition to the remission rate, are other indicators such as SLEDAI score, 24-hour urine protein, etc.
different between the two drugs? Prof.
Zhaohui Zheng: The primary endpoint of this study is to observe the proportion of patients with complete or partial remission at 24 weeks
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It can also be seen from the study results that at 24 weeks, the complete remission rate of tacrolimus was 49.
6%, the partial remission rate was 33.
3%, and the overall remission rate was 83%; the complete remission rate of cyclophosphamide was 36.
3%, and the partial The response rate was 38.
7%, and the overall response rate was 75%
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This result is basically consistent with the results of previous small-scale studies
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Note: Complete remission is defined as proteinuria <0.
5 g per 24 hours, serum albumin ≥3.
5 g/dl, and stable renal function (ie, SCr within the reference range or an increase of ≤15% of baseline)
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Partial remission was defined as proteinuria <3.
5g per 24 hours and a decrease of more than 50% from baseline, serum albumin ≥3.
0g/dl, and stable renal function
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In addition, different pathological types of LN respond differently to drug efficacy
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In the study, it can be seen that the remission rate of tacrolimus is higher than that of cyclophosphamide in all LN types except for type IV+V LN, especially in type V LN - tacrolimus reaches 68.
4%.
, while cyclophosphamide was only 44.
4%
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This result is consistent with a previous study in Hong Kong, China: patients with type V LN who received tacrolimus as initial therapy had a higher response rate at 6 months than patients who received mycophenolate mofetil (100% vs 75% %)
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This indicates that the use of tacrolimus as initial treatment in patients with type V LN may be more beneficial
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Of course, this guess also needs more large-sample, multi-center studies to confirm
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 Secondary efficacy measures of the study included the SLE Disease Activity Index (SLEDAI) score, immune parameters (complement C3, C4, and anti-dsDNA antibodies) and renal function [24-hour proteinuria, serum albumin, SCr levels and estimated glomerular] filtration rate (eGFR)]
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 Among them, the SLEDAI score was also different between the two groups
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At 12 and 24 weeks, the trend of decreasing SLEDAI score in the tacrolimus group was better than that in the cyclophosphamide group
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Moreover, urinary protein decreased more rapidly in the tacrolimus group
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 Although there was a small increase in creatinine levels over the 24-week observation period, the increase did not exceed 15% of baseline
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Other indicators, including plasma albumin, complement, and the probability of negative conversion of anti-dsDNA antibodies, did not differ between the two groups
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The application of tacrolimus is safer than cyclophosphamide Q medical community: research points out that the safety of tacrolimus is better than that of cyclophosphamide.
What is the clinical significance of this? Professor Zheng Zhaohui: Tacrolimus and cyclophosphamide had some adverse events during the initial treatment of LN, but most of the adverse events were mild or moderate
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The incidence of serious adverse events was lower in the tacrolimus group than in the cyclophosphamide group (8.
9% vs 16.
2%)
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 In addition, the biggest advantage of tacrolimus over cyclophosphamide is that it can reduce the risk of premature ovarian failure
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If tacrolimus is used as the initial treatment for LN, it is of great help in reducing ovarian toxicity
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 Overall, this study has yielded a very encouraging result
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In future clinical practice, tacrolimus may be an option for the initial treatment of LN
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Although there are limitations, still look up to the stars Q medical community: In your opinion, does this research still have certain limitations? Where will your future research direction be? Professor Zheng Zhaohui: The limitations of this study are reflected in the following aspects: In terms of design, this study is an open-label design, not double-blind
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In terms of observation time, this study is only 24 weeks, which is relatively short (but still obtained the expected results)
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In subgroup analysis, there were relatively fewer patients in certain pathological groups
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In terms of the applicable population, all Chinese patients were included in this study, which may limit the application of the study results to non-Asian populations
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Future related studies can further confirm an application of tacrolimus in other ethnic groups and expand the indications of tacrolimus in the initial treatment of LN
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In our study, I think long-term follow-up can be carried out to understand the effect and safety of tacrolimus on renal function
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 References: [1] Zheng Z, Zhang H, Peng X, Zhang C, Xing C, Xu G, Fu P, Ni Z, Chen J, Xu Z, Zhao MH, Li S, Huang X, Miao L, Chen X , Liu B, He Y, Li J, Liu L, Kadeerbai H, Liu Z, Liu Z.
Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis: A Randomized Clinical Trial.
JAMA Netw Open.
2022 Mar 1;5(3):e224492.
Expert Profile Prof.
Zhaohui Zheng Chief physician, professor of the Department of Rheumatology and Immunology, The First Affiliated Hospital of Zhengzhou University, a well-known expert at the provincial level, and a tutor for postgraduate students.
He is currently the deputy director of the Henan Rheumatology Association, and the Chinese Society for Biological Immunology.
National Committee Member of Rheumatology Branch, Standing Committee Member of Infectious Science Group of Rheumatology and Immunology Professional Committee of Cross-Strait Medical and Health Exchange Association, Head of Physical Rehabilitation Professional Committee of Henan Provincial Rehabilitation Association for Persons with Disabilities Member of the 9th National Youth Committee, member of the Rheumatology Immunology Group of the Organization Biobank Branch of the China Medical Biotechnology Association, and member of the first committee of the Rheumatology Immunology Branch of the Asia-Pacific Medical Bioimmunology Society.
Presided over and participated in 1 National Natural Science Foundation of China and Henan Province Science and Technology Research Program 3 projects, 1 Henan Provincial Natural Science Foundation Project, 1 Henan Provincial and Ministry Co-constructed Project Participated in 3 national multi-center Phase III clinical trials of lupus nephritis, published more than 40 academic papers, and more than 10 papers were included in SCI.
1 first prize of the Henan Provincial Medical Science and Technology Progress Award, 3 second prizes of the Henan Provincial Science and Technology Progress Award.
In 2013, he was sent to the United States to study for one and a half years.
He studied under Professor Diamond Betty, an internationally renowned lupus expert, mainly engaged in systemic erythema Lupus-related research work