What new information does the release of the new diagnosis and treatment guidelines bring to the treatment of lupus nephritis?

*Only for medical professionals to read for reference.
Facing the "grand wolf" who is good at disguising, explore more potential treatment options to better see through it and capture it
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 Lupus nephritis (LN) is kidney damage caused by systemic lupus erythematosus (SLE) and is one of its most common complications
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The clinical manifestations of LN are complex and diverse, with large individual differences, often disguised as the characteristics of other diseases, repeatedly invading patients, and difficult to identify
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According to statistics, about 50% of SLE patients have clinical manifestations of kidney damage.
If it is allowed to continue to develop, the persistence and recurrence of the disease may lead to renal insufficiency, leading to end-stage renal disease (ESRD)
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Compared with the general population, the mortality rate of patients with LN or ESRD has increased by 6-26 times [1]
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How to effectively prevent the attack of the "wolf" and protect the kidney is a topic we have been exploring
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With the release of the new version of the diagnosis and treatment specifications, challenges and opportunities coexist.
With the deepening of LN research, the optimization of its clinical diagnosis and treatment has received more and more attention and attention
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In the past two years, relevant foreign guidelines such as the European Anti-Rheumatism Alliance/European Nephrology Association-European Dialysis and Kidney Transplant Association (EULAR/ERA-EDTA) and the draft version of the Global Kidney Disease Prognosis Organization (KDIGO) have all carried out LN management recommendations.
Update [2-3]
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In September of this year, the Rheumatology Branch of the Chinese Medical Association released the latest version of the "Guidelines for the Diagnosis and Treatment of Lupus Nephritis" on the basis of current domestic and foreign experience and guidelines, which is of great significance to the scientific and standardized diagnosis and treatment of LN in clinical practice and the improvement of treatment efficacy.
Meaning [1]
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Figure 1: Lupus nephritis diagnosis and treatment specifications (2021 edition) The diagnosis and treatment specifications emphasize the following points: the goal of LN treatment is to reduce urine protein, protect the kidneys, prevent or delay the deterioration of renal function and improve the prognosis of patients; hormones and hydroxychloroquine are still LN The basic drugs for treatment, and the use of immunosuppressants should be selected according to the pathological type of the disease, pathological activity and combined with extrarenal lesions; if the effect of conventional treatment is not good, hormones combined with calcineurin inhibitors or multiple targets can be used Scheme
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Among them, the multi-target approach can be used for induction therapy and maintenance therapy; the current trend of maintenance therapy for LN is to use lower doses of hormones as much as possible
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Although the specification has provided detailed recommendations on common clinical problems, it should be noted that there are still many unmet needs and challenges in LN treatment: Compared with the significant increase in the treatment remission rate, the recurrence rate of LN is still high ( 33%-40%); although the low-dose use of hormones is emphasized, the overall treatment plan for LN is still based on hormones.
Data from the Chinese Systemic Lupus Erythematosus Research Cooperative Group (CSTAR) also shows that about 90% of SLE patients in China receive hormone therapy , It may increase the risk of organ damage [4]; in addition, there are not many alternatives for the conversion treatment of refractory cases, and treatment options are limited.
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As the saying goes, "the danger is organic, the crisis can be turned"-how to reduce The amount of hormones that can effectively improve the renal response of the treatment and reduce the recurrence rate are issues that we should consider when exploring new treatment options for LN
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The specifications have repeatedly emphasized that when conventional treatments are not effective, a multi-target approach can be tried
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The multi-target program not only helps to improve the remission rate of LN and protects the kidney tissue, but also has better safety.
It may be a new way to overcome the problem of LN treatment in the future
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Team combat, multi-target solutions or more advantageous multi-target solutions in LN include multi-drug multi-targets, fixed-dose combination drugs and single-drug multi-targets
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At present, the multi-target plan referred to in LN treatment is mainly multi-drug multi-target, that is, the treatment of diseases by using a variety of drugs with different mechanisms
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For diseases with complex etiologies, the multi-target solution can act on multiple targets associated with the disease, and by simultaneously adjusting multiple links in the disease network system, it produces a "teamwork" effect and improves curative effects
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Due to the complexity of the LN mechanism and the diversity of pathological changes, the efficacy of single-target drugs for disease control is relatively limited, and the application of multi-target programs for the treatment of LN has become increasingly popular
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At this stage, the multi-target plan for LN treatment includes hormones combined with a variety of immunosuppressants, with the most common combination of hormones combined with mycophenolate mofetil (MMF) and tacrolimus (TAC)
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There have been many research reports showing the efficacy advantages of multi-target programs in the treatment of LN [5]
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Taking the combination of hormones with MMF and TAC as an example, a single-center study by Bao Hao and others at the Nanjing General Hospital showed that this program can achieve better curative effect when used in the treatment of IV+V refractory LN, and the disease at 6 months The complete remission rate was significantly higher than that of the cyclophosphamide (CTX) group (50% vs.
5%, Figure 2) [6-7]; prospective controlled clinical studies of multi-target induction treatment of proliferative and membranous LN showed that this program The curative effect is significantly better than the traditional intravenous CTX pulse therapy, and the patients are well tolerated [8]; follow-up multi-center clinical studies also show that under the treatment of hormones combined with MMF and TAC, the complete remission rate of LN patients was significantly higher than that of the CTX group (45.
6%) vs.
22.
9%), once again proved the superiority of the therapy in the treatment of type V+IV LN [5]; a long-term follow-up study of 24 months showed that the use of multi-target programs to induce and maintain treatment of type IV+V LN can achieve High remission rate and good safety [9]
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Figure 2: After 6 and 9 months of treatment, the remission rate comparison between the multi-target therapy and intravenous CTX pulse therapy groups (*Compared with the multi-target therapy group, P<0.
05) In addition, other multi-target programs such as hormone combined with MMF and CTX, hormone combined with leflunomide (LEF) and azathioprine (AZA), hormone combined with CTX and TAC have also shown good efficacy in clinical studies [5]
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Based on the above research evidence, the updated LN management guidelines of EULAR/ERA-EDTA in 2020 proposed that for patients with refractory LN, multi-target therapy is recommended [3]
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From multi-drug multi-target to single-drug multi-target, can LN treatment take another step? Although the efficacy of multi-drug and multi-target has been confirmed in research and clinical practice, is it the "optimal solution" for LN treatment? Can we still take a step forward on this basis? In fact, the multi-drug multi-target overlapping medication still has certain drawbacks: complex dosing schedules and adverse reactions caused by drug interactions may cause poor patient compliance and increased safety risks [10]
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Compared with multi-drug multi-targets, single-drug multi-targets (that is, a single drug modulates multiple targets at the same time) can not only achieve true multi-target activity, but also help reduce the type and dose of administration and avoid combination Adverse reactions caused by the interaction between different drug components in the medication
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Iramod (IGU) is a small molecule anti-rheumatic drug (DMARD) independently developed by China, which has a multi-target immunomodulatory effect
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IGU can regulate the cellular immune balance mediated by T cell subsets and related inflammatory factors [11-12]; it can also regulate the terminal differentiation of B cells, inhibit the production of immunoglobulin, and help reduce autoantibody titers [13] In addition, studies have also found that IGU has an inhibitory effect on IL-17 and NF-κB signaling pathways [14-15]
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These mechanisms and pathways have played a role in the progression of LN disease, suggesting that IGU may be a feasible option for the treatment of LN.
Then, what are the findings when studying the potential efficacy of IGU in the treatment of LN? In pre-clinical studies, IGU has shown to improve immune nephritis in lupus mice, which can effectively reduce the amount of proteinuria and the deposition of immune complexes [16-17]; and Professor Bao Chunde’s latest clinical research shows that 14 After receiving IGU treatment for 24 weeks, the remission rate of renal treatment in a patient with refractory LN can reach 92.
3% (12/13), of which 38.
5% (5/13) even achieved complete remission, 53.
8% (7/13) ) Achieve partial relief (Figure 3) [18]
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Figure 3: Follow-up results of 14 patients in the group after 24 weeks of IGU induction therapy.
Although the above preliminary research results show good efficacy of IGU, research evidence is still relatively scarce.
In order to further clarify its existence in LN treatment Risks and benefits, many studies are ongoing or in preparation, such as a multi-center, randomized, 52-week parallel positive drug control study (iGeLU study) aimed at evaluating the feasibility of IGU as an LN induction or maintenance treatment drug.
The study compares the efficacy of IGU with CTX and AZA on LN.
The primary endpoint is renal remission rate.
The study design is shown in the figure below [19]
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Figure 4: The continuously accumulated research data of iGeLU research design will provide clinical basis for IGU treatment of LN patients, and bring new options for refractory LN treatment, let us wait and see
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Summary: There are still many unmet needs in the LN treatment field.
Diversified treatment options are an effective way to solve the treatment dilemma and help the realization of individualized treatment
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The multi-target approach is currently one of the main research directions for LN therapy, and it is also a possible mainstream treatment trend in the future.
The new small molecule DMARD with multiple targets and multiple mechanisms has shown great development potential in it, and it is expected to be a refractory LN patient Bring new choices and new hopes
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Prospective clinical study of multi-target treatment of refractory lupus nephritis [J].
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Successful treatment of class IV+V lupus nephritis with muItitarget therapy[J].
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A prospective controlled clinical study of multi-target induction treatment of proliferative and membranous lupus nephritis [J].
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Long-term follow-up of multi-target treatment of type V+IV lupus nephritis[J].
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Development strategy and research of multi-target drugs[J].
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Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis[J].
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