Guide
With the increasing number of biologics approved for the treatment of systemic lupus erythematosus (SLE), how to use them rationally, effectively and safely has become an urgent clinical problem. Recently, the Chinese Expert Consensus on the Application of Biological Agents in Systemic Lupus Erythematosus (2024 Edition) (hereinafter referred to as the Consensus) was jointly formulated by the Chinese Society of Rheumatology and Immunology Branch of the Chinese Medical Association and the SLE Group of the Rheumatology and Immunology Committee of the China Primary Health Care Foundation, and a total of 34 rheumatology and immunology experts and 1 renal rheumatology expert from 20 provinces, municipalities and autonomous regions across the country [1].
The consensus puts forward recommendations for 10 clinical application issues, such as the applicable population, timing of use, efficacy evaluation, and safe drug use of biological agents, so as to provide reference for clinicians and promote the standardized and reasonable application of biological agents in clinical practice. This article summarizes the key recommendations of the consensus, please refer to it.
Biologics are on the rise
How to choose to escort SLE patients
With the continuous improvement of diagnosis and treatment, the 5-year survival rate of SLE patients in mainland China has reached 94%, but the standardized mortality rate is still significantly higher than that of the general population, and there are many problems in clinical practice, such as low disease remission rate, high recurrence rate, and organ damage caused by adverse drug reactions, which bring a serious burden to patients and society. In addition, SLE patients, especially young women, also have higher demands for appearance, fertility, and quality of life, posing new challenges for the long-term standardized management of the disease [1].
Biologics provide a new means of treatment for SLE. At present, the biologics approved for the treatment of SLE in China include belimumab and tetanercept, while rituximab has not been approved for SLE in China (see Table 1 for details).
B-cell immunity is the core pathogenesis of SLE, and B-cell targeted therapy has become a widely studied therapeutic direction. Rituximab, which targets B-cell CD20, was first approved for the treatment of lymphoma, and its two clinical trials for SLE and LN did not meet the primary endpoint and therefore did not receive an indication for SLE. Belimumab is a single-target inhibitor of B lymphocyte-stimulating factor (BLyS) that blocks the development and maturation of immature B cells by blocking BLyS [2-3], and the SRI-4 response rate of belimumab to SLE patients was 43.2 percent compared with 33.5 percent in the placebo group (p=0.017) in addition to standard therapy [4]. As the world's first "dual-target" biologics approved for the treatment of SLE, tetanercept can block APRIL in addition to inhibiting BLyS to inhibit the differentiation of mature B cells into plasma cells and reduce the release of autoantibodies, thereby delaying disease progression and reducing recurrence[3]. The results of the phase III clinical trial showed that at 52 weeks of treatment, the SRI-4 response rate in the tetatercept group was 82.6%, which was significantly higher than that in the placebo group (38.1% (p<0.001), and this significant difference existed from the fourth week of treatment and continued until the 52nd week. In addition, immunological markers in the tetaercept group were also significantly improved. Overall, tetanercept has demonstrated a favorable safety and tolerability profile in the treatment of SLE[5]. It is worth noting that for pediatric patients with SLE, tetanercept has also shown satisfactory efficacy. In a study of 15 children aged 5~18 years with refractory SLE who were hormone intolerant in mainland China, the SRI-4 response rate of tetanercept treatment for 5~26 weeks was 66.7%, and the prednisone dose in 12 patients was reduced from 40 mg/d to 17.5 mg/d with no serious adverse events[6].
Grasp the three key principles
Assist in the standardized application of biologics
Biologics can help control disease activity, reduce hormone use, and are more conducive to achieving target therapy than conventional therapy, while improving serologic markers, reducing the risk of recurrence, and delaying the progression of organ damage [7]. In order to bring better treatment outcomes to patients with SLE, how to standardize the use of biologics is the key to ensure safe and effective treatment for patients.
The goal of biologic therapy for SLE is to achieve disease remission (DORIS) or lupus low disease activity (LLDAS) as soon as possible, while reducing recurrence and minimizing adverse drug reactions, thereby reducing the accumulation of organ damage, reducing mortality and improving the quality of life of patients. Ensuring the safety of medication in patients with SLE is a prerequisite for achieving treatment goals, therefore, consensus recommends that patients should be carefully asked about their past medical history and carefully screened for tuberculosis, hepatitis B and C, herpes zoster, AIDS, and opportunistic infections before initiating biologics, avoid use in patients with severe active infections and severely impaired immunity, and use caution in patients with a history of chronic or recurrent infections after fully weighing the risks and benefits [1].
Consensus recommends consideration of combination biologic therapy for patients with SLE who are still active or relapsed with hydroxychloroquine (monotherapy or in combination with corticosteroids) or who are unable to reduce corticosteroids to a maintenance dose (eg, ≤prednisone 5 mg daily). The specific combination of regimens should be based on the patient's disease activity, affected organs, drug characteristics, fertility requirements, and price. Hydroxychloroquine is used as a basic drug for the treatment of SLE, and long-term use is recommended if there are no contraindications. Corticosteroid regimens are usually tailored to the individual patient's individual situation, and should be reduced and discontinued if feasible. Immunosuppressants are suitable for different patient types according to their efficacy advantages, and the appropriate immunosuppressants should be selected based on comprehensive consideration of efficacy and safety. The consensus gives clear suggestions on the strategy of reducing the dose of hormones and immunosuppressants after initiating biologics, pointing out that under the condition of stable disease control, the dose of hormones should be reduced to prednisone ≤5 mg/d within 6~12 months, and then rapid reduction within 3 months should be avoided. Patients with persistent LLDAS or in remission should be tapered off with corticosteroids before immunosuppressants or biologics. During the dose reduction period, patients should be closely monitored for recurrence [1].
In the process of biologics use, attention should also be paid to the evaluation of efficacy and safety. Specifically, for patients treated with tetanercept or belimumab, the efficacy evaluation should be carried out at 1~3 months, and then every 3 months, and a comprehensive efficacy evaluation should be carried out at 6~12 months after treatment, and if there is no improvement, discontinuation of the drug can be considered. Patients who have achieved clinical remission of LLDAS after treatment can have a comprehensive efficacy evaluation every 3~6 months. During treatment, infections and infusion/injection reactions should be closely monitored during treatment, and potential adverse reactions should be highly vigilant, and if necessary, prevention should be taken in advance and active response should be taken [1].
summary
The release of the Chinese Expert Consensus on the Use of Biologics in the Treatment of SLE (2024 Edition) has promoted the standardized and rational application of biologics in clinical practice. The consensus provides guidance on key issues such as applicable population, timing of use, efficacy evaluation, and safe drug use, and provides in-depth medication strategies that are in line with the characteristics of Chinese patients. For patients with SLE who do not respond well to, are intolerant, or relapse with hormonal and/or immunosuppressive agents, consensus recommends that combination biologic therapy be considered. With stable disease control, the corticosteroid dose is tapered to prednisone ≤5 mg/day. In patients with persistent LLDAS or in remission, consider stopping corticosteroids first, followed by stopping immunosuppressants or biologics.
bibliography
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[2] Krustev E, Clarke AE, Barber MRW. B cell depletion and inhibition in systemic lupus erythematosus[J]. Expert Rev Clin Immunol. 2023 Jan; 19(1):55-70.
[3] Cai J, Gao D, Liu D, et al. Telitacicept for autoimmune nephropathy[J]. Front Immunol. 2023 Jun 5;14:1169084.
[4] Furie R, Petri M, Zamani O,et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus[J]. Arthritis Rheum. 2011 Dec; 63(12):3918-30.
[5] Wu D, Li J, Xu D, et al. Telitacicept, a human recombinant fusion protein targeting b lymphocyte stimulator (Blys) and a proliferation-inducing ligand (April), in systemic lupus erythematosus (Sle): results of a phase 3 study[C]//ARTHRITIS & RHEUMATOLOGY. 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY, 2022, 74: 4546-4548.
[6] Sun L, Shen Q, Gong Y, et al. Safety and efficacy of telitacicept in refractory childhood-onset systemic lupus erythematosus: A self-controlled before–after trial[J]. Lupus, 2022, 31(8): 998-1006.
[7] Sun F, Wu H, Wang Z, et al. Effectiveness and Safety of Belimumab in Chinese Lupus Patients: A Multicenter, Real-World Observational Study[J]. Biomedicines, 2023, 11(3): 962.
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