A traditional Chinese medicine composition for preventing and treating systemic lupus erythematosus combined with infection, a traditional Chinese medicine compound preparation and application thereof

Abstract

This invention relates to the field of traditional Chinese medicine (TCM) technology. More specifically, it relates to a TCM composition for the prevention and treatment of systemic lupus erythematosus (SLE) complicated with infection, its compound preparation, and its application. The TCM composition comprises the following raw materials: Artemisia annua, Hedyotis diffusa, Paeonia lactiflora, Paeonia suffruticosa, Astragalus membranaceus, Rehmannia glutinosa, Centella asiatica, and Poria cocos. This invention also discloses the above-mentioned TCM composition in compound preparation and its application in the preparation of drugs for the prevention and treatment of SLE complicated with infection. The TCM composition provided by this invention has a scientifically sound formula, based on the principles of clearing heat and detoxifying, cooling blood and dispersing blood stasis, and tonifying qi and nourishing yin. It helps reduce the incidence of complicated with infection events in SLE patients and highly aligns with the core TCM theory of "harmonizing the body's resistance and eliminating pathogenic factors."

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology. More specifically, it relates to a traditional Chinese medicine composition for the prevention and treatment of systemic lupus erythematosus complicated with infection, as well as its compound preparation and application. Background Technology

[0002] Maintenance therapy for systemic lupus erythematosus (SLE) faces numerous challenges. SLE is characterized by its tendency to relapse. Secondly, drug intolerance and adverse drug reactions are significant factors affecting patients' willingness to take treatment, creating a vicious cycle of irregular medication use, relapse, and poor disease control. Furthermore, the withdrawal of therapeutic drugs (such as glucocorticoids) carries the risk of triggering disease activity, necessitating thorough assessment by clinicians to develop effective withdrawal plans. More importantly, infection is not only a common complication of SLE due to immune dysregulation but also a major contributing factor to SLE exacerbations. SLE patients have an increased risk of infection due to immune dysfunction and the use of glucocorticoids and immunosuppressants. The high dosages and cumulative doses of hormones used by patients in my country further increase the risk of infection. SLE patients are 24 times more likely to be hospitalized for opportunistic infections than the general population, and infection is increasingly becoming the leading cause of death among SLE patients in my country.

[0003] Traditional Chinese medicine (TCM) has a long history and unique advantages in treating SLE. Its treatment philosophy of "harmonizing the body's resistance and eliminating pathogens" and "treating both the body and internal organs" is highly compatible with the complex and ever-changing pathological mechanisms of SLE. Clinical observations related to the applicant's team's previous application for "a TCM composition for stabilizing and maintaining the activity of systemic lupus erythematosus and its preparation method and application" suggest that yin-nourishing, heat-clearing, and blood-cooling formulas can significantly improve the clinical symptoms and laboratory indicators of SLE patients, maintain the long-term stability of SLE, and have good safety. However, it was found that some patients still experienced unsatisfactory efficacy with this formula, mainly due to disease activity following secondary infections. Based on the applicant's team's previous establishment of the first national multicenter prospective clinical cohort for the diagnosis and treatment of systemic lupus erythematosus (SLE) using integrated traditional Chinese and Western medicine (registration number: ITMCTR2024000266), our follow-up and prevention of SLE patients who received ≥3 months of standardized treatment in a real medical environment revealed that the use of the above-mentioned formulas did not significantly reduce the incidence of secondary infections in SLE patients.

[0004] In response, the applicant's team explored the mechanism of action of the aforementioned Yin-nourishing, heat-clearing, and blood-cooling formula in treating SLE based on network pharmacology. The MAPK pathway may be the core pathway for this compound to treat SLE. In addition, ultra-high performance liquid chromatography-tandem high-resolution mass spectrometry (UHPLC-HRMS) was used to analyze all components of the Yin-nourishing, heat-clearing, and blood-cooling formula. The results showed that a total of 139 components were found in the compound, including flavonoid glycosides, iridoid glycosides, coumarins, and triterpenoid saponins. The top 5 core intersection targets with the highest degree of adsorption were selected as receptors: AKT1, IL6, TNF, INS, and IL1B. Through comprehensive analysis of the mass spectrometry components and blood-entry components of the Yin-nourishing, heat-clearing, and blood-cooling formula, the top 5 core active ingredients were screened as ligands for molecular docking: loganic acid, isopropionol, paeonol C, paeoniflorin, and dehydrocostunolide. Although molecular docking verification and screening of the core active ingredients can demonstrate that the core components and key targets of the Yin-nourishing, heat-clearing, and blood-cooling formula can be stably bound, answering the relevant mechanism of the multi-component synergistic stabilization of SLE, it also reflects that the formula still has limitations in regulating adaptive immunity (especially T lymphocyte subsets), which may explain the difference in its efficacy in SLE complicated with infection.

[0005] Therefore, it is still very necessary to further develop traditional Chinese medicine compound prescriptions for systemic lupus erythematosus complicated with infection. Summary of the Invention

[0006] To address the aforementioned technical problems, one objective of this invention is to provide a traditional Chinese medicine composition for the prevention and treatment of systemic lupus erythematosus complicated with infection.

[0007] Another object of the present invention is to provide various traditional Chinese medicine compound preparations based on the above-mentioned traditional Chinese medicine composition.

[0008] Another object of the present invention is to provide the application of the above-mentioned traditional Chinese medicine composition and traditional Chinese medicine compound preparation in the preparation of a drug for the prevention and treatment of systemic lupus erythematosus complicated with infection.

[0009] To achieve the first objective mentioned above, the present invention adopts the following technical solution: In a first aspect, the present invention discloses a traditional Chinese medicine composition for the prevention and treatment of systemic lupus erythematosus complicated with infection, the traditional Chinese medicine composition comprising the following raw materials: Artemisia annua, Hedyotis diffusa, Paeonia lactiflora, Paeonia suffruticosa, Astragalus membranaceus, Rehmannia glutinosa, Centella asiatica, Poria cocos.

[0010] Furthermore, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Artemisia annua 3-60 parts, Hedyotis diffusa 3-60 parts, Paeonia lactiflora 3-30 parts, Paeonia suffruticosa 3-30 parts, Astragalus membranaceus 3-120 parts, Rehmannia glutinosa 3-60 parts, Centella asiatica 3-60 parts, Poria cocos 3-120 parts.

[0011] Furthermore, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Artemisia annua 10-45 parts, Hedyotis diffusa 10-60 parts, Paeonia lactiflora 5-30 parts, Paeonia suffruticosa 5-30 parts, Astragalus membranaceus 5-60 parts, Rehmannia glutinosa 5-30 parts, Centella asiatica 10-45 parts, Poria cocos 10-30 parts.

[0012] Based on the applicant's understanding of SLE complicated with infection in Traditional Chinese Medicine (TCM), the pathogenesis is mainly characterized by heat-toxin stagnation and blood stasis, and deficiency of Qi and Yin. The main treatment principles are clearing heat and detoxifying, cooling blood and dispersing blood stasis, and tonifying Qi and nourishing Yin. The applicant has revised the prescription (involving adjustments to the ingredients, dosage changes, and alterations to the "principal, assistant, adjuvant, and guide" relationships) and developed a TCM compound for SLE complicated with infection. Based on clinical research, this TCM compound can effectively control the disease, improve TCM syndromes, and increase the overall clinical efficacy rate. It also helps reduce the incidence of infection events in SLE patients, which is highly consistent with the core TCM theory of "harmonizing the body's resistance and eliminating pathogens." It has a solid clinical practice foundation and addresses the core challenge of infectious complications in the treatment of systemic lupus erythematosus (SLE), meeting unmet clinical needs for therapeutic efficacy.

[0013] The formula heavily uses Artemisia annua and Hedyotis diffusa as the principal herbs for clearing heat and detoxifying, while Paeonia lactiflora and Paeonia suffruticosa are used as the assistant herbs for cooling the blood and dispersing blood stasis. Astragalus membranaceus, Rehmannia glutinosa, Centella asiatica, and Poria cocos are used as the adjuvant herbs for tonifying qi and nourishing yin, clearing heat and cooling the blood, and detoxifying and resolving turbidity. When all the herbs are used together, they work together to clear heat and detoxify, cool the blood and disperse blood stasis, and tonify qi and nourish yin.

[0014] In this invention, Artemisia annua has a bitter and pungent taste, is cold in nature, and enters the liver and gallbladder meridians. It is good at clearing away deficiency heat, cooling the blood and relieving steaming sensation, clearing summer heat and relieving exterior symptoms, and stopping malaria and reducing fever. Its aroma is fragrant and penetrating, and it can penetrate deep into the yin to expel latent pathogens. It is often used for night fever and morning coolness in the later stage of febrile diseases, bone steaming fever due to yin deficiency, summer heat and external invasion of vexation, and various symptoms of malaria with chills and fever.

[0015] Oldenlandia diffusa has a slightly bitter and sweet taste, is cold in nature, and enters the stomach, large intestine, and small intestine meridians. It is good at clearing heat and detoxifying, promoting diuresis and resolving stagnation, and clearing away blood stasis and toxins. It can clear damp-heat and evil toxins in the body, and dissipate stagnation and depression. It is often used for syndromes of internal accumulation of damp-heat and blood stasis. Its medicinal properties are mild and moistening, making it a commonly used and effective medicine for detoxification and diuresis.

[0016] Red peony root has a bitter taste and slightly cold nature, and it specifically enters the liver meridian. It has the functions of clearing heat and cooling blood, dispersing blood stasis and unblocking collaterals, reducing swelling and relieving pain. It is good at clearing away excess heat in the blood, clearing blood stasis throughout the body, and resolving discomfort caused by poor blood circulation. It cools the blood while also having the power to remove blood stasis.

[0017] Moutan bark is bitter and pungent in taste, slightly cold in nature, and enters the heart, liver, and kidney meridians. It can clear heat from the blood and remove blood stasis, as well as promote blood circulation and remove blood stasis, and reduce deficiency heat. It cools the blood without leaving blood stasis, and promotes blood circulation without harming the body's vital energy. It can be used in combination with other herbs for both deficiency and excess blood heat, and for blood stasis obstruction.

[0018] Astragalus has a sweet taste and slightly warm nature, and it enters the spleen and lung meridians. It is an essential medicine for tonifying qi and strengthening the body's foundation. It can replenish the body's vital energy, strengthen the spleen and replenish qi, expel pathogens, support the body's original qi, promote the normal circulation of qi, blood and body fluids, harmonize the body's qi mechanism, and moderate the cold and cooling properties of other medicines.

[0019] Rehmannia glutinosa has a sweet and bitter taste, is cold in nature, and enters the heart, liver, and kidney meridians. Its main functions are clearing heat and cooling the blood, nourishing yin and blood, generating fluids and moistening dryness. It is good at nourishing the body's yin fluids, clearing internal heat due to yin deficiency and heat in the blood, and relieving dryness and discomfort caused by yin and blood deficiency.

[0020] Centella asiatica has a bitter and pungent taste, is cold in nature, and enters the liver, spleen, and kidney meridians. It can clear heat and dampness, cool blood and detoxify, reduce swelling and repair, clear damp-heat and blood stasis in the skin and internal organs, relieve swelling and pain caused by blood stasis and heat, and help the body metabolize stagnant and turbid substances. Its medicinal properties are mild and gentle.

[0021] Poria cocos is sweet and bland in taste, neutral in nature, and enters the heart, spleen, and kidney meridians. Its medicinal properties are mild; it can strengthen the spleen and eliminate dampness, promote urination and harmonize the middle jiao, calm the mind and regulate the spleen. It can transform and transport water and dampness, remove dampness and turbidity from the body, nourish the spleen and stomach's digestive functions, and moderate the cold nature of other herbs.

[0022] Furthermore, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: 30 parts Artemisia annua, 30 parts Hedyotis diffusa, 15 parts Paeonia lactiflora, 15 parts Paeonia suffruticosa, 30 parts Astragalus membranaceus, 15 parts Rehmannia glutinosa, 15 parts Centella asiatica, and 15 parts Poria cocos.

[0023] The basic formula of the above-mentioned traditional Chinese medicine composition of the present invention can be adjusted according to clinical symptoms during specific implementation to achieve the purpose of preventing and treating systemic lupus erythematosus and improving certain accompanying clinical symptoms, thereby further enhancing the adaptability of the composition of the present invention and improving the therapeutic effect. These adjustments made based on the basic formula of the present invention are also within the scope of protection of this application.

[0024] To achieve the second objective mentioned above, the present invention adopts the following technical solution: Secondly, the present invention discloses a traditional Chinese medicine compound preparation for the prevention and treatment of systemic lupus erythematosus complicated with infection, wherein the raw materials of the traditional Chinese medicine compound preparation include the traditional Chinese medicine composition as described above.

[0025] Furthermore, the dosage forms of the traditional Chinese medicine compound preparations include decoctions, soups, granules, capsules, tablets, powders, pills, or oral liquids.

[0026] Furthermore, the raw materials of the traditional Chinese medicine compound preparation also include pharmaceutically acceptable excipients.

[0027] Furthermore, the dosage form of the traditional Chinese medicine compound preparation is a decoction, and its preparation steps are as follows: Weigh each Chinese herbal medicine ingredient according to the formula, add 6-10 times the weight of water to the total amount of Chinese herbal medicine ingredients, boil under normal pressure for 30-40 minutes, filter to obtain a primary filtrate and a filter residue, add 4-6 times the weight of water to the filter residue, boil under normal pressure for 25-30 minutes, filter, collect the secondary filtrate, mix the two filtrates to obtain the decoction.

[0028] Furthermore, the dosage form of the traditional Chinese medicine compound preparation is granules, and its preparation steps are as follows: Weigh each Chinese herbal raw material according to the formula, add 6-10 times the weight of water to the total Chinese herbal raw materials, soak, heat and reflux for a first extraction, filter, collect the first extract, add 4-6 times the weight of water to the filter residue, heat and reflux for a second extraction, filter, collect the second extract, mix the two extracts, concentrate under reduced pressure to a clear paste with a density of 1.30-1.33 g / ml (55-60℃), add excipients, mix well and make granules.

[0029] To achieve the third objective mentioned above, the present invention adopts the following technical solution: Thirdly, the present invention discloses the application of the traditional Chinese medicine composition or compound preparation described above in the preparation of a drug for the prevention and treatment of systemic lupus erythematosus complicated with infection.

[0030] In addition, unless otherwise specified, all raw materials of the traditional Chinese medicine composition of the present invention can be obtained commercially available. Any traditional Chinese medicine composition of any range described in the present invention, including any value between the endpoints and any sub-ranges formed by the endpoints or any value between the endpoints, can achieve the purpose of preventing and treating systemic lupus erythematosus complicated with infection.

[0031] The beneficial effects of this invention are as follows: The traditional Chinese medicine composition provided by this invention for the prevention and treatment of systemic lupus erythematosus complicated with infection is based on the principles of clearing heat and detoxifying, cooling blood and dispersing blood stasis, and nourishing qi and yin. When combined with conventional Western medicine treatment, it can effectively reduce the activity of SLE, improve the syndrome of yin deficiency and blood heat, and significantly reduce the incidence of infection events, demonstrating good advantages in synergistic effect, toxicity reduction and infection prevention. Attached Figure Description

[0032] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0033] Figure 1 A flowchart illustrating the efficacy of the granules in Study Example 3 in treating SLE complicated with infection is shown. Detailed Implementation

[0034] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0035] Example 1 A traditional Chinese medicine composition for the prevention and treatment of systemic lupus erythematosus complicated with infection includes the following raw materials: Artemisia annua 30g, Hedyotis diffusa 30g, Paeonia lactiflora 15g, Paeonia suffruticosa 15g, Astragalus membranaceus 30g, Rehmannia glutinosa 15g, Centella asiatica 15g, and Poria cocos 15g.

[0036] Example 2 A decoction for the prevention and treatment of systemic lupus erythematosus complicated with infection, namely Qingbai Chidan Decoction, is prepared as follows: Step 1: According to the formula of Example 1, take the above-mentioned drugs and put them into a cooking container, add 1000-1500ml of water, boil at normal pressure for 30 minutes, and then filter to obtain filtrate a and residue a, for later use. Step 2: Add 700-900ml of water to the filter residue a obtained in Step 1, boil at normal pressure for 25-30 minutes, and then filter to obtain filtrate b and filter residue b, for later use. Step 3: Mix the filtrate a obtained in Step 1 and the filtrate b obtained in Step 2 evenly to obtain the traditional Chinese medicine decoction.

[0037] Example 3 A granule preparation for the prevention and treatment of systemic lupus erythematosus complicated with infection, namely Qingbai Chidan granules, is prepared as follows: The above-mentioned drugs were measured according to the formula in Example 1. For the first extraction, 10 times the amount of water was added, and the mixture was soaked at room temperature for 1 hour. After soaking, it was heated under reflux for 2 hours. The decoction was then filtered. For the second extraction, 5 times the amount of water was added, and the extraction time was 1.5 hours. The two extracts were combined and concentrated under reduced pressure to a clear extract with a density of 1.30-1.33 (55-60℃). Dextrin was added, mixed well, granulated, dried, and packaged to obtain the final product.

[0038] The applicant systematically studied the efficacy of the granules in Example 3 in the treatment of SLE complicated with infection using a single-center, prospective, randomized controlled clinical trial (registration number: ChiCTR2300073848). The specific study content is as follows.

[0039] 1. Research Design This study employed a prospective, randomized, double-blind, placebo-controlled design. Participants were randomly assigned in a 1:1 ratio to either the control group (Western medicine treatment group) or the treatment group (integrated traditional Chinese and Western medicine group). Both groups received treatment and were followed up for 24 weeks. The control group received prednisolone acetate tablets combined with hydroxychloroquine sulfate tablets, along with oral placebo granules; the treatment group received the same basic Western medicine treatment plus Qingbai Chidan granules prepared in Example 3. Details of clinical efficacy, safety, and concomitant medication information collected during the study period can be found in [link to study report]. Figure 1 .

[0040] 2. Research Plan 2.1 Source of research subjects The study included SLE patients who visited the outpatient and inpatient departments of the Rheumatology Department at Guang'anmen Hospital of the China Academy of Chinese Medical Sciences. This was an exploratory clinical trial, primarily aimed at preliminarily evaluating the safety and efficacy trends of the intervention, providing a basis for subsequent confirmatory studies. The sample size was not calculated based on the effect size of the primary outcome; a planned enrollment of 40 patients was determined by considering feasibility, clinical operability, and standard practices for exploratory research. All participants signed informed consent forms.

[0041] 2.2 Inclusion Criteria (1) Informed consent, voluntary participation and completion of the trial process; (2) The 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus (SLE) are classified as mild to moderate active SLE [Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) ≤ 12 points]. (3) Meets the diagnostic criteria for Yin deficiency and blood heat syndrome: Refer to the Yin deficiency and blood heat syndrome in the "TCM Diagnosis and Treatment Plan for Yin-Yang Toxin (Systemic Lupus Erythematosus)" of the "TCM Clinical Pathways and TCM Treatment Plans for 92 Diseases (2017 Edition)". (4) Age 18-65 years, with stable vital signs; (5) No glucocorticoid pulse therapy was received within 30 days prior to enrollment, and the treatment regimen was stable: moderate or lower dose of glucocorticoids (prednisone equivalent ≤ 0.5 mg / kg·d) combined with conventional dose of hydroxychloroquine sulfate, with regular follow-up.

[0042] 2.3 Exclusion Criteria (1) Those who have received glucocorticoid pulse therapy, cyclophosphamide pulse therapy or intravenous immunoglobulin therapy within the past 30 days, or who need to use moderate or higher doses of glucocorticoids, or who need to use other immunosuppressants except hydroxychloroquine sulfate; (2) Those with serious cardiovascular, brain, liver, lung, kidney and hematopoietic system diseases, acute and chronic infectious diseases, malignant tumors or serious mental illness; (3) Those who are intolerant to traditional Chinese medicine, glucocorticoids or hydroxychloroquine sulfate, or who have serious eye diseases such as retinopathy; (4) Other circumstances where the researchers deem it unsuitable for enrollment.

[0043] 2.4 Elimination Criteria (1) Those who, after enrollment, are found to have seriously violated the inclusion criteria or met the exclusion criteria, and whose actions directly affect the validity or safety evaluation of the trial results; (2) Those who did not use any medication after enrollment; (3) Those who had no data available for analysis after enrollment; 2.5 Termination Criteria for the Study The entire study may be terminated if any of the following conditions occur: (1) Discovery of major safety issues, significantly insufficient efficacy, or major errors in the protocol; (2) Unable to continue due to reasons such as funding or management; (3) The administrative department may revoke the test, etc.

[0044] 2.6 Randomization and Blinding A central randomization system was used to implement randomization to reduce selection bias. The study employed a double-blind design, meaning neither researchers nor participants were aware of the group assignments. The randomization protocol was generated and the blinded data was sealed by an independent statistical unit using SAS software and stored at the drug clinical management center or research management department. Personnel involved in the development and storage of the randomization protocol were not involved in randomization, clinical treatment, or efficacy evaluation, ensuring allocation secrecy and isolation of responsibilities.

[0045] 2.7 Treatment Plan 2.7.1 Intervention Measures ① Control group: Based on the medication recommendations for mild to moderate active SLE proposed by the European League Against Rheumatism (EULAR) in 2019 and the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus, prednisolone acetate tablets + hydroxychloroquine sulfate tablets were selected, and placebo granules were administered orally.

[0046] ② Treatment group: Chinese medicine granules (Qingbai Chidan granules from Example 3) + prednisone acetate tablets + hydroxychloroquine sulfate tablets.

[0047] Both groups received continuous treatment for 24 weeks.

[0048] 2.7.2 Research Drugs ① Traditional Chinese Medicine Granules: Qingbai Chidan granules are made from herbs such as Rehmannia glutinosa, Artemisia annua, Hedyotis diffusa, and Paeonia lactiflora. Each box contains 7 granules. Take one granule orally with boiled water half an hour after meals, twice a day. Manufacturer: Sichuan Xinlvse Pharmaceutical Technology Development Co., Ltd.

[0049] ② Placebo granules: The main ingredient is dextrin, containing 5% traditional Chinese medicine components, and colored with caramel. The appearance, color, taste, smell, and packaging are identical to the treatment drug, and the method of administration is the same. Manufacturer: Sichuan Xinlvse Pharmaceutical Technology Development Co., Ltd.

[0050] ③ Prednisolone acetate tablets: Oral administration, ≤0.5mg / (kg·d) (the specific dosage and withdrawal plan are selected according to the condition), specification: 5mg / tablet, manufacturer: Tianjin Lisheng Pharmaceutical Co., Ltd., national drug approval number H12020123.

[0051] ④ Hydroxychloroquine Sulfate Tablets: Oral administration, 200mg, twice daily. Specification: 200mg / tablet, Manufacturer: Shanghai Shangyao Zhongxi Pharmaceutical Co., Ltd., National Drug Approval Number H19990263.

[0052] 2.7.3 Management of Combined Medication Use During the trial, if gastrointestinal discomfort, abnormal liver function, infection, or abnormal bone metabolism occur, symptomatic treatments such as proton pump inhibitors, hepatoprotective drugs, antibiotics, calcium supplements, or drugs that regulate bone metabolism are permitted, and the drug name, dosage, and course of treatment must be fully recorded. No new biologics or other immunosuppressants may be added during the study, and no other traditional Chinese medicine or decoctions for treating SLE may be used; if adjustments to the glucocorticoid dosage are necessary due to disease activity, this must be recorded and included in the statistical analysis.

[0053] 2.8 Observation Indicators 2.8.1 Key Outcome Indicators The primary outcome measure was the SLEDAI-2000 score and its percentage decrease from baseline, as detailed in Table 1. Disease activity was stratified as follows: 0-6 points indicated mild activity, 7-12 points indicated moderate activity, and >12 points indicated severe activity.

[0054] Table 1 Systemic lupus erythematosus disease activity score

[0055] 2.8.2 Secondary Outcome Indicators Secondary outcome measures included the rate of change in TCM syndrome efficacy scores and efficacy grade, and the incidence of infection events.

[0056] The efficacy of TCM syndrome differentiation was evaluated using the rate of change in syndrome scores, calculated as [(pre-treatment score - post-treatment score) / pre-treatment score] × 100%. Efficacy was determined according to the relevant standards in the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (2002)": Clinical remission was defined as the disappearance or near-disappearance of TCM clinical symptoms and signs, with a ≥95% reduction in syndrome scores; significant improvement in TCM clinical symptoms and signs, with a ≥70% reduction in syndrome scores; effective treatment was defined as improvement in both TCM clinical symptoms and signs, with a ≥30% reduction in syndrome scores; and ineffective treatment was defined as no significant improvement in TCM clinical symptoms and signs, or even worsening, with a <30% reduction in syndrome scores. The quantitative scoring table for TCM syndrome score grading is shown in Table 2.

[0057] Table 2. Quantitative Scoring Table for TCM Syndrome Grading

[0058] The infection event rate is calculated as [number of infection events / total number of cases] × 100%.

[0059] 2.8.3 Safety Evaluation Indicators This includes routine blood / urine tests, biochemical function tests (liver and kidney function, blood lipids, creatine kinase, etc.), records of concurrent medications, and adverse events.

[0060] 2.9 Visit and Testing Timing The study included a screening period (-7 to 0 days), an enrollment period (0 days), a first follow-up (4 weeks ± 3 days), a second follow-up (12 weeks ± 5 days), and an endpoint visit (24 weeks ± 7 days). The examinations performed at each visit were conducted according to the study flowchart (see Table 3).

[0061] Table 3 Research Flowchart

[0062] (1) Screening period: routine blood test, routine urine test, CRP, ESR, 24-hour urine protein quantification, anti-dsDNA antibody, biochemical tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea (Urea), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), creatine kinase (CK), C3, C4, ACTH and COR assays; past medical history and medication history; (2) Enrollment period: SLEDAI-2000; Traditional Chinese Medicine syndrome scoring; (3) First follow-up: blood pressure, heart rate, routine blood and urine tests, CRP, biochemical tests (ALT, AST, Cr, Urea); infection events; adverse events and records of concomitant medications; (4) Second follow-up: blood pressure, heart rate, routine blood and urine tests, CRP, ESR, 24-hour urine protein quantification, anti-dsDNA antibody, biochemical tests (ALT, AST, Cr, Urea, CK, C3, C4); SLEDAI-2000; TCM syndrome score; infection events; adverse events and records of combined medications; (5) Endpoint visit: blood pressure, heart rate, electrocardiogram, routine blood and urine tests, 24-hour urine protein quantification, CRP, ESR, anti-dsDNA antibody, biochemical tests (ALT, AST, Cr, Urea, TC, TG, LDL-C, HDL-C, CK, C3, C4), ACTH measurement and COR measurement; SLEDAI-2000; TCM syndrome score; infection events; adverse events and concomitant medication records.

[0063] 2.10 Adverse Event Monitoring Adverse events were continuously monitored throughout the study, and their relevance to the study drug was assessed. An adverse event (AE) was defined as any adverse medical event occurring after a subject received the study intervention, and its occurrence was not necessarily causally related to the study treatment. All adverse events were recorded in the original data and transcribed into the case report form (CRF), with follow-up continuing until the event resolved or the condition stabilized. Management of adverse events included: no treatment, dose adjustment or short-term discontinuation of the drug, permanent discontinuation, administration of concomitant medications, non-pharmacological treatments, and hospitalization or extended hospitalization. At each follow-up visit, the investigator proactively inquired about and recorded all adverse events that occurred since the last visit and their outcomes, including whether they resolved, their severity, and frequency.

[0064] 2.11 Statistical Analysis All statistical analyses employed two-tailed tests, with the significance level set at α. = 0.05. Data processing was performed using SPSS software. Continuous data were described as mean ± standard deviation or median (P25, P75) according to their distribution characteristics, while categorical data were expressed as number of cases and percentages. For inter-group comparisons, continuous data were analyzed using independent samples t-tests if normality and homogeneity of variance were met; otherwise, Wilcoxon rank-sum tests were used. Categorical data were analyzed using χ² tests or Fisher's exact tests. Ordinal data were analyzed using Wilcoxon rank-sum tests. For intra-group comparisons, paired t-tests were used for normally distributed data, and Wilcoxon signed-rank tests were used for non-normally distributed data. For key efficacy endpoints with uneven baseline distribution, baseline correction analysis was further performed: continuous variables were analyzed using analysis of covariance (ANCOVA), and categorical variables were adjusted using the Cochran-Mantel-Haenszel χ² test (CMH χ² test).

[0065] 2.12 Data Management Researchers must complete the Clinical Research Request (CRF) for all enrolled cases (including dropouts). The CRF, after being reviewed and signed by the monitor, should be promptly transferred to the data administrator; modifications are generally not permitted after transfer. A dedicated record should be maintained for data transfer between researchers, monitors, and the data administrator, and this record should be properly preserved. Clinical studies will develop corresponding data safety monitoring plans based on the level of research risk. All adverse events should be meticulously documented, properly managed, and continuously monitored until the event is resolved or the patient's condition stabilizes; serious adverse events and unexpected events should be reported to the ethics committee promptly as required. The principal investigator will periodically conduct a cumulative review of adverse events and, when necessary, assess the risk-benefit profile of the study. Emergency unblinding may be implemented in double-blind trials when absolutely necessary to ensure the safety and rights of participants.

[0066] 2.13 Ethical Requirements This study followed the Declaration of Helsinki and related ethical guidelines, and was approved by the Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (Approval No.: 2023-005-KY-01). All participants signed written informed consent forms.

[0067] 3. Research Results (1) Baseline data Table 4 shows a comparison of baseline characteristics between the control group and the treatment group.

[0068] Table 4 ( ±s)

[0069] A total of 34 patients completed the study (16 in the treatment group and 18 in the control group). After 24 weeks of treatment, the SLEDAI-2000 score in the treatment group decreased significantly from baseline compared to the control group (P=0.017), and the decrease in TCM syndrome score and the overall effective rate (68.8% vs 27.8%) were also significantly better in the treatment group than in the control group (P<0.05). The incidence of urinary tract infection in the treatment group at 24 weeks was significantly lower than that in the control group (6.3% vs 44.4%, P=0.012). No serious adverse events occurred in either group. Specific data are as follows.

[0070] (2) Changes in SLEDAI-2000 scores Table 5 compares the SLEDAI-2000 scores and the percentage decrease from baseline between the control and treatment groups.

[0071] Table 5 [M (P25, P75)]

[0072] Note:* P <0.05.

[0073] (3) Changes in TCM syndrome scores The changes in TCM syndrome scores of the control group and the treatment group at different time points are shown in Table 6.

[0074] Table 6 ( ± s, minutes)

[0075] Note:* P <0.05.

[0076] (4) Infection rate During the follow-up period, the overall infection incidence in both groups was statistically analyzed at 4, 12, and 24 weeks, as shown in Table 7. At 4 weeks, 6 cases (30.0%) were infected in the control group and 7 cases (35.0%) in the treatment group, with no statistically significant difference between the two groups (χ² = 0.114, P = 0.736). At 12 weeks, 11 cases (55.0%) were infected in the control group and 9 cases (45.0%) in the treatment group, with no statistically significant difference between the groups (χ² = 0.400, P = 0.527). At 24 weeks, 8 cases (40.0%) were infected in the control group and 3 cases (15.0%) in the treatment group, showing a decreasing trend in infection incidence in the treatment group (χ² = 3.135, P = 0.077). In conclusion, the combined use of Qingbai Chidan Decoction can effectively reduce the incidence of SLE complicated with infection.

[0077] Table 7 Comparison of overall infection incidence at different time points in the two groups [n (%)]

[0078] Note: The control group included patients with both respiratory and urinary tract infections.

[0079] Further analysis of infection types was conducted, observing the incidence of respiratory and urinary tract infections in both groups during the follow-up period. At 4 weeks, 1 case (5.0%) of respiratory infection was observed in the control group and 3 cases (15.0%) in the treatment group, with no statistically significant difference (χ² = 1.111, P = 0.292); 5 cases (25.0%) and 4 cases (20.0%) of urinary tract infection were observed in the control group and treatment group, respectively, with no statistically significant difference (χ² = 0.143, P = 0.705). At 12 weeks, 3 cases (15.0%) of respiratory infection were observed in the control group and 4 cases (21.1%) in the treatment group, with no statistically significant difference between the two groups (χ² = 0.242, P = 0.622); 11 cases (55.0%) and 5 cases (26.3%) of urinary tract infection were observed in the control group and treatment group, respectively, with no statistically significant difference (χ² = 3.313, P = 0.069). At 24 weeks, there was 1 case of respiratory infection in the control group (5.6%) and 2 cases in the treatment group (12.5%), with no statistically significant difference (χ² = 0.508, P = 0.476); there were 8 cases of urinary tract infection in the control group (44.4%) and 1 case in the treatment group (6.3%), with a statistically significant difference between the groups (χ² = 6.349, P = 0.012).

[0080] Conclusion: This prescription combined with conventional Western medicine treatment can effectively reduce SLE disease activity, improve TCM syndrome scores, and significantly reduce the incidence of infection events, demonstrating good advantages in synergistic efficacy, toxicity reduction, and infection prevention.

[0081] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A traditional Chinese medicine composition for preventing and treating systemic lupus erythematosus with infection, characterized in that, The traditional Chinese medicine composition includes the following raw materials: Artemisia annua, Hedyotis diffusa, Paeonia lactiflora, Paeonia suffruticosa, Astragalus membranaceus, Rehmannia glutinosa, Centella asiatica, Poria cocos.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Artemisia annua 3-60 parts, Hedyotis diffusa 3-60 parts, Paeonia lactiflora 3-30 parts, Paeonia suffruticosa 3-30 parts, Astragalus membranaceus 3-120 parts, Rehmannia glutinosa 3-60 parts, Centella asiatica 3-60 parts, Poria cocos 3-120 parts.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Artemisia annua 10-45 parts, Hedyotis diffusa 10-60 parts, Paeonia lactiflora 5-30 parts, Paeonia suffruticosa 5-30 parts, Astragalus membranaceus 5-60 parts, Rehmannia glutinosa 5-30 parts, Centella asiatica 10-45 parts, Poria cocos 10-30 parts.

4. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Artemisia annua 30 parts, Hedyotis diffusa 30 parts, Paeonia lactiflora 15 parts, Paeonia suffruticosa 15 parts, Astragalus membranaceus 30 parts, Rehmannia glutinosa 15 parts, Centella asiatica 15 parts, and Poria cocos 15 parts.

5. A traditional Chinese medicine compound preparation for the prevention and treatment of systemic lupus erythematosus complicated with infection, characterized in that, The raw materials of the traditional Chinese medicine compound preparation include the traditional Chinese medicine composition according to any one of claims 1-4.

6. The traditional Chinese medicine compound preparation according to claim 5, characterized in that, The dosage forms of the traditional Chinese medicine compound preparations include decoctions, soups, granules, capsules, tablets, powders, pills, or oral liquids.

7. The traditional Chinese medicine compound preparation according to claim 5, characterized in that, The raw materials for the traditional Chinese medicine compound preparation also include pharmaceutically acceptable excipients.

8. The traditional Chinese medicine compound preparation according to claim 6, characterized in that, The dosage form of the traditional Chinese medicine compound preparation is a decoction, and its preparation steps are as follows: Weigh each Chinese herbal medicine ingredient according to the formula, add 6-10 times the weight of water to the total amount of Chinese herbal medicine ingredients, boil under normal pressure for 30-40 minutes, filter to obtain a primary filtrate and a filter residue, add 4-6 times the weight of water to the filter residue, boil under normal pressure for 25-30 minutes, filter, collect the secondary filtrate, mix the two filtrates to obtain the decoction.

9. The traditional Chinese medicine compound preparation according to claim 6, characterized in that, The dosage form of the traditional Chinese medicine compound preparation is granules, and its preparation steps are as follows: Weigh each Chinese herbal raw material according to the formula, add 6-10 times the weight of water to the total Chinese herbal raw materials, soak, heat and reflux for a first extraction, filter, collect the first extract, add 4-6 times the weight of water to the filter residue, heat and reflux for a second extraction, filter, collect the second extract, mix the two extracts, concentrate under reduced pressure to a clear paste with a density of 1.30-1.33 g / ml, add excipients, mix well and make granules.

10. The use of the traditional Chinese medicine composition according to any one of claims 1-4 or the traditional Chinese medicine compound preparation according to any one of claims 5-9 in the preparation of a drug for the prevention and treatment of systemic lupus erythematosus complicated with infection.

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