Combined pharmaceutical composition for treating Crohn's disease and application thereof

Abstract

The invention discloses a combined pharmaceutical composition for treating Crohn's disease and application of the combined pharmaceutical composition in treating Crohn's disease. The composition comprises an interleukin inhibitor, L-ornithine or pharmaceutically acceptable salt thereof, the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23. According to the combined pharmaceutical composition, the L-ornithine derived from microorganisms or the pharmaceutically acceptable salt of the L-ornithine is combined with the interleukin inhibitor capable of inhibiting interleukin-12 and interleukin-23, so that the combined pharmaceutical composition has a synergistic anti-inflammatory function and can effectively solve the problem of low clinical remission rate of treating Crohn's disease by singly using the ulinamab; and meanwhile, the potential adverse reaction of treating Crohn's disease by singly using the usteronmab can be effectively reduced. According to the application of the combined pharmaceutical composition in treatment of Crohn's disease, a more effective and safer drug choice is provided for treatment of Crohn's disease.

Description

Technical Field

[0001] The present invention relates to a combined pharmaceutical composition for treating Crohn's disease, in particular to a pharmaceutical composition combining an interleukin inhibitor and an amino acid metabolite and application thereof in treating Crohn's disease. Background Art

[0002] Crohn's disease (CD) is a complex chronic inflammatory bowel disease whose etiology is not yet fully understood. Studies have shown that the interaction of genetic susceptibility, immune dysfunction, and environmental factors plays an important role in the pathogenesis of the disease. Ustekinumab (UST) is a fully humanized antibody that targets the interleukin-12 (IL-12) and interleukin-23 (IL-23) pathways, blocking their binding to the corresponding receptors and thereby inhibiting the inflammatory response. Since UST was approved for the treatment of Crohn's disease in the United States and the European Union in 2016, it has achieved widespread clinical application and was approved by Chinese regulators in 2020. Clinical trials have confirmed that UST has a good therapeutic effect on patients with moderate to severe Crohn's disease, especially in patients who have a poor response to traditional treatments or other biologics. In addition, the fully humanized structural design of UST reduces immunogenicity and allergic reactions associated with chimeric antibodies. However, although UST has shown significant clinical potential in the treatment of Crohn's disease, approximately 40% of patients still experience primary non-response or secondary loss of response during treatment.

[0003] Recent studies have found that changes in intestinal microbiota and metabolites may be one of the important factors affecting the therapeutic effect of UST. Metabolites are not only the product of microbial metabolic activities, but also play an important role in regulating host immune and inflammatory responses. In addition, changes in the composition of the intestinal microbiota may change the host's response to drugs by regulating metabolic pathways. This suggests that in the future, when evaluating the efficacy of UST, more attention should be paid to the dynamic changes of intestinal microbiota and metabolites, so as to provide more personalized and precise treatment strategies for Crohn's disease patients.

[0004] L-ornithine is a non-essential amino acid that plays a key role in the urea cycle in the body. It helps to excrete excess ammonia mainly through metabolic cycles with L-arginine and L-citrulline. In addition, L-ornithine is also a precursor for the synthesis of polyamines, which play an important role in cell proliferation, tissue repair and immune regulation. Therefore, L-ornithine is not only crucial in maintaining normal metabolic function, but may also be closely related to inflammatory response. Although the importance of L-ornithine in metabolism and immune regulation is known, its specific mechanism of action in patients with Crohn's disease is still being explored. In particular, in patients receiving ustekinumab (UST), the relationship between changes in L-ornithine levels and drug response is unclear. At present, there is a lack of in-depth research on how L-ornithine affects the efficacy of UST. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies in the above-mentioned prior art and provide a combined pharmaceutical composition with synergistic anti-inflammatory effects, which can significantly improve the clinical remission rate of ustekinumab in the treatment of Crohn's disease. At the same time, the present invention also provides the use of an interleukin inhibitor in combination with L-ornithine or a pharmaceutically acceptable salt thereof for the treatment of Crohn's disease.

[0006] To achieve the above-mentioned purpose, the technical solution adopted by the present invention is: a combination pharmaceutical composition for treating Crohn's disease, the combination pharmaceutical composition comprising an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof; the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

[0007] Preferably, the interleukin inhibitor is ustekinumab.

[0008] In view of the problem that some patients cannot get good relief from ustekinumab treatment during the treatment of Crohn's disease with ustekinumab, the inventors of this application first used multi-omics high-throughput sequencing technology (metagenomics, metabolomics and transcriptomics) to conduct an interactive analysis of "microorganism-metabolite-host phenotype" and found that microbial-derived L-ornithine inhibits the expression of IL12RB1 on Th17 cells and thus inhibits the inflammatory phenotype. Further research has found that compared with the single use of ustekinumab to treat Crohn's disease, the combination of ustekinumab and L-ornithine or its pharmaceutically acceptable salt can effectively solve the low clinical remission rate of ustekinumab and reduce potential adverse reactions.

[0009] Preferably, the pharmaceutically acceptable salt of L-ornithine is L-ornithine hydrochloride. The present invention is used in combination with ustekinumab, and L-ornithine or a pharmaceutically acceptable salt thereof can be used. When a pharmaceutically acceptable salt of L-ornithine is selected, L-ornithine hydrochloride is preferred but not limited thereto.

[0010] Preferably, the mass ratio of the interleukin inhibitor to L-ornithine or a pharmaceutically acceptable salt thereof is 1:(400-600). In the pharmaceutical composition, the mass ratio of the interleukin inhibitor to L-ornithine or a pharmaceutically acceptable salt thereof is preferably but not limited to 1:(400-600), for example, it can be any value of 1:400, 1:420, 1:440, 1:460, 1:480, 1:500, 1:520, 1:540, 1:560, 1:580, 1:600 ​​or a value therebetween.

[0011] Preferably, when ustekinumab is used in combination with L-ornithine or a pharmaceutically acceptable salt thereof, the Crohn's disease patient is treated with standardized ustekinumab, and at the same time, the patient is orally administered three L-ornithine capsules per day for 8 consecutive weeks, each capsule containing 500 mg of L-ornithine.

[0012] In a second aspect, the present invention also provides the use of an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination in the preparation of a drug for treating Crohn's disease, wherein the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

[0013] Preferably, the interleukin inhibitor is ustekinumab.

[0014] The present invention provides an application of ustekinumab, L-ornithine or a pharmaceutically acceptable salt thereof in combination for treating Crohn's disease. The inventors of the present application have found through research that the combined application of L-ornithine or a pharmaceutically acceptable salt thereof and ustekinumab can exert a synergistic anti-inflammatory function and effectively improve the clinical remission rate of ustekinumab in treating Crohn's disease, compared with the use of ustekinumab alone to treat Crohn's disease.

[0015] When L-ornithine or a pharmaceutically acceptable salt thereof is used in combination with ustekinumab to treat Crohn's disease, Crohn's disease patients are treated with standardized ustekinumab and simultaneously three L-ornithine capsules are orally taken daily for 8 consecutive weeks, each capsule containing 500 mg of L-ornithine.

[0016] Preferably, the pharmaceutically acceptable salt of L-ornithine is L-ornithine hydrochloride.

[0017] Preferably, the mass ratio of the interleukin inhibitor to L-ornithine or a pharmaceutically acceptable salt thereof is 1:(400-600).

[0018] Preferably, the dosage form of the drug is an oral preparation or an injection. The dosage form of the drug includes but is not limited to an oral preparation and an injection.

[0019] In a third aspect, the present invention also provides the use of an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination in the preparation of an anti-inflammatory drug, wherein the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

[0020] The inventors of the present application have discovered in their research that the combined use of L-ornithine or a pharmaceutically acceptable salt thereof and an interleukin inhibitor, especially the combined use with ustekinumab, can significantly reduce the Th17 cell content and the expression level of Il12rb1 on Th17 cells, thereby exerting a synergistic anti-inflammatory function. The combination of the two provides a new drug option for anti-inflammatory treatment.

[0021] This application comprehensively utilizes multi-omics high-throughput sequencing technology (metagenomics, metabolomics and transcriptomics) to conduct an interactive analysis of "microorganism-metabolite-host phenotype", and found that L-ornithine or its pharmaceutically acceptable salts derived from microorganisms and interleukin inhibitors that can inhibit interleukin-12 and interleukin-23, especially in combination with ustekinumab, have synergistic anti-inflammatory functions, which can effectively improve the low clinical remission rate of Crohn's disease treated with ustekinumab alone, and at the same time can effectively reduce the potential adverse reactions of Crohn's disease treated with ustekinumab alone. The use of the interleukin inhibitor, L-ornithine or its pharmaceutically acceptable salts in the preparation of a drug for treating Crohn's disease according to the present invention provides a more effective and safe drug option for the treatment of Crohn's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 KEGG modules related to microorganisms enriched in CD patients who respond to ustekinumab treatment;

[0023] Figure 2 for metabolites that are enriched in CD patients who respond to ustekinumab treatment;

[0024] Figure 3 Correlation analysis between L-ornithine and IL12 / 23 to JAK / STAT signaling pathway;

[0025] Figure 4 Schematic diagram for comparison of colon lengths of mice in each group;

[0026] Figure 5 This is a comparative diagram of HE staining of the colon of each group of mice;

[0027] Figure 6 The results of flow cytometry sorting of Th17 cells from colon tissues of mice in each group;

[0028] Figure 7 The effect of L-ornithine on the expression of IL12RB1 on Th17 cells;

[0029] Figure 8 Schematic diagram showing the comparison of endoscopic results among the patients in each group. DETAILED DESCRIPTION

[0030] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0031] The sources of the reagents described in the following examples are only for illustrative purposes and are not intended to limit the scope of protection thereof. Other substances whose sources are not specified can be purchased directly or prepared using conventional methods known in the art.

[0032] Example 1

[0033] Screening process of the combined drug composition for treating Crohn's disease according to the present invention

[0034] The combined pharmaceutical composition for treating Crohn's disease of the present invention is obtained by multi-omics analysis, and specifically comprises the following steps:

[0035] 1. Sample collection and sequencing

[0036] This example relies on the clinical and scientific research platform of the Department of Gastroenterology of Renji Hospital Affiliated to Shanghai Jiaotong University and the Department of Gastroenterology of the Third Xiangya Hospital Affiliated to Central South University, and collected stool samples from 85 Crohn's disease patients (CD) who were about to receive standard therapy of ustekinumab (UST) (the first injection dose was 6 mg / kg, and then 90 mg was subcutaneously injected every 8 weeks) for metagenomic sequencing to evaluate the effect of intestinal microorganisms on the efficacy of UST. Among them, 48 patients also collected intestinal mucosal samples, so the inventors of this application also performed targeted metabolomics and bulk-RNA sequencing on the stool samples and intestinal mucosal samples of these 48 patients.

[0037] 2. Data Analysis

[0038] Metagenomic data: The BioBakery shotgun workflow was used to generate taxonomic and functional profiles. To obtain high-quality microbial sequences, host sequences were first filtered using KneadData. Taxonomic analysis was completed using MetaPhlAn3, and functional analysis was obtained using HUMAnN3 with default parameters. For those sequences that were not classified at the nucleotide level, a translation search based on the UniRef90 protein sequence catalog was subsequently performed to generate the final gene family abundance table stratified by species contribution. Next, the gene families were mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) KOs. To facilitate the interpretation of the functions of the KOs, we mapped the KOs to KEGG modules.

[0039] In this embodiment, the TopHat-HTSeq-DeSeq2 framework is used to analyze Bulk-RNA sequencing data to achieve accurate transcriptome expression analysis. First, the RNA-Seq data is compared with the reference genome by the TopHat tool to identify and annotate transcripts containing splicing variations, providing accurate positioning information for subsequent analysis. Then, the HTSeq comparison results are counted to generate an expression table for each gene to ensure the quantitative accuracy of the expression level. Subsequently, DESeq2 standardizes the count data, and evaluates the differences in gene expression under different experimental conditions through statistical models (such as negative binomial distribution), identifying genes that are significantly upregulated or downregulated.

[0040] In this study, MultiQuant and Analyst software were used to analyze metabolomics data, providing powerful data processing and quantitative analysis capabilities. First, MultiQuant software was used to process and quantitatively analyze raw mass spectrometry data. It can extract characteristic signals from complex metabolite peak graphs, perform peak detection, baseline correction, and noise removal, thereby obtaining high-quality metabolite quantitative data. Analyst software is used for further advanced analysis and data visualization. With this software, researchers can identify and annotate metabolites, compare metabolite changes in different samples or experimental conditions, use statistical methods to identify differential metabolites, and reveal changes in metabolic networks through multidimensional analysis (such as principal component analysis PCA and cluster analysis).

[0041] 3. Multi-omics analysis results

[0042] According to the Crohn's Disease Activity Index (CDAI), the inventors of this application evaluated the differences in KEGG modules and metabolite composition between CD patients who achieved clinical remission (n=43) and those who did not achieve clinical remission (n=42) after receiving UST standard therapy. The results are shown in the attached Figure 1 As shown. Figure 1 It can be seen that the KEGG modules related to amino acid metabolism are significantly enriched in the clinical remission group, including KEGG modules such as Ornithine biosynthesis, Arginine and proline metabolism, and Cysteine ​​and methionine metabolism.

[0043] In addition, it is interesting that, through the analysis of metabolomics data, the inventors of the present application found that metabolites of various amino acids were significantly enriched in patients with clinical remission, as shown in the attached Figure 2 shown.

[0044] Among the metabolites enriched in the clinical remission group, L-ornithine can be associated with the microbial-related KEGG module (Ornithine biosynthesis). Therefore, the inventors of the present application speculate that microbial-driven L-ornithine synthesis may play a vital role in the UST treatment response of CD patients. Figure 3 As shown in the attached Figure 3 It can be seen that L-ornithine showed a significant negative correlation with the IL12 / 23to JAK / STAT signaling pathway, which is closely related to the therapeutic effect of UST.

[0045] The above data suggest that L-ornithine may exert a synergistic anti-inflammatory function with UST, which improves the clinical remission rate of UST treatment.

[0046] Example 2

[0047] Animal experiment on the combined drug composition of the present invention for treating Crohn's disease

[0048] This example uses an animal model experiment to examine the effect of L-ornithine combined with ustekinumab in treating Crohn's disease, which specifically includes the following steps:

[0049] 1. Animal model making

[0050] Five-week-old C57BL / 6 male mice were purchased from Jiangsu Jicui Pharmaceutical (Jiangsu, China). All mice were housed in an SPF-grade environment at the Animal Center of Renji Hospital, Shanghai Jiao Tong University School of Medicine. To avoid the influence of dietary L-ornithine on the experimental results, 5-week-old mice were fed a diet without L-ornithine (AIN93G, Dyets, USA) for 7 days before colitis induction. For the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis model, the modeling method was as follows: 150 μL of TNBS sensitization solution was applied to the back of the shaved mice for immunization, and 7 days later, 100 μL of 2.5% (w / v) TNBS containing 50% ethanol was administered rectally through a catheter at 4 cm. Mice in the UST-treated group were injected with 0.1 mg / 1 mg UST on day 0, and 400 mg / kg L-ornithine hydrochloride was gavaged daily starting from the first day of TNBS induction. Colon histology was performed on day 4 after TNBS treatment. The animal experiments were approved by the Ethics Committee of Renji Hospital, and the experimental protocol number was 21-E-05.

[0051] 2. Animal model grouping

[0052] According to the needs of the experimental design, the animal models were randomly divided into Control group (normally raised mice), TNBS group, TNBS+L-ornithine group, TNBS+0.1mg UST group, TNBS+0.1mg UST+L-ornithine group, TNBS+1mg UST group and TNBS+1mg UST+L-ornithine group, with 10 mice in each group.

[0053] 3. Experimental testing process

[0054] (1) Colon length measurement: At the end of the experiment, the mice were anesthetized and killed, and the colon was dissected out and gently straightened along the mesenteric axis. The colon was rinsed with saline and excess tissue was removed. The total length of the colon from the cecum to the rectum was measured using a ruler and the data were recorded for the assessment of the degree of colon damage.

[0055] (2) HE tissue staining: The mouse colon tissue was fixed in 10% neutral formalin solution, then dehydrated, embedded, and 4 μm thin sections were made using a paraffin slicer. The thin sections were dewaxed with xylene and dehydrated with gradient ethanol, and then stained with hematoxylin and eosin (HE). After staining, the changes in tissue structure were observed under a microscope, with a focus on evaluating pathological features such as inflammatory cell infiltration, epithelial cell damage, and tissue edema.

[0056] (3) Flow cytometry results: Mouse colon tissue or related lymph nodes were obtained to prepare single cell suspensions. Cd4 antibody was used for cell surface staining and Il-17a antibody was used for intracellular staining. Then, flow cytometry was used to detect the content of Th17 cells.

[0057] 4. Experimental results

[0058] On the 4th day after each group of mice were treated with the above method, the inventors of the present application conducted colon histological examination. The results are shown in the attached figure. Figure 4 As shown. Figure 4 It can be seen that the use of L-ornithine significantly reduced the TNBS-induced reduction in colon length, and L-ornithine and UST exerted a synergistic effect.

[0059] At the same time, the inventors of the present application conducted pathological examinations on each group of mice, and the results are shown in the attached Figure 5 As shown. Figure 5 The results also show that L-ornithine and UST exert synergistic anti-inflammatory functions.

[0060] At the same time, the loss sorting is carried out, and the results are as shown in the attached Figure 6 As shown. Figure 6 It can be seen that L-ornithine can significantly reduce the cell content of Th17.

[0061] Example 3

[0062] Cell experiment on the combined drug composition of the present invention for treating Crohn's disease

[0063] This example uses a cell model experiment to investigate the effect of L-ornithine combined with ustekinumab in treating Crohn's disease, which specifically includes the following steps:

[0064] 1. Cell model preparation

[0065] Naive CD4+T cells were isolated from mouse spleens using a mouse naive CD4+T cell isolation kit (STEMCELL), cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin-streptomycin, and activated for 24 hours with anti-CD28 (Bio X Cell) and plate-bound anti-CD3 (Bio X Cell). To induce T cell polarization, naive CD4+T cells were seeded in culture plates and cultured under the following Th17 polarization conditions:

[0066] Control group (Control): 20 ng / mL IL-6, 2.5 μg / mL anti-IL-4, 2.5 μg / mL anti-interferon-γ, 0.3 ng / mL TGF-β.

[0067] L-Ornithine treatment group (L-Ornithine): 20 ng / mL IL-6, 2.5 μg / mL anti-IL-4, 2.5 μg / mL anti-interferon-γ, 0.3 ng / mL TGF-β, 1 mM L-ornithine.

[0068] Anti-mouse IL-4 and anti-mouse IFNγ antibodies were from Bio X Cell, and mouse IL-6 and TGF-β were from PeproTech.

[0069] 2. Experimental process and results

[0070] The mRNA experiments were performed on the extracted Th17 cells as follows: Total RNA was extracted from the cells using Trizol reagent (Takara, Japan). Reverse transcription was performed using the PrimeScript RT kit (Takara, Japan). The mRNA expression level of Il12rb1 was calculated using the 2-ΔΔCt method based on the Ct value obtained from the StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA), with β-actin as an internal reference. The results are shown in the attached figure. Figure 7 shown.

[0071] By the attached Figure 7 It can be seen that L-ornithine significantly reduced the expression level of Il12rb1 on Th17 cells.

[0072] Example 4

[0073] Clinical trial of the combined drug composition of the present invention for treating Crohn's disease

[0074] A randomized controlled clinical trial using the combined drug composition of the present invention specifically includes the following steps:

[0075] 1. Patient grouping

[0076] Relying on the gastroenterology platform of the Third Xiangya Hospital affiliated to Central South University, the inventors of this application conducted a single-center, randomized controlled clinical study on the effect of L-ornithine on the efficacy of UST in CD patients (ClinicalTrials.gov ID: NCT06455267). This example recruited 16 CD patients and randomly divided them into two groups, an L-ornithine supplementation group and a control group, with 8 people in each group. The treatment conditions of each group are as follows:

[0077] L-Ornithine supplementation group (UST+L-Ornithine): Patients received standardized UST treatment for 8 weeks and took three L-ornithine capsules orally twice a day for 8 consecutive weeks, each capsule containing 500 mg of L-ornithine.

[0078] Control group (UST): patients only received standardized UST treatment for 8 weeks.

[0079] The control group received only standardized UST treatment for 8 weeks, and the Harvey-Bradshaw index (HBI) was significantly reduced, but endoscopic remission was not achieved. The primary outcome measure for both groups was the use of endoscopic scores.

[0080] 2. Experimental results

[0081] The endoscopic scoring results of the two groups are shown in the attached Figure 8 As shown in the attached Figure 8 It can be seen that the endoscopic lesions in the same segment of patients supplemented with L-ornithine were more significantly improved and the endoscopic scores were more significantly reduced.

[0082] The above statistics and data analysis were performed in R (version 4.3.1, https: / / cran.r-project.org / ) and Graphpad Prism (version 8.0.1). For normally distributed data, the independent sample t test was used to compare the measurement data between the two groups, otherwise a non-parametric test was used. The statistical test was a two-tailed test, and P < 0.05 was considered statistically significant.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A combined pharmaceutical composition for treating Crohn's disease, characterized in that: The combined pharmaceutical composition comprises an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof; The interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

2. The combined pharmaceutical composition for treating Crohn's disease according to claim 1, characterized in that: The interleukin inhibitor is ustekinumab.

3. The combined pharmaceutical composition for treating Crohn's disease according to claim 1, characterized in that: The pharmaceutically acceptable salt of L-ornithine is L-ornithine hydrochloride.

4. The combined pharmaceutical composition for treating Crohn's disease according to claim 1, characterized in that: The mass ratio of the interleukin inhibitor to L-ornithine or a pharmaceutically acceptable salt thereof is 1:(400-600).

5. Use of an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination for preparing a drug for treating Crohn's disease, wherein the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

6. Use of the interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination with the preparation of a medicament for treating Crohn's disease as claimed in claim 5, characterized in that: The interleukin inhibitor is ustekinumab.

7. Use of the interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination with the preparation of a medicament for treating Crohn's disease as claimed in claim 5, characterized in that: The pharmaceutically acceptable salt of L-ornithine is L-ornithine hydrochloride.

8. Use of the interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination in the preparation of a medicament for treating Crohn's disease as claimed in claim 5, characterized in that: The mass ratio of the interleukin inhibitor to L-ornithine or a pharmaceutically acceptable salt thereof is 1:(400-600).

9. The use of the interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination for preparing a medicament for treating Crohn's disease as claimed in claim 5, characterized in that: The dosage form of the medicine is oral preparation or injection.

10. Use of an interleukin inhibitor, L-ornithine or a pharmaceutically acceptable salt thereof in combination in the preparation of an anti-inflammatory drug, wherein the interleukin inhibitor is a substance capable of inhibiting interleukin-12 and interleukin-23.

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