Application of tofacitinib in preparation of medicine for treating inflammatory knee osteoarthritis

Abstract

The invention relates to an application of tofacitinib in preparation of a medicine for treating inflammatory knee osteoarthritis, and relates to the technical field of biological medicine.Clinical patients are screened, different administration comparison is carried out, continuous treatment is carried out for one year, and clinical symptom evaluation, inflammatory factor detection and safety evaluation are carried out in the treatment period; iconography detection and evaluation before and after treatment find that in middle-aged and elderly inflammatory knee osteoarthritis patients with poor or intolerant curative effect on NSAIDs, tofacitinib (5 mg is adjusted to 5 mg twice a day and once a day if necessary) can significantly relieve pain, improve joint functions and life quality, reduce inflammatory factor level and delay joint structure degeneration, and the tofacitinib is good in safety and free of toxic and side effects. And no serious adverse reaction occurs. The discovery provides a practical basis for clinical application of tofacitinib in the patients, and the tofacitinib has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the use of tofacitinib in the preparation of a medicament for treating inflammatory knee osteoarthritis. Background Technology

[0002] Knee osteoarthritis (KOA) is a common chronic degenerative joint disease among middle-aged and elderly people. The incidence of symptomatic KOA in people over 45 years old in my country is 8.1%. Among them, inflammatory KOA is more difficult to treat because of active synovial inflammation, repeated pain exacerbation, poor response to traditional nonsteroidal anti-inflammatory drugs (NSAIDs), and long-term use of NSAIDs can easily cause gastrointestinal and cardiovascular adverse reactions.

[0003] Tofacitinib is the world's first approved oral Janus kinase (JAK) pathway inhibitor. Its active ingredient is tofacitinib citrate. It exerts anti-inflammatory and immunomodulatory effects by inhibiting the JAK1 and JAK3 signaling pathways, blocking abnormal activation of immune cells and excessive production of inflammatory factors (such as interleukin-6 and tumor necrosis factor-α). It is mainly used to treat adult patients with moderate to severe active rheumatoid arthritis (RA) who are intolerant to or have an inadequate response to methotrexate. Its anti-inflammatory efficacy has been demonstrated in diseases such as rheumatoid arthritis and ankylosing spondylitis, but its therapeutic effect in inflammatory KOA in middle-aged and elderly patients has not yet been confirmed. Summary of the Invention

[0004] The purpose of this invention is to address the above-mentioned problems by providing the use of tofacitinib in the preparation of a medicament for treating inflammatory knee osteoarthritis.

[0005] The use of tofacitinib in the preparation of a medicament for treating inflammatory knee osteoarthritis, wherein the inflammatory knee osteoarthritis is inflammatory knee osteoarthritis (KOA) in middle-aged and elderly patients who have poor response to or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).

[0006] Preferably, in the application solution, the therapeutic effect of tofacitinib includes at least one of the following effects:

[0007] (1) Improves clinical symptoms;

[0008] (2) Reduce the expression levels of inflammatory factors;

[0009] (3) Reduce the depth of suprapatellar bursa effusion and the thickness of the synovium.

[0010] Preferably, tofacitinib is the sole active ingredient in the drug.

[0011] Preferably, the dose of tofacitinib in a single administration of the drug is 5 mg.

[0012] Preferably, the drug is administered 1 to 2 times daily.

[0013] In summary, this application includes at least one of the following beneficial technical effects:

[0014] 1. This application demonstrates that tofacitinib has a therapeutic effect on middle-aged and elderly patients with inflammatory KOA who have poor response to or intolerance to NSAIDs. The treatment duration is one year. During the treatment period, clinical symptoms are monitored and evaluated, inflammatory factors are detected, and safety is monitored. Imaging evaluations are performed before and after treatment.

[0015] 2. This application found that in middle-aged and elderly patients with inflammatory knee osteoarthritis who had poor response to or were intolerant to NSAIDs, tofacitinib (5 mg twice daily, adjusted to 5 mg once daily if necessary) could significantly relieve pain, improve joint function and quality of life, reduce inflammatory factor levels, delay joint structural degeneration, and had good safety with no serious adverse reactions.

[0016] 3. This application represents a new use of a drug, directly utilizing the known safety, pharmacokinetics, and large-scale production data of existing drugs, which greatly shortens the research and development cycle, reduces development costs and clinical translation risks, and provides a new approach for the treatment of inflammatory knee osteoarthritis in middle-aged and elderly patients. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Modifications or equivalent substitutions made by those skilled in the art based on their understanding of the technical solutions of this invention, without departing from the spirit and scope of the technical solutions of this invention, should all be covered within the protection scope of this invention; all scoring rules and testing standards mentioned in the embodiments of this application are based on industry-standard practices, and the Chinese interpretations of English abbreviations without specific explanation are also based on industry-standard knowledge.

[0018] Example 1

[0019] This embodiment investigates the therapeutic effect of tofacitinib on inflammatory KOA in middle-aged and elderly patients who have poor efficacy or intolerance to NSAIDs by screening clinical patients and comparing different drug administrations. During the treatment period, clinical symptoms were assessed, inflammatory factors were detected, and safety was evaluated. Imaging examinations and evaluations were conducted before and after treatment.

[0020] The specific experimental procedure is as follows:

[0021] 1. Screening medical records

[0022] 1.1 Source of Cases

[0023] Clinical data of 66 middle-aged and elderly patients with inflammatory KOA who had poor response to or intolerance to NSAIDs and received treatment at a traditional Chinese medicine hospital from June 2023 to June 2024 were screened. They were randomly divided into a treatment group and a control group, with 33 patients in each group.

[0024] 1.2 Medical Record Inclusion Criteria

[0025] The inclusion criteria are as follows:

[0026] ① Meets the diagnostic criteria for osteoarthritis (KOA) in the 2010 Guidelines for the Diagnosis and Treatment of Osteoarthritis issued by the Chinese Rheumatology Branch of the Chinese Medical Association;

[0027] ② Age 45-65 years old;

[0028] ③ Meets the criteria for inflammatory KOA classification in the 2023 Chinese Expert Consensus on Clinical Drugs for Knee Osteoarthritis issued by the Rheumatology and Immunology Branch of the Chinese Medical Association (based on MOAKs scores: the highest score for Hoffa synovitis or effusion synovitis is 2-3 points, the sum of the two characteristic scores is 5-6 points, or effusion synovitis is 3 points and Hoffa synovitis is 0-1 points).

[0029] ④ The knee joint X-ray shows a KL grade of I-II;

[0030] ⑤ Previous NSAID treatment for more than 1 month with poor efficacy (VAS score decrease <30%) or intolerance (gastrointestinal discomfort, elevated liver enzymes).

[0031] ⑥ Voluntarily sign the informed consent form.

[0032] 1.2 Exclusion criteria for medical records

[0033] The exclusion criteria are as follows:

[0034] ① Comorbid rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, and other rheumatic and immune diseases;

[0035] ② The patient has severe heart disease (such as NYHA class III-IV heart failure), liver or kidney dysfunction (ALT / AST > 2 times the upper limit of normal, creatinine clearance < 60 ml / min), or active peptic ulcers;

[0036] ③ History of tumors, tuberculosis, or severe infection within the past 3 months;

[0037] ④ Women who are pregnant, breastfeeding, or trying to conceive;

[0038] ⑤ Allergic to tofacitinib.

[0039] 1.3 Screening Results and Grouping

[0040] Treatment group: 18 males (54.5%) and 15 females (45.5%); age range 48-65 years, mean (63.6±8.2) years; disease duration 1-8 years, mean (3.5±1.2) years; BMI (26.8±4.0) kg / m²; past medication history: 19 patients had taken meloxicam for more than 6 months, 11 patients had taken diclofenac sodium for more than 6 months, and 3 patients had taken etoricoxib for more than 6 months. All patients discontinued medication due to poor efficacy or adverse reactions such as stomach pain and acid reflux.

[0041] Control group: 17 males (54.5%) and 16 females (45.5%); age 45-65 years, mean (55.7±11.7) years; disease duration 1-8 years, mean (4.0±1.9) years; BMI (28.8±3.3) kg / m²; all treated with NSAIDs for more than 6 months.

[0042] 2. Treatment Plan

[0043] Treatment group: All patients received oral tofacitinib citrate tablets (drug source: Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd., specification 5mg / tablet), with an initial dose of 5mg twice daily, taken with warm water. During treatment, other anti-inflammatory and analgesic drugs should be avoided. Moderate knee joint function exercises (such as leg raises in sitting or lying positions) are permitted, while strenuous exercise and weight-bearing should be avoided. If mild adverse reactions occur (such as gastrointestinal discomfort or fatigue), the dose should be adjusted to 5mg once daily; if still intolerable, the medication should be discontinued.

[0044] Control group: All patients took meloxicam tablets orally (drug source: Chengdu Shuangxin Pharmaceutical Co., Ltd., specification 7.5mg / tablet), with a maintenance dose of 7.5mg once daily, taken with warm water. During treatment, other medications were avoided, and moderate knee joint function exercises (such as leg raises in sitting or lying positions) were allowed. Strenuous exercise and weight-bearing were avoided. If mild adverse reactions (such as gastrointestinal discomfort or fatigue) occurred, the dose could be adjusted to 3.75mg once daily. If the patient still could not tolerate the medication, the medication should be discontinued.

[0045] 3. Observation Indicators

[0046] 3.1 Clinical Indicators

[0047] Pain level: VAS score (Visual Analog Scale, 0-10 points, the higher the score, the more severe the pain).

[0048] Joint function: The WOMAC score (Osteoarthritis Index, 0-96 points, the higher the score, the worse the function) was used.

[0049] Quality of life: The Karnofsky Performance Status Scale (KPS) is used, ranging from 0 to 100 points, with higher scores indicating better quality of life.

[0050] Evaluation timeframes: before treatment, 3 months after treatment, 6 months after treatment, and 1 year after treatment.

[0051] 3.2 Detection of inflammatory factors

[0052] Fasting venous blood was collected to test ESR (Williams erythrocyte sedimentation rate) and CRP (immunoturbidimetric assay). The assessment time was consistent with the clinical indicator assessment time.

[0053] 3.3 Imaging Assessment

[0054] Perform knee ultrasound: measure the depth of suprapatellar bursa effusion and synovial thickness, with assessments performed before treatment and one year after treatment.

[0055] 3.4 Safety Monitoring

[0056] Blood and urine routine tests, liver and kidney function (ALT, AST, creatinine, blood urea nitrogen) were tested at 3 months, 6 months and 1 year of treatment, and adverse reactions (such as infection, gastrointestinal reaction, cardiovascular event, tuberculosis infection, thrombosis, etc.) were recorded.

[0057] 3.5 Statistical Methods

[0058] This study used SPSS 26.0 statistical software to analyze the data. Quantitative data were presented as follows: normally distributed data were expressed as mean ± standard deviation, and between-group comparisons were performed using independent samples t-tests or corrected t-tests (Welcht test), while within-group comparisons were performed using paired samples t-tests. Non-normally distributed data were expressed as median and interquartile range (M[P25, P75]), and between-group and within-group comparisons were performed using the Mann-Whitney U test and the Wilcoxon signed-rank test, respectively. All tests were considered statistically significant with a p-value < 0.05.

[0059] 4. Results

[0060] 4.1 Treatment completion status

[0061] In the treatment group, 27 out of 33 patients (81.8%) completed one year of treatment at the original dose, 2 out of 6.0% had their dose adjusted to 5 mg once daily due to mild gastrointestinal discomfort (the adverse reactions were relieved after the adjustment, and the treatment was continued), and 3 out of 9.1% discontinued the medication midway due to personal reasons (1 relocated and 2 switched to traditional Chinese medicine on their own). No serious discomfort occurred when the medication was discontinued.

[0062] Control group: Of the 33 patients, 29 completed 1 year of treatment (87.8%), and 4 patients discontinued treatment midway due to gastrointestinal adverse reactions (12.1%).

[0063] 4.2 Clinical efficacy

[0064] 4.2.1 Changes in clinical scores

[0065] The changes in the patients' clinical scores before and after treatment are shown in Table 1:

[0066] Table 1. Changes in Clinical Scores During Treatment (x±s, points)

[0067]

[0068] As shown in the table, after 3 months of treatment, the VAS and WOMAC scores of both groups decreased significantly compared with those before treatment (P<0.05), while the KPS score of the treatment group increased significantly (P<0.05). Furthermore, the improvement continued with the extension of treatment time. After 1 year of treatment, the VAS score of the treatment group decreased from (5.10±0.6) points at baseline to (3.03±0.4) points, the WOMAC score decreased from (57.76±8.8) points to (22.83±11.9) points, and the Karnofsky Performance Status (KPS) score increased from (57.59±5.1) points to (75.52±6.3) points. The improvement at each time point (3 months, 6 months, and 1 year) was significantly better than that of the control group (meroxicam). The improvement at 1 year was further consolidated, demonstrating greater advantages in long-term patient management. In the intergroup comparison, the treatment group showed a more significant decrease in levels compared with the control group (P<0.05), indicating that the treatment group had a more prominent therapeutic effect. This suggests that tofacitinib can improve the clinical symptoms of middle-aged and elderly patients with inflammatory KOA who have poor response to or intolerance to NSAIDs.

[0069] 4.2.2 Changes in the expression of inflammatory factors

[0070] Table 2 shows the changes in inflammatory factors during the patient's treatment:

[0071] Table 2. Changes in inflammatory factors before and after treatment (x±s)

[0072]

[0073] As shown in the table, after 3 months of treatment, ESR and CRP levels significantly decreased (P<0.05), and further decreased at 6 months and 1 year. After 1 year of treatment, the treatment group's ESR decreased from baseline (44.90±19.26) mm / h to (7.9±3.5) mm / h, and CRP decreased from (36.52±11.5) mg / L to (1.65±1.1) mg / L, with reductions of 82.4% and 95.5%, respectively, significantly better than the control group (ESR reduction of 65.1% and CRP reduction of 92.3%), by reducing pro-inflammatory factors. This treatment addresses the inflammatory response at its source, unlike traditional NSAIDs such as meloxicam which only block pain signal transduction by inhibiting cyclooxygenase (COX). This explains why the difference in inflammatory factors between the two groups further widened after 6 months of treatment (P < 0.01). In the intergroup comparison, the reduction in levels in the treatment group was more significant, and the difference was significant compared with the control group (P < 0.05), indicating that the treatment group had a more prominent therapeutic effect. This demonstrates that tofacitinib can reduce the expression levels of inflammatory factors in middle-aged and elderly patients with inflammatory KOA who have poor response to or are intolerant to NSAIDs.

[0074] 4.2.3 Imaging assessment

[0075] The changes in imaging parameters of the patients before and after treatment are shown in Table 3:

[0076] Table 3. Changes in imaging parameters before and after treatment (x±s)

[0077]

[0078] As shown in the table, one year after treatment, knee ultrasound revealed a significant reduction in the depth of suprapatellar bursa effusion and the thickness of the synovium compared to before treatment (P<0.05). In the treatment group, the depth of suprapatellar bursa effusion decreased from (9.50±3.9) mm to (1.81±0.8) mm, and the synovial thickness decreased from (4.55±1.9) mm. The synovial thickness decreased to (2.98±1.4) mm, with reductions of 80.9% and 34.5% in the two indicators, respectively, significantly better than the control group (72.5% reduction in effusion depth and 10.7% reduction in synovial thickness). This result is related to the regulatory effect of tofacitinib on cartilage metabolism. The significant thinning of synovial thickness in this study also suggests that it can inhibit synovial hyperplasia and delay the process of joint degeneration. Compared with traditional NSAIDs such as meloxicam, which can only relieve symptoms and cannot prevent further damage to joint structures, tofacitinib highlights its unique value in structural protection. In the intergroup comparison, the reduction in levels in the treatment group was more significant, with a significant difference compared with the control group (P<0.05), indicating that the treatment effect of the treatment group was more prominent. This proves that tofacitinib can reduce the depth of suprapatellar bursa effusion and synovial thickness in middle-aged and elderly patients with inflammatory KOA who have poor efficacy or intolerance to NSAIDs.

[0079] 4.2.4 Safety Monitoring

[0080] Table 4 shows a comparison of safety monitoring between the treatment group and the control group during the treatment period:

[0081] Table 4. Safety Comparison between the Treatment Group and the Control Group

[0082]

[0083] As shown in the table, in the treatment group, 27 out of 33 patients (81.8%) completed the one-year treatment at the original dose, 2 patients (6.0%) completed the treatment after adjusting the dose due to mild gastrointestinal discomfort (acid reflux, abdominal distension), and 3 patients (9.1%) discontinued the medication for personal reasons; only 2 patients had mild gastrointestinal discomfort and 1 patient had mild fatigue. The total incidence of adverse reactions was 9.1% (3 / 33), and all of them did not discontinue the medication and the symptoms were relieved. There were no serious adverse reactions.

[0084] Of the 33 patients in the control group, 29 (87.8%) completed treatment, while 4 (12.1%) discontinued treatment midway due to gastrointestinal adverse reactions, with a total adverse reaction rate of 12.1% (4 / 33). No serious adverse reactions were reported. This difference may be due to the following reasons: tofacitinib does not inhibit COX-1 / 2, thus avoiding damage to the prostaglandin protective barrier of the gastrointestinal mucosa, while NSAIDs often cause gastrointestinal damage due to COX inhibition, especially in middle-aged and elderly patients with underlying gastrointestinal problems.

[0085] The χ² test was used to compare the total incidence of adverse reactions and the treatment completion rate between the two groups. The results showed that there were no statistically significant differences in the total incidence of adverse reactions (χ²=0.15, P>0.05) and the treatment completion rate (χ²=0.38, P>0.05) between the two groups. No infections or cardiovascular events occurred in either group. The treatment group had milder adverse reactions and no cases of drug discontinuation due to adverse reactions, while the discontinuation rate due to adverse reactions in the control group was 12.1%, indicating that the treatment group was better tolerated.

[0086] In summary, in middle-aged and elderly patients with inflammatory knee osteoarthritis who have poor response to or are intolerant of NSAIDs, tofacitinib (5 mg twice daily, adjusted to 5 mg once daily if necessary) significantly relieves pain, improves joint function and quality of life, reduces inflammatory factor levels, and slows joint structural degeneration, with good safety and no serious adverse reactions. This finding provides practical evidence for the clinical application of tofacitinib in this group of patients and has promising application prospects.

Claims

1. Use of tofacitinib in the manufacture of a medicament for the treatment of inflammatory knee osteoarthritis, characterized in that: The inflammatory knee osteoarthritis is middle-aged and old inflammatory knee osteoarthritis (KOA) which is poorly responsive to non-steroidal anti-inflammatory drugs (NSAIDs) or intolerable.

2. Use according to claim 1, characterized in that: The therapeutic effect of the tofacitinib includes at least one of the following effects: (1) improving clinical symptoms; (2) reducing the expression level of inflammatory factors; (3) reducing the depth of suprapatellar bursa effusion and the thickness of synovial membrane.

3. Use according to claim 1, characterized in that: In the medicine, tofacitinib is used as the only effective component.

4. Use according to claim 3, characterized in that: In a single administration dose of the medicine, the dose of tofacitinib is 5 mg.

5. Use according to claim 3, characterized in that: The administration mode of the medicine is 1-2 times per day.

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