Methotrexate Combined With Tofacitinib in Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title: Methotrexate Combined With Tofacitinib in the Treatment of Active Rheumatoid Arthritis With a Myeloid-stromal Pathotype: a Randomized, Controlled, Open Label, Multicenter Clinical Study

Status Not yet recruiting

Clinical Trial Summary

Rheumatoid arthritis (RA) is the leading cause of disability in Chinese women. We established a synovial pathology queue in the early stage and proposed a new synovial immunopathology classification. We found that baseline myeloid stromal RA patients had severe conditions and poor outcome. Early identification of synovial myeloid stromal RA patients and intensified treatment are key to improving RA efficacy.

This project aims to conduct a randomized, controlled, open label, multicenter clinical study on early intensified treatment of RA based on synovial pathology classification. 130 adult patients with synovial myeloid stromal type of primary treatment moderate to severe active RA were planned to be enrolled in three centers: Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University; Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, and Guangzhou Panyu Central Hospital. They were randomly divided into an intensive treatment group and a conventional treatment group in a 1:1 ratio. The intensive treatment group was treated with methotrexate combined with tofacitinib, while the conventional treatment group was treated with methotrexate monotherapy. The expected intervention period is 12 weeks, with a follow-up period of 48 weeks. The primary endpoint is the proportion of subjects who achieved ACR20 at week 12. Secondary endpoint indicators include improvement in disease activity and joint function among subjects at different follow-up points, safety, and the proportion of subjects who experienced joint destruction progression at week 48.

This project proposes the concept of achieving precise diagnosis of RA based on synovial pathology classification, and explores the efficacy of early methotrexate combined with tofacitinib intensified treatment for patients with synovial medullary stromal RA who have poor conventional treatment efficacy, providing high-level clinical evidence for achieving precise initial treatment of RA treatment guidelines.

Clinical Trial Description

Rheumatoid arthritis (RA) is the leading cause of disability in Chinese women, but it cannot be cured. About 25%-40% of RA patients experience bone erosion within 6 months after experiencing joint symptoms. The first year after the onset of RA is the best window of treatment opportunity, and the earlier standardized treatment is initiated, the more effective RA treatment will be. RA patients have strong heterogeneity and lack effective evaluation indicators for early identification of patients with poor prognosis. Therefore, currently, domestic and foreign RA treatment guidelines do not include adverse prognostic factors in the initial stage. All RA patients are recommended to start treatment with methotrexate (MTX) monotherapy. If the improvement is not good after 3 months or does not meet the standard after 6 months, csDMARDs or targeted drug biologics or JAK inhibitors should be combined. However, clinical studies have found that the effective rate of MTX monotherapy after 3 months is only 30% to 50%, and most patients require combination therapy.

The pathological basis of RA is synovitis. In the early stage, we established a synovial pathology cohort and proposed a new synovial immunopathology classification. We found that baseline medullary stromal type (58%) RA patients had severe conditions, poor efficacy, and a risk of joint destruction progression after 1 year of imaging was 3.2 times higher than other types (Front Immunol, 2021), Among them, the efficacy of combining traditional synthetic DMARDs or biological agents for 3 months in the treatment of newly treated synovial medullary stromal RA patients is not as good as other types of patients [the core criteria for RA disease activity assessment of the American Society of Rheumatology reached 20% improvement (ACR20): 52% vs. 75%]. Therefore, early identification of patients with synovial myeloid stromal RA and intensified treatment are key to improving the efficacy of RA.

The plan for intensified treatment of RA includes the combination of MTX and biological agents or JAK inhibitors, where biological agents only target specific immune cells or cytokines, are expensive, require intravenous medication, and are prone to producing anti drug antibodies. JAK inhibitors can target JAK related inflammatory pathways in different cells, are convenient to take orally, and do not produce anti drug antibodies. The JAK inhibitors that have been listed in China include tofacitinib, Barretinib, and Upatinib. Among them, tofacitinib has the longest use time, good efficacy and safety, and is affordable after national centralized procurement, with strong promotability.

The characteristic of medullary stromal synovium is multicellular activation, which can secrete inflammatory factors and a large amount of matrix metalloproteinases (MMPs). It has been reported that tofacitinib can inhibit the production of synovial MMP-3. Our preliminary retrospective analysis showed that in RA patients with poor efficacy of csDMARDs or biologics, MTX combined with tofacitinib was used for treatment for 3 months, resulting in a 56% ACR20 and a significant decrease in serum MMP-3. This suggests that MTX combined with tofacitinib can be used as an intensive treatment for synovial myeloid stromal RA patients.

Based on this, we propose clinical questions: Synovial immunopathological classification helps to achieve accurate diagnosis of RA. Can MTX combined with tofacitinib intensive treatment be applied to newly treated RA patients with synovial myeloid stromal type to achieve early disease control?

This project aims to conduct a randomized, controlled, open label, multicenter clinical study on early intensified treatment of RA based on synovial pathology classification. 130 newly treated adult patients with moderate to severe active rheumatoid arthritis (RA) of the synovial medullary matrix type were randomly divided into an intensive treatment group and a conventional treatment group in a 1:1 ratio. The intensive treatment group was treated with MTX combined with tofacitinib, while the conventional treatment group was treated with MTX monotherapy. The expected intervention period is 12 weeks, with a follow-up period of 48 weeks. The primary endpoint is the proportion of subjects who achieved ACR20 at week 12. Secondary endpoint indicators include improvement in disease activity and joint function among subjects at different follow-up points, safety, and the proportion of subjects who experienced joint destruction progression at week 48. The exploratory objective (sub topic) is to apply proteomics to screen serum biomarkers in patients with synovial myeloid stromal RA and establish a precise diagnostic system.

This project is based on the applicant's long-term research on synovial pathology of RA, proposing the concept of achieving accurate diagnosis of RA based on synovial pathology classification. At the same time, it aims to explore the efficacy of early MTX combined with tofacitinib in patients with synovial medullary stromal RA who have poor conventional treatment efficacy, providing high-level clinical evidence for achieving precise initial treatment of RA treatment guidelines. ;

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

• NCT number: NCT06301373
• Study type: Interventional
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 1, 2024
• Completion date: April 1, 2030