Evaluation of Tofacitinib Efficacy in Psoriatic Arthritis: A Stratification Study Using Clinical, Transcriptomic, Metabolomic, and Proteomic Data

The primary objective of this study is to identify pre-treatment profiles that integrate clinical, transcriptomic, metabolomic, proteomic, flow cytometric, and imaging data to predict the response to treatment with **tofacitinib** in patients with psoriatic arthritis (PsA) who are either DMARD-naïve or DMARD non-responsive. This objective is clinically relevant as it aims to enhance personalized treatment strategies by identifying biomarkers that can predict therapeutic outcomes, thereby optimizing patient management and improving clinical efficacy.

Secondary objectives include:

• Comparing the clinical efficacy of treatment with tofacitinib, methotrexate, and etanercept in DMARD-naïve and DMARD-non-responsive patients with active PsA.
• Determining medication-specific molecular mechanisms that predict and underlie the clinical response to tofacitinib in comparison to methotrexate and etanercept in active PsA.

The clinical trial focuses on individuals diagnosed with **psoriatic arthritis**, aiming to identify pre-treatment profiles that predict response to treatment with tofacitinib. The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a disease duration of at least 8 weeks and evidence of active arthritis, characterized by at least two swollen and two tender joints. The trial includes two groups: those who are DMARD-naïve and those who are non-responsive to DMARDs. Participants in the csDMARD-IR group must be on a stable dosage of methotrexate, sulfasalazine, or leflunomide for at least four weeks prior to randomization. The trial excludes individuals with a history of tsDMARD therapy use. Participants must meet the CASPAR criteria for psoriatic arthritis and discontinue active psoriasis treatment before enrollment. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **tofacitinib** in patients with **psoriatic arthritis**. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to span a duration of approximately seven years, with an estimated end date in May 2025. Participants will be involved in the study for a maximum treatment period of 16 weeks. The trial includes several key phases, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease duration, and prior treatment history. Participants must meet the CASPAR criteria for psoriatic arthritis and demonstrate active arthritis with at least two swollen and tender joints.

Following the screening, eligible participants will be randomized into one of two arms: the csDMARD-naïve group or the csDMARD-IR group. The study involves multiple follow-up visits, including assessments at weeks 4 and 16, to monitor changes in molecular network profiles and clinical disease activity scores. The primary endpoint is achieving Minimal Disease Activity (MDA) at week 16, while secondary endpoints include changes in molecular networks and clinical parameters such as PASI score, joint count, and quality of life measures. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment response and safety.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to identify pre-treatment profiles that predict response to tofacitinib, integrating clinical, transcriptomic, metabolomic, proteomic, flow cytometric, and imaging data. This research is crucial for understanding the immunological factors influencing treatment efficacy in psoriatic arthritis, potentially guiding personalized therapeutic strategies in the future.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Folic acid, anhydrous** is provided in the form of **Foliumzuur Aurobindo 5 mg tablets**. This medication is administered orally with a maximum daily dose of 1.5 mg and a total maximum dose of 160 mg over a treatment period of 16 weeks. The pharmaceutical form is a tablet, and the product is manufactured by Aurobindo Pharma B.V. in the Netherlands. Participant compliance is monitored to ensure adherence to the dosing schedule.

**Tofacitinib**, marketed as **XELJANZ 5 mg film-coated tablets**, is the primary experimental medication in this trial. It is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 1120 mg over a 16-week period. The film-coated tablet form is designed to facilitate oral administration, and the product is manufactured by Pfizer Europe MA EEIG. Compliance with the dosing regimen is closely monitored to assess the efficacy of the treatment in Psoriatic Arthritis (PsA) patients.

**Methotrexate disodium** is provided as **METHOTREXAAT SANDOZ 2.5 mg tablets**. This medication is administered orally with a maximum daily dose of 3.5 mg and a total maximum dose of 360 mg over 16 weeks. The tablets are produced by Sandoz B.V. in the Netherlands. Participant adherence to the dosing schedule is monitored to ensure accurate assessment of treatment outcomes.

**Etanercept** is administered as **Enbrel 50 mg solution for injection in a pre-filled syringe**. This protein-based medication is delivered via injection with a maximum daily dose of 50 mg and a total maximum dose of 800 mg over the course of 16 weeks. The product is manufactured by Pfizer Europe MA EEIG. Injection administration is monitored to ensure proper technique and compliance.

**Methotrexate** is also available in injectable form, provided as **Methotrexaat Teva 25.0 mg, 20.0 mg, and 15.0 mg solutions for injection in pre-filled pens**. These solutions are administered via injection with a maximum daily dose of 3.5 mg and a total maximum dose of 360 mg over 16 weeks. The products are manufactured by Teva Nederland B.V. Compliance with the injection schedule is monitored to ensure accurate dosing and assessment of treatment efficacy.

The efficacy of the clinical trial titled "TOFA-PREDICT" will be assessed using both primary and secondary endpoints. The primary endpoints include achieving **Minimal Disease Activity (MDA)** at week 16 and establishing a baseline molecular network profile through composite systems medicine analysis. Secondary endpoints will evaluate changes in the molecular network before and after treatment at weeks 4 and 16, as well as changes in composite clinical disease activity scores, such as MDA, ACR (20, 50, 70) response, and DAS28 at week 16. Additionally, changes in individual clinical parameters that contribute to these composite scores, including PASI score reductions (50%, 75%, 90%), joint count, **C-reactive protein (CRP)**, erythrocyte sedimentation rate (ESR), and quality of life measures, will be assessed at week 16.