Evaluation of Pain Sensitization in Rheumatoid Arthritis: Analysis on a Cohort of Tofacitinib Treated Patients (TOPRA)

Persistent pain and chronic fatigue are very common complaints in rheumatoid arthritis (RA) patients, whatever the anti-inflammatory treatment response. Interestingly, pain remaining despite good clinical response was associated with high disability and low inflammation at baseline, suggesting a mechanism of pain independent of inflammation in these patients. Such patients, with discordantly high patient-reported DAS28 components, fatigue and mood disturbance might represent a subgroup of RA patients who have specific clinical needs, not resolved by classical conventional or biologic DMARDs. In this way, neuropathic pain and pain sensitization have been demonstrated in 20 to 30% of RA patients, neuropathic pain scores being associated with worsen disease activity scores. Thus, pain sensitization may contribute to amplification of pain in active RA, and should be responsible for persisting pain and fatigue even after inflammation has resolved.

Pain sensitization is associated with neuroplastic changes in sensory pathways at peripheral and central levels. Interestingly, major mediators responsible for this neuroplasticity operate via a JAK/STAT signaling pathway, which is specifically targeted by new RA treatments. New drug targeting JAK/STAT signalling pathway have been recently designed for RA treatment, based on the implication of this pathway on the signaling of various cytokines implicated in the pathophysiology of RA, such as IL-6, IL-12, IL-23 and IFNs. Two Jak-inhibitors have been put on the market: Tofacitinib and Baricitinib. In randomized clinical trials, Tofacitinib have shown a remarkable efficacy on pain and other patient reported outcomes, suggesting a specific effect or jak-inhibitors on pain control. Recent data suggest that Jak-inhibitors could have a direct effect on sensory neurons.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Other: Clinical examination; Other: Pain assessment; Other: blood sample; Other: Patient Reported Outcomes

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas BARNETCHE, PhD; Email: thomas.barnetche@chu-bordeaux.fr
• Study Contact Backup: Name: Thierry SCHAEVERBEKE, Prof; Phone Number: +33 (0)556795556; Email: thierry.schaeverbeke@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France
    • CHU de Bordeaux - service de rhumatologie
  • Limoges, France
    • CHU de Limoges - service de rhumatologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged over 18 year-old ;
• Diagnosis of RA according to the ACR/EULAR 2010 classification criteria ;
• Active rheumatoid arthritis defined by a Disease Activity Score (DAS28) > 3.2 at inclusion ;
• Patient eligible for tofacitinib treatment in agreement with European treatment labelling and French recommendation for RA treatment ;
• Oral prednisone intake is allowed until 10 mg, stable for at least 1 week at study entry ;
• Starting tofacitinib treatment for an active RA defined by a DAS28-ESR > 3.2 ;
• Affiliated person or beneficiary of a social security scheme ;
• Having signed an informed consent (at the latest on the day of inclusion and before any examination required by research).

Exclusion Criteria:

• Diagnosis of a systemic autoimmune disease other than RA ;
• Peripheral neuropathy ;
• Centrally-acting pain medications use within 3 months of enrolment (amitriptyline, gabapentin, duloxetine), or during the study ;
• Any opioid use within 1 month of enrolment or during the study ;
• Corticosteroid treatment over 10 mg of prednisone or equivalent ;
• Patient who present contraindications to tofacitinib treatment ;
• Patient presenting with a history of active tuberculosis or chronic infectious disease with a need of regular use of antibiotic ;
• Patients with active bacterial or viral infection, or presenting with an episode of infection that required treatment with antibiotics within 30 days prior to screening ;
• Patient presenting with a history of lymphoma or leukaemia or other malignancy besides non-melanoma skin cancer within 5 years ;
• Patient presenting with any uncontrolled medical condition ;
• Pregnancy or breast-feeding ;
• Patient unable to understand and follow recommendations or unable to perform self-evaluation ;
• Patient who refuse to participate to the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rheumatoid Arthritis (RA) patients; RA according to the ACR/EULAR 2010 classification criteria

Other: Clinical examination; Number of painful joints,; Number of swollen joints,; Patient Global assessment VAS (0 - 100); and Physician Global assessment VAS (0 - 100); Other: Pain assessment; Pressure Pain Thresholds (PPTs),; Mechanical Temporal Summation (MTS); and Diffuse Noxious Inhibitory Control (DNIC); Other: blood sample; 18 ml whole blood for ELISA analysis and miRNAs detection; Other: Patient Reported Outcomes; Health Assessment Questionnaire (HAQ),; Rheumatoid Arthritis Impact of Disease score (RAID),; Daily joint pain intensity VAS (0-100),; Hospital Anxiety and Depression scale; and Coping Strategy Questionnaire.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Variation of the mean Pressure Pain Thresholds (PPTs)	At 6 months from baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variation of Mechanical Temporal Summation (MTS)		At 1, 3 and 6 months from baseline
Variation of Pressure Pain Thresholds (PPTs)		At 1, 3 and 6 months from baseline
Variation of Diffuse noxious inhibitory control (DNIC) values		At 1, 3 and 6 months from baseline
Variation of Daily joint pain intensity	daily evaluation of the previous 24h pain on a numeric pain scale 0 to 100	At 1, 3 and 6 months from baseline
Disease activity evaluated by the Disease Activity Score on 28 joints (DAS28)	which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the erythrocyte sedimentation rate.	At 1, 3 and 6 months from baseline
Disease activity evaluated by the Simple Disease Activity Index (SDAI)	which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), the physician global assessment of disease activity (between 0 and 100), and the C-reactive protein level.	At 1, 3 and 6 months from baseline
Disease activity evaluated by the Clinical Disease Activity Index (SDAI)	which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the physician global assessment of disease activity (between 0 and 100).	At 1, 3 and 6 months from baseline
Health Assessment Questionnaire (HAQ)		At 1, 3 and 6 months from baseline
Rheumatoid Arthritis Impact of Disease score (RAID)		At 1, 3 and 6 months from baseline
Hospital Anxiety and Depression scale	HAD scale aims at evaluating anxiety and depression symptoms with two separate scores (between 0 and 21) estimated grace to 14 items (7 for anxiety and 7 for depression) ranged between 0 and 3	At 1, 3 and 6 months from baseline
Coping Strategy Questionnaire: a 21-items self-report		At 1, 3 and 6 months from baseline
Levels of cytokines		At 3 and 6 months from baseline
Levels of neurotrophins		At 3 and 6 months from baseline
Levels of miR21, miR-124, miR-146a and miR-155		At 3 and 6 months from baseline

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Collaborators: Pfizer
• Investigators: Principal Investigator: Thierry SCHAEVERBEKE, Prof, CHU Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2019
• Primary Completion (Actual): April 28, 2023
• Study Completion (Actual): April 28, 2023

Study Registration Dates

• First Submitted: January 11, 2019
• First Submitted That Met QC Criteria: January 23, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: May 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: miRNA; Tofacitinib; pain sensitization
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: CHUBX 2017/39

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No