Methotrexate, Blood Pressure and Arterial Function in Rheumatoid Arthritis

The investigators will study the effects of methotrexate on blood pressure, arterial stiffness and endothelial function in patients with rheumatoid arthritis.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Endothelial Dysfunction; Cardiovascular Risk Factor; Stiffness, Aortic
• Intervention / Treatment: Drug: Methotrexate; Drug: Sulfasalazine; Drug: Other DMARDs

Detailed Description

Patients with rheumatoid arthritis have an increased risk of stroke and heart attack when compared to the rest of the population. Recent studies have shown that methotrexate, a disease-modifying antirheumatic drug (DMARDs) commonly prescribed for rheumatoid arthritis, reduces this risk. However, the mechanisms responsible for the protective effects of methotrexate on the heart and the brain are unknown.

The investigators have recently completed an observational study in participants with rheumatoid arthritis treated with either methotrexate or with other DMARDs. Participants on methotrexate had lower blood pressure and 'healthier' blood vessels than participants treated with other DMARDs. These differences were maintained over a period of 8 months. These results suggest that methotrexate lowers blood pressure and exerts salutary effects on blood vessels, which might explain the reduced risk of stroke and heart attack with this drug. However, the observational nature of this study does not allow establishing a clear cause-effect relationship between methotrexate treatment and the observed changes in blood pressure and blood vessels.

In order to address this issue, the investigators will recruit participants that have been recently diagnosed with rheumatoid arthritis and are about to start treatment with either methotrexate (Group 1) or another DMARD (Group 2). Then, the investigators will assess their blood pressure and blood vessels for 6 months. The investigators will use an injectable (subcutaneous) form of methotrexate because this might provide better effects on blood pressure and blood vessels. The investigators will also study a third group (Group 3) of rheumatoid arthritis participants already on treatment (> 1 year) with oral methotrexate, with or without other DMARDs. They will be switched to subcutaneous methotrexate, but continuing all their other medications, for 6 months to see whether the subcutaneous form can further reduce blood pressure and provide additional salutary effects on blood vessels. Finally, the investigators will study a fourth group (Group 4) of participants with rheumatoid arthritis already on treatment (> 1 year) with DMADRs other than methotrexate who will continue with the same medications for 6 months, to assess possible fluctuations in blood pressure and blood vessel markers over time.

Each participant will attend three study visits (baseline, 1 and 6 months), each lasting between 60 and 90 min.

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Arduino A Mangoni, MD, PhD; Phone Number: 0061882047495; Email: arduino.mangoni@flinders.edu.au

Study Locations

• Australia
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Recruiting
      • Southern Adelaide Local Health Network
      • Contact: Arduino Mangoni, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient with rheumatoid arthritis according to EULAR/ACR 2010 criteria.
• Age ≥18 years.
• Written informed consent, dated and signed before initiating any study-related procedure.

Exclusion Criteria:

• Contraindication to MTX or sulfasalazine.
• Patient who cannot be followed during 6 months.
• Active alcohol or substance abuse within the last 12 months.
• Participation in a clinical trial within 3 months prior to the start of the study.
• Body mass index >35 Kg/m2.
• Secondary causes of hypertension.
• Grade 2 (moderate) or 3 (severe) hypertension: clinic blood pressure >160/100 mm Hg.
• Resistant hypertension: clinical blood pressure ≥140/90 mm Hg despite concurrent use of three antihypertensive agents of different classes, one of which is a diuretic.
• Clinical systolic blood pressure <100 mm Hg or history of symptomatic orthostatic hypotension.
• Cardiovascular event, procedure, or hospitalization for unstable angina with the last 6 months.
• Atrial fibrillation.
• Heart failure.
• Treatment with nitrates.
• Estimated glomerular filtration rate (eGFR) <45 mL/min.
• Diagnosis of polycystic kidney disease.
• Glomerulonephritis treated with or likely to be treated with immunosuppressant drugs
• Uncontrolled diabetes with HbA1c >9.0% (>75 mmol/mol).
• Uncontrolled dyslipidaemia with total serum cholesterol >7.5 mmol/L or triglycerides >5.6 mmol/L.
• Clinical diagnosis of dementia, treatment with medications for dementia or, in the opinion of the study staff, the participant is cognitively unable to follow the protocol.
• Other medical, psychiatric, or behavioural factors that in the judgment of the study staff may interfere with study participation.
• Cancer diagnosed and treated within the past 2 years that, in the judgment of the study staff, would compromise a participant's ability to comply with the protocol and complete the study.
• Any organ transplant.
• Pregnancy, currently trying to become pregnant, or of child bearing potential and not using birth control.
• Significant illness within 2 weeks of study start.
• Patients with an unstable active medical condition that could impair evaluation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Newly diagnosed RA patients started on subcutaneous MTX - open randomisation vs. sulfasalazine. In this group, use of NSAIDs, steroids, and/or other DMARDs, is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice .	Drug: Methotrexate; See arm descriptions
Active Comparator: Group 2; Newly diagnosed RA patients started on sulfasalazine - open randomisation vs. subcutaneous MTX. In this group, use of NSAIDs, steroids, and/or other DMARDs (except MTX), is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.	Drug: Sulfasalazine; See arm description
Experimental: Group 3; RA patients on long-term treatment (> 1 year) with oral MTX, with or without other DMARDs, NSAIDs and/or steroids, switched to subcutaneous MTX (same dose). In these patients, treatment with other DMARDs, NSAIDs and/or steroids will continue. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.	Drug: Methotrexate; See arm descriptions
Active Comparator: Group 4; RA patients on stable treatment (> 1 year) with other (non-MTX) DMARDs, with or without NSAIDs and/or steroids, and continued on the same treatment. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.	Drug: Other DMARDs; See arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in peripheral systolic blood pressure	Change in peripheral systolic blood pressure	Change from baseline peripheral systolic blood pressure at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in peripheral and central blood pressure	Change in peripheral and central blood pressure	Change from baseline peripheral and central blood pressure at 6 months
Change in arterial stiffness	Change in pulse wave velocity	Change from baseline pulse wave velocity at 6 months
Change in arterial wave reflection	Change in augmentation index	Change from baseline augmentation index at 6 months
Change in adenosine	Change in adenosine concentrations	Change from baseline adenosine concentrations at 6 months
Change in arginine metabolites	Change in ADMA concentrations	Change from baseline ADMA concentrations at 6 months

Collaborators and Investigators

• Sponsor: Flinders University
• Collaborators: medac GmbH; University of South Australia

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2017
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: August 16, 2017
• First Submitted That Met QC Criteria: August 16, 2017
• First Posted (Actual): August 18, 2017

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Methotrexate; Arterial stiffness; Blood pressure; Cardiovascular risk; Rheumatoid arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Sulfasalazine
• Other Study ID Numbers: HREC/17/SAC/46

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No