Rheumatoid Arthritis Adrenal Recovery Study (RAAR)

Investigating Recovery of the Hypothalamus-pituitary-adrenal Axis in Patients With Rheumatoid Arthritis Following Exposure to Prednisolone

Cortisol is a naturally occurring stress hormone, made by the adrenal glands in response to hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol ('steroids', for example prednisolone) have been used for the treatment of rheumatoid arthritis since the 1950s; they are very effective at reducing inflammation.

A normal response to taking steroid treatment is that the body needs to make less cortisol. Following treatment with steroids, the system responsible for making cortisol can be slow to wake up. If someone does not make enough cortisol, they are less able to deal with stress and are at increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. It is not clear how common failure of recovery of the adrenal axis is, how long it can last for or, if any factors might predict which patients are most at risk.

This study aims to improve our understanding of hypothalamus-pituitary-adrenal (HPA) axis recovery in patients with rheumatoid arthritis treated with prednisolone. The investigators will also test potential predictive biomarkers of recovery.

The study will be conducted in hospital and a clinical research facility. Participants will undergo two visits for blood tests and will also be asked to supply three samples of saliva on six days over the three weeks of the study.

A better understanding of the physiology of HPA axis recovery should inform the development of tools which would allow prediction of patients at risk following withdrawal of steroid treatment. Such tools would be useful to improve patient safety.

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Arthritis; Adrenal Insufficiency

Detailed Description

Cortisol is a naturally occurring stress hormone. It is made by the adrenal glands in response to hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol ('steroids', for example prednisolone) have been used for the treatment of rheumatoid arthritis since the 1950s; they are very effective at reducing inflammation. Steroids are prescribed for a wide variety of inflammatory conditions. The British prevalence of chronic (greater than 3 months) steroid prescription is 1%.

A normal response to taking steroid treatment is that the body needs to make less cortisol. Following treatment with steroids, the system responsible for making cortisol (known as the hypothalamic pituitary adrenal axis (HPA axis)) can be slow to re-establish production. If someone does not make enough cortisol, they are less able to deal with stress and are at increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. The prevalence of inadequate cortisol production following treatment with steroids is between 10-30% of patients; its duration and whether any patient factors might predict which patients are at risk is unclear. Generally studies have been small in size and do not report sufficient information to determine if any potential factors maybe useful predictors; for example age, sex, length of treatment, length of time off treatment, other medications.

Rheumatoid arthritis (RA) has a prevalence of 1%. Patients are usually treated with a 13 week course of prednisolone in a reducing dose (treatment regimen known as COBRA-light) at diagnosis. 1-2 patients present each week to the rheumatology department in Edinburgh with a new diagnosis of RA. At the end of the initial COBRA-light treatment, the adrenal axis is not routinely assessed in these patients. It is assumed that the slow reducing dosage of steroids reduces the risk of ongoing adrenal insufficiency. It should be noted that the meta-analysis of Joseph et al. demonstrated weaning had little impact upon the recovery of the HPA axis. These patients are thus potentially at risk of the morbidity and mortality associated with an underactive HPA axis.

This study aims to improve our understanding of HPA axis recovery in patients with rheumatoid arthritis following treatment with prednisolone. The investigators will also test two novel potential predictive biomarkers of recovery.

A better understanding of the physiology of HPA axis recovery should inform the development of tools which would allow prediction of patients at risk following withdrawal of steroid treatment. Such tools would be useful to improve patient safety and wellbeing.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Thomas JG Chambers, PhD; Phone Number: 0131 537 3072; Email: tom.chambers@ed.ac.uk
• Study Contact Backup: Name: Mark Strachan, MD; Phone Number: 0131 537 3072

Study Locations

• United Kingdom
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Recruiting
      • Metabolic Unit, Western General Hospital, NHS Lothian, Crewe Road
      • Contact: Thomas JG Chambers, PhD; Phone Number: 0131 537 3072; Email: tom.chambers@ed.ac.uk
      • Contact: Mark Strachan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients recruited following 13 week weaning dose of prednisone for treatment of early arthritis

Description

Inclusion Criteria:

• Rheumatoid arthritis
• Treatment with prednisone via COBRA light regime
• Age over 18

Exclusion Criteria:

• Adrenal or pituitary disease
• Alcohol intake over 21 units/week
• Shift work (night shifts)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Synacthen test 1	Short synacthen test the after withdrawal of prednisone	Day 1
Synacthen test 2	Short synacthen test 21 days after withdrawal of prednisone	Day 21
Cortisol awakening curve	Salivary cortisol at waking, and 30 mins and 45 mins after waking	2 days in each of weeks 1, 2 and 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single Nucleotide Polymorphism	Assessment of an SNP as a predictor of prolonged HPA axis suppression	Assessed at day 0
Quality of life	SF-36 (Short Form Survey) assessed quality of life	Assessed at day 21
Metabolite panel	Assessment of a panel of metabolites which might predict HPA suppression	Day 0

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Investigators: Principal Investigator: Thomas JG Chambers, PhD, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2018
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: September 22, 2017
• First Submitted That Met QC Criteria: September 22, 2017
• First Posted (Actual): September 27, 2017

Study Record Updates

• Last Update Posted (Actual): October 11, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: HPA axis; Glucocorticoid
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Adrenal Gland Diseases; Arthritis; Arthritis, Rheumatoid; Adrenal Insufficiency
• Other Study ID Numbers: AC17080

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