Muscle Wasting and Rheumatoid Arthritis Flares

Rheumatoid Arthritis Clinical Trial

Official title:

Preventing Muscle Wasting During Rheumatoid Arthritis Flares: A Randomised Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06400316
• Other study ID #: 335887
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 13, 2024
• Est. completion date: December 31, 2024

Study information

• Verified date: May 2024
• Source: Leeds Beckett University
• Contact: Luke Aldrich, MSc
• Phone: 0113 812 5180
• Email: L.Aldrich[@]leedsbeckett.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

People living with Rheumatoid Arthritis (RA) often present with low muscle mass compared to their healthy counterparts. This affects their mobility, overall health and quality of life. Even though low muscle mass in RA has been recognised for decades, it is still highly prevalent and very little is known about its development, progression, and potential management.

The researchers hypothesise that flares of disease activity trigger acute events of muscle wasting due to high inflammation and reduced mobility. This is commonly observed in bed rest studies and people hospitalised for various reasons. If this holds true for RA, it would point towards a stepwise development of RC and potentially allow for time-targeted management of it.

A potential method to manage it is through the use of nutritional supplements. Specifically, amino acid supplementation (commonly used by athletes or people wanting to increase muscle mass) during and shortly after a flare may counteract some of the muscle wasting and allow for better long-term mobility and quality of life for people living with RA.

This study aims to investigate aspects of muscle health changes following a disease flare-up in people with Rheumatoid Arthritis (RA) and test potential interventions to minimise any such changes. The investigators will randomly assign participants to a standard care or a nutritional supplementation group and assess aspects of body composition, muscle health, disease activity and inflammation on five occasions over a 3-month period.

Description:

This study aims to investigate aspects of muscle health changes following a disease flare-up in people with Rheumatoid Arthritis (RA) and test potential interventions to minimise any such changes.

RA is the most common inflammatory arthritis manifesting mainly as joint swelling and pain, limiting mobility, and eventually leading to loss of functional capacity. RA also has severe extra-articular manifestations [1], affecting several tissues in the body including skeletal muscle [2]. People living with RA often present with an adverse body composition profile compared to the general population, characterised by low muscle mass at the presence of unchanged or even increased overall weight [3]. This condition, termed Rheumatoid Cachexia, may affect up to 2 out of 3 people with RA and associates with active disease, further reductions in mobility, and low quality of life [4].

While rheumatoid cachexia has been studied extensively, the course of its development, as well as potential causes or contributors to it are poorly understood. Inflammation, [5] as well as lifestyle factors, such as energy intake and physical activity, may contribute to the observed body composition changes [6].

People living with RA often experience flares of disease activity, where high levels of inflammation, cause an acute exaggeration of symptoms, leading to very low levels of mobility. This is commonly treated with corticosteroid injections which will rapidly reduce inflammation and allow the patient to regain mobility. However, that short period of high inflammatory load and low mobility may acutely affect muscle characteristics. Indeed, critically ill patients may lose up to 2% of skeletal muscle per day during the first week of hospitalisation [7]. This rapid decline in muscle health has been recently termed Acute sarcopenia (AS) by the European working group in sarcopenia and older persons (EWGSOP) [8]. Furthermore, recent work within this research team is currently under review (Aldrich et al., 2023 under review) demonstrating the rapid decline of muscle mass and quality in people suffering with various diseases. Additionally, corticosteroids themselves may further contribute to muscle wasting in RA [9]. Yet, the acute effects of flares and their treatment on muscle health in people with RA are not known.

Acute deterioration of muscle health following a flare may point towards a stepwise development of rheumatoid cachexia, i.e., bouts of acute deterioration that accumulate over time in steps rather than a continuous slow loss - which is the current understanding for the development of sarcopenia, the age-related muscle wasting. This would allow for target and potentially short-term interventions that could limit or even reverse muscle deterioration during a flare and help people with RA better maintain their functionality.

Exercise, and particularly resistance exercise, is the most effective way to increase muscle mass, strength, and quality. However, people during and shortly after a flare may not be willing to engage in such an intervention. Additional complexities around gym or home-based delivery, familiarisation, and safe execution render this a complex intervention with potentially limited applicability.

Nutritional supplementation on the other hand, is readily available, relatively cheap, and easy to administer. Specifically, for muscle health, amino acid supplementation, and particularly with leucine, has been shown to improve muscle mass and muscle function in older men and women [10]. Moreover, previous research has shown that these amino acid supplements do not suppress appetite, are well tolerated and easy to consume. Finally, recent unpublished data from this laboratory suggest that amino acid concentrations in the blood following consumption alongside a meal remain elevated vs placebo for over 2 hours. This indicates that consuming two supplements per day would provide sufficient amino acids to induce beneficial effects on muscle health.

Therefore, the aims of this investigation are:

1. To understand the effects of acute RA flares on muscle health

2. To assess the efficacy of amino acid supplementation vs. standard care in maintaining muscle health

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Diagnosis of a flare of rheumatoid arthritis

Exclusion Criteria:

• Consultation with RA physician greater than 7 days before

• Allergic to supplement ingredients

• Other health conditions that affect muscle wasting; such as cancer and fibromyalgia

• Previous joint replacement surgery within the last 6 months

• Anyone with underlying kidney conditions

• Currently partaking in other research projects involving treatments, exercise or nutritional interventions for rheumatoid arthritis

• Patients who may be pregnant

• Patients who are unable to provide their own informed consent

• Patients who are unable to speak or understand English

• Participants who have a diagnosis of dementia or Alzheimer's disease

• Disabled participants who require wheelchair access

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Atrophy
• Muscle Atrophy
• Muscular Atrophy
• Rheumatoid Arthritis

Intervention

Dietary Supplement:
• Amino Acid Supplement
The intervention lasts 4-week following the rheumatoid arthritis flare. It requires twice daily consumption of amino acid supplements alongside the breakfast and lunch time meals.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Leeds Beckett University

References & Publications (10)

Bonfiglioli KR, de Medeiros Ribeiro AC, Carnieletto AP, Pereira I, Domiciano DS, da Silva HC, Pugliesi A, Pereira LR, Guimaraes MFR, Giorgi RDN, Reis APMG, Brenol CV, Louzada-Junior P, da Cunha Sauma MFL, Radominski SC, da Mota LMH, da Rocha Castelar-Pinheiro G. Extra-articular manifestations of rheumatoid arthritis remain a major challenge: data from a large, multi-centric cohort. Adv Rheumatol. 2023 Jul 26;63(1):34. doi: 10.1186/s42358-023-00318-y. — View Citation

Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31. doi: 10.1093/ageing/afy169. Erratum In: Age Ageing. 2019 Jul 1;48(4):601. — View Citation

Efthymiou E, Grammatikopoulou MG, Gkiouras K, Efthymiou G, Zafiriou E, Goulis DG, Sakkas LI, Bogdanos DP. Time to Deal with Rheumatoid Cachexia: Prevalence, Diagnostic Criteria, Treatment Effects and Evidence for Management. Mediterr J Rheumatol. 2022 Sep 30;33(3):271-290. doi: 10.31138/mjr.33.3.271. eCollection 2022 Sep. — View Citation

Farrow M, Biglands J, Tanner S, Hensor EMA, Buch MH, Emery P, Tan AL. Muscle deterioration due to rheumatoid arthritis: assessment by quantitative MRI and strength testing. Rheumatology (Oxford). 2021 Mar 2;60(3):1216-1225. doi: 10.1093/rheumatology/keaa364. — View Citation

Fazzini B, Markl T, Costas C, Blobner M, Schaller SJ, Prowle J, Puthucheary Z, Wackerhage H. The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis. Crit Care. 2023 Jan 3;27(1):2. doi: 10.1186/s13054-022-04253-0. — View Citation

Ispoglou T, White H, Preston T, McElhone S, McKenna J, Hind K. Double-blind, placebo-controlled pilot trial of L-Leucine-enriched amino-acid mixtures on body composition and physical performance in men and women aged 65-75 years. Eur J Clin Nutr. 2016 Feb;70(2):182-8. doi: 10.1038/ejcn.2015.91. Epub 2015 Jun 17. — View Citation

Lemmey AB, Wilkinson TJ, Perkins CM, Nixon LA, Sheikh F, Jones JG, Ahmad YA, O'brien TD. Muscle loss following a single high-dose intramuscular injection of corticosteroids to treat disease flare in patients with rheumatoid arthritis. Eur J Rheumatol. 2018 Sep;5(3):160-164. doi: 10.5152/eurjrheum.2018.17148. Epub 2018 Apr 2. — View Citation

Masuko K. Rheumatoid cachexia revisited: a metabolic co-morbidity in rheumatoid arthritis. Front Nutr. 2014 Nov 24;1:20. doi: 10.3389/fnut.2014.00020. eCollection 2014. — View Citation

Ollewagen T, Powrie YSL, Myburgh KH, Smith C. Unresolved intramuscular inflammation, not diminished skeletal muscle regenerative capacity, is at the root of rheumatoid cachexia: insights from a rat CIA model. Physiol Rep. 2021 Nov;9(22):e15119. doi: 10.14814/phy2.15119. — View Citation

Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y, Nevill AM, Douglas KM, Jamurtas A, van Zanten JJ, Labib M, Kitas GD. Redefining overweight and obesity in rheumatoid arthritis patients. Ann Rheum Dis. 2007 Oct;66(10):1316-21. doi: 10.1136/ard.2006.060319. Epub 2007 Feb 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lean Tissue Mass	Whole-body composition will be assessed by dual energy x-ray absorptiometry scans and this will provide a value for lean tissue (muscle mass) in kilograms.	Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Quadriceps Lean Tissue Mass	Quadriceps lean tissue mass will be assessed by dual energy x-ray absorptiometry scans focussed in the quadriceps region. Lean tissue mass in this region will be provided in kilograms.	Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Rectus Femoris Cross-sectional Area	Rectus femoris will be assessed by ultrasound scans. The muscle belly will be imaged and cross-sectional area will be calculated from this image (cm2).	Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Handgrip Strength	Upper-body muscle strength will be assessed by handgrip dynamometry and the value will be recorded in kilograms.	Strength tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Knee Extensor Strength	Lower-body muscle strength will be assessed on a seated knee extension resistance machine and the highest value achieved will be recorded in kilograms.	Strength tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Short Physical Performance Battery	Muscle function will be assessed by the Short Physical Performance Battery. This battery includes measures of gait speed, lower-limb strength/functionality and balance. The score of all tests is combined to provide a total score where a higher score indicates better muscle function.	Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Timed Up and Go	Muscle function will be assessed by the Timed Up and Go Test. This test assesses mobility and balance. The time taken to complete standing, walking 3-metres, then returning to sit down is recorded and a shorter time indicates better functionality.	Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	6-minute Walk Test	Muscle function will be assessed by the 6-Minute Walk Test. This test assesses endurance and aerobic capacity. The total distance walked in 6 minutes is recorded and a higher score indicates greater aerobic capacity.	Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Plasma Amino Acid Content	Blood plasma amino acid content (µmol/L) will be assessed at all time points using liquid chromatography mass spectrometry.	Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Serum Steroid Hormone Content	Blood serum steroid hormone content (ng/ml) will be assessed at all time-points using liquid chromatography mass spectrometry.	Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Serum Vitamin D Content	Blood serum vitamin D content (ng/ml)will be assessed at all time-points using liquid chromatography mass spectrometry.	Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Diet Recall	Participants will be asked to recall their dietary intake over the preceding 24 hours to determine calorie intake.	24-hour diet recall tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Physical Activity	Physical activity habits will be assessed using the International Physical Activity Questionnaire (IPAQ) (short version). Time spent sitting, walking and exercising at various intensities will be recorded in days and hours.	24-hour diet recall tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Physical Ability, Social Support and Interaction, Pain, Health & Mood (Quality of Life - Rheumatoid Arthritis-Specific)	Quality of life will be assessed using the established Rheumatoid Arthritis quality of life (RAQoL) questionnaire. This will be assessed from a series of questions which will require answers ranked from 1 (very poor) to excellent (10).	Quality of life assessments will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary	Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Social Interaction & Pain (Quality of Life - PROMIS-29)	Quality of life will be assessed using the Patient Reported Outcome Measures Information System (PROMIS-29) questionnaire. This will assess physical function, anxiety, depression, fatigue, sleep disturbance, ability to take part in social roles and activities, pain interference and pain intensity. All answers will be on a scale from 1 to 5 except for pain intensity which is recorded on a scale from 1 to 10. Lower scores indicate negative answers except for questions regarding physical function and pain intensity.	Quality of life assessments will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.