Clinical trial NCT06400316: Muscle Wasting and Rheumatoid Arthritis Flares
Official title: Preventing Muscle Wasting During Rheumatoid Arthritis Flares: A Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Rheumatoid Arthritis
Muscle Atrophy
Keywords: Rheumatoid Arthritis
Muscle Atrophy
Lead sponsor: Leeds Beckett University
Sponsor class: OTHER
First posted: 2024-05-06
Enrollment: 40
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: One control group will receive standard care following diagnosis of a flare of rheumatoid arthritis. The parallel group will receive a 4-week intervention involving two daily amino acid supplements.
Primary purpose: PREVENTION

Brief 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.

Detailed 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

Eligibility criteria: 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

Primary outcomes:
measure: Lean Tissue Mass
timeFrame: Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Secondary outcomes:
measure: Quadriceps Lean Tissue Mass
timeFrame: Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Rectus Femoris Cross-sectional Area
timeFrame: Scans will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Handgrip Strength
timeFrame: Strength tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Knee Extensor Strength
timeFrame: Strength tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Short Physical Performance Battery
timeFrame: Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Timed Up and Go
timeFrame: Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: 6-minute Walk Test
timeFrame: Muscle function tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Plasma Amino Acid Content
timeFrame: Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Serum Steroid Hormone Content
timeFrame: Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Serum Vitamin D Content
timeFrame: Blood tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Diet Recall
timeFrame: 24-hour diet recall tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Physical Activity
timeFrame: 24-hour diet recall tests will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Physical Ability, Social Support and Interaction, Pain, Health & Mood (Quality of Life - Rheumatoid Arthritis-Specific)
timeFrame: Quality of life assessments will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
measure: Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Social Interaction & Pain (Quality of Life - PROMIS-29)
timeFrame: Quality of life assessments will take place at baseline and 1-week, 2-weeks, 4-weeks and 12-weeks after baseline.
Other outcomes:
Locations:
Study officials:
affiliation: Leeds Beckett University
name: Theocharis Ispoglou, PhD
role: STUDY_CHAIR
affiliation: Leeds Beckett University
name: Oliver Wilson, PhD
role: STUDY_CHAIR
References:
citation: 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.
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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.
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.
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.
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.
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.
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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.