Evaluation of the Mechanisms of Sarcopenia in Chronic Inflammatory Disease: Protocol for a Prospective Cohort Study

Evaluation of Mechanisms of Sarcopenia in Chronic Inflammatory Disease (Chronic Liver Disease, Inflammatory Bowel Disease and Inflammatory Arthritis) Pre and Post Standard of Care Intervention; an Observational Study

Prospective, observational study to assess sarcopenia across three chronic inflammatory diseases: chronic liver disease, Inflammatory Bowel Disease, Rheumatoid Arthritis both before and after therapeutic intervention (standard of care treatment i.e. nutrition/exercise; biologic for IBD etc).

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Arthritis; Inflammatory Bowel Diseases; Chronic Liver Disease
• Intervention / Treatment: Other: National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines)

Detailed Description

Introduction: Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, quantity and quality) and negatively impact on both morbidity and mortality. There is limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease specific mechanisms driving sarcopenia.

Methods: This prospective cohort study is unique; it provides a multi-modal approach to assess sarcopenia across three chronic inflammatory diseases: chronic liver disease, Inflammatory Bowel Disease, Rheumatoid Arthritis both before and after therapeutic intervention. A total of 170 patients will be recruited (50 with Chronic liver disease, 20 with non-cirrhotic nonalcoholic fatty liver disease, 50 with Inflammatory Bowel Disease and 50 with Rheumatoid Arthritis) and including a comparison cohort of n=20 age-sex matched healthy individuals.

Participants will undergo 4 assessments at defined time points; weeks 0, 2, 12 and 24, with blood tests to assess endocrine and inflammatory status; anthropometric (hand grip strength; mid-arm muscle circumference; triceps skinfold thickness); functional testing (short physical performance battery and isokinetic dynamometry); imaging ( ultrasound and Magnetic Resonance Imaging of the quadriceps), and vastus lateralis muscle biopsy. Physical activity and sleep will be monitored using actigraphy, and quality of life via questionnaires. Food diaries for nutritional intake analysis will be sampled between 0-2, 12 and 24 weeks. Stool and urine samples will be sampled for future microbiome and metabolomics analysis, respectively.

This study will identify mechanisms across the groups and within each cohort, to further target interventions to reduce sarcopenia in the future. This is the first study to use a multi modal assessment to characterise sarcopenia in chronic disease. The multi-modal assessment includes serological, anatomical, functional and histological analyses to evaluate the deep phenotyping of these patients. The observational study of small sample sizes will allow potential future targets for intervention.

• Study Type: Observational
• Enrollment (Anticipated): 170

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2WB
      • Institute of Inflammation and Ageing (IIA) University of Birmingham Research Laboratories

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Chronic liver disease patients will be selected from those who undergo assessment for liver transplantation . A Non-alcoholic fatty liver disease (NAFLD) subset will be screened and recruited from the NAFLD clinic. For Inflammatory bowel disease and Rheumatoid Arthritis, all patients commencing a new biologic treatment (via biologic clinic screening or biologic registry screening) will be screened prior to therapy commencement.

Description

Inclusion Criteria:

1. A formal confirmed diagnosis of their underlying chronic inflammatory condition:

   1. Inflammatory bowel disease cohort patients will have endoscopic or radiological evidence.

      Some of the Chronic liver disease cohort will have had a liver biopsy, serological and radiological confirmation will be sufficient.

   2. RA cohort, clinical, serological and radiological confirmation will be sufficient.
   3. Biologic therapy naïve on recruitment or commencing a new biologic if in the IBD or IA cohort.
2. Adults aged ≥ 18 years
3. Able to confirm written consent to the study
4. Biologic therapy naïve on recruitment or commencing a new biologic if in the IBD or RA cohort Pre-existing or current use of immunosuppressant agents or Disease Modifying Antirheumatic Drugs (DMARDs) are acceptable in all cohorts.
5. Meeting ACR (American College of Rheumatology) /EULAR (European League Against Rheumatism) 2010 or ACR 1987 Criteria for rheumatoid arthritis and starting DMARD therapy.
6. Meeting criteria of an inflammatory arthritis as per the American College of Rheumatology
7. Meeting criteria of liver cirrhosis including all Child Pugh scores from A-C as per British Association for the Study of the Liver guidance.
8. Meeting criteria for Inflammatory bowel disease as per the British Society of Gastroenterology guidance.
9. For muscle biopsy sampling (does not preclude patients from participating if they do not meet the below criteria) INR ≤ 1.6 Platelet count > 30

Exclusion Criteria:

1. Refusal or lack capacity to give informed consent.
2. Currently enrolled in an interventional trial with active treatment for their chronic disease condition.
3. Previously undergone LT or biliary intervention in the Chronic liver disease cohort.
4. Underlying or active cancer.
5. Biliary intervention if Chronic liver disease

6. For Muscle biopsies only (able to continue in study):

   1. Obvious injury to both thighs.
   2. Active bleeding of site, pre-procedure,
   3. Abnormal observation parameters.
   4. Acute illness.
   5. INR > 1.6.
   6. Platelet count < 30.
   7. Anticoagulation which cannot be paused due to increased risk to pre-existing co-morbidity.

7. For undergoing an Magnetic resonance imaging (MRI)

   1. Pacemaker.
   2. Metal work inserted that is not MRI compatible or further information cannot be obtained.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Chronic Liver Disease; Patients with end-stage liver disease. Standard of care treatment will be nutrition and exercise as per European Association Study of Liver nutrition guidelines.	Other: National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines); National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines)
Rheumatoid Arthritis/Psoriatic arthropathy; Patients requiring biological therapy due to ongoing inflammation (requiring anti-Tumour Necrosis Factor therapy) - i.e. standard of care - escalation in therapy	Other: National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines); National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines)
Inflammatory Bowel Disease; Patients with Crohns or Ulcerative Colitis with ongoing inflammation (requiring anti-Tumour Necrosis Factor therapy) - i.e. standard of care - escalation in therapy	Other: National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines); National Healthcare System Standard of care for each disease type (National Institute for Health and Care Excellence guidelines)
Healthy volunteers (n=20); Healthy volunteers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sarcopenia (Muscle Area) using Magnetic Resonance Imaging	Vastus lateralis and rectus femoris muscle axial cross sectional assessment will be measured at 50% of femur length	6 months
Sarcopenia (Muscle Area) using ultrasound	Vastus lateralis and rectus femoris muscle axial cross sectional assessment will be measured at 50% of femur length.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life questionnaire	Short Form-36 health-related Quality of Life questionnaire (Quality Metric Health Outcomes Solutions, Lincoln, USA)	6 month
Muscle biopsy of the Vastus lateralis	Muscle structure using standardised haemotoxylin/eosin and immunohistochemistry	6 month
Leg (Quadricep/Hamstring) strength	Leg strength/power by Isokinetic Dynamometry - the patient will be asked to extend the leg as strong as possible and then to flex, for 5 repetitions	6 month
Handgrip strength	Both hands using handheld Dynamometer (North Coast Medical, Morgan Hill)	6 month

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: National Institute for Health Research, United Kingdom
• Investigators: Study Chair: Janet Lord, PhD, University of Birmingham

Publications and helpful links

General Publications

• Dhaliwal A, Williams FR, Quinlan JI, Allen SL, Greig C, Filer A, Raza K, Ghosh S, Lavery GG, Newsome PN, Choudhary S, Breen L, Armstrong MJ, Elsharkawy AM, Lord JM. Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study. Skelet Muscle. 2021 Dec 11;11(1):27. doi: 10.1186/s13395-021-00282-5.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): April 1, 2020
• Study Completion (Anticipated): September 1, 2021

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: January 27, 2021
• First Posted (Actual): February 2, 2021

Study Record Updates

• Last Update Posted (Actual): February 2, 2021
• Last Update Submitted That Met QC Criteria: January 27, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Nervous System Diseases; Neurologic Manifestations; Gastrointestinal Diseases; Joint Diseases; Musculoskeletal Diseases; Gastroenteritis; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Liver Diseases; Arthritis; Inflammatory Bowel Diseases; Sarcopenia; Intestinal Diseases
• Other Study ID Numbers: RG 18-053; 238190 (Other Identifier: IRAS)

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