Osteoarthritis, Rheumatoid Arthritis, Sarcopenia
Conditions
Keywords
exercise therapy, RMD, strength training, muscle endurance, rheumatoid arthritis, osteoarthritis, sarcopenia
Brief summary
C4M hypothesizes that patients with low muscle strength may respond differently to different types of exercise intervention, dependent on the underlying aetiology, i.e. impaired protein synthesis versus metabolic dysfunction and that this response is predictable based on the clinical diagnosis, i.e. rheumatoid arthritis (RA), osteoarthritis (OA) and Sarcopenia alone (SARC) and a number of clinical, blood based and muscle metabolic and architectural biomarkers. Understanding the underlying biochemical response of each patient group to the different type of exercise loading could help with the development of disease-specific training, making it more effective and more predictable on outcomes.
Detailed description
Rationale: C4M hypothesizes that patients with low muscle strength may respond differently to different types of exercise intervention, dependent on the underlying aetiology, i.e. impaired protein synthesis versus metabolic dysfunction and that this response is predictable based on the clinical diagnosis, i.e. rheumatoid arthritis (RA), osteoarthritis (OA) and Sarcopenia alone (SARC) and a number of clinical, blood based and muscle metabolic and architectural biomarkers. Understanding the underlying biochemical response of each patient group to the different type of exercise loading could help with the development of disease-specific training, making it more effective and more predictable on outcomes. Objective: to explore effectivity, interaction and predictability of two types of exercise intervention in patients with RA, OA and SARC alone. The primary outcome of this study will be isokinetic muscle strength of the quadriceps in all three target groups. Study design: two-arm parallel-group exploratory trial including a total of 69 patients: study population 23 patients with OA, 23 patients with RA and 23 patients with SARC alone (according to the revised European Working Group on Sarcopenia in Older People consensus definition (EWGSOP-II criteria, Cruz- Jentoft 2019). Intervention: Exercise intervention for 3 times a week for 8 weeks. Main study parameters/endpoints: the main study parameter is the difference in isokinetic muscle strength pre- and post-intervention in all three patient groups. The secondary study parameters include muscle endurance; mitochondrial respiration, gene and protein expression and histology via muscle biopsies; inflammation via bloodwork and feasibility. Intervention: Exercise intervention for 3 times a week for 8 weeks. Main study parameters/endpoints: the main study parameter is the difference in isokinetic muscle strength pre- and post-intervention in all three patient groups. The secondary study parameters include muscle endurance; mitochondrial respiration, gene and protein expression and histology via muscle biopsies; inflammation via bloodwork and feasibility.
Interventions
OTHERHigh load exercise type
Heavier load, fewer reps
BEHAVIORALLow load exercise type
Lighter load, more reps
Sponsors
Amsterdam UMC, location VUmc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
two-arm parallel-group exploratory trial including a total of 69 patients
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
For all patients * Low muscle strength defined as hand grip strength (HGS) <27 kg and <16 kg for males and females respectively. If HGS is not possible due to interfering pain or joint- deformity, the chair stand test is used instead, with low muscle strength defined as not able to rise from the chair without arms or a time >15 sec (Cruz Jentoft 2019). * Gait speed of >0.8m/s to exclude patients who are too disabled to participate in the study (Cruz Jentoft 2019). OA patients * Age between 50 and 70 * Patients with either knee and/or hip OA according to clinical American College of Rheumatology (ACR) criteria (Altman 1986). * Kellgren and Lawrence grading score of 2-4 for hip and/or knee OA (Altman 1991). * C-reactive Protein (CRP) levels <10mg/L within 3 months prior to enrolment (Sanchez 2014). Rheumatoid arthritis patients * Age between 50 and 70 * Diagnosed with RA according to European Alliance of Associations for Rheumatology (EULAR)/ACR criteria (Aletaha 2010). * Disease activity score in 28 joints (DAS28) 2.8<5.6, as defined by the EULAR criteria (Aletaha 2010), either de novo or despite Disease-Modifying Antirheumatic Drug therapy. * Stable disease three months prior to the start of the exercise intervention. * Stable rheumatic medication three months prior to the start of the exercise intervention. * Stopped the usage of corticosteroids 3 months prior to the start of the exercise intervention. * Disease duration >1 year and <15 years Sarcopenia patients * Age between 50 and 80. * Sarcopenia without joint involvement (no OA, RA), according to the EWGSOPII criteria (Cruz Jentoft 2019) of low muscle strength defined as HGS <27kg and <16 kg for males and females respectively (dynapenia). This group will therefore primarily involve participants with probable sarcopenia (dynapenia) but may also encompass participants with confirmed sarcopenia (appendicular muscle Lean Mass (ALM)/height2 <7.0 kg/m2 for males and <5.5 kg/m2 for females) as this is not a selection criterion. Severe sarcopenia will be excluded (gait speed <0,8 m/s). * Exclude patients with joint complaints (RA, OA, or other joint disease).
Exclusion criteria
* Body mass index (BMI) < 18 and > 35 Kg/m2 * Contra-indications for exercise testing and prescription as indicated by the ACSM guideline (i.e. progressive increase in heart failure symptoms, myocardial infarction less than three months before the start of the training programme, severe cardiac ischemia upon exertion, respiratory frequency of more than 30 breaths per minute and heart rate at rest >110 beats per minute). * Participants taking beta-blockers for the duration of the intervention. * Diagnosed with other neurologic or cachectic diseases or major surgery that may interfere with muscle quality (i.e. multiple sclerosis, ongoing cancer treatment or radiotherapy/ chemotherapy in the previous 6 months). * Participating in another regular and intense (i.e. high physical loading training such as high-load circuit training for muscle gain and fat loss > 2 times a week) physical training programme within 2 months prior to enrolment. * Ligament/muscle tear and/or other injuries within 6 months. * Taking drugs (e.g. performance enhancing drugs) or nutritional supplements (e.g. protein powder) known to increase muscle mass. * Inability to be scheduled for exercise therapy * Insufficient comprehension of Dutch language or no informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Isokinetic muscle strength in Nm/kg | Measured before and after the 8 week- exercise block. | Maximal net joint moment measurements of muscle strength will be assessed using an isokinetic dynamometer (EnKnee, Enraf-Nonius, Rotterdam, the Netherlands). An initial practice attempt will be used for familiarization. Participants will perform three maximal test repetitions to measure the isokinetic strength of the quadriceps and hamstrings for each knee, at 60°/s. Mean quadriceps and hamstring muscle strength per leg will be calculated (in Nm) and divided by the participant's weight (in kg). Muscle strength data (in Nm/kg) of the index knee (most affected knee) will be used (de Zwart 2022). The 1-RM will be defined as the maximal weight in kg a patient could lift for only one repetition |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myogenesis | Measured before the 8 week- exercise block. | SETD3; MYOD1; MYOG |
| Apoptosis & proteolysis | Measured before the 8 week- exercise block. | CASP1; CASP3; MURF1; MAFBX; BCL2; Gene + protein USP19 |
| Oxidative stress & endogenous antioxidants | Measured before the 8 week- exercise block. | 3NT, Cys-S-NO, MDA\*, NOS, NOX, GTHP, GTHO & SOD2; SOD1; CAT; HMOX1; NQO1; NRF2; GPX1 |
| Muscle endurance in number of repetitions | Measured before and after the 8 week- exercise block. | this will be measured by the knee extension test of both legs using an isokinetic dynamometer (EnKnee, Enraf-Nonius, Rotterdam, the Netherlands). The patients will be asked to perform the knee extension exercise at 30% 1RM until muscular failure. The number of repetitions obtained until muscular failure will be the indication of muscle endurance. |
| Glucose metabolism | Measured before the 8 week- exercise block. | GLUT4; SIRT1; FOXO1; AMPK-P |
| General inflammatory markers | Measured before and after the 8 week- exercise block. | CRP, ESR |
| Cytokines | Measured before and after the 8 week- exercise block | TNFa; IL1b; IL6; IFNy & myokines |
| Mitochondrial biogenesis & function | Measured before the 8 week- exercise block. | PPARGC1A; mitochondrial complex I-V (Ci-Cv); NDUFA1, NDUFA2, SDHA, SHDB, UQCRC1, CYC1, COX4I1, COX5A, ATP5B, ATP5A1, CCO, C15ORF48 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Smoking use | Measured before 8 week- exercise block. | Smoking yes or no |
| Smoking frequency per day | Measured before and after the 8 week- exercise block. | If patients smoke, the amount of cigarettes per day |
| Alcohol frequency | Measured before and after the 8 week- exercise block. | If patients drink, the frequency in a day/week |
| Alcohol use | Measured before and after the 8 week- exercise block. | Alcohol yes or no |
| BMI in kg/m^2 | Measured before and after the 8 week- exercise block. | Anthropometric |
| Absolute & relative muscle mass in kilograms | Measured before and after the 8 week- exercise block. | InBody S10, Biospace Co., Ltd, Seoul, South Korea) will be used to measure muscle mass. DSM-BIA has been validated for assessing segmental and whole-body composition against dual energy X-ray absorptiometry (DEXA) (Ling 2011). DSM-BIA will not be performed in patients with 1) electronic internal medical devices or implants such as cardiac pacemakers; 2) plasters or bandages interfering with the placement of the electrodes; 3) amputation. |
| Short-form mini-nutritional assessment | Measured before and after the 8 week- exercise block. | Anthropometrics |
| Muscle physiological cross-sectional area (PCSA) | Measured before and after the 8 week- exercise block. | PCSA will be calculated by dividing muscle volume by ℓfasc. Muscle volume and PCSA will are prime determinants of maximal muscle power and muscle strength, respectively. |
| Age in years | Measured before 8 week- exercise block. | Subject characteristic |
| Short physical performance battery test (score 0-12) | Measured before and after the 8 week- exercise block. | The total score of the SPPB is the sum of the number of points achieved (range between 0 and 12) in each of the test components. The higher the score, the better the patient's performance. Persons with a score between 4 and 9 have an increased risk of new disabilities and are therefore a suitable target group for interventions to improve functioning. People with a higher score are not yet in the danger zone. People with a lower score already experience many limitations and are therefore more likely to be eligible for interventions to maintain functioning and possibly deal with limitations. |
| 6 minutes walk test in metres | Measured before and after the 8 week- exercise block. | The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. |
| FitMáx© survey in score | Measured before and after the 8 week- exercise block. | The FitMáx© is a questionnaire consisting of three single answer questions, about the maximum capacity of walking, climbing stairs and cycling. The questionnaire consists of a scale from 0-13 to rate maximum capacity of walking, a scale from 0-11 for maximum capacity of cycling and for the maximum capacity of stair climbing a scale from 0-10 is used. |
| Patient-Reported Outcome Measures (PROMs) | Measured before and after the 8 week- exercise block. | PROMIS-CAT short forms will be used to self-report of core symptoms and health-related quality of life according to the Item Response Theory. We will assess the domains pain, fatigue, physical function, social function (Witter 2016) |
| Muscle volume in m^2 | Measured before and after the 8 week- exercise block. | Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated. |
| Average fascicle length (ℓfasc) | Measured before and after the 8 week- exercise block. | Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated. |
| Pennation angles (αfasc) | Measured before and after the 8 week- exercise block. | Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated. |
| Handgrip strength in kilograms | Measured before and after the 8 week- exercise block. | A hand-held dynamometer (JAMAR, Sammons Preston, Inc., 119 Bolingbrook, IL, USA will be used to measure handgrip strength. Subjects will be in a sitting position with elbows flexed at 90 degrees, shoulders adducted and forearms in a neutral position without support and instructed to squeeze the dynamometer maximally three times for each hand, alternating between the right and the left- hand side. Maximal value will be reported in kg. |
| Gender (male or female) | Measured before 8 week- exercise block. | Subject characteristic |
| Height in centimetres | Measured before and after the 8 week- exercise block. | Subject characteristic |
| Weight in kilgorams | Measured before and after the 8 week- exercise block. | Subject characteristic |
| Co-morbidities | Measured before 8 week- exercise block. | If any is present |
| Medication | Measured before 8 week- exercise block. | Any current medication use or medication use in the past 3-6 months will be recorded. |
| Educational level | Measured before 8 week- exercise block. | Highest level of education received |
| Employment status | Measured before 8 week- exercise block. | Employed or unemployed |
| Marital status | Measured before 8 week- exercise block. | Single, married, divorce, widow etc. |
Contacts
Primary ContactCarel Meskers Prof.Dr.
Outcome results
None listed