Transcript Anabolic Interventions in Rheumatoid Arthritis

Rehabilitation of Musculoskeletal
Disorders with Exercise Sciences
(ReMeDES) group
Prof. Andrew Lemmey
School of Sport, Health and Exercise Sciences
Bangor University, UK
Benefits of exercise* in the general population
Reduced all-cause mortality risk (e.g. Blair et al., 1989; n=10,224 men, 3,120
women , 8 yr follow-up – lowest fitness quintile vs highest: ↑3.44 ♂, ↑4.65♀)
Reduced CVD – events and death; ≈50%↓ fittest v least fit quintile (independent
of: dyslipidemia, hypertension, insulin sensitivity, obesity, inflammation, vascular
endothelial function)
* Kodama et al., JAMA 2009; meta-analysis (33 studies; 103,000 subjects, mean
follow-up ≈ 12yrs) each MET ↑ V02 max → 13%, 15% ↓ in all-cause and CVD
mortality
Reduced T2D
Reduced obesity
Reduced metabolic syndrome
Reduced cancers (especially colon, breast, endometrial, prostate, pancreas, +
lung)
Reduced osteoporotic fractures (↑ BMD, ↓ falls).
Improved function (inc. independent living for the elderly)
Improved mood (↑self-efficacy, ↓ depression, anxiety)
WHO, NICE, U.S. Surgeon General, ACSM, AHA, various national health
authorities recommend regular, moderate-intense PA (e.g. “accumulate
≥30min on most, preferably all, days of the week”; “additional health
benefits for greater amounts of PA”)
Particular benefits of exercise for RA patients
Reduced CVD (2x↑ risk RA vs general population; event and death)
Countering the effects of “Rheumatoid cachexia” (i.e. ↓muscle mass, ↑
fat mass; 2/3’s of patients with controlled RA are sig. muscle wasted,
80% are obese)
Reduced TIID, metabolic syndrome
Reduced osteoporotic fractures
Improved function (Sokka et al., 2003: RA ↑ risk of disability 7x’s; BSR
Biologics Register, 2010 (n=16,194): mean HAQ’s of 2.1 (biologics), 1.6
(DMARD’s) i.e. moderate-severe disability)
Improved QoL, and psychological factors
NICE, BSR, ACR, EULAR, ACSM recommend aerobic and
progressive resistance training (PRT) for RA patients
Rheumatoid Cachexia
• Rheumatoid cachexia is defined as:– ‘An involuntary loss of BCM that predominates in
skeletal muscle mass and occurs with little or no
weight loss in the presence of stable or increasing
fat mass’ (Walsmith and Roubenoff, 2002)
• Sig. muscle loss present in 2/3 RA
patients and thought to play important
role in disease pathogenesis (Walsmith and
Roubenoff, 2002)
• In RA – “rheumatoid cachexia”
– Lean body mass (LBM) = 14-16% lower
(Roubenoff et al., 1994, Rall et al., 1996;
Lemmey et al., 2005-2012)
– Strong dose relationship between BCM and
disease activity (Roubenoff et al., 1994)
– 80% RA patients are obese (i.e ♀≥ 38% BF, ♂≥
27% BF, Baumgartner et al, Am J Clin Nutr,
1999) (Lemmey et al., 2005-12; StavropoulosKalinoglou et al., 2007, 2009; Westhovens et al.,
1997; Elkan et al., 2009)
– Thus, high incidence of “cachectic-obesity” /
“sarcopenic-obesity”
Cachexia / sarcopenia &
obesity are both associated
with poor outcome
↓ function
↓ QoL
↑ morbidity
↑ mortality
Consequences of Sarcopenia: Disability
(Morley et al., 2001, J Lab Clin Med)
Standard medical
treatment does not
prevent rheumatoid
cachexia
Controlling disease activity by
standard drug therapy,
including anti-TNF therapy,
fails to restore muscle mass
(or reduce fat mass) in RA
patients
Consequently, there is a need
for anabolic therapy
Progressive Resistance
Training
Exercise Dose
Variable
Lemmey et al. (2009)
Marcora et al. (2005)
Dynamic
Dynamic
1-2 s concentric and
eccentric
1-2 s concentric and
eccentric
8
8
80% of 1-RM
80% of 1-RM
3
3
1-2 min
1-2 min
Number of exercises
per training session
8
8
Training frequency
2
3
Total number of lifts
per week
384
576
24 weeks
12 weeks
Muscle action
Velocity
Reps per set
Load
Sets per exercise
Rest periods
Duration
Intense Progressive Resistance
Training
Can 24 wks progressive resistance training
reverse cachexia in rheumatoid arthritis patients?
A RCT
Characteristic
PRT group
(n=13)
ROM controls
(n=15)
p
Age (yrs)
55.6 ± 8.3
60.6 ± 11.2
0.201
Gender (F/M)
11/2
12/3
0.686
Disease duration
(yrs)
6.2 ± 6.3
10.4 ± 9.4
0.146
Disease activity
score (DAS 28)
3.29 ± 1.27
3.28 ± 1.07
0.989
Postmenopausal
9
9
HRT
1
0
Lemmey et al., Arthritis & Rheum (2009) 61:1726-34
Effects of 24 wks high intensity PRT on body
composition in RA patients
PRT group
(n=13)
ROM controls
(n=15)
p
ή
Lean body mass (kg)
pre
post
37.3 ± 4.0
38.8 ± 4.2
40.4 ± 8.9
40.0 ± 8.7
0.006
0.26
Appendicular lean mass (kg)
pre
post
14.3 ± 1.8
15.5 ± 2.2
15.7 ± 4.1
15.5 ± 4.0
0.002
0.33
Total body protein (kg)
pre
post
6.40 ± 2.02
8.20 ± 1.84
7.66 ± 3.56
7.25 ± 3.93
0.004
0.28
Total fat mass (kg)
pre
post
27.8 ± 12.0
25.5 ± 10.8
31.3 ± 8.7
29.9 ± 10.4
0.657
Trunk fat mass (kg)
pre
post
14.0 ± 6.5
11.5 ± 5.2
16.1 ± 5.7
14.8 ± 6.1
0.489
Variable
Effects of 24 wks high intensity PRT on body
composition in RA patients
Variable
PRT group
(n=13)
ROM controls
(n=15)
Cachectic
pre
Post
9
4
7
7
Obese
pre
post
10
7
12
12
Cachectic-obese
pre
post
5
2
5
5
Lemmey et al., Arthritis & Rheum (2009) 61:1726-34
Effects of 24 wks high intensity PRT on
physical function in RA patients
30
Arm Curls (reps)
25
Pre
*
Post
20
15
10
5
B
30s sit-to-stand (reps)
A
18
15
12
9
6
3
0
0
PRT
PRT
Cont
C
D
12
9
Knee extensor strength (N)
15
50 ft walk (s)
***
21
*
6
3
0
PRT
Cont
**
500
400
300
200
100
0
Cont
PRT
* p<0.05, ** p<0.01, *** p<0.001 (group x time interaction).
“healthy control” values (gender and age weighted)
Cont
Line represents
•Efficacy of oral creatine supplementation in
restoring muscle mass and function to
rheumatoid arthritis patients (RCT, n=50)
•The prevalence of rheumatoid cachexia in
recently diagnosed rheumatoid arthritis patients
(x-sectional / longitudinal study, n=100)
•Association between aerobic capacity and
CVD risk factors in patients with RA / Validation
of Siconolfi step test in RA patients (n=100;
n=24)
• Joint health and exercise in rheumatoid arthritis
patients: effects of acute and chronic exercise (n=16
(inc. matched HC’s), n=9), (qualitative studies; n=18
(focus groups), n=247)
• Efficacy of early, home-based progressive
resistance training in improving physical function in
elective total hip replacement patients (RCT, n=40)
• Patello-femoral pain syndrome; reliability and
validity of common outcome measures (qualitative
and quantitative studies; n=40, n=52)
• Developing a multidisciplinary rehabilitation
package following total hip replacement
surgery for hip fracture; Fracture in the
Elderly Multidisciplinary Rehabilitation
(FEMuR) (HTA, ≈ £600k)
• Efficacy of behavioural change strategies in
improving long-term adherence to exercise
in rheumatoid arthritis patients (grant
application to ARUK)
• Prof. Peter Maddison; Rheum. Dept., Ysbyty Gwynedd, BCUHB;
SSHES , BU
• Drs. Tom O’Brien, Jeanette Thom, Jonathon Moore; SSHES, Dr.
Val Morrison; Psychology, BU
• Drs. Jerry Jones, Yasmeen Ahmad, Verena Matschke, Sarang
Chitale, Rheum. Dept., Peter Maddison Rheumatology Center, Ysbyty
Llandudno, BCUHB
• Mr. Glynne Andrew, Dr. Tosan Okoro, Dept of Orthopedics, Ysbyty
Gwynedd, BCUHB
• Dr. Nefyn Williams, NWORTH, BU; Cardiff Medical School
• PhD students: Sam Marcora, Francesco Casanova, Sally Wilson,
Verena Matschke, Becki Law, Tosan Okoro, Jennifer Cooney, Tom
Wilkinson, Kostas Papadopoulos; MPhil students: Kath Chester,
Rebecca Clayton, plus MSc and intercollated degree medical students
• Prof. Claire Stewart; Liverpool John Moores Univ.
Metsios et al., Rheumatology (2007) 46:1824-27
n=20 established (disease duration mean, 17.3
yrs) RA patients
12 wks anti-TNF-α therapy
No change LBM, increased trunk FM (p<0.05)
Engvall et al., Arthritis Res Ther (2010) 12(5):R197
RCT; early (mean, 5.4 mths) RA patients, n=11 on
MTX+infliximab for 21 mths vs. 14 on DMARDs
(MTX+sulphasalazine+hydroxychloroquine)
No change LBM, increased FM (+3.4 kg , p<0.05
vs comb. DMARDs)
Role of Anti-TNF Therapy with Etanercept in
Preventing Muscle Wasting in RA Patients
• Single-blind, randomised, parallel, controlled trial
• 24 patients (mean age 52 ± 13) with early (< 6 months)
and active RA randomly assigned to:
• A) 25 mg of etanercept sc twice a week (9 F, 3 M)
• B) 10 to 20 mg methotrexate once a week (9 F, 3 M)
• Duration 24 weeks
• Body composition by DXA and BIS
• Objective (hand grip strength and functional tests) and
subjective (HAQ) functional capacity
• Disease activity
Marcora et al., Am J Clin Nutr (2006) 84:1463-72
Efficacy of exercise training in RA patients
Strength (resistance) training: 1966 – present, n=24
Aerobic (CV) training: 1975 – present, n=36
Evidence is overwhelming that exercise training improves:
strength, aerobic capacity, functional capacity, and body
composition, with NO exacerbation of inflammation, disease
activity, pain, fatigue or joint damage*
Limited evidence that it ↓bone loss (RAPIT study), ↑BMD
(Hakkinen et al., 2001, 2004)
2 Cochrane Reviews (van den Ende et al., 2000; Hurkmans
et al., 2009) - only considered RCT’s; confirmed benefits of
exercise and concluded: “aerobic training combined with
muscle strength training is recommended for routine
practice in patients with RA”
NO reports of exercise training exacerbating pain, fatigue or
disease activity
(e.g. Pain, no. of swollen, tender, painful joints, morning stiffness, ESR,
CRP, DAS28/DAS4, fatigue)
JOINT DAMAGE: initial concerns from the RAPIT study (de Jong et
al., 2003; Munneke et al., 2005); 2 yrs HI aerobic + strength training
accelerated damage to large jts with extensive pre-existing damage.
However, after 18 mth follow-up (de Jong et al., 2009) this conclusion
was retracted.
Revised conclusion: exercise, even HI, is safe for small and large jts,
including those with extensive pre-existing damage
This agrees with others (Nordemar et al., 1981; Hakkinen et al., 1994,
2001, 2004)