Transcript Marcora et al.

Effects of “treat-to-target” therapy
on body composition and physical
function in RA patients
RJ Clayton1,2, F Sheikh2, T O’Brien1, T Wilkinson1, J
Whale1, H Jones1, Y Ahmad2, AB Lemmey1
1 School
of Sport, Health and Exercise Sciences, Bangor University;
2 Peter Maddison Rheumatology Centre, BCUHB
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)
• Significant muscle loss is present in
≈2/3 RA patients and plays an important
role in disease pathogenesis (Walsmith and
Roubenoff, 2002)
• In RA – “rheumatoid cachexia”
– Lean body mass (LBM) = 11-16% 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 (independently)
associated with poor outcome:
↓ function (Giles et al., 2008; Stavropoulos-Kalinoglou et al., 2009)
↓ QoL
↑ morbidity (Giles et al., 2010; Inaba et al., 2007)
↑ mortality
Time course of body composition
changes (?)
Preliminary data only (Marcora et al., Am J Clin Nutr, 2006) recently diagnosed,
treatment naive RA patients (< 6mths from 1st symptoms):
n=24 (18♀)
60% sig. muscle wasted (DXA, ALM), mean 40.4±8.3% BF
(Lemmey et al., Arthritis Care & Res, 2012)
3 yr follow-up study (n=9; 6♀), established, diseasecontrolled patients
↓ 0.1kg/yr LM vs ≈ 0.1kg/yr LM age, sex-matched
sedentary HC’s (literature)
↑ 0.8kg/yr FM vs ≈ 0.4kg/yr LM age, sex-matched
sedentary HC’s (literature)
Standard medical
treatment does not
prevent rheumatoid
cachexia
Anti-TNF Therapy in RA
Immunex Corporation and
Wyeth-Ayerst Pharmaceuticals
Washington, USA
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
Effect on Appendicular Lean Mass
Etanercept
Methotrexate
18.0
Appendicular lean mass (kg)
17.5
17.0
16.5
¶
#
16.0
15.5
15.0
14.5
14.0
0
12
24
¶ Group x time interaction, P = 0.16 # Main effect for time, P = 0.26
Marcora et al., Am J Clin Nutr (2006) 84:1463-72
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)
Treat-to-Target
• Structured management of RA patients aiming for a
treatment target, usually remission (DAS28<2.6) or low
disease activity , Smolen et al (international task force;
T2T Expert Committee) Ann Rheum Dis 2010
• Features earlier and more aggressive DMARD treatment
e.g. greater use of combination therapy (2-3 DMARDs),
biologics
• Frequent assessment of DAS, with drug therapy
adjusted @ least every 3 mths till target is reached
• → ↓ DAS, inflammation, joint damage vs traditional drug
treatment
Effects of “treat-to-target” therapy on body
composition and physical function in RA patients; a
cross-sectional and longitudinal study
• RA patients: n=100 (“recent”, <12 mths since diagnosis, n≈40; “established”, 15 yrs since diagnosis, n≈60; ALL patients diagnosed and exclusively treated
post-Jan 2008 i.e. in the “treat-to-target” era)
• Health controls: n=100, age- and sex-matched
• “recent” patients to be followed-up annually for 8 yrs
Outcome measures:
• Body composition (DXA; total & regional lean mass (LM), fat mass (FM), and
bone mass/BMD. Appendicular LM (ALM) = surrogate measure of muscle mass)
• Objective physical function: 30s sit-to-stand, 8’ up and go, 50’ walk, isometric
knee extensor strength (IKES), handgrip strength
• Subjective function: MDHAQ, SF-36 (physical, mental)
• Disease activity: DAS28
• CVD risk factors
Characteristics of RA patients and matched healthy controls
Variable
RA
N=40
Healthy controls
N=38
p
61.8±10.9
63.9±8.4
0.359
25/15
(62.5)
27/11
(71.1)
0.430
Height (cm)
163.9±8.3
168.0±8.6
0.032
Waist circ. (cm)
97.5±15.8
86.1±10.8
<0.001
Hip circ. (cm)
104.2±13.7
101.7±7.6
0.311
Waist:hip ratio
0.92±0.2
0.84±0.1
0.019
Disease duration (mths)
18.3±15.6
Age (years)
Sex, female/male
(% female)
DAS28 score
2.9±2.0
MDHAQ
0.6±0.5
0.1±0.3
<0.001
MDHAQ pain
3.7±2.4
0.9±1.7
<0.001
SF36 physical health
43.1±8.9
54.8±7.5
<0.001
SF36 mental health
44.3±10.8
49.6±6.8
0.013
Values are means ± sd. Sig. p’s are in bold
Body composition of RA patients and matched healthy controls
Variable
RA
N=40
Healthy
controls
N=38
Absolute
difference
(% difference)
p
Body mass (kg)
79.7±18.6
73.8±12.3
↑ 5.9 (↑ 8.0%)
0.163
BMI (kg/m2)
28.8±5.5
25.9±3.5
↑ 2.9 (↑ 11.2%)
0.007
% Lean mass (LM/BM %)
63.4±7.3
66.5±6.6
↓ 3.1 (↓ 4.7%)
0.050
% ALM (ALM/BM %)
25.7±4.1
27.6±3.8
↓ 1.9 (↓ 6.9%)
0.039
Fat mass (kg)
26.5±9.2
22.5±6.4
↑ 4.0 (↑ 17.8%)
0.033
Trunk FM (kg)
14.2±6.1
10.6±4.0
↑ 3.6 (↑ 34.0%)
0.006
% Body fat (FM/BM %)
33.8±7.7
30.5±6.9
↑ 3.3 (↑ 11.1%)
0.082
% Trunk FM (trFM/FM %)
51.3±5.5
47.8±7.4
↑ 3.5 (↑ 7.3%)
0.014
Values are means ± sd. Sig. p’s are in bold
Objective physical function of RA patients (n=40) and age- and
sex-matched healthy controls (n=38)
30% ↓
17% ↓
Values are means ± SE
22% ↓
24% ↓
22% ↓
Correlation matrix showing the association between body composition
and physical function measures of RA patients and healthy controls
Variable
IKES
Hand grip 30s Sit-to- 8’ up-andstrength
stand
go
50’ walk
RA patients
(n=40)
% ALM
0.67
0.63
0.31
-0.53
-0.46
% BF
-0.52
-0.51
-0.31
0.48
0.38
% ALM
0.57
0.72
0.25
-0.11
-0.35
% BF
-0.60
-0.64
-0.36
0.18
0.35
Healthy Controls
(n=38)
Values are Pearson’s r. Significant r’s in bold green. IKES = isometric knee extensor
strength
CONCLUSIONS (from preliminary analyses)
T2T appears to:
• attenuate but not prevent muscle loss in RA
patients
• to have no effect on adiposity of RA patients
Despite substantially reducing DAS,
inflammation and joint damage, T2T appears
to have no benefit on objectively assessed
physical function
Recommendations (i)
Assessment of treatment efficacy should include function measures
(preferably objective)
This position is also taken by Pincus et al. (J Rheum 2013 40:9), who point
out that “In RA, the most significant indicator of mortality is a … measure of
physical function”, “a measure of physical function … is more significant
than any laboratory test or radiographic score to predict costs, work
disability, or even joint replacement surgery”
EULAR recommendations and principles of T2T (Smolen et al., 2010):
Principle 2 – the primary goal of treating the patient with RA is to maximise
long-term health related QoL through control of symptoms, prevention of
structural damage, and normalisation of function and social participation
2012 update of ACR recommendations (Singh et al., AC&R 2012) also
highlight the expectation that early intensive treatment (i.e. T2T) “may
provide the best opportunity to preserve physical function”
Recommendations (ii)
Since even well treated (i.e. “remission
or low DAS”) RA patients have poor
physical function (≈ 20-30%< normal for
sedentary matched controls), it
underlines the need for adjunct
treatments to improve function and
body composition
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
384
576
24 weeks
12 weeks
Muscle action
Velocity
Reps per set
Load
Sets per exercise
Rest periods
Total number of lifts
per week
Duration
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
Training Progression
12000
Mean increase of 119%
av. training session load (kg)
11000
10000
9000
8000
* P < 0.0001
7000
6000
5000
4000
week 2
week 12
week 24
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
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