Rheumatoid cachexia in rheumatoid arthritis patients treated in the current treat-to-target era

291 Pages·2016·3.05 MB·English

Rheumatoid cachexia in rheumatoid arthritis
patients treated in the current treat-to-target era:
An exploration of the incidence, mechanisms,
effects on physical function, and a potential
nutritional treatment

School of Sport, Health and Exercise Sciences,
College of Health & Behavioural Sciences

Thomas James Wilkinson

Submitted in partial satisfaction of the requirements for the
Degree of Doctor of Philosophy
Sport, Health & Exercise Sciences, Bangor University

Supervisors: Professor Andrew B. Lemmey & Dr Thomas D. O’Brien

2016

Summary

Rheumatoid cachexia (RC), i.e. muscle wasting and adiposity gain in rheumatoid arthritis (RA),
is driven by inflammation and is a major contributor to reduced strength and physical function.
Current treatment for RA is based on approaches that aim to tightly control inflammation from
diagnosis onwards. This is best exemplified by ‘treat-to-target’ (T2T), which targets low
disease activity, preferably ‘clinical remission’. The success of T2T in controlling inflammation
is well-established, but whether it has attenuated RC is unknown. In a cross-sectional trial, we
demonstrated that, despite well controlled disease activity, RC and substantially impaired
physical function was still present in patients treated by T2T.

Consequently, adjunct interventions are required to restore body composition and function.
Nutritional creatine (Cr) supplementation may provide a safe and easy means of improving
muscle mass and physical function. In a randomised control trial, 12 weeks Cr
supplementation significantly increased muscle mass, but was unable to improve objective
measures of physical function.

To investigate their associations with body composition, using serum from RA patients with:
treated versus untreated disease; patients versus healthy controls; and patients before and
after anabolic interventions (PRT or Cr supplementation), we were unable to identify serum
biomarkers (i.e. tumor necrosis factor (TNF)-α, soluble TNF-α receptor-I, interleukin-6, insulin-
like growth factor (IGF)-1, IGF-binding protein 3, myostatin, adiponectin, and leptin) for RC.

Following an unexpected, and substantial, loss of muscle mass in a patient in our Cr
supplementation trial, we investigated and identified a probable catabolic effect of
intramuscular (IM) corticosteroid (CS) injections used to treat active disease. Preliminary
findings from an ongoing study revealed significant muscle loss in all five RA patients tested
within 4 weeks of IM CS injection to treat a disease flare. These findings raise concerns about
this routine and recommended treatment, and provide a further potential mechanism for RC.
Table of contents

Page
List of tables ii
List of figures v
List of common abbreviations used vi
Acknowledgments viii
Impact and achievements x
Declaration and consent xiv

1 – General introduction 1
o 1.1. Rheumatoid arthritis 2
o 1.2. Rheumatoid cachexia 3
o 1.3. Pathogenesis of rheumatoid cachexia 4
o 1.4. Effects of pharmacological treatment for rheumatoid arthritis on 4
rheumatoid cachexia
o 1.5. Anabolic interventions for rheumatoid cachexia 5
o 1.6. Thesis design and hypotheses 7

2 – Extended literature review 11
o 2.1. What is rheumatoid cachexia? 12
 2.1.1. Prevalence of rheumatoid cachexia 13
 2.1.2. When does rheumatoid cachexia occur? 15
 2.1.3. Consequences of rheumatoid cachexia 16
o 2.1.3.1. Effect on functional capacity 16
o 2.1.3.2. Effect on strength 17
o 2.1.3.3. The role of adiposity on strength and physical function 17
o 2.1.3.4. Rheumatoid cachexia, mortality, and co-morbidity 18
o 2.1.3.5. Other factors that effect functional disability in rheumatoid 19
arthritis
 2.1.4. Pathogenesis of rheumatoid cachexia 19
o 2.1.4.1. Inflammation and cytokines 19
o 2.1.4.2. Adipokines 21
o 2.1.4.3. Muscle-protein suppressant hormones 22
o 2.2. Pharmacological treatment of rheumatoid arthritis and its effect on 23
rheumatoid cachexia
 2.2.1. Fundamental principles of modern treatment 23
 2.2.2. Existing treatment guidelines for rheumatoid arthritis 25
o 2.2.2.1. Assessment of physical function in rheumatoid arthritis 26
patients
 2.2.3. If treatment suppresses disease activity and inflammation in 27
rheumatoid arthritis, does it reverse rheumatoid cachexia?
o 2.2.3.1. Pharmaceutical therapy has no favourable effect on 27
rheumatoid cachexia
o 2.2.3.2. Effect of corticosteroid therapy on body composition 27
o 2.2.3.3. Does rheumatoid cachexia still exist in the modern treatment 28
era?
o 2.3. Potential adjunct interventions for attenuating rheumatoid cachexia and 29
improving physical function
 2.3.1. Is there still a need for adjunct interventions that may restore 29
muscle mass and physical function?
o 2.3.1.1. Exercise and progressive resistance training 29
o 2.3.1.2. Nutritional supplementation 31
o 2.4. Literature review summary 33

3 – Has ‘treat-to-target’ therapy attenuated rheumatoid cachexia and 34
improved physical function in patients with rheumatoid arthritis? A
cross-sectional study
o 3.1. Introduction 35
 3.1.1. Aims and hypothesises 37
o 3.2. Patients and methods 39
 3.2.1. Study population 39
o 3.2.1.1. Inclusion/exclusion criteria 39
o 3.2.1.2. Local patient care and treatment strategy 39
 3.2.2. Outcome measures 40
o 3.2.2.1. Anthropometric measures 40
o 3.2.2.2. Body composition measures 40
o 3.2.2.3. Strength and objective physical function measures 40
o 3.2.2.4. Aerobic capacity 42
o 3.2.2.5. Clinical measures 42
o 3.2.2.6. Physical activity 43
o 3.2.2.7. Cardiovascular risk profile 43
 3.2.3. Statistical analysis 44
o 3.3. Results 46
 3.3.1. Primary analysis: Rheumatoid arthritis versus healthy control 46
group
o 3.3.1.1. Descriptive data and participants 46
o 3.3.1.2. Anthropometry and body composition 48
o 3.3.1.3. Strength and objective physical function 48
o 3.3.1.4. Subjective measures of disability and health 49
o 3.3.1.5. Correlational analysis 51
 3.3.2. Sub-analysis: ‘Recent-onset’ versus ‘established’ cohorts 53
o 3.3.2.1. Descriptive data and participants 53
o 3.3.2.2. Anthropometry and body composition 56
o 3.3.2.3. Strength and objective physical function 56
o 3.3.2.4. Subjective measures of disability and health 57
o 3.3.2.5. Relative cardiovascular risk and lipid profile 57
 3.3.3. Sub-analysis: ‘In remission’ versus ‘not in remission’ 60
 3.3.4. Sub-analysis: Sex differences 60
o 3.4. Discussion 71
 3.4.1. Summary of key results 71
 3.4.2. Interpretation of results 71
 3.4.3. Differences in ‘recent-onset’ versus ‘established’ rheumatoid 75
arthritis
 3.4.4. Study strengths and limitations 77
o 3.5. Conclusion 79

4 - Oral creatine supplementation; a potential adjunct intervention 81
for treating rheumatoid cachexia and impaired physical function in
rheumatoid arthritis patients. A review
82
o 4.1. Introduction
83
 4.1.1. What is creatine?
84
 4.1.2. What does creatine do?
84
o 4.1.2.1. Changes in adenosine triphosphate energy synthesis
85
o 4.1.2.2. Changes in muscle mass and protein synthesis
87
o 4.1.2.3. Reduction in inflammatory cytokines
o 4.1.2.4. Creatine and bone degradation 87
o 4.1.2.5. Athletic performance 88
o 4.2. Critical review of relevant clinical literature 90
 4.2.1. Aim 90
 4.2.2. Search methods 90
 4.2.3. Search results 91
o 4.2.3.1. Rheumatoid arthritis 91
o 4.2.3.2. Aging and sarcopenia 92
o 4.2.3.3. Trials in other clinical populations 93
 4.2.4. Review conclusions 97
 4.2.5. Factors affecting creatine effectiveness in certain individuals or 100
populations
 4.2.6. Safety of creatine 100
 4.2.7. Prescription of creatine to patients 101
o 4.2.7.1. Type of creatine 101
o 4.2.7.2. ‘Loading’ dosage 102
o 4.2.7.3. ‘Maintenance’ and frequency 102
o 4.3. Conclusion 102

5 - Can oral creatine supplementation improve body composition, 103
strength, and objective physical function in rheumatoid arthritis
patients? A randomised placebo-controlled trial
104
o 5.1. Introduction
106
o 5.2. Patients and methods
106
 5.2.1. Study population
106
 5.2.2. Supplementation and randomisation protocol
108
 5.2.3. Assessments and outcome measures
108
o 5.2.3.1. Anthropometric and body composition measures
108
o 5.2.3.2. Strength and objective physical function measures
109
o 5.2.3.3. Aerobic capacity
109
o 5.2.3.4. Clinical measures and self-reported physical disability
109
 5.2.4. Statistical analysis
110
o 5.2.4.1. Missing data
112
o 5.3. Results
112
 5.3.1. Baseline demographics
112
 5.3.2. Treatment safety and compliance
 5.3.3. Treatment effectiveness 114
o 5.3.3.1. Body composition measures 114
o 5.3.3.2. Strength and physical function measures 115
o 5.4. Discussion 118
o 5.5. Conclusion 121

6 – Serum biomarkers of muscle anabolism and catabolism, and 122
systemic inflammation in rheumatoid arthritis patients: Potential
markers of rheumatoid cachexia?
123
o 6.1. Introduction
124
o 6.2. Potential biomarkers of interest: a review
124
 6.2.1. Overview and justification of biomarkers selected
125
 6.2.2. Inflammatory biomarkers
125
o 6.2.2.1. Tumor necrosis factor-α (TNF-α)
125
o 6.2.2.2. Soluble tumor necrosis factor-alpha receptor-I (sTNFR-I)
126
o 6.2.2.3. Interleukin-6 (IL-6)
126
 6.2.3. Anabolic biomarkers
126
o 6.2.3.1. Insulin-like growth factor-I (IGF-I) and insulin-like growth

factor-binding protein 3 (IGFBP-3)
127
 6.2.4. Catabolic biomarkers
127
o 6.2.4.1. Myostatin
128
 6.2.5. Adipokines
128
o 6.2.5.1. Adiponectin
128
o 6.2.5.2. Leptin
129
 6.2.6. Effect of current pharmaceutical therapy
129
o 6.2.6.1. Effect of current pharmaceutical treatment on body

composition
129
o 6.2.6.2. Effect of pharmaceutical treatment on anabolic factors
130
o 6.2.6.3. Effect of pharmaceutical treatment on catabolic factors
130
o 6.2.6.4. Effect of pharmaceutical treatment on adipokines

(adiponectin and leptin)
130
 6.2.7. Adjunct treatments that improve muscle mass in rheumatoid

arthritis
131
o 6.2.7.1. Effect of progressive resistance training
132
o 6.2.7.2. Effect of oral creatine supplementation
132
 6.2.8. Aims and hypothesis
o 6.2.8.1. Disease states and the effects of pharmaceutical DMARD 133
treatment
o 6.2.8.2. Effects of non-pharmaceutical anabolic interventions 134
o 6.3. Patients and methods 135
 6.3.1. Participants 135
o 6.3.1.1. Disease states and the effects of pharmaceutical DMARD 135
treatment
o 6.3.1.2. Effects of non-pharmaceutical anabolic interventions 136
 6.3.2. Serum preparation 136
 6.3.3. Assay outcome measures and methods 136
o 6.3.3.1. Serum biomarkers and assay procedure 136
o 6.3.3.2. Assay preparation and equipment 137
o 6.3.3.3. Routine clinical disease activity measures 138
o 6.3.3.4. Anthropometric measurements and body composition 138
measures
 6.3.4. Statistical analysis 138
o 6.3.4.1. Treatment of missing or unknown data 139
o 6.4. Results 140
 6.4.1. Disease states and the effects pharmaceutical DMARD treatment 140
o 6.4.1.1. Rheumatoid arthritis patients versus sedentary healthy 140
controls (1a)
o 6.4.1.2. ‘Recent-onset’ and ‘established’ disease (1b) 144
o 6.4.1.3. Untreated, uncontrolled disease versus treated, controlled 144
disease (2a)
o 6.4.1.4. Etanercept versus methotrexate therapy (2b) 145
 6.4.2. Non-pharmaceutical anabolic interventions 150
o 6.4.2.1. Effect of progressive resistance training (3) 150
o 6.4.2.2. Effect of oral creatine monohydrate supplementation (4) 152
o 6.5. Discussion 155
 6.5.1. Summary of key findings 155
 6.5.2. Disease states and the effects pharmaceutical DMARD treatment 156
o 6.5.2.1. Rheumatoid arthritis patients versus sedentary healthy 156
controls (1a)
o 6.5.2.2. Untreated versus treated disease / (2b) etanercept versus 160
methotrexate (2a)
 6.5.3. Non-pharmaceutical anabolic interventions 162
o 6.5.3.1. Effect of progressive resistance training (3) 162
o 6.5.3.2. Effect of oral creatine monohydrate supplementation (4) 163
 6.5.5. Similarities in biomarker changes in the scenarios investigated 164
 6.5.6. Study limitations 165
o 6.5.6.1. Intramuscular activity 165
o 6.5.6.2. Assay methodology 166
o 6.5.6.3. Sample condition 166
o 6.5.6.4. Low sample sizes 166
o 6.5.6.5. Other biomarkers of rheumatoid cachexia 167
o 6.6. Conclusion 168

7 - Significant muscle loss following intramuscular corticosteroid 169
injection used to treat active rheumatoid arthritis: A case report
o 7.1. Background 170
o 7.2. Case presentation 170
o 7.3. Discussion 171
o 7.4. Conclusion 173

8 - Does a single high-dose intramuscular corticosteroid injection 174
used to treat disease flare exacerbate muscle loss in rheumatoid
arthritis patients? A pilot trial
175
o 8.1. Introduction
177
o 8.2. Methods
177
 8.2.1. Study population
178
 8.2.2. Assessments and outcome measures
178
o 8.2.2.1. Anthropometric and body composition measures
178
o 8.2.2.2. Clinical measures
178
 8.2.3. Statistical analysis
180
o 8.3. Results (preliminary)
180
 8.3.1. Recruitment and participant flow
180
 8.3.2. Descriptive data and participants
180
 8.3.3. Body composition changes
181
 8.3.4. Disease activity changes
182
o 8.3.4.1 Patient 03, F, 67
187
o 8.4 Discussion
187
 8.4.1. Main findings