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Blockade of tumour necrosis factor-
in rheumatoid arthritis: effects on components of rheumatoid cachexia
1School of Sport, Performing Arts and Leisure, University of Wolverhampton, Walsall, 2Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russell's Hall Hospital, Dudley, West Midlands, UK and 3Research Institute in Physical Performance and Rehabilitation, Centre for Research and Technology, Thessaly, Trikala, Greece.
Correspondence to: G. S. Metsios, Department of Biomedical Sciences, University of Wolverhampton, Wolverhampton, West Midlands, UK. E-mail: gm{at}wlv.ac.uk
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Abstract |
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Objectives. Rheumatoid arthritis (RA) is accompanied by increased resting energy expenditure (REE) and decreased fat-free mass (FFM). This is referred to as rheumatoid cachexia and is attributed to high levels of tumour necrosis factor-
(TNF-). This study aimed to investigate the effects of anti-TNF- therapy on REE, body composition, physical activity and protein intake in RA patients.
Methods. Twenty RA patients [50% female; age: (mean ± S.D.) 61.1 ± 6.8 yrs; body mass index (BMI): 28.3 ± 3.7 kg/m2] and 12 age–sex–BMI-matched healthy controls were assessed. REE (indirect calorimetry), body composition (bioelectrical impedance), the International Physical Activity Questionnaire (IPAQ), diet, Health Assessment Questionnaire (HAQ), disease activity [disease activity score 28 (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein] and serum TNF- were measured before (Baseline) as well as 2 weeks (Time-1) and 12 weeks (Time-2) after initiation of anti-TNF- treatment. Controls were only assessed at Baseline.
Results. RA patients had significantly higher REE than controls at Baseline (1799.4 ± 292.0 vs 1502.9 ± 114.5 kcal/day, P = 0.002). Within the RA group, REE increased significantly between Time-1 and Time-2 (P = 0.001) but not between Baseline and Time-2. Sustained significant increases were observed in IPAQ (P = 0.001) and protein intake (P = 0.001). There were no significant changes in FFM or body fat. ESR (P = 0.002), DAS28 (P < 0.001), HAQ (P < 0.001) and TNF- (P = 0.024) improved significantly. Physical activity (P = 0.001) and protein intake (P = 0.024) were significant between-subject factors for the elevation of REE.
Conclusions. After 12 weeks of anti-TNF- therapy, there were significant improvements in disease activity and physical function, as well as physical activity and protein intake, but no significant changes in REE or FFM. There is a need for longer-term studies in this field.
KEY WORDS: Anti-TNF-, Resting energy expenditure, Metabolism, Rheumatoid cachexia, Rheumatoid arthritis, Adipose tissue, Cytokines, Inflammation, Muscle, Biological therapy
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Introduction |
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Rheumatoid arthritis (RA) is a common chronic inflammatory condition characterized by a symmetrical inflammatory polyarthritis and accompanied by systemic upset. It is associated with increased resting energy expenditure (REE), loss of fat-free mass (FFM) and accumulation of body fat [1, 2] compared with healthy individuals: a metabolic abnormality known as ‘rheumatoid cachexia’. This phenomenon has been attributed, at least in part, to increased pro-inflammatory cytokine production, particularly tumour necrosis factor-
(TNF-) [3].
Resistance training potentially stimulates muscle growth and prevents muscle wasting in RA [4]. It has been suggested that anti-TNF- therapies may slow, or even reverse, rheumatoid cachexia [3, 5]. A recent study [6] demonstrated that body composition remained unchanged after anti-TNF- therapy but did not assess either physical activity or protein intake. Both these factors can significantly affect body composition, or REE, that may decrease as a result of controlling inflammation-induced hypermetabolism with anti-TNF- [3, 5]. The aim of the present study was to investigate the immediate (2 weeks) and early (3 months) effects of anti-TNF- therapy on REE, body composition, physical activity and protein intake in RA patients.
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Methods |
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Participants
Twenty RA patients, who had a clinical indication for treatment with any anti-TNF-
therapy as per current British Society for Rheumatology/National Institute for Health and Clinical Excellence (BSR/NICE) guidelines [7], participated. They all met retrospective application of the revised 1987 American College of Rheumatology classification criteria for RA [8] and were recruited consecutively from specialist nurse-led clinics at the Department of Rheumatology, Dudley Group of Hospitals NHS Trust, UK. At baseline, they were compared with 12 healthy controls (clinical and laboratory personnel) who were matched (post hoc) for age, sex and body mass index (BMI). The demographic and baseline anthropometric characteristics of all participants are shown in Table 1. All participants gave written informed consent after full explanation of the procedures involved. The study was approved by the local research ethics committee and the Dudley Group of Hospitals Research and Development Directorate.
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Procedures
Each RA patient fasted between 08:00 and 09:00 h and underwent an identical assessment on three separate occasions. In order to evaluate both immediate and any subsequent early changes in the studied variables, the baseline assessment occurred within 2 weeks of the initial anti-TNF-
treatment, Time-1 assessment at 2 weeks and Time-2 assessment at 12 weeks of therapy. In every visit, anthropometric characteristics were recorded prior to the REE, followed by a fasting blood sample and assessment of clinical disease activity and functional capacity. The control group was assessed only at baseline and only for REE.
Resting energy expenditure
REE was assessed via indirect calorimetry; participants were instructed to visit the laboratory after a 12 h overnight fast after refraining from strenuous exercise for 72 h. The automated gas analyser (Metalyzer, Cortex Biophsik, Borsdorf, Germany) was calibrated before each test using standard gases of known concentration. The analyser recorded respiratory parameters every 20 s, while subjects inspired room air through a free-breathing face mask for 40 min, in a quiet, thermoregulated room.
Body composition analysis
Body composition was evaluated via bioelectrical impedance (Tanita BC-418-MA). Patients had to stand on the apparatus holding the provided grips for 30 s. Data were collected for total body and truncal fat (%) as well as FFM (kg). In addition to avoiding exercise, we explicitly asked participants to also avoid excessive consumption of water or alcohol and to report any changes in their overall health state (e.g. any intervening infections) prior to the assessments.
International physical activity questionnaire (IPAQ) and food diary
The long version of the IPAQ was utilized to record physical activity (up to 3 days prior to REE assessment). This questionnaire is divided into five parts requesting information about the physical activities (job-related, transportation, housework, leisure time and time spent sitting) that the participants had undertaken over the previous 7 days. The same nurse always helped the patients to fill in the questionnaire. The IPAQ has been extensively used for research purposes, and its validity and reliability have been assessed in 12 countries, including the UK [9].
After relevant verbal and written instructions, a simple food diary was distributed to all participants, with the request to write in detail about all the food they consumed for 3 days (including a weekend day) during the week before REE assessment. Percentages of carbohydrate, fat and protein intake were calculated for the whole week using a simple diet analysis software (Recipe Calc 4.0).
Disease activity, physical function and serum TNF-
Disease activity was assessed clinically using the disease activity score 28 (DAS28) and serologically using C-reactive protein (CRP) (Vitros®5.1-FS, USA). Erythrocyte sedimentation rate (ESR) (Starrsed compact Mechatronics BV, The Netherlands) and Health Assessment Questionnaire (HAQ) were also assessed. Serum was collected for measurement of TNF- levels. This was frozen immediately at –70°C until analysed by multi-analyte Biochip Array Technology (Evidence analyzer, Randox, USA) on a single occasion for all specimens.
Statistical analyses
Values are reported as mean ± S.D. Preliminary analyses were conducted to detect if the studied variables were normally distributed. The t-tests were employed to compare REE and anthropometric characteristics between RA patients and controls. Repeated-measures analysis of variance (ANOVA) with Bonferroni correction was used to detect differences between the three times of assessment for all studied variables. In the repeated-measures ANOVA, a median split was employed in the total physical activity score and percentage of protein intake variables, in order to assess their significance as between-subject factors on the observed REE changes. Statistical significance was set at P < 0.05. All statistical analyses were performed with SPSS software (version 11.0, SPSS Inc., Chicago, IL, USA).
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Results |
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There were no significant differences in any of the baseline anthropometric characteristics between RA patients and controls. However, baseline REE was significantly higher in patients than controls (1799.4 ± 292.0 vs 1502.9 ± 114.5 kcal/day, P = 0.002) (Table 1).
REE
Repeated-measures ANOVA revealed a significant difference between times of assessment (Baseline = 1799.4 ± 292.0 vs Time-1 = 1684.1 ± 302.4 vs Time-2 = 1849.5 ± 305.8 kcal/day, P = 0.002), with the baseline values appearing to initially decrease (2 weeks) and then increase (12 weeks). However, using Bonferroni correction, REE was found to be significantly different only between Time-1 and Time-2 (P = 0.001).
IPAQ
Physical activity changed significantly, with a continuous increase from baseline to 12 weeks (Baseline = 1331.9 ± 1575.5 vs Time-1 =1950 ± 1915.7 vs Time-2 = 3025.1 ± 2672.9 metabolic equivalent min/week, P = 0.001). Significant differences were observed between Baseline vs Time-2 (P = 0.002) and Time-1 vs Time-2 assessment (P = 0.001). IPAQ was a significant between-subject factor for the observed changes in REE (P = 0.001).
Body composition
Mean ± S.D. values and results from repeated-measures ANOVA appear in Table 2. Significant changes were observed only in truncal fat (P = 0.036), with the significant difference being present only between Baseline and Time-1 (P = 0.033).
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Food diary
Protein intake showed a significant increase (Baseline = 15.9 ± 3.6 vs Time-1 = 16.5 ± 3.5 vs Time-2 = 20.2 ± 6.2%, P = 0.001), with the significant differences occurring between Baseline vs Time-2 and Time-1 vs Time-2 (both at P = 0.001). Protein intake was a significant between-subject factor for the alterations in REE (P = 0.024). Carbohydrate intake significantly reduced (Baseline=51.3 ± 6.7 vs Time-1 = 51.7 ± 5.4 vs Time-2 = 47.1 ±4.5%, P = 0.001), with the difference being between Baseline vs Time-2 (P = 0.012) and Time-1 vs Time-2 (P = 0.001). No changes were observed in fat intake (Baseline = 32.7 ± 9.4 vs Time-1 = 32.1 ± 8.1 vs Time-2 = 32.7 ± 9.6%, P > 0.05).
Disease activity
The values and comparisons between time-points for contemporary serological and clinical disease activity measurements and levels of serum TNF- appear in Table 2. ESR (P = 0.002), DAS28 (P < 0.001), HAQ (P < 0.001) and TNF- (P = 0.024) reduced significantly within the 12-week observation period. DAS28 revealed significant differences among all the times of assessment (P < 0.001). HAQ was significantly decreased between Baseline vs Time-1 and Baseline vs Time-2 (both at P = 0.001). ESR was significantly different between Baseline vs Time-1 (P = 0.001) and Baseline vs Time-2 (P = 0.01). The significant changes for TNF- (P = 0.024) were observed between Baseline vs Time-2 (P = 0.05) and Time-1 vs Time-2 (P = 0.014). CRP did not change significantly between any of the times of assessment.
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Discussion |
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The main aim of the present study was to investigate the early effects of anti-TNF-
therapy on rheumatoid cachexia. We have evaluated changes in two factors that characterize this metabolic abnormality: REE and body composition. We also assessed physical activity and protein intake [10, 11] because, together with control of systemic inflammation, they may have a major impact on both REE and body composition.
Previous studies have shown that REE is significantly elevated in RA patients as a result of excessive TNF- production [3, 5] and this is further supported by the comparison between the RA and control groups in the present study. RA presents with a whole spectrum of inflammatory disease activity, from very little to very severe within a patient population, and even within an individual patient at different stages of the disease. Such a wide spectrum is not present either in a healthy control population or within individual healthy people other than when they have an acute illness, e.g. infection. The patients included in the present study were, by definition, at the worst end of the spectrum of RA disease activity (and thus more likely to be hypermetabolic), as they would not otherwise qualify for treatment with anti-TNF- under current guidelines used in the British National Health Service (NHS). Hypermetabolism in RA leads to enhanced protein degradation, increased fat deposition, reduced strength and functional disability [2] and may be important in the context of the high cardiovascular morbidity and mortality associated with this disease [12].
It has been suggested that anti-TNF- therapy may reverse the process of rheumatoid cachexia [3, 5]. However, a recent, very interesting randomized study by Marcora et al. [6] found that fat and FFM did not change significantly in patients with early RA after 12 or even 24 weeks of treatment with either anti-TNF- or methotrexate, despite control of systemic inflammation. Our study suggests that this is also evident in patients with long-standing RA, at least up to 3 months of treatment with anti-TNF-. In our study, there appears to be a significant short-term change in truncal fat, as assessed by bioelectrical impedance. We chose that method because it is non-invasive, quick, highly reproducible, has reasonable agreement with the total body water method in individuals with RA [13] and is valid in both normal and obese individuals [14, 15]. However, it is not as accurate for assessing segmental body fat and is very susceptible to changes in total body water: it is possible, therefore, that this finding is artefactual and thus, assessment of body composition by superior methods, including dual energy x-ray absorptiometry as used by Marcora et al. [6], would have been preferable. However, taken together, these two studies, would suggest that anti-TNF- effects, if any, on the body composition of RA patients with either early or long-standing disease, are likely to be long-term, and this requires further investigation.
Our study provides important additional information on possible anti-TNF- effects on components of rheumatoid cachexia since, along with the evaluation of body composition and control of inflammation, we have also assessed REE, physical activity and protein intake. Our findings support the possibility that an initial, non-significant reduction of REE between Baseline and 2 weeks is possibly due to the early significant change in disease activity, without any changes in physical activity and protein intake; the subsequent significant REE increase between 2 and 12 weeks of treatment is due to continuing control of disease activity (without much further improvement), but concurrent significant increases in physical activity and protein intake, both of which were significant ‘between-subject’ predictors of REE. Research on the effects of exercise on REE has revealed some contradictory results but most studies suggest that exercise increases REE [10]. This may occur even if FFM does not change (as in this and Marcora's study), because FFM in individuals who engage in physical activities is metabolically more active compared with their non-exercising counterparts [16].
Increased protein intake on the other hand, such as that observed in the present study, may cause REE elevation due to enhancement of muscle anabolic processes [11]. The significant increase in protein intake and decrease in carbohydrate in our patients is an unexpected and interesting finding that merits further investigation, as any possible causes remain speculative. Food diaries have significant limitations in terms of accuracy, but this cannot be an explanation for the present finding, as the same instrument was used to record all three main nutrients. In clinical practice, it is a common observation that appetite improves significantly after anti-TNF- therapy, but we are not aware of any evidence to suggest that there is selectivity for particular nutrients. In other diseases, increased severity may cause reduced protein intake; this coupled with the enhanced protein catabolism that accompanies RA [3] may have caused a drive for this particular nutrient [17]. High-protein food stuffs usually require frequent purchase (to be fresh) and preparation, whereas carbohydrates are readily available and can be stored for long periods; it is therefore possible, that improvement of disease activity facilitates a better diet by patients compared with when their disease is uncontrolled.
In line with multiple large randomized controlled trials, anti-TNF- treatment in this study was associated with significant decrease in systemic inflammation and increase in physical activity. The increased cardiovascular mortality in RA may relate both to classical cardiovascular risk factors [18] and to systemic inflammation [12]; increased levels of physical activity are effective in reducing cardiovascular mortality in the general population [19]. Anti-TNF- therapy appears to associate with a reduction of cardiovascular mortality in RA, probably by inhibiting systemic inflammation [20] and based on the current findings possibly by improving functional ability and physical activity.
The emerging body of evidence from the original studies by Rall and Roubenoff [3], the recent randomized controlled trial by Marcora et al. [6] and the present study suggests that in the short term, anti-TNF- therapy appears to improve processes involved in the causation of rheumatoid cachexia, including systemic inflammation and cytokine release, physical inactivity and dysfunction, and reduced protein intake; through these, it may have a stabilizing effect on REE but no obvious effect on body composition. There is a need for long-term controlled studies to identify whether these phenomena are sustainable and specific to anti-TNF- therapy and to further characterize their net metabolic and cardiovascular effects and underlying mechanisms.
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Acknowledgements |
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Funding: This study was funded by the Dudley Group of Hospitals, R&D Directorate Cardiovascular Programme Grant and a Wolverhampton University Equipment Grant. G.S.M. is funded through a Greek Government postgraduate scholarship [Greek State Scholarship's Foundation (I.K.Y.)]. The Department of Rheumatology has an infrastructure support grant from the Arthritis Research Campaign (number: 17682).
Disclosure statement: The authors have declared no conflicts of interest.
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