ORIGINAL ARTICLEDietary treatment of rheumatoid cachexia with β-hydroxy-β-methylbutyrate, glutamine and arginine: A randomised controlled trial
Introduction
Rheumatoid arthritis (RA) is a common, often progressive, chronic, inflammatory, autoimmune joint disease leading to erosion of articular cartilage and bone, disability and shortened life span.1, 2 However, RA is also a truly systemic disease with several extra-articular features including cytokine-driven alterations in protein and energy metabolism, muscle wasting and, in some patients, anorexia and weight loss.3, 4, 5, 6 In most RA patients, however, wasting is not apparent as energy intake is normal and the decrease in skeletal muscle mass is masked by an increase in fat mass consequent to reduced physical activity and resultant low levels of total energy expenditure.7 This form of secondary malnutrition, named rheumatoid cachexia, affects more than 50% of RA patients6 and is thought to contribute to the poor outcome of this disease.8
Although the efficacy and safety of dietary therapy for the treatment of protein-energy malnutrition has been investigated in cancer9 and many other chronic non-malignant conditions, there is a striking lack of published studies on this topic in RA patients.10 Most studies on the nutritional management of RA have focused on special diets and/or dietary supplements to reduce joint symptoms.11 The only exception being the pilot study of Willer et al.12 which investigated the effect of short-term creatine supplementation on muscle weakness. Importantly, some dietary manipulations popular among RA patients such as fasting and elimination diets worsen malnutrition despite a reduction in disease activity.13 Clearly, more research is necessary before comprehensive nutritional recommendations for RA patients can be made.
In this paper, we report the results of a randomised controlled trial of dietary supplementation with β-hydroxy-β-methylbutyrate, glutamine and arginine (HMB/GLN/ARG) for the treatment of rheumatoid cachexia. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine, is safe for human consumption14 and is one of the few dietary supplements proven to have anabolic and functional effects in humans undergoing resistance training.15 Interestingly, there is evidence that HMB reduces muscle proteolysis in type II fibres,16 the fibre type most affected by catabolism in RA patients.17 The important role of glutamine in skeletal muscle protein turnover is well established18 and several studies have demonstrated that increasing glutamine intake is beneficial in catabolic patients.19 Dietary supplementation with arginine has also been shown to safely induce positive nitrogen balance in both healthy elderly humans20 and surgical patients,21 possibly by increasing muscle protein synthesis22 and inhibiting muscle proteasome activity.23 These amino acids have been combined in a dietary supplement (HMB/GLN/ARG) specifically designed for patients with catabolic diseases and tested in wasted HIV24 and cancer25 patients. In both these randomised, double-blind, placebo-controlled trials, HMB/GLN/ARG proved to be safe and superior to placebo in reversing weight loss and increasing fat-free mass (FFM).
The primary aim of this study was to investigate whether HMB/GLN/ARG is also effective in improving nutritional status (i.e., increase FFM) in RA patients. As suggested by Akner and Cederholm,10 we also investigated its effects on clinically relevant outcomes such as physical function.26 As HMB, glutamine, and arginine, alone and in combination, have been shown to affect the immune system,24, 27, 28, 29 disease activity was monitored in order to establish the specific safety of this dietary supplement in RA patients.
Section snippets
Study population
Adult patients fulfilling the American Rheumatism Association 1987 revised criteria for the diagnosis of RA,30 and with stable disease activity (defined as no changes in medications in the previous 3 months), were recruited from outpatient clinics in the Department of Rheumatology of Gwynedd Hospital. Patients were excluded if they had any condition preventing safe participation in the required physical function tests (i.e., uncontrolled hypertension or musculoskeletal injury) or for which an
Retention, subjects characteristics and compliance
Fifty-nine RA patients were recruited and screened. Of these patients, 11 refused to participate and eight were excluded for various reasons. The remaining 40 patients were allocated to treatment with either HMB/GLN/ARG (12 females and eight males) or placebo (13 females and seven males). Four subjects were lost to follow-up because of relocation to a different area (one female in the HMB/GLN/ARG group), sickness (one female in the HMB/GLN/ARG group), or because they withdraw themselves from
Discussion
This is the first study to investigate the efficacy and safety of a nutritional intervention for the treatment of cachexia in RA patients. Contrary to our initial hypothesis, dietary supplementation with HMB/GLN/ARG was not more effective than the mixture of alanine, glutamic acid, glycine and serine used to control for the effects of increased nitrogen and calorie intake (i.e., placebo). In fact, both formulas of high-dose oral amino acids induced a significant increase in FFM in our patients
Acknowledgements
We want to thank Dr. John Rathmacher of Metabolic Technologies Inc. (Ames, IA) for his precious collaboration throughout this study. We are also grateful to the staff of the Rheumatology and Biochemistry Departments of Gwynedd Hospital for their assistance in conducting this study, and to the subjects who volunteered to participate.
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