Elsevier

Clinical Nutrition

Volume 24, Issue 3, June 2005, Pages 442-454
Clinical Nutrition

ORIGINAL ARTICLE
Dietary treatment of rheumatoid cachexia with β-hydroxy-β-methylbutyrate, glutamine and arginine: A randomised controlled trial

https://doi.org/10.1016/j.clnu.2005.01.006Get rights and content

Summary

Background & Aims

Rheumatoid arthritis (RA) is complicated by cytokine-driven alterations in protein and energy metabolism and consequent muscle wasting (cachexia). The aim of this randomised controlled trial was to investigate the efficacy of a mixture of β-hydroxy-β-methylbutyrate, glutamine and arginine (HMB/GLN/ARG) as nutritional treatment for rheumatoid cachexia.

Methods

Forty RA patients supplemented their diet with either HMB/GLN/ARG or a nitrogen (7.19 g/day) and calorie (180 kcal/day) balanced mixture of alanine, glutamic acid, glycine, and serine (placebo) for 12 weeks. Body composition and other outcomes were assessed at baseline and follow-up, and analysed by mixed ANOVA.

Results

Dietary supplementation with HMB/GLN/ARG was not superior to placebo in the treatment of rheumatoid cachexia (group×time interactions P>0.05 for all outcomes). Both amino acid mixtures significantly increased (main effect of time) fat-free mass (727±1186 g, P<0.01), total body protein (719±1703 g, P=0.02), arms (112±183 g, P<0.01) and legs (283±534 g, P<0.01) lean mass, and some measures of physical function. No significant adverse event occurred during the study, but patients in the HMB/GLN/ARG group reported fewer gastrointestinal complaints compared to placebo.

Conclusions

Dietary supplementation with HMB/GLN/ARG is better tolerated but not more effective in reversing cachexia in RA patients compared to the mixture of other non-essential amino acids used as placebo. Further controlled studies are necessary to confirm the beneficial anabolic and functional effects of increased nitrogen intake in this population.

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.

References (61)

  • P. Newsholme

    Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?

    J Nutr

    (2001)
  • J. Kim et al.

    Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method

    Am J Clin Nutr

    (2002)
  • R.C. Lee et al.

    Total-body skeletal muscle mass: development and cross-validation of anthropometric prediction models

    Am J Clin Nutr

    (2000)
  • K.F. Schulz et al.

    Sample size slippages in randomised trials: exclusions and the lost and wayward

    Lancet

    (2002)
  • D. Bruce et al.

    Nutritional supplements after hip fracture: poor compliance limits effectiveness

    Clin Nutr

    (2003)
  • L.J. Hoffer

    Protein and energy provision in critical illness

    Am J Clin Nutr

    (2003)
  • N.J. Minaur et al.

    Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality

    J Rheumatol Suppl

    (2004)
  • H.M. Hulsmans et al.

    The course of radiologic damage during the first six years of rheumatoid arthritis

    Arthritis Rheum

    (2000)
  • R. Roubenoff et al.

    Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation

    J Clin Invest

    (1994)
  • L.C. Rall et al.

    Protein metabolism in rheumatoid arthritis and aging. Effects of muscle strength training and tumor necrosis factor alpha

    Arthritis Rheum

    (1996)
  • R. Munro et al.

    Prevalence of low body mass in rheumatoid arthritis: association with the acute phase response

    Ann Rheum Dis

    (1997)
  • K.C. Fearon et al.

    Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial

    Gut

    (2003)
  • K.L. Rennie et al.

    Nutritional management of rheumatoid arthritis: a review of the evidence

    J Hum Nutr Diet

    (2003)
  • B. Willer et al.

    Effects of creatine supplementation on muscle weakness in patients with rheumatoid arthritis

    Rheumatology (Oxford)

    (2000)
  • J. Kjeldsen-Kragh

    Rheumatoid arthritis treated with vegetarian diets

    Am J Clin Nutr

    (1999)
  • S.L. Nissen et al.

    Effect of dietary supplements on lean mass and strength gains with resistance exercise: a meta-analysis

    J Appl Physiol

    (2003)
  • P. Ostaszewksi et al.

    The leucine metabolite 3-hydroxy-3-methylbutyrate (HMB) modifies protein turnover in muscles of laboratory rats and domestic chickens in vitro

    J Animal Physiol Animal Nutr

    (2000)
  • M.G. Fiori et al.

    Selective atrophy of the type IIb muscle fibers in rheumatoid arthritis and progressive systemic sclerosis (scleroderma). A biopsy histochemical study

    Eur J Rheumatol Inflamm

    (1983)
  • M. Hurson et al.

    Metabolic effects of arginine in a healthy elderly population

    J Parenter Enteral Nutr

    (1995)
  • J.M. Daly et al.

    Immune and metabolic effects of arginine in the surgical patient

    Ann Surg

    (1988)
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