Effects of Creatine Supplementation on RA Cachexia

Data from a new study suggests that creatine (Cr) supplementation increases muscle mass in patients with rheumatoid arthritis (RA), but had no effects on strength or objective measures of physical function.¹  While a small increase in fat mass (FM) was also noted in patients receiving Cr supplementation, the increases in appendicular lean mass (ALM) were proportionally greater. These results were published in Arthritis Care & Research.

Loss of lean muscle mass (LM) is seen in patients with RA, and is referred to as rheumatoid cachexia. LM loss is one of the causes of decreased strength and physical function impairments associated with disease morbidity.²  Tight RA disease control using treat-to-target strategies and biologic agent do not appear to reverse the loss of LM.³

Adjunctive nutritional supplementation with anabolics has been suggested as a potential treatment response for RA cachexia to increase physical function. Researchers therefore sought to determine whether supplementation with Cr could change body composition, increase strength, and improve objective measurements of physical function.

A randomized, double-blind, placebo-controlled trial recruited patients from a rheumatology center in North Wales, UK, who had stable RA, as defined by no change in RA in rheumatic medications in the previous 3 months. 

American College of Rheumatology/European League Against Rheumatism 2010 revised criteria were used for the diagnosis of RA. Eligible patients did not have a history of other cachectic conditions, renal impairment, current participation with high-intensity exercise, or prior anabolic supplement use. 

Study participants in the Cr supplement group received a loading dose of 20 grams of Cr monohydrate (MyProtein©, U.K.) mixed with a mango-flavored drink powder (Foster Clark Products) for 5 days, followed by a maintenance dose of 3 grams/day for the next 12 weeks.  

Study participants in the placebo group received only the mango-flavored drink powder and were age- and sex-matched, with both experimenter and study participants blinded to the treatment arm.

The color, taste, and appearance of both mixtures were similar in both the treatment and placebo groups. In both groups, adherence was monitored by asking participants to return empty packets and participants maintained routine physical activity and diet. 

All study participants were assessed at 4 time points: at baseline, day 6 (after dose loading), week 12 (after supplement/placebo cessation), and week 24 (considered followup).  During each visit, body mass, height, lean mass, body fat, and bone mass were measured via whole body fan-beam dual x-ray absorptiometry (DXA). Bioelectrical impedence spectroscopy was used to measure total body water, intracellular water, and extracellular water fluid compartments. 

An isokinetic dynamometer was used to take 3 measurements of isometric maximal voluntary knee extensor strength (IKES), with the best score from the left and right leg being used in the analysis.  Physical function was measured by 3 objection functional tests including the sit-to-stand in 30 seconds test (STS-30), the 8-foot up and go test (8′UG), and the 50-foot walk test (50′W).  Predicted aerobic capacity, Vo2 max, was estimated with the submaximal Siconolfi step test.

Disease Activity Score in 28 joints (DAS28) was used to qualify disease activity, along with C-reactive protein (CRP) to measure overall systemic inflammation. The Multidimensional Health Assessment Questionnaire (MD-HAQ) was used to assess physical disability. 

After 12 weeks of oral Cr supplementation (n=15) or placebo (n=20), ALM was increased by 0.52 kg ± 0.13 kg (P=.004 versus placebo) and total LM increased by 0.60 kg  ± 0.37 kg (P=.158).  An increase in intracellular water accompanied the noted change in LM (0.64 L ± 0.22 L; P=.035). 

Most notably, the increases in ALM and total LM were not accompanied by increases IKES or handgrip strength. The lack of strength and functional improvement found in this study contrasted with earlier studies evaluating Cr supplementation in older patients and patients with fibromyalgia that showed measurable improvements in STS and 6-meter tandem walk test.^4,5  

Throughout the study period, no changes in DAS28 scores were noted in either treatment arms.  No treatment-related adverse side effects were identified in any of the study participants.  Renal function, diet, and physical activity remained stable in all participants. 

The authors of this study hypothesized that prior evaluation of strength and function were not definitive, with varying results based on the test used to assess strength.  They also noted that the “learning effect” may have influenced results, as both treatment groups demonstrated similar enhancements in functional testing.

Summary and Clinical Applicability

Oral Cr supplementation for 12 weeks increased muscle mass, but did not increase strength or improve physical function in patients with stable RA.  No treatment-related adverse effects were observed in the Cr supplement group, and renal function remained unchanged in the followup period. 

“Although the lack of effect on strength and physical function are disappointing, the increase in LM we demonstrated suggests that Cr supplementation may be beneficial in patients with severe rheumatoid cachexia, since a marked loss of LM both impairs the body’s ability to fight infection, due to limited expendable protein reserve for immune cell production, and increases the risk of mortality,” the authors stated. 

Researchers concluded that Cr supplementation is a safe and acceptable treatment option for patients with RA and cachexia to increase muscle mass, but that resistance training is necessary to increase functional strength. 

Limitations and Disclosures

Changes in diet, medication, and lifestyle during the study were all self-reported.  Cr supplement compliance could not directly be assessed. Exclusion of patients with renal insufficiency must be noted. Head-to-head comparisons with various formulations of Cr at different doses, stratified to patient weight and/or level of cachexia should be performed.  It is also not known whether supplementation changes long-term outcomes, or if lean mass is maintained. 

References

1. Wilkinson TJ, Lemmey AB, Jones JG, et al. Can Creatine Supplementation Improve Body Composition and Objective Physical Function in Rheumatoid Arthritis Patients? A Randomized Controlled Trial. Arthritis Care Res (Hoboken). 2016;68(6):729-37.

2.     Summers G, Deighton C, Rennie M, Booth A. Rheumatoid cachexia: a clinical perspective. Rheumatology (Oxford). 2008;47:1124–31.

3.     Lemmey AB, Clayton R, Wilkinson T, Sheikh F, Ahmad Y, Whale J, et al. Treat-to-target treatment fails to restore either body composition or objectively assessed physical function in rheumatoid arthritis patients. Rheumatology (Oxford). 2015;54:i78.

4.      Brose A, Parise G, Tarnopolsky MA. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J Gerontol A Biol Sci Med 2003;58:B11–9.5

5.      Alves CR, Santiago BM, Lima FR, Otaduy MC, Calich AL, Tritto AC, et al. Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken) 2013;65:1449–59.