This article appears in the following Rheumatology issue: Update in systemic sclerosis [View the issue table of contents]
The 6-minute walk test in scleroderma—how measuring everything measures nothing
1University of Michigan Scleroderma Program, Ann Arbor, MI, USA.
Correspondence to: J. R. Seibold, University of Michigan Scleroderma Program, 3918 Taubman Center/0358, Ann Arbor, MI 48109-0358, USA. E-mail: jseibold{at}umich.edu
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The 6-min walk test (6MWT) is a standardized measure of submaximal exercise capacity that has served as the primary measure of outcome in studies of pulmonary arterial hypertension. Never fully validated in scleroderma, a variety of data suggest that many non-pulmonary aspects of scleroderma contribute to its results thereby blunting the ability of the 6MWT to measure change in lung function. Although reproducible, the lack of correlation with measures of parenchymal lung disease demonstrates an insurmountable lack of both construct and content validity. The 6MWT should be abandoned as an outcome measure in lung disease complicating scleroderma.
KEY WORDS: Six-minute walk test, Pulmonary arterial hypertension, Interstitial lung disease, Scleroderma, Systemic sclerosis, Outcome measures
The 6-min walk test (6MWT) is a simple standardized measure of the distance walked during a defined period of time which assesses the submaximal level of functional capacity. Since most activities of daily living are performed at submaximal level of exertion, the 6MWT may reflect the functional exercise level for daily physical activities [1]. The 6MWT is influenced by the status of all organ systems involved in exercise (pulmonary, cardiac, peripheral vascular, neuromuscular unit and muscle metabolism) as well as by specifics of test conditions. The 6MWT does not provide specific information as to the relative contribution of each of these systems nor about the mechanism of exercise limitation [1].
The 6MWT test has been partially validated in studies of pulmonary arterial hypertension (PAH), serving as a surrogate for WHO/New York Heart Association (NYHA) functional classification, haemodynamics and survival [2], although virtually all available data derive from study of idiopathic PAH. The sensitivity to change of the 6MWT and its affordability and accessibility have led to consideration of its possible utility in clinical trials of interstitial lung disease (ILD) in SSc (scleroderma) although it is yet to be validated for use in this population [3, 4]. ILD and pulmonary vasculopathy are the current leading causes of death in patients with SSc. There is a pressing need for validated response measures for use in clinical trials to truly determine the efficacy of treatments and to serve as guides in the clinical management of individual patients.
American Thoracic Society guidelines [1] point out that using the 6MWT in a variety of settings does not prove that the test ‘is clinically useful for determining functional capacity or change in functional capacity due to an intervention’. Most typically, change in 6MWT is expressed and analysed as absolute change in distance, for example, 20 m improvement. In a subject with a baseline value of 200 m, this 10% change may or may not correlate with improved functional capacity while it is unlikely that improvement from 500 to 520 m (4% change) would be noticed by the less symptomatic and more functional subject. There are simply no data on clinically minimally important difference (MCID) in SSc, i.e. that level of change perceived by the patient to have subjective benefit. MID would correlate change in 6MWT with some other outcome measure such as functional class or survival, yet data are completely lacking in SSc [3]. Alternatively, categorical response might be considered, e.g. the percentage of patients that improve to above a threshold level associated with another outcome, such as survival.
Many factors can influence the distance walked: sources of variability in test conduct, training effect, technician experience, subject encouragement, medication, supplemental oxygen, other activities on day of testing, deconditioning and the effect of musculoskeletal conditions. Studies have looked at exercise capacity in SSc patients with and without pulmonary involvement [5, 6]. In one study, 18 women with SSc were studied by bicycle ergometer [5]. Results showed a marked limitation of exercise performance in SSc patients compared with normal controls. Patients with baseline pulmonary hypertension had an even further decrease in exercise performance compared with scleroderma patients with normal baseline pulmonary pressure levels. More recently, patients with SSc judged free of both cardiac and pulmonary diseases were confirmed to have reduced V02 peak but also a reduced metabolic equivalent at V02 peak [6]. Although not directly measured, this infers that muscle perfusion is an unrecognized influence on exercise capacity in SSc.
In studies of PAH, the change in 6MWT has been reduced in patients with SSc in comparison with those with idiopathic PAH. A statistically significant effect of bosentan therapy has yet to be demonstrated in a controlled study of PAH secondary to SSc [7]. In studies of sitaxsentan and ambrisentan, drug effect on 6MWT has achieved significance although magnitude of response was far reduced in comparison with other forms of PAH [8, 9].
One major trial has employed 6MWT as a primary outcome measure in ILD secondary to SSc. The Bosentan Use in Interstitial Lung Disease (BUILD)-2 study compared bosentan with placebo in SSc patients with ILD and used 6MWT at 12 months as the primary measure of outcome. No difference in effect on 6MWT was found [10]. Follow-up analyses by Buch et al. [4] show the high reproducibility of the 6MWT in patients with SSc–ILD. A within-subject intertest Pearson's correlation coefficient (r) of 0.95 (P < 0.001) on repeated 6MWT was reported. However, the weak correlation of 6MWT with standard physiological parameters [Borg dyspnoea index, r = –0.28, %pred forced vital capacity (FVC) r = 0.19, %pred diffusing capacity for carbon monoxide (DLCO), r = 0.06] suggests a multifactorial basis of limited exercise capacity in patients with SSc.
Further analyses of the BUILD-2 data using only placebo-treated patients showed differences between lcSSc and dSSc [11]. Data in the limited SSc subgroup showed significant correlations between the 6MWT and DLCO (0.51, P 
0.05) at baseline and 12-month follow-up as well as with the Borg dyspnoea index at baseline (–0.44, P 0.01). The diffuse SSc subgroup showed no significant correlations between 6MWT, Borg, FVC, DLCO at baseline and significant correlations between 6MWT and Borg index (–0.38, P 0.01) and FVC (0.37, P 0.01) at follow-up but no correlation with DLCO. Baseline data on the 86 patients randomized to the placebo arm of the BUILD-2 study were further analysed for relationships between 6MWT and several objective and subjective measures of pulmonary functioning [12]. Variables investigated include 6MWT, FVC, DLCO, modified Rodnan skin score, Borg dyspnoea and Scleroderma Health Assessment Questionnaire – Disability Index (SHAQ-DI). All correlations between these variables and 6MWT were significant with the exception of DLCO and skin score. However, most of these correlations were very low ranging from r = 0.26 for FVC to r = –0.48 for SHAQ-DI. It is interesting to note that the highest correlation between these variables and 6MWT is with a subjective, patient-reported measure of functional assessment. SHAQ-DI is a measure of functional ability and does reflect activities of daily living. A higher correlation between 6MWT and SHAQ-DI is to be expected given that the 6MWT is designed to measure submaximal exercise level at which most activities of daily living are performed.
In addition to the distance walked, researchers have looked at oxygen desaturation during the 6MWT [13, 14]. In a study of 110 SSc patients, two dichotomous variables were used: oxygen saturation after 6MWT 
4% and 6 minute walk distance (MWD) <400 m [13]. Age, dyspnoea index, fibrosis on chest radiography, pulmonary arterial systolic pressure (PASP) 30 mm Hg and desaturation 4% were statistically associated with 6MWD. Age, positive anti-Scl-70 autoantibody, dyspnoea, fibrosis on radiography, <80% of predicted FVC, PASP 30 mmHg and ground-glass or reticular opacities on high resolution computerized tomography (HRCT) were associated with desaturation. Age, race and dyspnoea index were significant in the multivariate logistic regression when tested with 6MWD while age, dyspnoea, positive anti-Scl-70 autoantibody and <80% of predicted FVC were significant when tested with oxygen desaturation. Desaturation provides additional information regarding severity of disease in scleroderma patients with pulmonary manifestations and would appear to be a more specific measure of lung function. Others have indicated the usefulness of oxygen desaturation in studies of pulmonary functioning and concluded that stratifying patients by degree of desaturation during 6MWT is important in interpreting serial changes in patients with parenchymal lung disease [2, 14].
These results call into question the utility of the 6MWT as an outcome measure in SSc–ILD studies as a surrogate for pulmonary functioning. Lack of improvement from therapy under investigation has stimulated a discussion on the usefulness and even more importantly the validity of the 6MWT in this patient population. While having face validity and meeting some of the requirements put forth by the OMERACT filter, important elements of its validation are missing and not reflected in studies to date (Table 1). Scleroderma is a multifaceted and complex disease and it is likely that the 6MWT and the outcome measure of total distance walked is affected by other variables whose impacts manifest themselves differently in the different SSc disease classifications as well as for different types of pulmonary involvement.
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The basic question that needs answering is what is being measured with the 6MWT in SSc patients. This test was designed as a measure of submaximal functional ability representative of activities of daily living. It has been proven valid in IPAH as a surrogate for pulmonary functioning but the evidence for this leap in SSc is missing. There is evidence that 6MWT in SSc patients does measure functional status as evident by its correlation with SHAQ-DI. Too much faith may have been put in 6MWT as a measure of pulmonary functioning in SSc patients. It is time to start the search for a valid outcome measure directly reflective of pulmonary function in SSc.
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Supplement: This paper forms part of the supplement entitled ‘Update in systemic sclerosis’. This supplement was supported by an unrestricted grant from Encysive.
Disclosure statement: J.R.S. has received research support and is a consultant to Actelion, Gilead, Pfizer, Encysive, Pipex, Celgene, Roche, Centocor and United Therapeutics all with regard to treatments of scleroderma and its complication. A.J.I. has received grants/research support from Actelion and Pfizer. The other author has declared no conflicts of interest.
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