Assessment of Lung Involvement and Prognostic Value of the 6-Minute Walking Test for Pulmonary Involvement in Patients with Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a chronic multisystemic immune-mediated disease with multifactorial etiology, variable clinical symptomatology, and treatment with limited efficacy. In recent years, biomarkers of SSc and predictors of disease progression and organ’s involvement have been intensively studied in order to identify the most appropriate therapeutic choice for the patients. The lungs are frequently affected in the pathological processes in patients with SSc, and this is often the main cause of death in these patients due to involvement of the lung parenchyma or pulmonary vessels. In daily clinical practice, it is necessary to have a relatively accurate and easily reproducible methods for assessing functional capacity of this organ. The comparative characterization of the “field tests” shows that the 6-minute walk test is a convenient test for assessing functional activity in patients with moderately severe and severe connective tissue diseases. It is easy to administer, well reproducible, acceptable to patients, sensitive to therapeutic procedures. The 6MWT is the method of choice for assessing functional capacity in systemic connective tissue diseases such as SSc with pulmonary involvement, and the pilot study shows that it can be used as a novel biomarker for assessing of pulmonary involvement.

1. Introduction

Systemic sclerosis (SSc) is a chronic multisystemic immune-mediated disease with a multifactorial etiology, variable clinical symptomatology, and treatment with limited efficacy [1, 2, 3]. SSc is a disease of significant social importance, as patients suffering from this disease have health, economic, social and family problems [4, 5, 6].

SSc remains one of the challenging disease in rheumatology. Despite decades of intensive clinical and basic research, as well as dozens of clinical trials, the causes and pathophysiological mechanisms of the disease remain largely unrecognized. In real clinical medicine, there is still a lack of fully effective therapies to cure all affected tissues and organs from the pathological process [7, 8].

Chifflot et al. studied the incidence and prevalence of SSc in adults [9]. According to their publication, based on a systematic review of the literature, the authors found that the prevalence of SSc ranges from 7/million to 489/million and its incidence from 0.6/million/year to 122/million/year [9]. According to the authors, there is a trend towards an increase in the incidence of SSc over time. The authors conclude that there is a need to continue research into various aspects of the disease [9]. The incidence and prevalence of SSc vary widely depending on geographic location and analysis methods.

There has been an increasing trend in the incidence of SSc over time [3]. Overall survival has improved over the past few decades and is approximately 12 years from diagnosis [3, 9]. Nevertheless, a major problem is still high mortality due to multiorgan involvement, and lung disease has emerged as the leading cause of death [5].

In recent years, biomarkers of SSc and the possibilities of distinguishing its subtypes, predictors of disease progression and intra-organ involvement have been intensively studied in order to identify the most appropriate therapeutic choice for the specific patient [10].

The pathogenesis of SSc is complex, multifactorial and not fully understood. Evidence of three processes can be found in any patient with SSc - vascular injury, immune dysfunction and tissue remodeling. These processes do not occur in isolation, but are interconnected and mutually modulated [11, 12]. The triad of vasculopathy, autoimmunity/inflammation, and connective tissue remodeling underlies the clinical and laboratory manifestations of scleroderma, ranging from clinical manifestation of Raynaud’s phenomenon, autoantibody synthesis, or pulmonary fibrosis [13]. Vascular and endothelial damage are early and possibly primary events in the evolution of the disease and can be detected on initial examination in most patients. While initially vascular damage is associated with reversible functional changes, progressive and irreversible structural vascular changes increase over time. This is followed by progressive vascular damage with obliteration of small and medium-sized arteries in multiple vascular beds and associated activation of thrombotic and coagulation cascades. Reduced blood supply leads to tissue hypoxia, ischemia and its complications [14, 15].

According to Guiducci et al., damage to the vascular wall is characterized by the formation of megacapillaries and avascular zones [15]. The authors reported that decreased capillary density leads to clinical manifestations such as digital ulcers [15]. Guiducci et al., reported that despite reduced blood flow and reduced levels of oxygen partial pressure, there is paradoxically no evidence of sufficient angiogenesis in the skin of patients with SSc [15]. Angiogenesis is severely impaired in SSc, as evidenced by nail videocapillaroscopy changes, vessel damage develops progressively from early to late stages [15]. Many of the severe internal organ complications of SSc are vascular, including pulmonary arterial hypertension (PAH) and scleroderma renal crisis. Structural vascular damage occurs in many vascular beds and contributes to pulmonary, renal, cardiac, and gastrointestinal complications. Vascular damage has a role in the activation of the innate and acquired immune systems and contributes directly or indirectly to tissue fibrosis [16, 17].

Immune dysfunction induces synthesis of highly specific autoantibodies and activation of fibroblasts in most parenchymal tissues and around blood vessels [18].

Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells (T cells, B cells, dendritic cells, mast cells, macrophages and others) and the production of autoantibodies (anti-TOPO-I, kinetochore proteins, RNA polymerase enzyme (anti-RNAP III), ribonuclear proteins (anti-U11/U12 RNP, anti-U1 RNP, anti-U3 RNP, nucleolar antigens (anti-Th/To, anti-NOR 90, anti-Ku, antiRuvBL1/2, and anti-PM/Scl and others) and cytokines (transforming growth factor (TGF)-β, interleukin (IL)-6 and IL-4, chemokines). Immune dysfunction in SSc leads to significant matrix synthesis and deposition that disrupts the architecture and function of the affected organ (lung, spleen, liver, skin, heart, peri-articular soft tissues) [19].

The lungs are frequently affected in SSc patients and are the main cause of mortality in patients with the disease [20, 21]. Current studies have investigated gene expression in the lungs of patients with SSc, analyzing patterns associated with PAH and interstitial lung disease (ILD) [21, 22].

According to Distler et al., ILD is the leading cause of death in SSc [21]. In their article, the authors report that there are no valid biomarkers for predicting the onset of SSc-ILD, although anti-topoisomerase I autoantibodies and several inflammatory markers are candidate biomarkers that need further evaluation [21]. Again in the same article, they reveal that auscultation of the chest, the presence of dyspnea, and pulmonary function testing are important diagnostic tools, but they lack sensitivity for detecting early IBD [21]. Therefore, baseline screening with high-resolution computed tomography (HRCT) is required to confirm the diagnosis of SSc-ILD [21]. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus on which diagnostic tools to use or how often monitoring should be performed.

According to Distler et al., there is no valid definition of disease progression of SSc-ILD. The authors suggest that a decrease in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5–9% in association with a decrease in the diffusing capacity of the lung for carbon monoxide of ≥15% should be counted as progression of the disease [21]. According to the same authors, patients with SSc should be analyzed every 12–24 months to monitor disease progression/regression.

SSc-related PAH shows increased expression of inflammatory genes [21, 22]. A significant number of genes with increased expression are shared between SSc-related pulmonary fibrosis (SSc-PF) and idiopathic pulmonary fibrosis (IPF), as well as SSc-PAH and idiopathic PAH, highlighting possible overlaps in pathogenetic mechanisms between these two, which sometimes occur together in SSc [23, 24, 25].

Increased knowledge about systemic sclerosis and improved diagnostic methods in recent decades have led to the possibility of diagnosing systemic sclerosis in earlier stages of the disease and its earlier treatment. This matters for each patient and increases the quality of care for them by the rheumatologist [26, 27, 28, 29].

2. Serum biomarkers for pulmonary fibrosis

Markers of organ-specific fibrosis would be of great clinical importance because pulmonary involvement is a severe complication of SSc [26]. Intensive research efforts have focused on identifying biomarkers of lung involvement early in the course of the disease and also as prognostic factors for response to treatment [26]. Transforming growth factor is a pleiotropic factor that regulates various biological processes such as cell development, tissue regeneration, immune responses, and others. TGF is required for lung homeostasis [30], and is important for epithelial-mesenchymal interactions during lung morphogenesis and alveolarization. Upregulation of TGF-β ligands is observed in pulmonary fibrosis, emphysema, bronchial asthma, etc. TGF-β regulates multiple cellular processes, such as suppression of epithelial cell growth, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization matrix. These effects are closely related to tissue remodeling in pulmonary fibrosis [30]. TGF-β1 has a central role in the pathogenesis of fibrotic diseases and is a candidate biomarker in SSc [31, 32]. Higher levels of TGF-β1 have been found in the serum of patients with SSc compared with healthy controls [31].

Other candidate biomarkers for lung involvement have been identified and are the Krebs von den Lungen-6 antigen (KL-6) and protein surfactants A and D (PS-A and D) [33]. Serum levels of KL-6 and PS-D are significantly higher in SSc patients compared to healthy subjects and are associated with ILD activity as measured by lung function and high-resolution computed tomography - HRCT [34]. Serum levels of KL-6 are closely related to changes in FVC, making it a promising marker for the follow-up of ILD activity after treatment, and high serum levels of PS-D are a predictor of FVC decline in dynamics [34] and are in close association with pulmonary fibrosis [33, 34]. The two biomarkers KL-6 and PS-D correlate and show similar sensitivity and specificity for the diagnosis of ILD [35, 36]. In the Scleroderma Lung Study group, baseline PS-D and KL-6 levels were examined in patients with and without alveolitis as determined by HRCT. Higher serum levels of both biomarkers have been confirmed in SSc patients compared to healthy controls, as well as in SSc patients with alveolitis compared to those without alveolitis [36].

A biomarker for lung involvement is interleukin-6 (IL-6), which is a pleiotropic cytokine associated with Th2 lymphocytes [37, 38]. Despite the key importance of IL-6 in physiological processes, elevated levels have been described in several lung diseases [38] as well as in the serum of patients with SSc, and there is a significant correlation between them and the results of instrumental studies of the lung and cardiovascular system [38].

In the exploratory analysis, only serum IL-6 among IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factors (VEGFs), fibroblast growth factor-2 and CX3CL1 was shown to be an independent predictor of respiratory failure decline in patients with systemic sclerosis. At a value of 7.7 pg./mL, serum IL-6 predicted decline in FVC (HR 2.58) and DLCO (HR 3.2) in the first year and predicted death in the first 30 months (HR 2.69). In SSc-ILD, serum levels of IL-6 appear to predict early disease progression [39]. Serum levels of another pleiotropic cytokine, IL-15, a T- and B-lymphocyte survival and growth factor, are associated with impaired lung function in SSc [40]. Th17 lymphocyte-associated IL-17A and IL-23 levels are elevated in SSc and are associated with the presence of ILD [41]. Circulating IL-22- and IL-17-producing T cells are increased in patients with SSc-ILD compared with those without ILD [40].

Truchetet et al. found increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis and this is with association with interstitial lung disease [41, 42].

3. Pulmonary function tests

Pulmonary function tests are not a sensitive screening method for determining lung involvement in SSc, therefore, using only this test at follow-up may miss a number of patients with ILD [43]. In the context of ILD, involvement of more than one-third of the lung parenchyma and the presence of reduced FVC early in the disease classifies patients at higher risk of disease progression, thus identifying a subset of patients with greater potential benefits of immunosuppression [44]. In patients with milder disease, it is more difficult to establish a cut off for the risk of progression. After multivariate logistic regression analysis of two cohorts, lower peripheral oxygen saturation (SpO2) < 94% after the 6-minute walking test (6MWT) and the presence of arthritis at any time during the follow-up period were found to be independent predictors of progression of ILD at 1 year. Based on this, a prediction model was developed that was able to stratify the risk of mild ILD progression with a positive predictive value of 91.7% and a specificity of 98.6% [45].

4. Lung ultrasound (LUS)

In recent years, much data has become available on the role of transthoracic lung ultrasound (TTUS) in the evaluation of various lung conditions [46]. Although the role of ultrasoundgraphy (US) has been described in detail in the literature, in recent years the validity of the technique in the assessment of pulmonary fibrosis in patients with SSc has been investigated [46]. Lung ultrasonography has established itself as a noninvasive, inexpensive, easily applicable, radiation-free method with high sensitivity and specificity for diagnosis, even in the early preclinical phase of pulmonary fibrosis [46, 47]. This methodology has been established as a technique for evaluating superficial chest structures such as pleural effusion, pleural and subpleural findings (tumors), or pleural motion for the diagnosis of pneumothorax, as well as for ultrasound-guided manipulations [46, 47]. In one of the first publications on the application of ultrasonography in patients with diffuse parenchymal lung disease, a close relationship was demonstrated between the diagnosis of ILD and the three special sonographic findings: number of B-lines, pleural changes (roughness, thickening, fragmentation) and subpleural changes [48].

The ultrasound characteristic of pulmonary fibrosis consists in the detection and quantification of the so-called US comets (B-lines). B-lines are defined as discrete laser-like vertical hyperechoic reverberations emanating from the pleural line, from US beam reflection from the thickened subpleural interlobular septa (described as “comet tails”), reaching the bottom of the screen without fading, and move synchronously with lung movement [48].

Ultrasound B-lines are an excellent noninvasive method for assessing ILD in patients with SSc [49]. In a single-center study of 40 patients with SSc, the excellent correlation between the number of B-lines assessed by US and the Warrick score was confirmed (Spearman rho: 0.958, p = 0.0001). ROC curve analysis revealed that 10 US B-lines was the cut-off with the highest risk of the probability of significant SSc-ILD [49]. Thus, the detection of at least 10 B-lines is highly predictive of the presence of SSc-ILD on HRCT. In patients with SSc, evaluation of the lungs as the first-line imaging tool can be an effective means of determining the most appropriate time to perform HRCT of the chest [49].

The lung in patients with rheumatic diseases [50]. The author studied 30 patients with SSc and found that the number of B-lines was higher in Scl-70 positive than in negative patients [50]. In the following years, other researchers proved the correlation between B-lines and HRCT result [51]. The specificity and sensitivity of ultrasonography with respect to HRCT were found to be 70% and 85% for cardiac probe and 60% and 85% for linear [51].

In healthy individuals, the pleural line is visualized as a hyperechoic line resulting from the reflection of the parietal and visceral pleura. The normal pleural line is thin, continuous, and without nodular thickening. Pleural line thickening >2.8 mm was considered pathologic [52].

The degree of distribution of pleural irregularities and B-lines compared with clinical, spirometric and DLCO indices, systems assessments (Warrick and Wells) and quantification of ILD severity using HRCT demonstrates that pleural assessment is an equally reliable finding in the diagnosis and stratification of severity according to the degree of ILD [53].

5. High-resolution computed tomography (HRCT) of the lung

Conventional chest radiography is widely used as the first-choice tool for the imaging assessment of pulmonary fibrosis, but low sensitivity in the early stages limits its use in daily clinical practice [54, 55, 56]. HRCT is a highly sensitive diagnostic method for the routine detection and evaluation of pulmonary complications of patients with SSc and is the gold standard method for the diagnosis of both SSc-related ILD [46] and for the evaluation of pulmonary involvement—early changes and subclinical involvement, but the routine its application is limited by high cost and exposure to high doses of ionizing radiation [56].

All these methods significantly indicate the state of the patient’s pulmonary involvement and correlate very well with each other, but require expensive equipment and a trained specialist in the relevant field.

6. 6-minute walking test (6MWT)

In daily clinical practice, it is necessary to have a relatively accurate and easily reproducible method for assessing the patient’s functional capacity, which would reflect his condition to a significant extent.

“Physical capacity” (fitness, performance) represents the body’s ability to successfully perform physical activity without applying excessive stress and within safe limits. Physical capacity is a complex indicator of the general functional state of a person and his motor abilities. It depends on physical development, gender, age and hereditary predispositions [57, 58].

There are different methods for objectifying functional physical capacity. Some are high-tech and provide a comprehensive assessment of all systems relevant to physical activity, while others provide only basic information but require simpler technology and are easier to implement. The choice of functional testing method should be based on clinical requirements and available options [58, 59].

Methods for measuring physical capacity can generally be divided into two groups - laboratory and field. Laboratory conditions allow maximal, symptom-limited tests to be performed using a cycle ergometer or treadmill with parallel measurement of ventilation parameters, hemodynamics and important metabolic parameters. They provide useful information about limiting factors and the maximum load that an individual can reach and allow precise analysis of the load/response relationship, but are difficult to perform in disabled patients [60]. These tests are known in the literature as cardiopulmonary exercise tests [60].

Exercise walking, on the other hand, is an inexpensive and accessible means of determining exercise tolerance in the absence of resources to perform cardiopulmonary exercise testing [61].

Walking tests are also called “field tests” because they are conducted outside a laboratory. Field tests include the step test and walking tests. Despite its simplicity and accessibility, the step test has failed to establish itself permanently in clinical practice, due to a lack of consensus regarding its standardization in human patients [61]. In turn, walking tests are divided into time-limited (time walk tests) and shuttle walk tests (shuttle walk tests).

For the first time in the early 1960s, a simplified test for assessing functional capacity was proposed by Balke [61]. The twelve-minute test was first applied by Cooper K. in 1968 [62]. He found that the distance covered in 12 minutes by young men correlated excellently (r = 0.9) with maximal oxygen consumption (VO2max.) measured by treadmill exercise [62].

In pulmonology, a simplified test to assess functional lung capacity was first introduced by McGavin et al. in 1976, who modified this outdoor running test into a 12-min indoor walking format to measure exercise tolerance in chronic bronchitis patients [63]. An interval of 12 “working” minutes is associated with significantly increased demands in sick individuals and in 1982 Butland et al. divides the walking test into 2- and 6-minute modules [62]. While the 6MWT correlates well with the 12-min test, the short-term 2-MWT may overestimate physical capacity in well-motivated subjects [62]. It is argued that the 6MWT is easy to perform, well tolerated, and adequately reflects daily activities for functional diagnostic needs [62].

The 6MWT is a practically simple test that requires the presence of a corridor 30 meters long, without special equipment and technical training. Walking is an activity performed daily by all but the most severely ill patients. This test measures the distance a patient can walk quickly on a smooth, hard surface in 6 minutes. The test evaluates the global and integrated response of all systems involved in motor activity – respiratory and cardiovascular, systemic circulation, blood, neuromuscular units and muscle metabolism. The test does not provide information about the function of the various organs and systems involved in the motor act and about the mechanism of motor limitation, as does the cardiopulmonary physical test. The 6MWT assesses the submaximal level of functional capacity [64].

Most patients do not reach maximal physical capacity during the 6MWT – they have control over walking intensity and can rest during the test. Because most daily activities are performed at submaximal exertion, the 6MWT better reflects daily functional exertion.

6MWT, it is reliable in the majority of patients with SSc. The 6MWT is a good basis for comparing values in the individual patient at different time points, rather than relying on reference standards, because the general population cannot provide a reliable comparison in these individuals [65, 66]. Performing the 6MWT on SSc patients twice, at a minimum interval of 3 months, showed strong reproducibility of this test and indicated that mRSS, arthralgias and tendon friction, FVC, DLCO, left ventricular EF were associated with lower 6MWT [65, 66]. Given that 6MWT at first examination is an independent predictor of overall mortality and SSc-related mortality, this test is considered useful for assessing overall prognosis in patients with SSc [67]. To detect progression of pulmonary fibrosis, reduced HRCT can be an alternative to standard HRCT and be used in patients with SSc to detect early progression of pulmonary fibrosis [68].

The indications for conducting 6MWT are many, as it is often used for pre- and postoperative comparison of results in lung transplants, lung resection, lung parenchyma reduction, COPD, lung rehabilitation, heart failure, and others. It is very often used in determining the functional status of patients with COPD, HF, peripheral vascular disease, cystic fibrosis, in adult patients. Based on the results of the 6MWT test, it is also possible to make a prediction about the survival and mortality of these diseases [66].

There are also absolute contraindications for conducting the 6MWT are unstable angina and myocardial infarction in the previous month. Relative contraindications are resting heart rate > 120 bpm, systolic blood pressure > 180 mmHg, and diastolic blood pressure > 100 mmHg [66].

Stable angina on exercise is not an absolute contraindication for the 6MWT, but in patients with these symptoms the test should be performed after antianginal medication and in the presence of nitrates during the test. Each patient determines their own exercise intensity, and the test (without electrocardiographic monitoring) has been performed in very elderly patients [64] and patients with heart failure and cardiomyopathy without serious adverse effects [63].

The contraindications listed were used by the study investigators based on their perceptions of the safety of the 6MWT, but the occurrence of adverse side effects when performing the 6MWT in these patients is unknown; therefore, it is about relative contraindications.

Preparing for the test:

1. The test must be carried out in a place where it is possible to apply appropriate and timely emergency medical care.

2. The test should be conducted with the availability of emergency medication.

3. The test taker must be qualified to perform cardiopulmonary resuscitation, with proficiency in advanced CPR techniques desirable.

4. It is not necessary to have a doctor present during the test. The doctor appoints the test to be performed; the presence of a doctor is at individual discretion.

5. If the patient is on chronic oxygen therapy, oxygen should be administered at a standard dose or per protocol. Reasons for immediate termination of the 6MWT may include: chest pain, intolerable dyspnea, limb cramps, vertigo, profuse sweating, or pallor [66, 67].

If the test is stopped for any of these reasons, the patient should sit or lie down depending on the severity of the condition and the risk of syncope. Blood pressure, pulse rate, oxygen saturation should be measured and a medical examination should be performed. Administration of oxygen is appropriate [66, 67].

7. Technical aspects of 6MWT

The 6MWT should be performed indoors – a long, straight, level, enclosed corridor with a hard surface. If the weather is suitable, the test can also be performed outside. The length of the corridor should be 30 meters. The corridor must be marked along its length every 3 meters. The end point must be marked (eg with an orange sign). The starting line, which marks the beginning and end of each 60-meter transition, must be marked with a bright tape. The shorter corridor requires patients to change direction multiple times, reducing the 6MWD value. Most studies used a 30-m corridor, but some used a 20- or 50-m corridor [69]. A multicenter study found no significant effect of corridor length (9 to 50 meters) [69].

Necessary equipment includes – timer, mechanical counter, two small cones to mark the end of the corridor, chair that can be easily moved while walking, patient data form, oxygen source, sphygmomanometer, telephone, defibrillator.

Measurements:

1. Repeat testing should be performed at the same time of day to minimize time-of-day variability.

2. No “warming up” should be done before the test.

3. The patient must stand or sit in a chair placed near the starting position at least 10 minutes before the start of the test. During this time, contraindications should be checked, pulse and blood pressure should be measured, and shoes and clothing should be checked for comfort. The first page of the form is filled out.

4. Pulse oximetry is optional. When performed, baseline heart rate and oxygen saturation (SpO2) were recorded, following the manufacturer’s instructions to amplify the signal and minimize motor artifacts. The pulse should be regular and the quality of the oximetry signal good [69].

5. In the standing position of the patient, dyspnea and general fatigue are measured according to the Borg scale (0 Absence, 0.5 – very, very weak (almost imperceptible), 1 very weak, 2 – weak, 3 – moderate, 4 – moderately severe, 5 – heavy, 6, 7 - very heavy, 8, 9, 10 – very, very heavy (maximum)

   At the beginning of the 6-minute test, the scale is shown to the patient with the words: “Please rate your degree of shortness of breath on the scale” and then: “Please rate your degree of fatigue on this scale.” At the end of the study, the patient is reminded of the values he chose and asked to rate his dyspnea and fatigue again.

6. The counter is reset and the timer is set to 6 minutes. The patient stands at the starting line.

7. The patient is given instructions aimed at standardizing the examination and avoiding errors. In addition, it is necessary that the patient be trained and given detailed information about possible difficulties that he would have when performing it.

8. The patient is positioned at the starting line. The technician remains near the starting line during the test and does not accompany the patient. The timer starts as soon as the patient starts walking.

9. The technician must not speak during the test. The same tone of voice is used to pronounce standard phrases.

10. After the test, the Borg’s dyspnea and fatigue are recorded and the patient is asked: “Is there anything that would prevent you from walking a greater distance?”

11. When using a pulse oximeter, measure the SpO2 pulse rate, then remove the sensor.

12. The number of laps is recorded in the form.

13. The additional distance is marked (the meters traveled from the last incomplete lap are added) using the markers with which the corridor is mapped. The total distance traveled is calculated, rounded to the nearest meter and recorded on the form.

14. At the beginning and at the end of the 6-minute test, the scale is shown to the patient with the words: “Please rate your degree of shortness of breath on the scale” and then: “Please rate your degree of fatigue on this scale.”

Only standardized phrases should be used during the test. Encouragement significantly increases the distance traveled. The reproducibility of tests with and without encouragement was similar. Encouragement every minute with standardized phrases is recommended [66, 69].

Among the factors lowering the value of 6MWD are short stature, advanced age, increased body weight, female gender, impaired cognitive function, shorter corridor (more turns), various pulmonary and cardiovascular diseases, musculoskeletal disease and others [69].

When the patient is tall, male, informed in advance about the nature of the test and highly motivated, we can respectively expect higher values for 6MWD [69].

8. Interpretation of functional status

There are still no standard reference values derived from healthy populations. These values can be calculated based on the results in healthy people of the same age. For them, a distance covered between 400 and 700 m is considered the norm, but there are various publications in which this value differs by about 30% among different researchers [70, 71].

Age, height, weight, and gender independently affect the 6MWT value in healthy subjects, and these factors should be taken into account when interpreting the results of single tests to determine functional status. A low 6MWD value is not specific and has no diagnostic value [70, 71].

The comparative characteristic of “field tests” shows that the 6MWT is a convenient test for assessing functional activity in patients with moderate and severe diseases. It is easy to administer, well reproducible, acceptable to patients, sensitive to therapeutic procedures and very well related to daily activities. Currently, the 6MWT is the test of choice when functional walking tests are to be applied for clinical and research purposes.

Garin and colleagues investigated the factors that influence 6MWT in patients with SSc - interstitial lung disease (ILD), SSc-pulmonary hypertension (PH) and idiopathic pulmonary fibrosis (IPF). They studied 48 patients with IPF, 33 patients with SSc-ILD, 13 with SSc-PH, 19 with both SSc-ILD and SSc-PH (SSc-Both), and 15 with SSc without ILD or PH (SSc-Neither either) and found that mean 6MWT did not differ between groups [72].

Someya and colleagues studied the cardiac hemodynamic response during exercise in 59 patients with systemic sclerosis and 27 age- and sex-matched healthy controls using a 6MWTt with a noninvasive impedance cardiograph [73]. The authors found that stroke volume and cardiac output in patients with systemic sclerosis were significantly lower than in controls at rest and at the end of the 6-minute walk test, and the distance traveled was significantly shorter in patients.

Someya and colleagues concluded that impaired stroke volume in patients with systemic sclerosis was observed at rest and during exercise, and factors related to the cardiac response appeared to be pulmonary function and the degree of pulmonary hypertension [73].

Vandecasteele et al. investigated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) in patients with SSc, as they considered that although the 6MWT is used to assess ILD and PAH in clinical practice, no data are available for it and oxygen desaturation in SSc patients without ILD and PAH. The authors analyzed prospectively collected 6MWT data at baseline and 6-month follow-up of 300 consecutive patients with SSc [74].

Vandecasteele et al. found that the mean 6MWT of 165 SSc patients without ILD and PAH who performed the 6MWT at baseline or at the 6-month visit was 484 ± 93 m [74].

Vandecasteele et al. concluded that in SSc without ILD and PAH, 6MWD and oxygen desaturation were clinically stable over a 6-month period. The DcSSc subgroup walked less than the LSSc and LcSSc subgroups [74].

Sanges and colleagues investigated the 6MWT in the evaluation of patients with SSc and assessed various disease parameters [75]. Their data were systematically collected during a comprehensive standardized assessment that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores (European Scleroderma Study Group Activity Index, assessment of Medsger severity, Health Assessment Questionnaire-Disability Index (HAQ-DI)) and treatments [75].

Sanges et al. concluded that 6MWT was independently associated with baseline heart rate and its variability, suggesting that pulmonary vasculopathy may have a greater impact on functional limitation than parenchymal involvement; and with global markers of disease activity and patient disability. These results provide clinicians with additional insight into how to interpret 6MWD in the context of SSc [75].

The 6MWT is the method of choice for assessing functional capacity in systemic connective tissue diseases with pulmonary involvement [64, 70, 71, 72, 73, 74].

In routine practice, functional and imaging methods are used to confirm and assess the extent of lung involvement. In daily clinical practice, it is necessary to have a relatively accurate and easily reproducible method for assessing functional capacity, which would significantly reflect the patient’s condition. The comparative characterization of the “field tests” shows that the 6-minute walk test is a convenient test for assessing functional activity in patients with moderately severe and severe connective tissue diseases. It is easy to administer, well reproducible, acceptable to patients, sensitive to therapeutic procedures and very well related to daily activities. Currently, the 6-minute walk test is the test of choice when functional walking tests are to be applied for clinical and research purposes.

The 6-minute walk test is the method of choice for assessing functional capacity in systemic connective tissue diseases with pulmonary involvement, and the pilot study shows that it can be used as a novel biomarker for assessing pulmonary involvement in patients with systemic connective tissue diseases [64, 71, 72, 73, 74].

Future trends in the field of SSc, also outlined by EULAR, include validation of biomarkers for early diagnosis, subgroup classification, predictors of different organ involvement, identification of prognostic biomarkers as well as therapeutic efficacy biomarkers, some of which are likely to be and 6MWD.

According to our pilot study, 6MWT provides information regarding functional capacity, response to therapy and prognosis in patients with SSc and desaturation during a test an important prognostic indicator for patients.