PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0211895 PONE-D-18-21517 Research Article Medicine and health sciencesPublic and occupational healthPhysical activityBiology and life sciencesAnatomyMusculoskeletal systemBody limbsLegsKneesMedicine and health sciencesAnatomyMusculoskeletal systemBody limbsLegsKneesMedicine and health sciencesHealth careQuality of lifeMedicine and health sciencesClinical medicineClinical immunologyAutoimmune diseasesVasculitisBiology and life sciencesImmunologyClinical immunologyAutoimmune diseasesVasculitisMedicine and health sciencesImmunologyClinical immunologyAutoimmune diseasesVasculitisMedicine and health sciencesInflammatory diseasesVasculitisMedicine and health sciencesRheumatologyVasculitisBiology and life sciencesAnatomyMusculoskeletal systemBody limbsArmsElbowMedicine and health sciencesAnatomyMusculoskeletal systemBody limbsArmsElbowMedicine and health sciencesPublic and occupational healthPhysical activityPhysical fitnessExerciseStrength trainingMedicine and health sciencesSports and exercise medicineExerciseStrength trainingBiology and life sciencesSports scienceSports and exercise medicineExerciseStrength trainingBiology and life sciencesAnatomyMusculoskeletal systemBody limbsLegsMedicine and health sciencesAnatomyMusculoskeletal systemBody limbsLegsResearch and analysis methodsBioassays and physiological analysisMuscle analysis Leg muscle strength is reduced and is associated with physical quality of life in Antineutrophil cytoplasmic antibody-associated vasculitis Muscle strength and quality of life in ANCA-associated vasculitis http://orcid.org/0000-0001-8820-5454 Hessels Arno C. Conceptualization Data curation Formal analysis Investigation Methodology Project administration Visualization Writing – original draft 1 * van der Hoeven Johannes H. Conceptualization Methodology Resources Supervision Writing – review & editing 2 Sanders Jan Stephan F. Conceptualization Methodology Supervision Writing – review & editing 1 Brouwer Elisabeth Methodology Resources Writing – review & editing 3 Rutgers Abraham Conceptualization Methodology Resources Supervision Writing – review & editing 3 Stegeman Coen A. Conceptualization Methodology Project administration Resources Supervision Writing – review & editing 1 Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Robson Joanna C. Editor University of the West of England Bristol, UNITED KINGDOM

The authors have declared that no competing interests exist.

 * E-mail: a.c.hessels@umcg.nl 4 2 2019 2019 14 2 e0211895 20 7 2018 22 1 2019 2019 Hessels et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective

Physical quality of life is reduced in ANCA-associated vasculitis (AAV). This study aims to investigate whether this may be explained by reduced muscle strength and physical activity resulting from disease damage and steroid myopathy.

 Methods

Forty-eight AAV patients were sequentially included from the outpatient clinic. Patients in different stages of disease and treatment underwent measurements of muscle strength and anthropometric parameters. Patients filled in physical activity (Baecke) and quality of life questionnaires (RAND-36) and carried an accelerometer for a week. Muscle strength and physical activity were compared to quality of life, prednisolone use and disease duration.

 Results

Most AAV patients had lower knee extension (76%) and elbow flexion (67%) forces than expected based on healthy norms. Also, physical (P<0.001) and mental (P = 0.01) quality of life were significantly reduced compared to healthy norm values. Lower knee extension force (P = 0.009), younger age <70 (P<0.001) and relapse of vasculitis (P = 0.003) were associated with lower age-adjusted physical quality of life. Lower Baecke index (P = 0.006), higher prednisolone dose (P = 0.005) and ENT involvement (P = 0.006) were associated with lower age-adjusted mental quality of life. Leg muscle strength showed no association with current or cumulative prednisolone use. Disease duration was longer in patients with knee extension force below healthy norms (P = 0.006).

 Conclusion

Knee extension force and physical activity are positively associated with quality of life in AAV. Knee extension force decreases with longer disease duration, suggesting that disease- and treatment-related damage have a cumulative negative effect on muscle strength.

 http://dx.doi.org/10.13039/501100002997 Nierstichting 13OKJ39 Sanders Jan Stephan F. http://dx.doi.org/10.13039/501100003246 Nederlandse Organisatie voor Wetenschappelijk Onderzoek 907-14-542 Sanders Jan Stephan F. Jan Stephan Sanders is supported by personal grants from the Dutch Kidney Foundation (grant no. 13OKJ39; website https://www.nierstichting.nl/) and the Netherlands Organization of Scientific Research NWO (Clinical Fellow grant no. 907-14-542; website https://www.nwo.nl/en).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability All relevant data are within the paper. Introduction

ANCA-associated vasculitis (AAV) is a group of primary vasculitides associated with inflammation of the small and medium sized blood vessels. The most frequent forms are Granulomatosis with Polyangiitis (GPA, formerly Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) [1].

Mortality has drastically decreased after introduction of immunosuppressive therapy and most patients can now be brought into remission. Unfortunately, the disease and its treatment are associated with damage that accumulates with prolonged disease duration, recurrent disease episodes and treatment exposure [2,3].

Quality of Life (QoL), especially physical QoL, is reduced in AAV patients compared to the general population [4–6]. It is important to identify modifiable factors associated with health-related QoL [5,7], as these factors will guide development of new treatments that improve the outcome.

One of the factors previously associated with reduced physical QoL is prednisolone use [4,5]. A well-known adverse effect of glucocorticoids (GCs) such as prednisolone is skeletal muscle atrophy [8]. GC-induced skeletal muscle atrophy results from a combination of reduced protein synthesis and increased muscle proteolysis [8,9]. Mainly fast-twitch (type II) muscle fibres are affected [8]. Proximal muscles are more severely affected than distal and cranial muscles [9]. GC-induced skeletal muscle atrophy develops after approximately 4 weeks of therapy, and is most frequently seen with higher doses of GCs (prednisolone 40-60mg/d or equivalent doses of other GC) [9].

GC-induced skeletal muscle atrophy might partly explain the relation between prednisolone use and impaired physical QoL in AAV. In our clinical experience, many patients with AAV suffer from a significant loss of leg muscle strength during prednisolone treatment. They report difficulties rising from a chair and walking stairs. In several studies that focused on patient perspectives, patients reported muscle weakness as an important disease burden [10,11]. In a study by Newall et al, AAV patients had a reduced exercise capacity, which correlated with quadriceps force [12]. These findings suggest an impact of leg muscle force on exercise performance in AAV patients, which might in turn affect QoL.

Muscle strength can be improved through exercise [13]. Therefore, reduced muscle strength and an association of muscle strength with QoL in AAV patients would warrant intervention studies regarding exercise programs or improvement of muscle strength for this population.

The first goal of this cross-sectional study performed at the outpatient clinic of the Vasculitis Expertise Center Groningen was to investigate the relation between leg muscle force, physical activity and health-related QoL in AAV patients. The second goal was to study the relation of leg muscle force with disease duration and treatment exposure, especially GC treatment.

 Patients and methods Study population

GPA and MPA patients were recruited from the outpatient clinic of the University Medical Center Groningen (UMCG) between July 2015 and October 2017. Patients were eligible for inclusion if they met the following inclusion criteria: age ≥18 years, diagnosis of Granulomatosis with Polyangiitis (GPA) or Microscopic Polyangiitis (MPA) according to the Chapel Hill criteria [1], first diagnosis or most recent relapse of disease activity within 3 years prior to inclusion, and treatment with a high dose of prednisolone (1mg/kg/day, tapered according to local protocol) and an additional immunosuppressive drug (e.g., cyclophosphamide, rituximab) as induction therapy. Patients with comorbidity causing reduced mobility or muscle strength and patients with active disease were excluded. More specifically, patients with neurological disease (cerebrovascular accident, hernia nuclei pulposi, peripheral motor nerve damage, critical illness neuropathy), pulmonary disease (dyspnea and activity limitations due to pulmonary involvement of AAV, chronic obstructive pulmonary disease, restrictive pulmonary disease), cachexia and fractures (vertebral fractures, radial fracture) were excluded. All patients signed written informed consent for participation in the study. The study was performed according to the principles of the Declaration of Helsinki and has received ethical approval by the local Medical Ethical Committee of the University Medical Center Groningen (METc 2015/184).

 Design

All patients received an initial cross-sectional measurement after a regular visit to the outpatient clinic. Patients with a prednisolone dose ≥30mg/d at the first study visit were approached and asked informed consent for a follow-up measurement at a later time point, at a low prednisolone dose (< = 2.5mg/d), or after discontinuation of prednisolone.

 Measurements Demographic and clinical characteristics

Demographic data and clinical characteristics were collected from the patients’ medical records. The following data were collected: age, sex, diagnosis (GPA or MPA), ANCA specificity (PR3, MPO, negative), disease activity at most recent disease episode as measured by the Birmingham Vasculitis Activity Score (BVAS) version 3 [14,15], ear-nose-throat (ENT) and neurological vasculitis activity (derived from BVAS), drug used for induction therapy, drug used for maintenance therapy, prednisolone use (initial dose (mg/d), current dose (mg/d), cumulative dose of last six months (g)), C-reactive protein (CRP) levels (mg/l) and 24-hour urinary creatinine excretion (mmol/24h).

 Measurement of muscle strength

Isometric knee extension, elbow flexion and hip flexion strength were measured using a handheld dynamometer (CIT Technics, Groningen, The Netherlands) and expressed in Newton (N), as described by Van der Ploeg et al [16]. Test positions for the muscle strength measurements are the same as described by Bohannon [17] and shown by Douma et al [18]. The ‘break’ method was used, in which the researcher slightly overcomes the maximum force of the subject [19]. The measurements were performed by four operators. All operators received instructions and training before performing measurements for the study. Hand-held dynamometry of hip and knee force has previously been shown to have a good to excellent (ICC > = 0.75) intra- and inter-rater reliability as well as a good to excellent concurrent validity compared to gold-standard measurement using an isokinetic dynamometer [20]. The measurements were performed twice on each side, alternating measurements between sides. The highest measured value per muscle group was used as the maximum muscle force of that muscle group. Expected elbow flexion and knee extension forces for each patient were calculated based on age, sex, height and weight using a regression equation derived from a Dutch healthy population sample [18]. Elbow flexion and knee extension force were expressed as a percentage of this expected value.

 Bioelectric impedance analysis

Bioelectric Impedance Analysis (BIA) was performed using electrodes on the right hand and foot using the Bodystat Quadscan 4000 (Bodystat Ltd, British Isles). The fat free mass index (kg/m^2) was calculated using a built-in formula of the Bodystat.

 Physical activity

The Baecke questionnaire was used as generic (i.e., not disease-specific) self-report measure of physical activity. It has been validated for use in the general Dutch population [21,22]. The Baecke questionnaire measures physical activity at work, leisure time and sports. The scores are summarised into work, sports and leisure time indices which are added into a total score. Calculations have been described by Baecke et al [21]. The intensity levels of sports were derived from the Ainsworth compendium [23,24].

The Actiwatch 7 (Camntech, Papworth Everard, United Kingdom) was used as an objective measure of physical activity. Accelerometry is a reliable method for measurement of physical activity in patients with rheumatic disease [25]. Participants were instructed to wear the accelerometer day and night on the non-dominant wrist, except for activities involving water, such as swimming or taking a bath. The accelerometer output was expressed as the average kilo-counts per waking day.

 Health-related quality of life

Health-related quality of life (HRQoL) was assessed using the RAND-36 questionnaire. This questionnaire contains eight subscales with scores ranging from 0 to 100. These can be further summarised into a physical component summary (PCS) and mental component summary score (MCS), which are calculated in such a way that the reference population has a mean of 50 and a standard deviation of 10 [26]. Age-adjusted reference values used for calculating the PCS and MCS were derived from a Dutch general population sample [27]. Background information on the questionnaire and its subscales can be found elsewhere [28].

 Statistics

All analyses were performed using SPSS Statistics version 23 (IBM). A two-sided P-value <0.05 was considered statistically significant. Variables were presented as n (percent [%]) or median (interquartile range [IQR]). Reliability of muscle strength measurements was assessed by comparing repeated muscle strength measurements using intraclass correlation coefficients (ICC) with an absolute agreement definition. Point estimates of ICC were assessed as poor (<0.50), moderate (0.50–0.74), good (0.75–0.89) or excellent (> = 0.90) as described previously [20]. Muscle strength and physical activity were compared with all subscales of the RAND-36, prednisolone dose and disease duration using Spearman Rank correlation. Disease duration was compared between patients with muscle strength below and above 100% of their predicted value[18]. For patients who received paired measurements, muscle strength (N) and self-reported physical activity were compared between the first (prednisolone dose >30mg/d) and second (prednisolone dose < = 2.5mg/d) visits using the Wilcoxon signed rank test. Finally, linear regression was performed with the age-adjusted PCS and MCS of the RAND-36 as dependent variables and previously reported factors associated with these scores in AAV [5,7], as well as muscle strength and physical activity, as independent variables in univariable analysis. Subsequently, a multivariable model was built for age-adjusted PCS and MCS with statistically significant factors from univariable analysis, as well as previously reported potential confounders [5,7], included as independent variables in the model. For age-adjusted PCS, these potential confounders were: age >69 years, sex, current prednisolone dose >5mg/d, nervous system involvement and previous vasculitis relapse. For age-adjusted MCS, potential confounders were: age >69 years, sex, current prednisolone dose >5mg/d, ENT involvement and previous vasculitis relapse.

 Results

In total, 92 patients were considered for inclusion. A flowchart of inclusion is shown in Fig 1. Characteristics of the 48 patients included in the study are shown in Table 1. At the day of measurement, 12 patients (25%) had an elevated CRP (≥5mg/l). Incomplete variables include fat free mass index (present for 37/48, 77%), urinary creatinine excretion (present for 43/48, 90%) and total accelerometer score (present for 28/48, 58%).

10.1371/journal.pone.0211895.g001 Flowchart of patient selection. 10.1371/journal.pone.0211895.t001 Patient characteristics.
N (%) or Median (IQR)
Variable All New Relapsing P-value
(n = 48) (n = 13) (n = 35)
Age (years) 62 (52–69) 64 (56–69) 61 (51–71) 0.86
Sex (n, % male) 25 (52%) 5 (39%) 20 (57%) 0.34
Diagnosis (N, % GPA) 41 (85%) 9 (69%) 32 (91%) 0.08
ANCA specificity (n,%) 0.30
    Proteinase 3 (PR3) 35 (73%) 8 (62%) 27 (77%)
    Myeloperoxidase (MPO) 11 (23%) 5 (39%) 6 (17%)
    Negative 2 (4%) 0 (0%) 2 (6%)
Treatment duration (weeks) 35 (11–104) 30 (9–62) 36 (14–119) 0.31
Months since diagnosis 83 (17–194) 7 (2–14) 141 (76–203) <0.001***
Induction therapy (n, %) 0.001**
    Cyclophosphamide 21 (44%) 11 (84%) 10 (29%)
    Rituximab 14 (29%) 0 (0%) 14 (40%)
    Other 13 (27%) 2 (16%) 11 (31%)
    Prednisolone 48 (100%) 13 (100%) 35 (100%)
Currently on prednisolone 33 (69%) 6 (46%) 27 (77%) 0.08
Prednisolone dose (mg/d) 10.0 (0.0–28.8) 0.0 (0.0–50.0) 10.0 (3.8–25.0) 0.72
Cumulative prednisolone (g in last six months) 1.8 (0.1–3.3) 1.1 (0.0–3.8) 1.9 (0.6–2.9) 0.71
BVAS (diagnosis/relapse) 13 (11–17) 17 (13–21) 12 (8–16) 0.01*
CRP (mg/l) (at day of visit) 2.0 (0.7–5.2) 1.8 (0.8–2.8) 2.2 (0.6–5.5) 0.75

*P<0.05,

**P<0.01,

***P<0.001.

In total, seven patients have received paired measurements. Median prednisolone dose of these patients was 40mg/d (IQR 30–60) at the first measurement, versus 0mg (IQR 0–2.5) at follow-up. Median time between measurements was 6 months (IQR 4–25).

Muscle strength and quality of life

Out of all 48 patients, 46 had a successful measurement of knee extension. Overall intra-rater reliability was good to excellent. Intraclass correlations, overall and per assessor, are shown in S1 Table. Of 46 measured patients, 35 (76%) had a knee extension force less than 100% of their predicted value based on age, sex, height and weight. Elbow flexion force was below 100% of predicted for 30/45 measured patients (67%).

Fat free mass index (kg/m^2) showed a significant positive correlation with hip flexion (Rho = 0.56, P<0.001), knee extension (Rho = 0.51, P = 0.001) and elbow flexion force in N (Rho = 0.68, P<0.001). Urinary creatinine excretion (mmol/24h) also showed an association with hip flexion (Rho = 0.47, P = 0.002), knee extension (Rho = 0.47, P = 0.002) and elbow flexion force (Rho = 0.33, P = 0.04).

Knee extension force (% of predicted) showed a significant positive correlation with the RAND-36 subscales physical functioning (Rho = 0.31, P = 0.04), physical role functioning (Rho = 0.34, P = 0.02), emotional role functioning (Rho = 0.31, P = 0.04) and general health (Rho = 0.30, P = 0.04). Elbow flexion force (% of predicted) did not show a significant correlation with any subscale of the RAND-36.

 Physical activity and quality of life

Baecke score showed a positive trend with hip flexion force (Rho = 0.29, P = 0.05), but not with elbow flexion (Rho = 0.22, P = 0.15) or knee extension force (Rho = 0.20, P = 0.18). Accelerometer counts did not show a correlation with muscle strength (not shown).

Baecke total score showed positive associations with the RAND-36 subscales physical functioning (Rho = 0.32, P = 0.04), role limitations (physical problem) (Rho = 0.33, P = 0.03), role limitations (emotional problem) (Rho = 0.46, P = 0.001), mental health (Rho = 0.41, P = 0.005) and general health (Rho = 0.42, P = 0.003), as well as positive trends with vitality (Rho = 0.28, P = 0.06) and pain (Rho = 0.26, P = 0.08). Accelerometer counts did not show a significant correlation with any subscale of the RAND-36.

 Associations of health-related quality of life

The age-adjusted PCS of the RAND-36 was significantly lower in AAV patients (mean 42, SD 10) compared to Dutch norm values (mean 50, SD 10, P<0.001). To a lesser degree, this was also true for the age-adjusted MCS (mean 46, SD 9, versus mean 50, SD 10; P = 0.01). In univariable linear regression, knee extension force, Baecke total score and neurological vasculitis activity at most recent disease episode (peripheral neuropathy (n = 4) or cranial nerve palsy (n = 1)) were associated with the age-adjusted PCS. Prednisolone dose >5mg/d, ENT vasculitis activity and lower Baecke score were associated with lower age-adjusted MCS, see Table 2.

10.1371/journal.pone.0211895.t002 Univariable linear regression for quality of life in ANCA associated vasculitis.
Independent variables Physical component summary Mental component summary
B (95% CI) P Adj. R2 B (95% CI) P Adj. R2
Relapsing (versus new) -6 (-13 to 0) 0.07 0.05 -1 (-7 to 6) 0.87 -0.02
Prednisolone dose >5 mg/d -3 (-9 to 3) 0.35 0.00 -7 (-12 to -2) 0.01* 0.11
CRP ≥5mg/l -4 (-11 to 3) 0.23 0.01 3 (-3 to 9) 0.25 0.01
ENT vasculitis activity -1 (-7 to 6) 0.87 -0.02 -5 (-10 to 0) 0.04* 0.07
Neurological vasculitis activity -12 (-22 to -1) 0.03* 0.08 -3 (-13 to 6) 0.49 -0.01
Knee extension (% of predicted) 0.1 (0.0 to 0.3) 0.04* 0.07 0.1 (0.0 to 0.2) 0.17 0.02
Elbow flexion (% of predicted) 0.1 (0.0 to 0.2) 0.06 0.06 0.0 (-0.1 to 0.1) 0.46 -0.01
Baecke total 3 (1 to 5) 0.01* 0.12 3 (1 to 4) 0.008** 0.13

Univariable linear regression of factors potentially associated with age-adjusted physical and mental quality of life. B coefficient of independent variable in linear regression. Adj. R2 adjusted R squared.

*P<0.05.

**P<0.01.

In multivariable linear regression, age < = 69 years, previous relapse of vasculitis, elevated CRP and lower knee extension force were associated with lower age-adjusted physical quality of life, with a total adjusted R2 of 0.55 for the regression model. Prednisolone dose >5mg/d, ENT involvement and lower Baecke total index were associated with lower age-adjusted mental quality of life, with a total adjusted R2 of 0.36 for the regression model, see Table 3.

10.1371/journal.pone.0211895.t003 Multivariable linear regression for quality of life in ANCA-associated vasculiits.
Independent variables B (95% CI) P-value Beta
Age-adjusted Physical Component Summary
Knee force (% of pred.) 0.19 (0.08 to 0.29) <0.001*** 0.41
Baecke total index 1.6 (-0.1 to 3.3) 0.06 0.21
Age >69 years 13 (7 to 19) <0.001*** 0.52
Relapsing (vs new) -9 (-14 to -3) 0.003** -0.36
Elevated CRP (≥5mg/l) -8 (-13 to -2) 0.005** -0.32
Neurological vasculitis -8 (-16 to 1) 0.07 -0.21
Female sex -3 (-8 to 1) 0.16 -0.15
Prednisolone >5mg/d 0 (-5 to 5) 0.99 0.00
Age-adjusted Mental Component Summary
Baecke total index 2.4 (0.7 to 4.1) 0.006** 0.36
Prednisolone (>5mg/d) -7.1 (-11.9 to -2.3) 0.005** -0.38
ENT involvement -6.9 (-11.7 to -2.1) 0.006** -0.38
Age >69 years 3.9 (-2.0 to 9.8) 0.19 0.17
Relapsing (vs new) 2.2 (-3.4 to 7.9) 0.43 0.11
Female sex -0.3 (-4.9 to 4.2) 0.88 -0.02

Multivariable final model of physical and mental quality of life. B coefficient of independent variable in linear regression. Beta standardised regression coefficient.

*P<0.05.

**P<0.01.

***P<0.001.

 Prednisolone use versus muscle strength and physical activity

Knee extension, hip flexion and elbow flexion forces were not correlated to current or cumulative prednisolone dose. Physical activity according to the accelerometer and Baecke total score showed significant negative correlations with cumulative prednisolone use, but not with current prednisolone dose, see Table 4. In paired measurements (n = 7), median elbow flexion, hip flexion and knee extension increased after discontinuation of GC therapy. However, this difference was only statistically significant for hip flexion force, see S1 Fig.

10.1371/journal.pone.0211895.t004 Correlation of muscle strength and physical activity with prednisolone use.
Variable Rho current prednisolone P-value Rho cumulative prednisolone P-value
Muscle strength
    Knee extension (N) -0.14 0.37 -0.03 0.86
        % of predicted -0.14 0.34 -0.13 0.38
    Hip flexion (N) -0.11 0.45 0.05 0.74
    Elbow flexion (N) 0.01 0.97 0.18 0.23
        % of predicted 0.04 0.81 0.17 0.26
Physical activity
    Actiwatch (kcount/d) -0.23 0.25 -0.39 0.04*
    Baecke total index -0.17 0.24 -0.33 0.03*

Results of Spearman Rank correlation for measures of muscle strength and physical activity versus current prednisolone dose (mg/d) and cumulative use over the past six months (g).

*P<0.05

 Disease duration versus muscle strength and physical activity

In relapsing patients, a longer time after diagnosis showed a trend with lower knee extension force (% of predicted) (Rho = -0.32, P = 0.07) and lower Baecke index (Rho = -0.31, P = 0.08), but not with elbow flexion force (Rho = -0.23, P = 0.19). By contrast, in newly diagnosed patients, a longer time after diagnosis was associated with a higher Baecke index (Rho = 0.58, P = 0.04). Time after diagnosis still showed no significant correlation with knee extension force (Rho = -0.08, P = 0.79) or elbow flexion force (Rho = -0.17, P = 0.60) in newly diagnosed patients.

Patients with knee extension force below 100% of predicted had significantly longer median follow-up (118 months, IQR 30–201) compared to patients with at least 100% of predicted knee extension force (22 months, IQR 7–80), P = 0.006. This remained significant (P = 0.03) after correction for age, sex, Baecke total score and cumulative prednisolone use. Patients with elbow flexion force below 100% of predicted did not have a significantly longer follow-up (median 123, IQR 32–202 months if below 100%; median 36, IQR 11–118 months if at or above 100% of predicted; P = 0.13).

 Discussion

In this study, we found that the majority of AAV patients have a muscle strength below their predicted values based on age, sex, height and weight [18], and that physical QoL was significantly reduced in AAV patients compared to healthy norm values [27]. We also identified an association of self-reported physical activity measured by the Baecke questionnaire with mental QoL in AAV.

The reduced leg muscle strength in AAV patients, found in this and previous studies [12,29], might be the result of steroid myopathy. Indeed, studies in several other disease populations have previously shown associations between chronic glucocorticoid use and reduced muscle strength [30–32]. While leg muscle strength did not show a correlation with prednisolone use in the present cross-sectional study, this might be explained by large inter-individual variation in muscle strength and GC sensitivity. Inclusion of muscle imaging to assess for typical signs of muscle atrophy, such as ultrasonography or MRI, might be interesting for a future study.

Interestingly, relapsing patients with longer disease duration more frequently had a muscle strength below norm values. This suggests that accumulating damage from relapses of AAV and treatment of these relapses results in a reduction of muscle strength over time.

Physical activity, as measured using an accelerometer and the Baecke questionnaire, showed a negative association with cumulative prednisolone exposure, as well as a positive association with follow-up time in newly diagnosed patients. This indicates that prednisolone therapy negatively impacts exercise capacity and that physical activity increases when tapering prednisolone. Alternatively, the association might be confounded my more recent disease activity in patients with a higher cumulative prednisolone exposure in the past 6 months, as disease activity might also result in reduced physical activity. Contrary to our expectations, we did not find an association of muscle strength with cumulative prednisolone dose.

In agreement with earlier studies [4,5], especially the age-adjusted PCS was reduced in AAV patients compared to general population norms [27]. Leg muscle strength was independently associated with PCS. Therefore, muscle strength might be part of the explanation for reduced QoL in vasculitis patients. Leg muscle strength showed only a positive trend with physical activity. Also, leg muscle strength, in contrast to self-reported physical activity, was associated with PCS in multivariable linear regression. This suggest that muscle strength directly affects physical QoL, not (only) through physical activity. Physical activity was a main factor associated with mental QoL. Based on these results, interventions focusing on improving muscle strength and exercise capacity might improve both physical and mental QoL in AAV patients.

This study has several limitations. First, due to logistic reasons, only some patients received accelerometer and bioelectric impedance analysis (BIA) measurements, limiting the sample size for these measurements. For this reason, these measurements were not included in linear regression analyses. Furthermore, due to the cross-sectional nature of the study, inferences about causality cannot be made and statistical power is limited by inter-individual variation in variables measured. Also, no matched control group was included, requiring comparison to literature values from an unmatched general population. Lastly, generic questionnaires were used for the study. While this enables comparison with reference values from literature, the questionnaires are less sensitive to change than disease-specific questionnaires would be.

Our findings that most AAV patients have a lower muscle strength than expected based on healthy population norms and that muscle strength and self-reported physical activity are positively associated with QoL suggest that AAV patients might benefit from interventions aimed at improving muscle strength and physical activity. Studies in other disease populations have demonstrated clinically relevant improvements with simple interventions. For example, improvement of fatigue and physical function was achieved in Rheumatoid Arthritis patients by giving them a pedometer and a step-monitoring diary [33]. As fatigue negatively influences QoL in AAV [34], and self-reported physical activity was positively related to QoL in the present study, physical activity interventions might also reduce fatigue and improve QoL in AAV patients.

In conclusion, the majority of AAV patients have reduced leg muscle strength and physical QoL compared to norm values. Knee extension strength is independently associated with physical QoL, while self-reported physical activity is independently associated with mental QoL. Therefore, interventions promoting leg muscle force and physical activity might improve both aspects of QoL and should be evaluated in clinical trials.

 Supporting information Intra-rater reliability of handheld dynamometry muscle groups, overall and per assessor.

Results shown are intraclass correlation coefficients (ICC) with 95% conficence intervals.

(DOCX)

 Paired comparisons of muscle strength during and after high-dose prednisolone.

Muscle strength of individual patients at visit V1 (prednisolone dose > = 30mg/d) and visit V2 (< = 2.5 mg/d) for elbow flexion (A), hip flexion (B) and knee extension (C). *P<0.05.

(DOCX)

The authors wish to thank Lukas Dijck (Technician*, Department of Neurology, University Medical Center Groningen [UMCG]) for technical support during the study, the researchers of Active Care after Transplantation (ACT) (ClinicalTrials.gov Identifier: NCT01047410) and TransplantLines (ClinicalTrials.gov Identifier: NCT03272841) for lending their measurement equipment for use in this study, and Suzanne Arends (Post-doctoral researcher [Postdoc], Department of Rheumatology and Clinical Immunology, UMCG), Linda Swart-Busscher (Dietician, Department of Dietetics, UMCG), Gerald Klaassen (PhD candidate), Janneke Tuin (PhD candidate*) and Dorien Zelle (Postdoc*) (Department of Internal Medicine/Nephrology, UMCG) for their assistance in choosing measurement tools for the study.

* Formerly, at the time of study conduction.

 References Jennette JC. Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 2013 Oct;17(5):603–606. doi: 10.1007/s10157-013-0869-6 24072416 Kallenberg CG. Pathogenesis and treatment of ANCA-associated vasculitides. Clin Exp Rheumatol 2015 Sep-Oct;33(4 Suppl 92):11–14. Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Hoglund P, et al. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials. Rheumatology (Oxford) 2015 Mar;54(3):471–481. Koutantji M, Harrold E, Lane SE, Pearce S, Watts RA, Scott DG. Investigation of quality of life, mood, pain, disability, and disease status in primary systemic vasculitis. Arthritis Rheum 2003 Dec 15;49(6):826–837. doi: 10.1002/art.11471 14673970 Basu N, McClean A, Harper L, Amft EN, Dhaun N, Luqmani RA, et al. The characterisation and determinants of quality of life in ANCA associated vasculitis. Ann Rheum Dis 2014 Jan;73(1):207–211. doi: 10.1136/annrheumdis-2012-202750 23355077 Faurschou M, Sigaard L, Bjorner JB, Baslund B. Impaired health-related quality of life in patients treated for Wegener's granulomatosis. J Rheumatol 2010 Oct;37(10):2081–2085. doi: 10.3899/jrheum.100167 20682665 Walsh M, Mukhtyar C, Mahr A, Herlyn K, Luqmani R, Merkel PA, et al. Health-related quality of life in patients with newly diagnosed antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Care Res (Hoboken) 2011 Jul;63(7):1055–1061. Schakman O, Kalista S, Barbe C, Loumaye A, Thissen JP. Glucocorticoid-induced skeletal muscle atrophy. Int J Biochem Cell Biol 2013 Oct;45(10):2163–2172. doi: 10.1016/j.biocel.2013.05.036 23806868 Gupta A, Gupta Y. Glucocorticoid-induced myopathy: Pathophysiology, diagnosis, and treatment. Indian J Endocrinol Metab 2013 Sep;17(5):913–916. doi: 10.4103/2230-8210.117215 24083177 Robson JC, Dawson J, Cronholm PF, Ashdown S, Easley E, Kellom KS, et al. Patient perceptions of glucocorticoids in anti-neutrophil cytoplasmic antibody-associated vasculitis. Rheumatol Int 2017 Nov 9. Herlyn K, Hellmich B, Seo P, Merkel PA. Patient-reported outcome assessment in vasculitis may provide important data and a unique perspective. Arthritis Care Res (Hoboken) 2010 Nov;62(11):1639–1645. Newall C, Schinke S, Savage CO, Hill S, Harper L. Impairment of lung function, health status and functional capacity in patients with ANCA-associated vasculitis. Rheumatology (Oxford) 2005 May;44(5):623–628. LaPier TK. Glucocorticoid-induced muscle atrophy. The role of exercise in treatment and prevention. J Cardiopulm Rehabil 1997 Mar-Apr;17(2):76–84. 9101384 Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 1994 Nov;87(11):671–678. 7820541 Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis 2009 Dec;68(12):1827–1832. doi: 10.1136/ard.2008.101279 19054820 van der Ploeg RJ, Oosterhuis HJ, Reuvekamp J. Measuring muscle strength. J Neurol 1984;231(4):200–203. 6512574 Bohannon RW. Reference values for extremity muscle strength obtained by hand-held dynamometry from adults aged 20 to 79 years. Arch Phys Med Rehabil 1997 Jan;78(1):26–32. 9014953 Douma RK, Soer R, Krijnen WP, Reneman M, van der Schans CP. Reference values for isometric muscle force among workers for the Netherlands: a comparison of reference values. BMC Sports Sci Med Rehabil 2014 Feb 25;6(1):10-1847-6-10. Bohannon RW. Make tests and break tests of elbow flexor muscle strength. Phys Ther 1988 Feb;68(2):193–194. 3340656 Mentiplay BF, Perraton LG, Bower KJ, Adair B, Pua YH, Williams GP, et al. Assessment of Lower Limb Muscle Strength and Power Using Hand-Held and Fixed Dynamometry: A Reliability and Validity Study. PLoS One 2015 Oct 28;10(10):e0140822. doi: 10.1371/journal.pone.0140822 26509265 Baecke JA, Burema J, Frijters JE. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr 1982 Nov;36(5):936–942. doi: 10.1093/ajcn/36.5.936 7137077 Hertogh EM, Monninkhof EM, Schouten EG, Peeters PH, Schuit AJ. Validity of the modified Baecke questionnaire: comparison with energy expenditure according to the doubly labeled water method. Int J Behav Nutr Phys Act 2008 May 27;5:30-5868-5-30. Ainsworth BE, Haskell WL, Leon AS, Jacobs DR Jr, Montoye HJ, Sallis JF, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 1993 Jan;25(1):71–80. 8292105 Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000 Sep;32(9 Suppl):S498–504. 10993420 Semanik P, Song J, Chang RW, Manheim L, Ainsworth B, Dunlop D. Assessing physical activity in persons with rheumatoid arthritis using accelerometry. Med Sci Sports Exerc 2010 Aug;42(8):1493–1501. doi: 10.1249/MSS.0b013e3181cfc9da 20139792 Ware JE, New England Medical Center Hospital. Health Institute. SF-36 physical and mental health summary scales: a user's manual. Boston: Health Institute, New England Medical Center,; 1994. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998 Nov;51(11):1055–1068. 9817123 Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey Manual and Interpretation Guide. New England Medical Center, The Health Institute; 1993. McClean A, Morgan MD, Basu N, Bosch JA, Nightingale P, Jones D, et al. Physical Fatigue, Fitness, and Muscle Function in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care Res (Hoboken) 2016 Sep;68(9):1332–1339. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994 Jul;150(1):11–16. doi: 10.1164/ajrccm.150.1.8025735 8025735 Levin OS, Polunina AG, Demyanova MA, Isaev FV. Steroid myopathy in patients with chronic respiratory diseases. J Neurol Sci 2014 Mar 15;338(1–2):96–101. doi: 10.1016/j.jns.2013.12.023 24380687 Hanada M, Sakamoto N, Ishimatsu Y, Kakugawa T, Obase Y, Kozu R, et al. Effect of long-term treatment with corticosteroids on skeletal muscle strength, functional exercise capacity and health status in patients with interstitial lung disease. Respirology 2016 Aug;21(6):1088–1093. doi: 10.1111/resp.12807 27173103 Katz P, Margaretten M, Gregorich S, Trupin L. Physical Activity to Reduce Fatigue in Rheumatoid Arthritis: A Randomized Controlled Trial. Arthritis Care Res (Hoboken) 2018 Jan;70(1):1–10. Basu N, Jones GT, Fluck N, MacDonald AG, Pang D, Dospinescu P, et al. Fatigue: a principal contributor to impaired quality of life in ANCA-associated vasculitis. Rheumatology (Oxford) 2010 Jul;49(7):1383–1390.