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Abstract
Objective Patients with axial spondyloarthritis (axSpA) suffer from clinical symptoms like morning stiffness and back pain. Mobility of patients with axSpA is often impaired. The aim of this study is to compare the performance of patients with axSpA regarding mobility measures including performance-based tests and objective electronic assessments with the Epionics SPINE device (ES) at different times of the day compared with healthy controls (HC).
Methods Observational trial, consecutive inpatients with axSpA (n=100) and 20 HCs were examined in the morning (V1: before 10:00 am) and in the afternoon (V2: after 02:00 pm) by the Bath Ankylosing Spondylitis Metrology Index (BASMI), the AS physical performance index (ASPI), the Short Physical Performance Battery (SPPB) and ES measurements, including range of motion (RoM) and range of kinematics (RoK).
Results The assessments of patients with axSpA performed in the morning clearly differed from those in the afternoon, especially regarding performance-based tests. Significant improvements were seen for BASMI (4.0±3.8 to 3.8±1.9; p<0.001), ASPI (36.2±18.3 to 28.8±11.9 s; p<0.001), SPPB (10.1±1.5 to 10.7±1.4 points; p<0.001) and for ES measures of speed (RoK; p<0.018) but not for RoM, except for lateral flexion (13.3±7.4 to 14.7±8.2°; p=0.002). This time of assessment-related variability was not observed in HC.
Conclusion The spinal mobility of patients with axSpA was worse in the morning but significantly improved in the afternoon. This was captured best by performance-based measures and was not seen in HC. The diurnal variation of mobility has implications for clinical studies, suggesting that the time of assessments needs to be standardised.
- Spondylitis, Ankylosing
- Low Back Pain
- Patient Reported Outcome Measures
- Physical Therapy Modalities
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients with axial spondyloarthritis (axSpA) often experience impairments of physical function and spinal mobility. Major clinical symptoms are back pain and morning stiffness, both part of established disease activity criteria.
WHAT THIS STUDY ADDS
In patients with axSpA, the mobility is impaired in the morning but significantly improved in the afternoon.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The diurnal variation of mobility has implications for clinical studies suggesting standardisation of time.
Introduction
Axial spondyloarthritis (axSpA), including radiographic (r-) and non-radiographic axSpA (nr-axSpA), is a chronic rheumatic disease characterised by inflammation and structural changes in the axial skeleton. In addition, patients with axSpA may have articular, entheseal and extramusculoskeletal disease manifestations.1 2 Due to inflammation and structural changes in the axial skeleton, patients with axSpA often experience impairments of physical function and spinal mobility.3 Major clinical symptoms are inflammatory back pain and morning stiffness.4 Back pain and morning stiffness are common symptoms and part of established disease activity criteria. Two out of six questions of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) are based on the level and duration of morning stiffness at the time of awakening.5 The assessment of the duration of morning stiffness is also included in the AS Disease Activity Score (ASDAS).6 However, the level and duration of morning stiffness is not included in assessments of physical function or mobility.
The core outcome set for clinical trials in axSpA has recently been updated and, in addition to different aspects of global functioning and health, it includes physical function as a mandatory domain for clinical trials and defines spinal mobility as important optional domains in axSpA.7 In patients with axSpA, physical function is usually assessed by the Bath AS Functional Index (BASFI) and spinal mobility by the Bath Ankylosing Spondylitis Metrology Index (BASMI). The geriatric Short Physical Performance Battery (SPPB)8 test was recently shown to be impaired in many patients with axSpA.9 Based on BASFI items, the disease-specific AS Performance Index (ASPI) measures the time needed to perform daily activities.10 11 Epionics SPINE (ES) is an electronic device capable of objectively assessing spinal mobility that was currently validated in axSpA.10–15
Cross-sectional use of the common instruments like the BASMI is informative in patients with axSpA, and it has recently been shown also for patients with early axSpA.16 However, the high variation of the measurements over time impairs their use at the individual patient level.16 As outcome parameter for clinical trials, it is of importance that measurements of mobility are of high accuracy and are performed in a more standardised way than the current standard.
The aim of this study is to compare the performance of patients with axSpA regarding measurements of mobility and physical function including electronic assessments with the ES at different times of the day and to compare the results with them of healthy controls.
Methods
This is an observational trial with control group but without randomisation. The Ethical Committee of the Ruhr University approved the study (reference number 19-6735-BR), and written informed consent was obtained from all patients.
Consecutive patients≥18 years diagnosed with axSpA by a rheumatologist were prospectively included if presenting with impaired physical function as defined by a BASFI score>2. Exclusion criteria encompassed patients aged over 70 years, those with a BMI exceeding 120 kg, individuals with a history of spinal surgery and pregnant women. The control group was comprised by a convenience sample of healthy people in similar age and sex range without any rheumatic or musculoskeletal disease and without impaired physical function.
For analyses, patients were divided based on the classification into r-axSpA or nr-axSpA according to the absence or presence of definite structural changes in the SIJ as assessed by conventional radiography and evaluated according to the modified New York criteria.17 The images were evaluated by two experienced readers (XB and DK).
Clinical assessments
Baseline data including demographic and clinical data such as age, sex and body mass index (BMI). Medication was categorically collected (no medication, non-steroidal anti-inflammatory drugs, biological (b)DMARDs). HLA-B27 and CRP were collected from data of the clinical routine.
Disease activity was assessed by ASDAS and BASDAI,5 7 physical function by BASFI),18 global functioning and health by the ASAS HI.19 20
Different measurements of mobility were performed (LS and NK). Besides the Bath AS Metrology Index (BASMI_lin)12 also performance-based tests, the AS Physical Performance Index (ASPI) and the SPPB as well as objective electronic measurements of spinal mobility with the ES were assessed. ES measurements were based on a choreography of predefined exercises to record spinal mobility including flexion, extension, rotation and lateral flexion of the spine. As described earlier in more detail,14 the ES uses strain gauge sensors attached in predefined positions at the back to provide a sensitive measure of electrical resistance, and thus of the aperture angles, according to the curvature in each of six 50 mm sensor segments. The ES is therefore capable to assess RoM, measured and calculated in angular degrees and the maximum speed with which the exercises have been performed (RoK), measured in angular degrees/s.14 21–24 Each part of the choreography was performed three times and the ES software calculated the mean results that were then used for analyses, while for lateral flexion and cervical rotation as part of BASMI, the mean of the best of two performances on each side was used in the analyses.
All participants were examined once in the morning (V1: before 10:00 am) and once in the afternoon (V2: after 02:00 pm). At V1 demographic and clinical data, ASDAS, BASDAI and BASFI) and ASAS HI was assessed. The performance-based tests (BASMI, ASPI and SPPB) and measurements with the ES were performed at V1 and V2. All individual visits were performed at the same day. The programme did not include a special warm up for both, the morning and the afternoon, study visits.
Statistics
For statistical analyses, patient demographics, clinical assessments and ES variables (V1 vs V2) were directly compared by t-tests. HCs were compared with patients using t-test. Effect sizes were calculated with Cohen’s d. Results of a two-sided p<0.05 were considered significant. All explorative statistical analyses were performed using the software SAS V.9.4 (SAS Institute, Cary, NC, USA).
The patient reported overall level and duration of morning stiffness (NRS 0–10: BASDAI questions 5 and 6) were correlated with mobility measurements by Spearman’s correlation coefficient. Correlations were only performed for results of patients with axSpA.
Results
A total of 120 individuals were included in the analyses: 100 patients with axSpA (63 with r-axSpA and 37 with nr-axSpA) and 20 HCs. AxSpA patients were mostly male (69%), mean age 45.2±11.7 years, mean BMI 28.1±5.5 kg/m2 and a mean CRP of 9.7±20.8 mg/L. HC were also mostly male (55%) with comparable results for age (44.6±14.8) and a slight difference for BMI (25.4±4.6, p=0.044), see table 1.
Patient’s demographics and clinical characteristics
Most (n=74) patients (74%) were HLA-B27 positive. Mean disease duration was 10.3±10.2 years and the mean onset of symptoms was 17.5±11.8 years (table 1). Laboratory tests were not performed in HC.
Disease activity as assessed by ASDAS was 3.1±0.8 and 5.4±1.6 by BASDAI, both indicating active disease. AxSpA patients had moderate impairments of global functioning (ASAS HI 8.6±3.0) and limitations of physical function (BASFI 5.4±2.0) and spinal mobility (BASMI 4.0±1.8). Mean of BASDAI questions Q5 (intensity of morning stiffness) and Q6 (duration of morning stiffness) was 4.3±2.1. The scores for these assessments were very low in HC (table 1).
All ASPI items were performed only by 71 patients (71%), since 29 were unable to perform these tasks due to physical problems and handicaps. The performance-based tests in patients with axSpA showed an ASPI of 36.2±18.3 s, while the mean SPPB (n=100) score was 10.0±1.5. The results of the HC were much better with an ASPI of 18.3±4.8 s and an SPPB score of 11.9±0.4. Only 14 axSpA patients (14%) and no HC had an SPPB score≤8 indicating a severe impairment.
The overall level of morning stiffness (BASDAI Q5) was 5.1±2.3 for patients with axSpA with no significant difference between r- and nr-axSpA (p=0.2), but scores were significantly higher compared with HC (0.1±0.3, p<0.001). Similar results were found for the duration of morning stiffness from the time of wake up (BASDAI Q6). In detail patients with axSpA had a mean duration of morning stiffness of 44.4±32.4 min (BASDAI Q6: 3.7±2.7) with no significant difference between r- and nr-axSpA (p=0.4), but scores were significantly higher than in HC (p=<0.001, 1.2±03.6 min; BASDAI Q6: 0.1±0.3).
Patients with r-axSpA had higher scores than those with nr-axSpA regarding ASDAS (3.2±0.9 vs 2.9±0.6; p=0.009), BASFI (5.8±2.0 vs 4.7±1.9; p=0.01) and BASMI (4.6±1.8 vs 3.0±1.1; p = <0.001), while BASDAI (5.4±1.6 vs 5.4±1.5) and and ASAS HI (8.6±3.0 vs 8.3±2.9), were comparable.
Differences in mobility measures in the morning and the afternoon
AxSpA patients showed significant differences between assessments performed in the morning versus the afternoon were seen. AxSpA patients improved in BASMI (p<0.001, r=0.46), but single BASMI items varied and showed significant changes only for lateral flexion (p<0.001, r=0.47) but not for tragus to wall distance, intermalleolar distance, cervical rotation and flexion. These results varied slightly for r-axSpA and nr-axSpA (table 2).
Differences in metric assessments in the morning (V1) and the afternoon (V2)
HC did not improve significantly in total BASMI and any single BASMI item but cervical rotation (p=0.009, r=−0.65).
AxSpA patients improved significantly in the ASPI (p<0001; r=0858) and SPPB (p<0001; r=0584) (table 2). In detail, the time for completing ASPI in the morning in axSpA was 36.2±18.3 s and significantly faster (−7.4±8.7 s) in the afternoon (28.8±11.9 s). Correspondingly for the SPPB, axSpA patients improved significantly by an average of 0.7±1.1 comparing 10.1±1.5 in the morning to 10.7±1.4 points in the afternoon (table 2). Furthermore, axSpA patients improved for ES measures of speed (RoK; all p<0.018) but not for RoM, except for lateral flexion (p=0.002), see table 3.
Differences in ES measurements (RoM and RoK) in the morning (V1) and the afternoon (V2) in patients with axSpA
In comparison, HC did slightly improve in ASPI (−1.5±2.0 s; p=0.003, r=0.78), but there was no significant difference in SPPB scores (table 2). Furthermore, HC did not improve in any of the measurements with the ES for RoM and RoK (all p<0.05; table 4).
Differences in ES measurements (RoM and RoK) in the morning (V1) and the afternoon (V2) in healthy controls
Of interest, neither patients classified as r-axSpA nor those with nr-axSpA showed a significant correlation of ROM or RoK with intensity or duration of morning stiffness (questions 4 and 5 of BASDAI).
As expected, significant differences were observed between r-axSpA and nr-axSpA patients in all RoM measures as well as in the RoK of flexion and extension in V1 and V2. RoM for rotation and lateral flexion improved in both groups, but there was only a numerical difference that could be attributed to the sample size selected for this subgroup analysis (online supplemental table 1,2).
Supplemental material
When comparing the impact of different treatments, no significant differences in mobility measures (V1) were observed between patients with and without treatment with bDMARDs (online supplemental table 3).
Discussion
The spinal mobility of patients with axSpA differed considerably at different times of the day, being worse in the morning and improving significantly in the afternoon.
Importantly, this was most prominently captured by performance-based measures and objective electronic measures with the ES in comparison to standard assessments such as BASMI, and this was not seen in HC.
When looking at ES data in more detail, significant differences between V1 and V2 were observed especially in the measurements of velocity, whereas RoM only improved in the lateral flexion. Patients with axSpA clearly were more limited in the morning and performed superior in the afternoon.
This was not observed in HC, except for a slight improvement in ASPI, mobility and velocity hardly changed between assessments in the morning and the afternoon. These data show that common symptoms of patients with axSpA such as morning stiffness have a negative influence on the velocity of spinal movements. However, and of interest, there was no correlation between the reported level or duration of morning stiffness and these objective mobility measures. These results are in line with previously reported data demonstrating a striking difference between patients’ perception as assessed by PROs and patients’performance if objectively measured.10 25–30 Spinal mobility and morning stiffness (BASDAI questions 5 and 6) are both outcome parameters used in clinical trials and included in the ASAS-OMERACT core outcome set for clinical trials in axSpA.31 High intensity exercises may reduce morning stiffness and improve spinal mobility in patients with axSpA.32 It is known that TNF, IL-17 and IL23 are key pathways in the pathogenesis of axSpA. These cytokines promote the release of other proinflammatory cytokines and chemokines, leading inflammation. Elevated levels of inflammatory cytokines have been observed in the serum, synovial fluid and affected tissues of axSpA patients.1 33–35 TNF inhibitors, IL17 inhibitors and JAK inhibitors have demonstrated significant efficacy in reducing morning stiffness and spinal mobility in patients with axSpA and improving overall disease activity also when compared with placebo.36–39
It is known that the diurnal rhythm of proinflammatory cytokines and cortisol peaks in the early morning hours and that changes of this circadian rhythm have effects on blood pressure and depression but effects on mobility has not been studied to date.40 Besides axSpA, morning stiffness affects patients with other inflammatory diseases like rheumatoid arthritis (RA). In RA, proinflammatory cytokines exhibit a peculiar rhythmicity, in particular serum TNF and serum IL-6, and together with other relevant immunological parameters display an elevation in the early morning hours in patients with RA and correlate with the duration of morning stiffness.41–43 These results let to the idea of chronobiological principles optimising the timing of treatments to the circadian rhythm of individual patients.44 Whether this also applies to axSpA has so far only been investigated preliminary.45 Patients with axSpA are in general less active and have a decreased mobility compared with HCs.46–48 If this lack of exercise plays a role in the pathogenesis of morning stiffness in patients with axSpA has not yet been investigated. However, a recent study demonstrated that exercises reduced disease symptoms including morning stiffness in patients with axSpA.32
Although we do not provide data on these markers, we assume such an effect, since patients had active disease and clinically relevant reported morning stiffness. The demonstrated improvement of morning stiffness by anti-inflammatory medication underlines this idea.
Taken together, our findings support the role of a diurnal rhythm of inflammatory processes by showing an association between the daytime and spinal mobility. Indeed, studies have demonstrated that inflammatory mediators can modulate nociception and are responsible for central sensitisation. Furthermore, sleep disturbances were shown to be associated with high disease activity and impaired function in patients with axSpA.49 50 In that line, systemic inflammation and elevated levels of cytokines such as TNFi, IL-6 and IL-1ß were shown to increase inflammatory and neuropathic pain, being a central factor in low back pain and associated with pain severity.51
As a potential limitation, we acknowledge the potential limitation of ‘learnt behaviour’ in relation to both physical activity and performance-based tests. Patients may improve their performance in these tests simply because of repeating them and, thus, becoming more skilled over time. However, as previously demonstrated, the correlation for repeated measurements on three different days (within 5 days, same time of the day) has been pretty good—with an average correlation coefficient of 0.84.23 Furthermore, even if the measurements did not include a special warm up prior to the study visits, one limitation simply is that it was not possible to know and compare what happened between the visits. However, this is the same in most studies on that topic. Another limitation is the slight gender and BMI difference between axSpA patients and HC, this is due to chance and the consecutive enrolment of patients and controls. Of course, there is a higher male prevalence in r-axSpA. Previous studies have reported that height, weight, and BMI, with a weight threshold of less than 120 kg, did not exhibit significant effects on ES results.23
The main finding of this study, the compromised velocity of spinal mobility of patients with axSpA in the morning compared with controls, may have effects on activity and participation of affected patients in their social and working life. Especially activities and work with a high physical demand may be better performed by patients at later times of the day, and this is mainly the case in phases of high disease activity.
Finally, our data on the striking diurnal variation of mobility have important implications for clinical studies, strongly suggesting that the daytime of assessments needs to be standardised.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and ethics approval was obtained from Ethics Ruhr-University Bochum, Germany (reference number 19-6735-BR). Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
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Footnotes
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Contributors DK, XB and JB: conceptualisation; formal analysis; funding acquisition; investigation; methodology; writing—original draft—review and editing. UK: formal analysis; methodology; investigation; writing—review and editing. NK, LS, IA, ST, BB, PS and SH: formal analysis; investigation; writing—review and editing. DK: guarantor.
Funding This work was supported by Novartis, Germany by an unrestricted grant. The Investigators retained full control of scientific and analytic content, and had final editorial responsibility.
Competing interests The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Dr DK has received grant and research support and consultancy fees from AbbVie, BMS, Boehringer Ingelheim, Chugai, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche and UCB. Dr JB has received honoraria for talks, advisory boards, paid consultancies and rants for studies from Abbvie (Abbott), Amgen, Baxter, Biogen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Hexal, Janssen, Lilly, Medac, MSD (Schering-Plough), Mylan, Mundipharma, Novartis, Pfizer (Wyeth, Hospira), Roche, Sanofi Aventis and UCB. Dr UK has received grant and research support and consultancy fees from AbbVie, Amgen, Biogen, Chugai, Eli Lilly, Grünenthal, GSK, Hexal, Janssen, MSD, Novartis, Pfizer, Roche and UCB. NK, LS and ST: none. Dr IA has received research support, consultancy fees and honoraria from Abbvie, Amgen, BMS, Chugai, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Sobi, Takkeda and UCB. Dr BB has received honoraria for talks, advisory boards, paid consultancies and/or travel support from Abbvie, Alexion, Amgen, Biogen, Boehringer Ingelheim, Gilead/Galapagos, Janssen, MSD, Theramex, Sanofi-Genzyme and UCB. Dr PS has received grant and research support and consultancy fees from AXIOM Health, AMGEN, AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Chugai Pharma Marketing/Chugai Europe, Deutscher Psoriasis-Bund, Gilead Sciences, Hexal Pharma, Janssen-Cilag, Johnson & Johnson, Lilly/Lilly Europe/Lilly Global, medi-login, Mediri GmbH, Novartis Pharma, Onkowissen GmbH, Pfizer, Roche Pharma, Rheumazentrum Rhein-Ruhr, Sanofi-Genzyme, Spirit Medical Communication, Swedish Orphan Biovitrum, UCB Pharma. SH has received consultancy fees of AbbVie and Novartis. Dr XB has received grant and research support and consultancy fees from AbbVie, Amgen, Chugai, Galapagos, Hexal, Lilly, MSD, Novartis, Pfizer and UCB.
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