The term spondyloarthritis (SpA) comprises a partially heterogeneous group of rheumatic diseases that have some characteristic features in common: in addition to inflammation in the axial skeleton (sacroiliitis, spondylitis), inflammation of peripheral joints (arthritis) and tendon insertions (enthesitis) does also frequently occur . In the long-term syndesmophytes and ankylosis dominate the clinical picture (mainly but not only in patients with persistent inflammation). Thus, limited mobility of the spine is pathognomonic for patients with axial SpA (axSpA), especially in advanced stages of ankylosing spondylitis (AS). This historically established term is almost synonymous with the subgroup radiographic axSpA (r-axSpA), which, for classification purposes, can be differentiated from non-radiographic axSpA (nr-axSpA) [2,3]. The main distinguishing feature between r-axSpA and nr-axSpA is the presence of definitive structural changes in the sacroiliac joints according to the 1984 NY criteria . The disease burden was shown to be similar in patients with r-axSpA and nr-axSpA  but there are also some important differences related to inflammation and new bone formation .
Patients with axSpA suffer from pain, functional disability, especially spinal stiffness, sleep problems, fatigue and limitation in activities and social participation  which has a strong impact on patient-reported outcomes and health related quality of life measures. In addition, socio-economic aspects such as education, employment, and economic status are affected by axSpA. Functional disability is a major contributor to the disease burden of axSpA. Compared with patients of other medical conditions, axSpA patients have low scores in the physical domains of generic instruments such as the short-form-36 (SF-36) (2. Compund measures) . It has been shown that longer disease duration and increasing age are associated with decreased functioning, whereas performing back exercises and having a greater degree of social support improved functioning . The level of pain has a considerable influence on health-related quality of life (HRQoL) in axSpA. As many as 83% of axSpA patients report problems with pain, and for one third it is of critical importance . Female patients are 2 to 3 times more likely than men to have greater pain levels. Fatigue, an important symptom in axSpA, is reported by 67% of patients . Although the physical aspects of health seem to be most severely affected, the disease impact on mental health is also considerable. Cohort studies showed that almost half of the patients with axSpA had a high risk for depression and anxiety [11,12]. Of interest, the level of disease activity in axSpA does correlate significantly with anxiety and depression.
Work loss is one of the most important outcomes in chronic inflammatory rheumatic diseases. Employment rates are 11% lower and work disability rates 15% higher than in the general Dutch population [13,14]. Furthermore, work productivity is reduced in up to 45% of patients with SpA . Work status is an important determinant influencing HRQoL in patients with axSpA . This of major importance in patients with low education levels . Thus, special attention on this aspect is needed and appropriate patient education mandatory to support successful coping strategies.
Patient-reported outcomes are based on subjective symptoms frequently reported by axSpA patients that are not easily assessed. These symptoms play an important role in the management of patients with axSpA. Outcome parameters assessing various aspects of functioning have been developed for symptoms such as pain and enthesitis, but also for domains such as disease activity, physical and emotionial functioning as well as mobility, quality of life and social participation (Table 1).
More than two decades ago, the Assessment of Spondlyoarthritis International Society (ASAS) has published a Core Set of Outcome Parameters, which includes subjective symptoms such as pain and fatigue as well as the assessment of spinal mobility and function and radiological progression (Figure 1) . The outcome parameters listed in the inner circle of the core set are considered mandatory and assessment must be done in clincical trials.
The Core set is currently being revised by ASAS in order to implement more recent findings and also to enable greater patient participation.
The aim of this article is to give an overview of the available instruments to assess various aspects of functioning in patients with axSpA. Moreover, the impact of axSpA on a wide range of HRQoL domains will be described. Since axSpA usually starts in early adulthood, the life-time impact of axSpA on HRQoL is also important. The level of HRQoL impairment in patients with axSpA was shown to be comparable to that of rheumatoid arthritis (RA) and is markedly reduced compared to the general population [17,19].
1) Individual symptoms
Individual clinical symptoms, such as general pain, global patient assessment and fatigue (bath AS disease activity index [BASDAI] Question 1) can all be recorded by use of numerical rating scales, where 0 means the best possible condition and 10 the worst possible . Assessment using a visual analogue scale (VAS, often as a 0∼100 mm variant) is also possible. Because use of VAS is more error-prone in respect to reproducibility of accurate metric results, ASAS favours usage of a numeric rating scale (NRS).
2) Compund measures
(1) Disease activity
A number of procedures are available to record disease activity in a standardized way: Questionnaires with several questions (e.g., BASDAI ) or individual questions (e.g., back pain or patient global assessment), laboratory parameters (e.g., C-reactive protein [CRP]) or composite assessments (e.g., AS disease activity index [ASDAS] ).
It is important to note that comorbidities can influence response pattern of individual patients. In patients with axSpA and degenerative spinal disease, the assessment of disease activity can be overestimated by superposition of the symptom back pain due to any other cause. In patients with axSpA and fibromyalgia, the disease activity of axSpA can be much overestimated by altered pain processing. In the observational study Predict-SpA it was shown that the presence of 3 BASDAI items with extreme values (defined as ≥8) had a high specificity for the presence of fibromyalgia . Since it was shown that firbomyalgia (FM) is rather prevalent in axSpA and since this was shown to influence the response to biologic therapy, a critical evaluation of the BASDAI and use of questionnaires developed to diagnose FM American College of Rheumatology (ACR) criteria seems necessary in order to avoid inappropriate escalation of treatment . To differentiate pain due to spondylitis from generalized pain due to FM can be challenging though.
In interventional studies, changes in disease activity after initiation of therapy can be assessed using a 50% improvement of BASDAI . In the majority of studies, the BASDAI-50 response has been replaced by the ASAS 40 response or ASDAS major improvements, which, as composite instruments, represent the various facets of the disease in a better way.
(2) Mobility and physical functioning
In patients with axSpA, physical functioning and mobility are closely related, but not identical. Under the generic term of functioning, various dimensions such as physical, emotional and social functioning are subsumed. The individual aspects of which are divided into the aspects of physical functional ability and global or social functioning for reasons of comprehensibility in this article. Mobility is the metric component of functional ability. Physical functioning is influenced both by disease activity and by structural damage and these influencing parameters should therefore also be assessed separately . While functioning is usually assessed by questionnaires to be subjectively filled out by the patient, spinal mobility is actively examined by a health professional. However, functioning can also be assessed by directly measuring the actual performance of patients.
Active inflammation of the sacroiliac (SI) joints (e.g., by Mennel’s sign) cannot be assessed on a sole clinical basis with sufficient certainty, nor can the extent and severity of the spinal infestation be determined clinically–thus, further imaging is needed.
A combined measurement tool for spinal mobility is the BASMI (which is frequently collected in clinical studies . The BASMI measures mainly the spinal mobility of the patient which is composed of the lateral lumbar flexion, the tragus-wall distance, the lumbar flexion, the maximum intermalleolar distance and the cervical angle of rotation. The BASMI score is the average of the 5 individual measurements. Of the three different BASMI definitions, ASAS recommends the 10 steps or the linear BASMI definition.
(3) Global functioning and HRQoL
Generic and disease-specific questionnaires have been developed to assess impairments in HRQoL. Some questionnaires rely only to the assessment of HRQoL, others address global functioning or focus on individual aspects such as activity and participation. Impairments and limitations in health are recognized to be a very important part of the construct of HRQoL. However, attributes of HRQoL are evaluated subjectively whereas impairments in global fucntioning can be assessed in a standardized manner by use of the International Classification for functioning, disability and health (ICF) published by the World Health Organization (WHO) [34,35].
In clinical studies, “SF-36” and “Euroquol 5 Dimensions” (EQ-5D) are used as generic instruments and ASAS health index (ASAS HI) are used as disease-specific questionnaires to assess global functioning or quality of life of patients with axSpA [22-25].
In recent years, focus has increasingly shifted to recording emotional symptoms such as anxiety or depressive symptoms. Although depressive symptoms are included in many questionnaires on health status and quality of life, they are often not considered as individual items. A large number of different questionnaires are suitable for screening—although none of these questionnaires are particularly recommended for patients with axSpA. Questionnaires like Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire 9 Questions (PHQ 9) or Beck Depressions Inventory (BDI) have been used in many clincal trials but has not been implemented into clinical routine [36-38].
3) Work productivity
Restrictions in working life represent a multifaceted problem and impairments are prevalent in many patients . Limitations can be recorded with various questionnaires of which the Work Productivity and Activity Impairment Questionnaire (WPAI) is most often used . The WPAI consists of 6 questions on current employment, number of hours missed due to SpA, number of hours missed for other reasons, number of hours actually worked and degree of impairment in work/leisure. Reporting time frame is the last 7 days before answering the questionnaire. This self-reort questionnaire consists of 4 domains: absenteeism, presenteism, work impairment and activity impairment. The WPAI score is calculated as a percentage for all domains, with a high percentage being a major limitation. The values in axSpA patients for the category absenteism vary between 2 and approx. 10%, those for the category presenteism and work satisfaction between 20% and 40% and those for the category impairment of everyday activity between 20% and 50%. WPAI is used in both clinical and epidemiological studies. In the British Biologicaregister it could be shown that after initiation of a biologika a reduction of the work incapacity and a decrease of the work and everyday life impairment of up to 17% could be achieved . For each WPAI outcome, an improvement of ≥7 points from baseline for an individual patient is considered the minimal clincially improtant improvement .
4) Assessment of physical performance
As explained above, physical function, as a patient-reported outcome, is often assessed by the BASFI questionnaire or by physical examination as range of movement. However, those assessments do not necessarily correlate with the current performance of an individual patient. Assessment of performance tests are standard of care in other diseases such as pulmonary diseases including pulmonary arterial hypertension in systemic sclerosis, in which, for example, measurement of gait speed is used for clinical decision making. Physical performance can be assessed as a single task such as grip strength or as a generic compound measure. Generic performance measures are widely used (e.g., short physical performance battery, SPPB) to assess physical performance more objectively . The SPPB has been developed for geriatric patients and can discriminate patients with high and low fall risk by testing three complex tasks (chair rising test, balance test and gait speed). Recent research in axSpA has paid some attention to measure physical performance in axSpA patients as well. In a monocentric, prospective and cross-sectional study that impairment in performance is frequent in patients with axSpA . Although tests were done in a quite young axSpA cohort (mean age 44.3 [12.5] year) an impairment in ≥1 performance test was seen in 87 patients (43.5%). A disease-specific performance test is available for patients with axSpA as well. The ankylosing spondylitis performance index (ASPI) is a performance-based measure for physical functioning, which has been validated in Dutch patients with r-axSpA. The ASPI measures the time to perform three daily activities (bending to pick up 6 pencils from the floor, putting on socks and standing up from the floor) [45,46]. The ASPI has previously shown an adequate to excellent (intraclass correlation coefficient>0.70) intra-rater test-retest reliability, good responsiveness (after TNFi initiation) and successfully measures different aspects of function compared to the BASFI questionnaire [47,48].
A large number of outcome parameters exist for both clinical routine and clinical studies. Instruments are used depending on the disease manifestation and its severity of axSpA. In clinical routine, the use of instruments is limited mainly to assessment of disease activity and physical functioning. In clinical trials, a large number of domains can be recorded in a standardized manner, depending on the focus of the study.
No potential conflict of interest relevant to this article was reported.
All authors had access to the literature and wrote and checked the manuscript.