Assessment and Monitoring

Introduction

It is important to distinguish symptoms that reflect active disease from symptoms of a mechanical or psychological nature before making specific treatment decision. Monitoring ankylosing spondylitis (AS) disease activity needs use of reliable standardized measurement methods to enable better comparison of assessment of response to various treatment options. Patient reported outcome (PRO) forms important measures of disease activity, such as pain, morning stiffness, fatigue, as well as physical function. Pain and spinal stiffness are measured by visual analog scale (VAS) or a numerical rating scale (NRS). Objective measures. such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) correlate only moderately with axial disease activity.

Several instruments have been developed by Assessment of Spondyloarthritis International Society (ASAS) since 1995 to assess and monitor disease activity and severity and can be found on its website (www.ASAS-group.org). A composite core set for clinical and functional assessment and monitoring of ankylosing spondylitis/ axial spondyloarthritis (AS/axSpA) was developed in collaboration with OMERACT for use in daily practice. Figure 12-1 and Table 12-1 list the minimum variables that should be collected for the following three different settings:

• Symptom-modifying anti-rheumatic drugs (SMARDs) and physical therapy
• Clinical record keeping
• Disease-controlling anti-rheumatic treatment (DC-ART).

The examples of symptom-modifying antirheumatic drugs (SMARDs) in AS are nonsteroidal anti-inflammatory drugs (NSAIDs), while disease-controlling antirheumatic therapies (DC-ARTs) in AS include biologics targeting TNF-α and IL-17A.

An update of this core set for the whole spectrum of axSpA has been proposed by ASAS and these core domains (Figure 12-2) have just recently been endorsed by the OMERACT and, except for imaging, have recently been reviewed by Ogdie and colleagues, 2020.

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ASAS/OMERACT Core Domains for Evaluation of SMARDs/Physical Therapy

The following six domains should be assessed in patients receiving SMARDs and/or physical therapy.

Pain

Pain is measured by two questions:

• How much pain of your spine due to AS do you have in the past week? (0-to-100 VAS)
• How much pain of your spine due to AS do you have at night in the past week? (0-to-100 VAS)

Spinal Stiffness

Spinal stiffness in the morning is measured by a simple question: How long does your morning stiffness last from the time you wake up in the past week?

Patient Global Assessment

It is measured by the question: How active was your spondyloarthritis last week? (0-to-100 VAS)

Fatigue

It can be measured by the question: How would you describe the overall level of fatigue/tiredness you have experienced? It can also be measured by using Multidimensional Fatigue Inventory (MFI) and/or Functional Assessment of Chronic Illness Therapy (FACIT). MFI is a 20-item self-report instrument to measure fatigue. It covers general, physical and mental fatigue and reduced motivation/activity. FACIT, fourth version, is a 13-item composite scale that is used to evaluate fatigue (FACIT – Fatigue). It uses a crosscultural approach to measures the broader concept of fatigue that includes vitality, and social, physical and role functions.

Physical Function

Physical function is an important outcome in AS/axSpA and is measured by the AS disease-specific Bath Ankylosing Spondylitis Functional Index (BASFI) and the Dougados Functional Index, but the latter index is hardly ever used and no longer recommended for clinical practice or research. BASFI is a 10-item questionnaire designed by medical professionals in conjunction with patients for measuring the impact of AS on the performance of everyday tasks (Table 12-2). It is an easy, reliable and sensitive-to-change index to measure functional ability and coping skills on a 10-cm VAS on which the two anchors are labeled easy and impossible. The BASFI questionnaire can be downloaded as PDF files from ASAS web site (www.asas-group.org).

The first eight questions consider activities related to functional abilities (e.g., putting on socks without help or aids), and the final two questions assess the patient’s ability to cope with everyday life (e.g., doing a full day of activities at home or work). BASFI scores can range from 0 to 10. Higher scores signify greater functional impairment. Scores range from 0 to 10, with higher scores indicating greater functional impairment. The first eight questions refer to aspects of functional ability (e.g., putting on socks without help or aids) and the final two questions pertain to the ability to cope with everyday life (e.g., doing a full day of activities at home or at work).

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Spinal Mobility Measurement

Spinal mobility measurement can be assessed by many instruments detailed at www.asas-group.org. However, ASAS has recommended the following five:

• Chest expansion
• Modified Schober’s test
• Occiput-to-wall distance
• Cervical rotation
• Lateral spinal flexion (or BASMI).

They have been very well described with illustrations in a booklet published by Ankylosing Spondylitis International Federation (ASIF) in collaboration with Spondyloarthritis Research Consortium of Canada (SPARCC) (www.spondylitis-international.org). BASMI (Bath Ankylosing Spondylitis Metrology Index) is a reproducible and sensitive method for assessing spinal mobility. It measures cervical extension using tragus-to-wall distance, lumbar flexion using the modified Schober’s test, cervical rotation using a goniometer, lumbar side flexion using fingertip-to-floor distance in standing and intermalleolar distance to measure bilateral hip abduction (Table 12-3). BASMI scores also range from 0 to 10; higher scores indicate greater impairment.

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ASAS/OMERACT Core Domains for Clinical Record Keeping

In addition to the above mentioned domains, there are two additional domains that are needed for clinical record keeping; these are acute phase reactants (CRP and ESR) and peripheral joints/entheses (Figure 12-1 and Table 12-1). The number of swollen joints (44-joint count) is easy to obtain, but currently there are no preferred instruments available for evaluating extent of enthesitis.

ASAS/OMERACT Core Domains for Evaluation of DC-ARTs

In addition to all of the above mentioned domains (Figure 12-1 and Table 12-1), it requires:

• Spine radiograph (AP plus lateral lumbar spine and lateral cervical spine)
• Radiograph of the pelvis showing sacroiliac and hip joints.

A few scoring methods have been proposed for assessing radiographic damage of the spine in AS/axSpA. The one recommended by ASAS is the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), in which the anterior parts of the cervical and lumbar spine at a lateral view are scored for the presence of squaring and/or erosion and/or sclerosis (1 point per site), non-bridging syndesmophytes (2 points per site) and/or bridging syndesmophytes (3 points per site or 6 points per vertebral unit) (Figure 12-3). The total score ranges from 0 to 72.

Definite radiographic progression is defined as a change in mSASSS score from 0 or 1 (suspicious damage) to >2 (syndesmophytes or ankylosis). However, there is still a need for a better scoring method because mSASSS focuses heavily on the formation of syndesmophytes and the occurrence of ankylosis (osteoproliferation), while erosive changes (osteolysis) have a minor influence on the total score. But it offers advantages over BASRI (Bath Ankylosing Spondylitis Radiology Index) for assessing the progression of structural damage in AS that combines the results of the BASRI-spine (which includes the scores of the sacroiliac joints and lumbar and cervical spine) and the BASRI-hip. A practical form for mSASSS and BASRI can be downloaded as PDF files from ASAS Web site (www.asas-group.org). Routine monitoring of radiographic changes with serial spine radiographs is not recommended by the ACR/SAA/SPARTAN guidelines.

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Assessment of Clinical Disease Activity

ACR/SAA/SPARTAN conditionally recommend the regular-interval use and monitoring of a validated AS disease activity measure.

BASDAI (Bath AS Disease Activity Index)

It is a validated, easy-to-use and sensitive-to-change measure. It consists of seeking the patient’s response to self-administered questionnaire that contains the following five questions:

• Fatigue and/or tiredness that has been experienced
• Axial musculoskeletal pain (spine, including neck and pelvis and hip and shoulder girdles)
• Pain and/or swelling in other (peripheral) joints
• Discomfort from any areas tender to touch or pressure
• Overall level of morning stiffness from the time awakening and duration of morning stiffness.

A visual analog scale (VAS) that uses a horizontal line 10 cm in length or a numeric 0-to-10 scale (with 0 being the best and 10 being the worst) can be used to answer the questions. The patient is asked to give an average score during the preceding week. Please note that there is one question each for the first four symptoms and the fifth question relating to morning stiffness has two subcomponents (one for severity and the other for duration).

Therefore, to give each symptom equal weighting, the average of the two scores relating to morning stiffness is used as the answer to the fifth question. The resulting total score of these five symptoms (the total can range from 0 to 50) is divided by five to give a final BASDAI score, which can range from 0 to 10. Scores of four or more suggest suboptimal disease control; these patients may be good candidates for a change in their medical therapy, for treatment with biologic therapies, or for enrollment in clinical trials evaluating new drug therapies directed at active AS. A cutoff of four to define active disease does not have a firm justification.

An important drawback of the BASDAI is that it is entirely expert-driven and many of the items are redundant. However, its advantages are that it is easy to complete and very well known. BASDAI needs to be used by rheumatologists (or by other healthcare providers who are familiar with fibromyalgia); otherwise, patients with isolated or concomitant fibromyalgia will have a high BASDAI score that may not necessarily reflect the inflammatory status of AS.

ASDAS (Ankylosing Spondylitis Disease Activity Score)

The ASDAS is a data-driven index, partially based on consensus, that combines questions (PROs) about back pain, peripheral pain/swelling and duration of morning stiffness (these three questions are derived from the BASDAI), as well as BASFI and acute phase reactants (CRP or ESR). The ASDAS with CRP (ASDAS-CRP) (CRP measured in mg/L) is the preferred version. A CRP value <2 mg/L is not allowed. If the conventional CRP is below the limit of detection or if the high sensitivity CRP is <2 mg/L, the constant value of 2 mg/L should be used. The individual items are weighted, and a free App is available from www.ASAS-group for easy calculation of the ASDAS score. It is a disease-specific index available for clinical practice for monitoring disease activity in patients with AS/axSpA. (Figure 12-4). It allows one to classify patients as having an inactive disease (ASDAS <1.3), a low disease activity (ASDAS <2.1), a high disease activity (ASDAS = 2.1-3.5) or a very high disease activity (ASDAS >3.5). The cutoffs selected for ‘clinically important improvement’ is a change of at least 1.1 units, and a change of at least 2.0 units for major improvement.

ASDAS does have some weaknesses because it fails to consider peripheral extraarticular manifestations of the disease, such as enthesitis and uveitis and does not include assessment of function that might result in patients with chronic deforming disease and extensive structural damage achieve “inactive disease” state. Moreover, it does not consider the presence of inflammation that can be detected on MRI. Lastly, it has feasibility issues that make it difficult to incorporate it into daily clinical practice because the ESR and CRP values are frequently unavailable at the time of the visit. Therefore, this measure is methodologically not good enough and it remains to be seen whether it will be included in the pending update of core set for axSpA. Magrey and Ritchlin recommend that in the busy office setting a simple and validated questionnaires like RAPID3 may be more practical because it is a composite index based on the three patient self-report core data set measures: physical function, pain and patient global estimate.

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Other ASAS Criteria for Response and Remission

ASAS has developed response criteria with 20% improvement (ASAS20), 50% improvement (ASAS50), or 70% improvement (ASAS70) as measure short-term improvement in AS; and they have both clinical and empirical validity. The ASAS20, -50 and -70 response criteria are designed to be used as summary outcomes measures in clinical trials. The ASAS20 response, which was developed on the basis of clinical trials with NSAIDs is defined as an improvement of at least 20% and absolute improvement of at least 10 units on a scale of 0 to 100 (or an absolute improvement of ≥1 unit on a 10-unit scale) in three of the following four domains: patient global assessment, pain, inflammation (mean of the last two BASDAI questions) and function (BASFI) (Table 12-4).

There must also be absence of deterioration in the potential remaining domain. Deterioration is defined as at least 20% worsening and net worsening of at least 10 units on a scale of 0 to 100 (or ≥1 unit on a 10-unit scale). The ASAS50 and ASAS70 response criteria have the same definition, except that they require an improvement of at least 50% and at least 70% respectively, in three of the four domains. They are more suitable than ASAS20 for demonstrating efficacy of TNF inhibitors. An ASAS5/6 response is similar to the ASAS20, -50 and -70 responses, except that it contains two more domains: the BASMI score and CRP. It requires achieving at least a 20% improvement in five of its six domains and absence of deterioration in the potentially remaining sixth domain. This level of response is more useful for assessing improvement in clinical trials of drugs such as TNF inhibitors in AS.

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Disease Remission

Just as disease remission is now the accepted goal of management of RA, it is being increasingly regarded as an appropriate therapeutic goal for AS because of the availability of more effective therapies. Early use of TNFi therapy in RA has been shown to lead to significant improvement in disease activity measures; that improvement is sustained in a high percentage of patients 1 year after stopping treatment. This suggests that early use of TNF-blocking therapy can produce a sustainable remission in some patients with early RA without the need for long-term administration.

This has important implications for health economics, and studies need to be performed to see if a similar result can be achieved in patients with early AS. This will also require defining the criteria for remission, which will include clinical, immunologic and imaging assessments. Furthermore, based on studies of anti-TNF therapy in AS, a state of low disease activity has been suggested empirically, but it needs further development and evaluations for defining a state of “true” disease remission in AS.

An ASAS criterion for partial remission (ASAS-PR) has been proposed that requires achieving a score of ≤2 unit in each of the four core ASAS 20 domains, ie, patient global assessment, pain, inflammation (mean of the last two BASDAI questions) and BASFI. For example, a BASFI score of 5 has to come down to at least 3. Various other criteria have been proposed for remission in axSpA, but as of yet, no definition has been universally accepted for both clinical trials and routine practice.

Other Instruments

BASDAI50

BASDAI50 is at least 50 reduction in BASDAI score, and it has been used to assess response to treatment. There are other validated measures of disease outcome including the following.

HRQoL

HRQoL (health related quality of life) can be assessed by Short Form 36 Health Survey (SF-36) and the AS Quality of Life (ASQoL) questionnaire. SF-36 is a widely used, self-administered 36-item questionnaire covering eight physical and mental domains of quality of life: physical functioning, pain, role limitations due to physical problems, role limitations due to emotional problems, mental health, social functioning, energy/fatigue and general health perceptions. Physical Component Summary (PCS) and Mental Component Summary (MCS) scores range from 0 to 100, with higher scores indicating better HRQoL. The SF-36 and EQ-5D are the most commonly used generic measures of HRQoL in axSpA clinical trials.

ASQoL

ASQoL (AS Quality of Life) is a disease-specific 18-item questionnaire measuring pain, fatigue, function, impact of the disease on sleep, mood, motivation, coping, activities of daily living, independence, relationships and social life. Each statement is given a score of 1 indicating a poor response or 0 indicating no impairment. The items can be summed up to give a total score ranging from 0 to 18, with higher scores indicating worse quality of life of patients with AS. It is the most widely used instrument to assess the quality of life in clinical AS trials.

HAQ-S

HAQ (Health Assessments Questionnaire) is a tool to evaluate functional disability and has been modified to assess spondylitis-specific measures (HAQ-S) by incorporating an additional five specific questions pertaining to impairment in physical function specific to patients with AS. These five items include neck function and static posture (driving a car, using a rear-vision mirror, carrying heavy groceries, sitting for long periods and working at a desk. It is routinely used for research purposes in axSpA but not in daily practice and has also been modified to assess the severity of PsA and included as an outcome measure in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry.

PASS

PASS (Patient Acceptable Symptom State) is a reliable and validated simple measure for assessing the health of AS patients. by asking them to respond yes or no to a single question: Considering all the different ways your disease is affecting you, if you would stay in this state for the next months, do you consider that your current state is satisfactory? The PASS scores, defined as the 75th percentile of the score for patients who considered their state satisfactory and shown on a 0-to-10 scale (10 being worst), are reported to be 3.4 for global pain, 2.8 for night pain, 3.6 for patient’s global disease assessment, 3.5 for BASDAI and 3.1 for BASFI.

ASAS Health Index

Important complaints of patients with axSpA are pain, fatigue and limitation in activities and social participation, and they are not adequately captured and assessed by using the currently used AS-specific questionnaires. ASAS has therefore recently developed an instrument for assessing health by using, as an approximate template, the International Classification of Functioning, Disability and Health (ICF) core set for patients with AS/axSpA. This ASAS Health Index (HI) is a linear composite index that comprises 17 items, which cover most aspects of the ICF core set, covering pain, emotional functions, sleep, sexual functions, mobility, self-care and participation in the community life with a dichotomous response option: I agree and I do not agree. It gives a single sum score ranging from 0 to 17, with a lower score indicating a better and a higher score indicating an impaired health status. A score of 5.0 was validated to differentiate between good/very good health vs moderate health state and a score of 12 or above indicates poor/very poor health.

ASAS HI has been validated in a large international study, and been translated into at least 15 languages and field tested in 23 countries. It has shown good clinimetric properties when tested in a real clinical setting and has been argued that the it could be used in daily practice to assess disease activity. However, a counter-argument has been raised pointing out that the ASAS HI was not developed for that purpose and most importantly it can be influenced by other domains from disease activity. ASAS HI has recently been used in clinical trials as a secondary efficacy outcome measure and as a primary endpoint in the TICOSPA study which evaluated the effectiveness of a treat-to-target strategy against standard treatment approach in patients with axSpA.

Contextual environmental factors (EF) are relevant to understand functioning and health. Therefore EF Item Set (EFIS) complementing the ASAS-HI has been developed to emphasize the importance of support and relationships, as well as attitudes of the patients and health services in relation to self-reported health.

Mental Health (Depression)

Depression was assessed with the Center for Epidem­iological Studies Depression (CES-D) scale, a 20-item questionnaire measuring depressive symptomatology over the preceding 1 week. Scores on the CES-D scale range from 0 to 60; higher scores indicate more depressive symptoms and patients with scores ≥16 are considered depressed.

Work Productivity

Work productivity can be assessed using two multidimensional instruments designed to capture various aspects of work impairment. The Work Productivity and Activity Impairment (WPAI) questionnaire measures the impact of AS on the amount of work-related absenteeism (reflecting time away from scheduled work), presenteeism (reflecting reduced productivity while at work), overall work impairment (the sum of absenteeism and presenteeism) and activity impairment (reflecting ability to perform daily non–work-related activities). The 25-item Work Limitations Questionnaire (WLQ-25) can be used to assess four dimensions of presenteeism: physical demands (six questions), time management demands (five questions), mental-interpersonal demands (nine questions) and output demands (five questions). The WPAI has been commonly used in some recent trials of axSpA.