Chapter 2 Criteria and Disease Activity Measures in Axial Spondyloarthropathies

Chapter 2 Criteria and Disease Activity Measures in Axial Spondyloarthropathies Jose Aliling 1 and Lawrence H Brent 1* Einstein Medical Center, USA * Corresponding Author: Lawrence H Brent, Einstein Medical Center, Philadelphia, PA 19141, USA, Tel: 215-456-7380; Fax: 215-456-3898; Email: brentl@einstein. edu First Published February 10, 2016 Copyright: 2016 Jose Aliling and Lawrence H Brent. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. Abstract Spondyloarthropathies are a group of diseases with certain common clinical features and are linked by the association with HLA-B27 and the presence of enthesitis. These diseases as a group are common and are an important cause of morbidity and disability around the world. New therapies have become available which have produced excellent clinical responses and in some cases have been shown to slow disease progression. It is therefore important to be able to accurately diagnose and to assess disease activity in these patients. Ankylosing spondylitis is the prototypical axial spondyloarthropathy but axial disease may also occur in patients with reactive arthritis, psoriatic arthritis, and inflammatory bowel disease associated spondyloarthropathy, although the pattern of disease is variable. Undifferentiated spondyloarthropathy and nonradiographic axial spondyloarthropathy are less well defined entities which may affect the axial spine. Diagnostic criteria are used to help diagnose a patient in clinical practice while classification criteria are used to define a group of patients for study, but in rheumatology classification criteria are often use to confirm a diagnosis in clinical practice. Disease activity measures are used to assess the effect of treatments particularly in clinical trials but are increasingly being used in clinical practice. Over time, new classification criteria for axial spondyloarthropathy have been developed to improve diagnostic accuracy especially in patients with early disease and disease activity measures have been refined to better assess the response of patients with axial spondyloarthropathy to new and emerging therapies. 2 3

Introduction Spondyloarthropathy (SpA) is a term applied to a heterogenous group of rheumatic diseases that classically consist of ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), and inflammatory bowel disease related spondyloarthropathy (IBD-SpA). Undifferentiated spondyloarthropathy (USpA) and nonradiographic axial SpA are less well defined spondyloarthropathies without specific set of criteria [1]. These diseases have several common clinical features including the association with HLA-B27 [2,3] and enthesitis [4,5]. Axial SpA is a common disease entity and the prevalence has been documented by a number of epidemiological studies using different methods. In the USA, the prevalence of all SpA is about 1% [6,7] and for AS about 0.5% [6]. Around the world, the prevalence of SpA is variable; 0.1-1% in South Asia and Southeast Asia, 0.5% in France and Greece, 1% in Italy, Turkey, and China, and 1.9% in Germany [8,9]. The prevalence of AS is about half that of SpA in general [6,9-14]. The shared manifestations of SpA include the association with HLA-B27 and enthesitis which is inflammation at sites where tendons, ligaments, and joint capsules attach to bone [4]. Other clinical features common to the SpA include inflammatory back pain, sacroiliitis and spondylitis, peripheral arthritis (synovitis), dactylitis, extra-articular manifestations with the most common being uveitis, and familial aggregation. All of these manifestations can occur in each of the SpA disease subgroups [15]. Categorization of patients into specific disease entity can be difficult due to a lack of universally accepted criteria for these diagnoses. There has been remarkable progress in the field of SpA and axial SpA in the last 15 years with innovative and breakthrough discoveries in genetics [16-18], epidemiology [8,9], and etiopathogenesis [18-20]. Advances in diagnostic imaging including the use of magnetic resonance imaging (MRI) [21-25] computed tomography (CT) [26], and ultrasound for evaluation of enthesitis [27-29] has shown greater sensitivity than plain radiographs allowing earlier identification of radiological changes related to axial SpA [24,30,31]. New therapies have become available in the treatment of axial SpA including TNF-α antagonists [32,33] which may slow disease progression. Recently, the first agent directed against IL-17 was approved for the treatment of AS, PsA, and PsO [34]. New biologic agents that block IL-17 and IL-12/23 have shown promising results in patients with AS in clinical trials [20]. New strategies in diagnosis, monitoring of disease activity, and advances in therapeutic modalities have led to early diagnosis and will hopefully translate into better long term outcomes. Diagnostic and classification criteria serve different roles [35]. Diagnostic criteria are designed to be used in 4 5

an individual patient in routine clinical practice to assist in confirming a suspected diagnosis by assessing the signs, symptoms, and laboratory features of that patient. High sensitivity is an important feature of diagnostic criteria in order for a clinician to make a diagnosis in patients early in the course of disease. Classification criteria are standardized definitions of disease entities that are used to create well-defined, homogeneous cohorts of patients for clinical research such as clinical trials. Specificity is more important in order to ensure a uniform population of patients for study. Before 2009, the diagnostic criteria for AS and axial SpA were heavily dependent or required the presence of changes in the sacroiliac joints on plain radiographs. Radiographic changes require the disease to be present for several years making it difficult to confirm an early diagnosis and include these patients in clinical trials. This delay in diagnosis has been documented in patients with AS [36]. The time between the onset of symptoms of axial SpA and diagnosis of AS (diagnosis delay) was longer for HLA-B27- patients than HLA-B27+ patients (11.4 vs. 8.5 years, [37]; 9.2 vs. 5.3 years, [38]). This delay in diagnosis of axial SpA leads to delay in treatment which could potentially result in increase in disease related damage, morbidity, and loss of physical function. The first sets of criteria for AS such as Rome 1961 [39], New York 1966 [40] and Modified New York 1984 [41] included clinical criteria and radiographic criteria. The importance or dependence on the presence of radiographic changes in the sacroiliac joints in these criteria would lead to a delay in diagnosis of AS by these criteria. In the early 1990s, general criteria for SpA were developed whereby a diagnosis could be confirmed using only clinical criteria [15,42,43]. However, these criteria were not specific for axial SpA or AS. In 2009, classification criteria for axial SpA [44] and peripheral SpA [45] were developed so that patients could be classified early in the course of their disease for inclusion in clinical studies and trialsbefore radiographic damage has occurred. Ultimately the goal is to diagnose patients early in the course of their disease and institute therapy before radiographic damage has occurred and prevent such damage. Diagnostic and Classification Criteria for Axial Spondyloarthropathy Rome, New York, Modified New York Criteria The Rome 1961 Clinical Criteria for Ankylosing Spondylitis (Table 1) include 5 clinical criteria and 1 radiographic criterion [39]. A diagnosis can be confirmed with 1 radiographic and at least 1 clinical criterion or 4 clinical criteria alone. Using clinical criteria only, the diagnostic sensitivity was 38% and specificity is 100%. The low sensitivity is due to the low sensitivity of each of the individual clinical criteria [41]. The New York 1966 Diag- 6 7

nostic Criteria for Ankylosing Spondylitis (Table 1) has 3 clinical criteria and 2 radiographic criteria [40]. The radiographic grading of sacroiliitis are listed in Table 2 [40,46]. A diagnosis is confirmed with grade 3 or 4 bilateral sacroiliitis and at least 1 clinical criterion or grade 3 or 4 unilateral or grade 2 bilateral sacroiliitis with clinical criterion 1 or clinical criteria 2 and 3. The sensitivity is low and the specificity is high due to the requirement of one of the radiographic criteria. This is due to the low sensitivity of the clinical criteria, especially limitation of chest expansion (sensitivity 10%) [41]. The Modified New York 1984 Diagnostic Criteria for Ankylosing Spondylitis (Table 1) [41] have been used for diagnosis and also classification of patients for over 25 years for clinical studies including clinical trials with biologic agents. There are 3 clinical criteria and 2 radiographic criteria. The modification was replacing the New York 1966 pain criterion with the Rome 1961 pain criterion with slight modification which is more consistent with inflammatory back pain. A definite diagnosis of AS is confirmed with the presence of 1 radiographic criterion and at least 1 clinical criterion. As with the New York 1966 Diagnostic Criteria for Ankylosing Spondylitis, the requirement for radiographic changes gives great specificity at the expense of sensitivity. With the Rome and both New York criteria, the importance of radiographic changes in the sacroiliac joints makes a diagnosis of AS in patients with early disease very difficult. Even with the Rome 1961 criteria, in which a diagnosis can be confirmed with only clinical criteria, some of the individual clinical criteria have low sensitivity (i.e. iritis) or occur late in the disease course (limited chest expansion). Therefore, using these criteria would have low sensitivity in early disease. Table 1: Rome and New York Criteria. Rome, 1961 Clinical Criteria for AS [39] 2. Pain and stiffness in thoracic spine 3. Limited motion in lumbar spine 4. Limited chest expansion New York, 1966 Diagnostic Criteria for AS [40] Modified New York, 1984 Diagnostic Criteria for AS [41] Clinical Criteria 1. Low back pain and stiffness for more than 3 months, not relieved by rest Clinical Criteria 1. Limitation of lumbar spine motion in all three planes: anterior flexion, lateral flexion, extension Clinical Criteria 1. Low back pain of at least 3 months duration improved by exercises and not relieved by rest At least four clinical criteria 2. Pain at dorsilumbar junction or in lumbar spine 3. Limitation of chest expansion to 2.5 cm or less measures at level of fourth intercostal space Grade 3 or 4 unilateral or grade 2 bilateral sacroiliitis with clinical criteria 1 or criteria 2 and 3 Probable AS Grade 3 or 4 bilateral sacroiliitis with no clinical criteria 2. Limitation of lumbar spine in sagittal and frontal planes 3. Chest expansion decreased relative to normal values for age and sex 5. History of evidence of iritis or its sequelae Radiographic Criteria 4. Grade 3 or 4 bilateral sacroiliitis Radiographic Criteria 4. Bilateral sacroiliitis grade 2 Radiographic Criterion 5. Grade 3 or 4 unilateral or grade 2 5. Unilateral sacroiliitis grade 3 or 4 6. Radiograph showing bilateral sacroiliac changes characteristic of AS bilateral sacroiliitis Definite AS Definite AS Definite AS Grade 3 or 4 bilateral sacroiliitis with Grade 3 or 4 bilateral sacroiliitis with Bilateral sacroiliitis grade 2 or at least one clinical criterion at least one clinical criteria Unilateral sacroiliitis grade 3 or 4 and at least 1 clinical criterion OR OR Probable AS Three clinical criteria are present OR Radiographic criterion is present without any clinical criteria 8 9

Table 2: Radiographic Grading of Sacroiliitis [40,46]. Grading of Sacroiliitis: New York Criteria Grade 0 Normal Grade 1 Grade 2 Grade 3 Grade 4 Suspicious Minimal sacroiliitis Moderate sacroiliitis Ankylosis General Classification Criteria for Spondyloarthropathies The Amor Classification Criteria for Spondyloarthopathy [42] and the European Spondyloarthropathy Study Group (ESSG) Classification Criteria for Spondyloarthropathy [15] were developed in the early 1990s in order to include patients with undifferentiated SpA who would not otherwise meet criteria for specific SpA such as AS as defined by the Modified New York 1984 Diagnostic Criteria for Ankylosing Spondylitis. The Amor Criteria (Table 3) [42] include 13 items, 10 of which are clinical features, one is radiologic, one is HLA-B27 or family history of SpA, and one is good response to NSAIDs. These criteria are additive with each of the individual criteria worth 1, 2, or 3 points. A diagnosis of SpA is confirmed if the sum of the positive criteria 6 points. Radiographic sacroiliitis is not required to make the diagnosis. The sensitivity of these criteria is 86.6% and the specificity 90.0%. However, since the presence of inflammatory back pain or radiographic sacroiliitis are not required, these criteria are not specific for axial SpA. Table 3: General Criteria for Spondyloarthropathy: Amor and ESSG. Amor Classification Criteria for Spondyloarthropathy [42] ESSG Classification Criteria for Spondyloarthropathy [15] Inflammatory back pain Unilateral buttock pain 1 pt 1 pt Non GC GU infection Acute diarrheal illness 1 pt 1 pt Inflammatory Spinal Pain or Synovitis Alternating buttock pain 2 pts Psoriasis, balanitis, IBD 2 pts and one of the following Enthesitis 2 pts Sacroiliitis on x-ray 3 pts Peripheral arthritis Dactylitis Acute anterior uveitis 2 pts 2 pts 2 pts HLA-B27+ or FH of SpA Good response to NSAIDs 2 pts 2 pts Positive family history of SpA Psoriasis Inflammatory bowel disease Diagnosis of SpA if the sum of positive criteria 6 points Urethritis, cervicitis, or acute diarrhea <1 month before arthritis Alternating buttock pain Enthesitis Sacroiliitis by plain radiography European Spondyloarthropathy Study Group (ESSG) Classification Criteria for Spondyloarthropathy (Table 3) [15] are designed with a hierarchy in that inflammatory spinal pain or synovitis must be present before any other criteria can be considered. This indicates that the experts who developed these criteria gave prime importance to inflammatory spinal pain and synovitis. The secondary criteria do include sacroiliitis by plain radiography and 10 11

positive family history of SpA in a 1 st or 2 nd degree relative with AS, psoriasis, acute uveitis, ReA, or IBD but the presence of HLA-B27 is not one of the criteria as exists in the Amor criteria. Therefore, in order to confirm a diagnosis of SpA, there must be inflammatory spinal pain or synovitis and one of the other criteria including positive family history of SpA, psoriasis. IBD, urethritis/cervicitis/acute diarrhea less than 1 month before the onset of arthritis, alternative buttock pain, enthesitis, or sacroiliitis by plain radiography yielding a sensitivity of 87% and a specificity of 87%. The presence of inflammatory spinal pain and sacroiliitis are specific for axial SpA but the ESSG criteria can be met without either of these criteria. The Rome 1961 Clinical Criteria for Ankylosing Spondylitis and the Modified New York 1984 Diagnostic Criteria for Ankylosing Spondylitis both have as the first clinical criterion low back pain with inflammatory features. Both the Amor and ESSG Classification Criteria for Spondyloarthropathy include the criterion of inflammatory back (spinal) pain. Therefore, the definition of inflammatory back pain is critical in forming diagnostic or classification criteria for axial SpA or AS. Inflammatory back pain has been defined with various clinical criteria over the past 40 years. The Calin Criteria for Inflammatory Back Pain (Table 4) [47] have been the most frequently used and are the basis of the definition of inflammatory spinal pain in the ESSG Classification Criteria for Spondyloarthropathy. Modified definitions of inflammatory back pain were used in the Modified New York 1984 Diagnostic Criteria for Ankylosing Spondylitis and the Amor Classification Criteria for Spondyloarthropathy. Several clinical criteria for inflammatory back pain include the Calin Criteria [47], the Berlin Criteria [48], and the ASAS Criteria [49] and can be seen in Table 4. The sensitivities and specificities of each of these sets of criteria from their references are also listed. In the validation of the ASAS criteria, the Calin Criteria and Berlin Criteria were also tested in the validation cohort and the ASAS Criteria performed better in this study (Table 4, lower right panel) [49]. ASAS Classification Criteria for Spondyloarthritis General criteria for SpA including the Amor and ESSG Classification Criteria for Spondyloarthropathy were a major improvement over previous criteria for AS in that there was no requirement for radiographic sacroiliitis. Therefore, a diagnosis of SpA could be confirmed in patients with early axial disease and those with SpA in which peripheral disease was dominant. There were criteria for AS but no widely accepted criteria for other forms of SpA such as PsA and ReA which tend to have more peripheral musculoskeletal involvement. The Amor and ESSG Criteria cannot differentiate patients with predominantly axial involvement and those with predominantly peripheral involvement. In the early 2000s, there was great 12 13

interest to revise criteria for SpA in order to increase the sensitivity in early disease [50]. During this time there was increasing interest in the use of MRI, especially with STIR and gadolinium imaging, as a way of identifying inflammatory lesions in the sacroiliac joint, the spine [21], and even peripheral entheses [25]. MRI was able to show evidence of inflammatory sacroiliac disease years before plain radiographs show the typical signs of sacroiliitis of AS. The term axial SpA was developed to include patients with pre-radiographic disease (undifferentiated axial SpA) as well as patient with radiographic disease (AS) [50]. The term non-radiographic axial SpA is now used to describe patients with axial SpA who have normal sacroiliac joints on plain radiographs and often have evidence of sacroiliitis on MRI [51]. Patients with non-radiographic and radiographic axial SpA share common epidemiological, genetic, and clinical characteristics suggesting that they may be different phases of the same clinical entity. About 10-20% of patients with non-radiographic axial SpA progress to AS over 2 years and elevated CRP and active sacroiliitis on MRI were the strongest predictors of such progression. USpA is a term used for patients who have more peripheral disease but do not have clinical features to support a diagnosis of a specific SpA. Table 4: Inflammatory Back Pain Diagnostic Criteria. Calin Criteria for Inflammatory Back Pain [47] Insidious onset Patient younger than 40 years Persisting for at least 3 months Associated with morning stiffness Improving with exercise Presence of 4 of 5 features is 95% sensitive and 85% specific ASAS Criteria for Inflammatory Back Pain [49] Improvement with exercise Pain at night Insidious onset Age of onset less than 40 years No improvement with rest If at least 4 of 5 parameters are fulfilled, 79.6% sensitive and 72.4% specific Berlin Criteria for Inflammatory Back Pain [48] Morning stiffness of > 30 minutes duration Improvement in back pain with exercise but not with rest Awakening because of back pain during the second half of the night only Alternating buttock pain Criteria fulfilled if at least 2 of the 4 parameters are present, 70.3% sensitive and 81.2% specific ASAS Validation Study (n=648) [49] Criteria Sensitivity Specificity Calin Berlin ASAS 89.9% 70.0% 79.6% 52.5% 81.4% 72.4% Table 5: Assessment in SpondyloArthritis international Society (ASAS) Classification Criteria for Axial Spondyloarthritis (Rudwaleit 2009) [44]. In patient with back pain for 3 months and age at onset < 45 years Sacroiliitis on imaging* plus 1 SpA feature** **SpA features Inflammatory back pain Arthritis Enthesitis Uveitis Dactylitis Psoriasis Crohn s disease/ulcerative colitis Good response to NSAIDs Family history of SpA HLA-B27 Elevated CRP OR HLA-A27 plus 2 other SpA features** *Sacroiliitis on imaging Sensitivity 82.9%, Specificity 84.4% Imaging arm alone: Sensitivity 66.2%, Specificity 97.3% Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA or Definite radiographic sacroiliitis according to modified New York criteria 14 15

The concept of Assessment of SpondyloArthritis international Society (ASAS) Classification Criteria developed in 2009 [44] and 2011 [45] proposed to classify SpA according to the leading clinical manifestation. Patients with axial SpA have predominantly axial inflammation including the sacroiliac joints and the spine. Patients with peripheral SpA demonstrate predominantly peripheral joint manifestations consisting of peripheral arthritis, enthesitis, and dactylitis. Some patients have a combination of axial and peripheral disease. Axial SpA is the preferred term that reflects the expanded diagnostic capabilities available today which leads to a reliable early diagnosis that can now be made in the absence of plain radiographic findings. The ASAS Classification Criteria for Axial Spondyloarthritis (Table 5) [44] includes patients with axial inflammation of AS and non-radiographic axial SpA. These criteria are set up with a hierarchy with 2 arms, one imaging and 1 clinical. The imaging arm is fulfilled by evidence of sacroiliitis using either plain radiographs or MRI plus 1 clinical SpA feature. The clinical arm is fulfilled by the presence of HLA- B27 plus 2 other clinical SpA features. Patients with normal plain radiographs of the sacroiliac joints would not fulfill the Modified New York1984 Diagnostic Criteria for AS but could fulfill the ASAS Classification Criteria for Axial Spondyloarthritis with a MRI showing sacroiliitis and at least 1 clinical SpA feature or HLA-B27 plus at least 2 other clinical features. The sensitivity and specificity of these criteria is 82.9% and 84.4%, respectively. Using the imaging arm, the criteria are less sensitive (66.2%) but highly specific (97.3%). The ASAS Classification Criteria for Peripheral Spondyloarthritis (Table 6) [45] are also set up with a hierarchy. The primary criterion is the presence of arthritis, enthesitis, or dactylitis. In order to fulfill the criteria a patient must have 1 extra-articular manifestation, HLA-B27, or sacroiliitis by plain radiographs or MRI or 2 other musculoskeletal manifestations or family history of SpA. These criteria have a sensitivity of 77.8% and a specificity of 82.9%. The ASAS Classification Criteria for Axial and Peripheral Spondyloarthropathy were compared to ESSG and Amor Classification Criteria for Spondyloarthritis without and with modification (including MRI) and the new ASAS criteria performed better than the ESSG and Amor criteria even when modified with the addition of use of MRI (Table 7) [44,45]. Addition of MRI increased the sensitivity of both the ESSG and Amor criteria. Disease Activity Measures for Axial Spondyloarthropathy Advancements and improvement in classification criteria for SpA improves the ability to capture patients especially those with early disease. This is important for inclusion of patients in clinical studies especially clinical trials. With the advent on new therapies available such as TNF-α 16 17

antagonists [32,33] and IL-17 antagonists [34] and evolving therapies such as those that block IL-17 and IL-12/23 [20], it is important to be able to measure disease activity in a reproducible way in order to determine efficacy of therapies in clinical trials. Measures of disease activity can also be used in clinical practice in individual patients to assess response to treatment. Table 6: Assessment in SpondyloArthritis international Society (ASAS) Classification Criteria for Peripheral Spondyloarthritis [45]. Arthritis or Enthesitis or Dactylitis. Plus 1 of the following (or) Plus 2 of the remaining Psoriasis Inflammatory bowel disease Preceding infection HLA-B27 Uveitis Sacroiliitis on imaging (radiographs or MRI) Arthritis Enthesitis Dactylitis Inflammatory back pain in past Positive family history of SpA Sensitivity 77.8%, Specificity 82.9% Table 7: Comparison of sensitivity and specificity of ESSG, Amor, and ASAS Classification Criteria for Spondyloarthropathy [44,45]. Criteria ASAS Axial SpA ASAS Peripheral SpA ESSG Criteria Modified ESSG (with MRI) Amor Criteria Modified Amor (with MRI) Sensitivity 82.9% --- 72.4% 85.1% 69.3% 82.9% Axial SpA (N=649) Specificity 84.4% --- 66.3% 65.1% 77.9% 77.5% Peripheral SpA Sensitivity --- (n=266) Specificity --- Axial and Peripheral SpA Sensitivity 79.5% (n=975) Specificity 83.3% Early efforts to develop measures of disease activity include the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [52], Bath Ankylosing Spondylitis Functional Index [53], and the Bath Ankylosing Spondylitis Metrology Index (BASMI) [54,55]. The BASDAI [52] is a questionnaire in which each item is scored by the patient using a visual analog scale (VAS) 0-10 based on symptoms during the past week. There are 5 parameters including fatigue, axial pain, pain and swelling of peripheral joints, overall level of pain, and morning stiffness which is evaluated by items 5 (level of pain in the morning) and 6 (length of morning stiffness). The BASDAI score is derived by adding 1 to 4 plus the mean of 5 and 6; this value is divided by 5 for a value of 0-10. This measurement tool measures absolute disease activity in patients with AS. The BASDFI [53] is also a questionnaire in which each item is 77.8% 55.1% 62.5% 35.2% 39.8% 82.9% 81.1% 81.1% 97.8% 97.8% 66.7% 79.1% 55.6% 67.5% 72.0% 68.8% 86.7% 86.7% 18 19

scored by the patient using a VAS, 0-10. There are 10 items evaluating the functional ability of the patient analogous to the Health Assessment Questionnaire (HAQ) [56] used in rheumatoid arthritis (RA). The items are scored by the patient based on their function during the past month. The items include physical activities that require the spine, hips, and shoulders. The BASFI score is derived by adding the scores of the individual items and dividing by 10 for a value of 0-10. The BASMI [54,55] is a metric of physical mobility of the spine and hips and consists of 5 items which are assessed by physical examination. These parameters include 5 elements: 1) Lumbar flexion (Modified Schober s or Finger to Floor), 2) Lumbar side flexion, 3) Tragus to Wall (Occiput to Wall), 4) Cervical rotation, 5) Intermalleolar distance. The range of motion for each item are scored on a 0-2 scale [54] or 0-10 or a linear scale [55] which is more sensitive to change. In clinical practice, most physicians use the Modified Schober s or Finger to Floor as a measure of lumbar flexion and Occiput to Wall as a measure of cervical spine and also thoracic kyphosis. In the early 2000s, there was interest by ASAS to develop criteria to measure symptomatic improvement in patients with AS in clinical trials. A core set of parameters for assessment of AS disease activity were refined by ASAS which included 8 different items (Table 9) [57,58]. From these 8 core elements, criteria for improvement were developed initially using data from clinical trials of NSAIDs in AS [59]. The ASAS20 Response Criteria includes 4 domains: Patient global assessment (disease activity during past week), Pain (back pain during past week), Function (BASFI score), Inflammation (average of items 5 and 6 of the BASDAI) (Table 9) [59,60]. A patient is considered an ASAS20 responder with improvement of at least 20% and at least 10 units (0-100 scale) in at least 3 of the 4 domains with no worsening of the remaining domain. The ASAS40 criteria are based on the same 4 domains but the improvement must be at least 40%. More stringent criteria are used to show greater clinical responses and are reflected in the ASAS5/6 Response Criteria and the ASAS Partial Remission Criteria. The ASAS5/6 Response Criteria include the 4 domains in the ASAS20 Response Criteria plus 2 additional domains: Spinal mobility (BASMI), Acute phase reactants (CRP). An ASAS5/6 responder is defined as improvement of at least 20% and at least 10 units (0-100 scale) in at least 5 of the 6 domains with no worsening of the remaining domain [59,60]. The ASAS20, ASAS40, ASAS5/6 are tools to measure improvement in patients with AS (compared to previous measurements) but they do not measure disease activity at the specific point in time and therefore, are not useful in routine clinical practice. This is analogous to the ACR20 Response Criteria for RA. The ASAS Partial Remission is achieved when all 4 domains have values of less than 2 [59,60]. These ASAS response criteria have been widely used to evaluate the clinical responses of patient with AS and axial SpA in clin- 20 21

ical trials of TNF-α antagonists and an IL-17A monoclonal antibody which have been approved for AS and other SpA, and more recently, new biologic agents which block IL-17 and IL-12/23. Table 8: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (Garrett 1994) [52]. Bath Ankylosing Spondylitis Functional Index (BASFI) (Calin 1994) [53]. Bath Ankylosing Spondylitis Metrology Index (BASMI) (Jenkinson 1994, van der Heijde 2008) [54,55]. The scores for each item in the BASDAI and BASFI are generated by the patient marking a visual analog scale (0-10) for each BASDAI item. BASFI During past week 1. How would you describe the overall level of fatigue/ tiredness you have experienced? 2. How would you describe the overall level of AS neck, back, or hip pain you have had? 3. How would you describe the overall level of pain/ swelling in joints other than neck, back, or hips you have had? 4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure? 5. How would you describe the overall level of discomfort you have had from the time you wake up? 6. How long does your morning stiffness last from the time you wake up? (0-2 or more hours) Score/10 During past month 1. Putting on your socks or tights without help or aids? 2. Bending forward from the waist to pick up a pen from the floor without an aids? 3. Reaching up to a high shelf without help or aids? 4. Getting out of an arm-less dining chair without using your hands or any help? 5. Getting up off the floor, without help, from lying on your back? 6. Standing unsupported for ten minutes without discomfort? 7. Climbing 12-15 steps without using a handrail or walking aid? 8. Looking over your shoulder without turning your body? 9. Doing physically demanding activities? 10. Doing a full day s activities at home or at work? Mean of 5 & 6 Total out of 100 Total of 1 to 4 added to mean of 5 & 6 (total out of 50) Total score 10 to give a final BASFI score (0-10) Total score 5 to give a final BASDAI score (0-10) Score/10 The BASMI is determined BASDMI by physical exam. Lumbar Flexion (modified Schober s) Lumbar Side Flexion Tragus to Wall Cervical Rotation Intermalleolar Distance Score/2 or 10 In 2009, ASAS developed a new measure of disease activity for AS that is a continuous measure and can measure disease activity at a single point in time, analogous to the DAS and DAS28 used in RA patients. A measurement tool with this feature could be used in clinical practice. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is based on various combinations of 4 clinical features including back pain, duration of morning stiffness, patient global assessment, peripheral joint pain and swelling, and acute phase reactants, the CRP and ESR [61]. Four different formulas were tested, validated, and all performed better that the BASDAI. The ASAS membership approved a preferred version (CRP) and an alternative version (ESR) (Table 10). The ASDAS-CRP was further tested and validated in other studies but has not generally been used in 22 23

clinical trials or clinical practice [62,63]. Table 9: Assessment in SpondyloArthritis international Society (ASAS) Criteria for Improvement: ASAS20, 40, ASAS Core set for assessment of disease[57,58] 5/6, Partial Remission [59,60]. Patient global assessment: Of disease activity during past week Pain: Patient assessment of back pain during past week Function: BASFI score Inflammation: Severity and Duration of Morning Stiffness (Average of item 5 & 6 of the BASDAI) Spinal mobility: BASMI Synovitis/Enthesitis score ESR/CRP Fatigue ASAS20(40) Response Criteria[59,60] Patient global assessment: Of disease activity during past week Pain: Patient assessment of back pain during past week Function: BASFI score Inflammation: Severity and Duration of Morning Stiffness (Average of items 5 & 6 of the BASDAI) Responder is defined as improvement of at least 20% (40%) and at least 10 units (0-100 scale) in at least 3 of 4 domains with no worsening of remaining domain ASAS5/6 Response Criteria ASAS Partial Remission Criteria[59,60] Patient global assessment: Of disease activity during past week Pain: Patient assessment of back pain during past week Function: BASFI score Inflammation: Severity and Duration of Morning Stiffness (Average of items 5 & 6 of the BASDAI) Spinal mobility: BASMI Acute phase reactants: CRP Responder is defined as improvement of at least 20% and at least 10 units (0-100 scale) in at least 5 of 6 domains with no worsening of remaining domain ASAS Partial Remission: Responders have values of less than 2 for all 4 ASAS20 domains Table 10: Assessment in SpondyloArthritis international Society (ASAS) Disease Activity Score for use in Ankylosing Spondylitis (ASDAS) Preferred version [61-63]. ASDAS-CRP = 0.12xBack Pain + 0.06xDuration of Morning Stiffness + 0.11xPatient Global + 0.07xPeripheral pain/swelling + 0.58xLn(CRP+1) Alternative version ASDAS-ESR = 0.08xBack Pain + 0.07xDuration of Morning Stiffness + 0.11xPatient Global + 0.09xperipheral Pain/Swelling + 0.29x (ESR) Biomarkers in Axial Spondyloarthropathy There have been several biomarkers identified which correlate with disease activity in AS or axial SpA. The CRP and MRI inflammation of the sacroiliac joints and spine are the most studied and best validated markers of disease activity in axial SpA [64]. In a study of patients axial SpA being treated with TNF-α antagonists, serum levels of several inflammatory biomarkers were shown to correlate with high ASDAS scores including IL-6, VEGF, MMP-3, total aggrecan, and osteocalcin while high BASDAI correlated with serum levels of CRP and IL-6 [65]. Conclusion Over the past 15 years, many changes have occurred in the terminology of SpA. The classic diseases AS, ReA, PsA, and IBD-SpA remain but now SpA are classified by 24 25

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