Clinical Adances in Spondylitis Clinical Adances in ... › wp-content › uploads › 2016 › 04 › CAS-15-02… · Diagnostic Criteria for AS [40] Modified New York, 1984 Diagnostic

2 3www.avidscience.com

Clinical Advances in Spondylitis Clinical Advances in Spondylitis

www.avidscience.com

AbstractSpondyloarthropathies are a group of diseases with

certain common clinical features and are linked by the association with HLA-B27 and the presence of enthesi-tis. 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 there-fore important to be able to accurately diagnose and to assess disease activity in these patients. Ankylosing spon-dylitis is the prototypical axial spondyloarthropathy but axial disease may also occur in patients with reactive ar-thritis, psoriatic arthritis, and inflammatory bowel disease associated spondyloarthropathy, although the pattern of disease is variable. Undifferentiated spondyloarthropa-thy 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 spondyloarthrop-athy have been developed to improve diagnostic accuracy especially in patients with early disease and disease ac-tivity measures have been refined to better assess the re-sponse of patients with axial spondyloarthropathy to new and emerging therapies.

Chapter 2

Criteria and Disease Activity Measures in Axial Spondyloarthropathies

Jose Aliling1 and Lawrence H Brent1*

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: [email protected]

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.



www.avidscience.com

IntroductionSpondyloarthropathy (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). Undif-ferentiated spondyloarthropathy (USpA) and nonradio-graphic axial SpA are less well defined spondyloarthropa-thies without specific set of criteria [1]. These diseases have several common clinical features including the as-sociation with HLA-B27 [2,3] and enthesitis [4,5].

Axial SpA is a common disease entity and the preva-lence has been documented by a number of epidemiologi-cal studies using different methods. In the USA, the preva-lence 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 associa-tion 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 in-clude 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 diagno-ses.

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], epidemiol-ogy [8,9], and etiopathogenesis [18-20]. Advances in di-agnostic 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 allow-ing earlier identification of radiological changes related to axial SpA [24,30,31]. New therapies have become avail-able in the treatment of axial SpA including TNF-α an-tagonists [32,33] which may slow disease progression. Re-cently, 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 promis-ing 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 di-agnosis 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



www.avidscience.com

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 ra-diographs. 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 long-er 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 dam-age, 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] in-cluded clinical criteria and radiographic criteria. The im-

portance 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 dis-ease for inclusion in clinical studies and trialsbefore ra-diographic damage has occurred. Ultimately the goal is to diagnose patients early in the course of their disease and institute therapy before radiographic damage has oc-curred 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 ra-diographic 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 di-agnostic 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-



www.avidscience.com

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 bilat-eral 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 expan-sion (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 radio-graphic criteria. The modification was replacing the New York 1966 pain criterion with the Rome 1961 pain cri-terion 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 re-quirement 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]

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

2. Pain and stiffness in thoracic spine

3. Limited motion in lumbar spine

4. Limited chest expansion

5. History of evidence of iritis or its sequelae

Radiographic Criterion

6. Radiograph showing bilateral sacroiliac changes characteristic of AS

Clinical Criteria

1. Limitation of lumbar spine motion in all three planes: anterior flexion, lateral flexion, extension

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

Radiographic Criteria

4. Grade 3 or 4 bilateral sacroiliitis

5. Grade 3 or 4 unilateral or grade 2 bilateral sacroiliitis

Clinical Criteria

1. Low back pain of at least 3 months’ duration improved by exercises and not relieved by rest

2. Limitation of lumbar spine in sagittal and frontal planes

3. Chest expansion decreased relative to normal values for age and sex

Radiographic Criteria

4. Bilateral sacroiliitis grade ≥2

5. Unilateral sacroiliitis grade 3 or 4

Definite AS

Grade 3 or 4 bilateral sacroiliitis with at least one clinical criterion

OR

At least four clinical criteria

Definite AS

Grade 3 or 4 bilateral sacroiliitis with at least one clinical criteria

OR

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

Definite AS

Bilateral sacroiliitis grade ≥2 or Unilateral sacroiliitis grade 3 or 4 and at least 1 clinical criterion

Probable AS

Three clinical criteria are present

OR

Radiographic criterion is present without any clinical criteria



www.avidscience.com

Table 2: Radiographic Grading of Sacroiliitis [40,46].

General Classification Criteria for Spondyloarthropathies

The Amor Classification Criteria for Spondyloarthop-athy [42] and the European Spondyloarthropathy Study Group (ESSG) Classification Criteria for Spondyloar-thropathy [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 Crite-ria 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 radio-graphic sacroiliitis are not required, these criteria are not specific for axial SpA.

Table 3: General Criteria for Spondyloarthropathy: Amor and ESSG.

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

Grading of Sacroiliitis: New York CriteriaGrade 0

Grade 1

Grade 2

Grade 3

Grade 4

Normal

Suspicious

Minimal sacroiliitis

Moderate sacroiliitis

Ankylosis

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

• Enthesitis

2 pts

2 pts

•Psoriasis, balanitis, IBD

•Sacroiliitis on x-ray

2 pts

3 pts

and one of the following

• 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

•Urethritis, cervicitis, or acute diarrhea <1 month before arthritis

•Alternating buttock pain

• Enthesitis

• Sacroiliitis by plain radiography

Diagnosis of SpA if the sum of positive criteria ≥ 6 points



www.avidscience.com

positive family history of SpA in a 1st or 2nd degree relative with AS, psoriasis, acute uveitis, ReA, or IBD but the pres-ence 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 synovi-tis 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 specific-ity 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 Spon-dylitis and the Modified New York 1984 Diagnostic Crite-ria for Ankylosing Spondylitis both have as the first clinical criterion low back pain with inflammatory features. Both the Amor and ESSG Classification Criteria for Spondy-loarthropathy 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 Spondyloarthropa-

thy. 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 crite-ria 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 specifici-ties 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 Spon-dyloarthritis

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 sacro-iliitis. 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 crite-ria 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 predomi-nantly axial involvement and those with predominantly peripheral involvement. In the early 2000s, there was great



www.avidscience.com

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 in-flammatory 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 sacroili-itis on MRI [51]. Patients with non-radiographic and ra-diographic axial SpA share common epidemiological, ge-netic, 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 periph-eral disease but do not have clinical features to support a diagnosis of a specific SpA.

Table 4: Inflammatory Back Pain Diagnostic Criteria.

Table 5: Assessment in SpondyloArthritis international Society (ASAS) Classification Criteria for

Axial Spondyloarthritis (Rudwaleit 2009) [44].

Calin Criteria for

Inflammatory Back Pain [47]

Berlin Criteria for

Inflammatory Back Pain [48]• Insidious onset

• Patient younger than 40 years

• Persisting for at least 3 months

•Associated with morning stiffness

• Improving with exercise

•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 painPresence of 4 of 5 features is 95% sensitive and 85% specific

Criteria fulfilled if at least 2 of the 4 parameters are present, 70.3% sensitive and 81.2% specific

ASAS Criteria for

Inflammatory Back Pain [49]ASAS Validation Study (n=648) [49]

• Improvement with exercise

• Pain at night

• Insidious onset

•Age of onset less than 40 years

•No improvement with rest

Criteria Sensitivity SpecificityCalin

Berlin

ASAS

89.9%

70.0%

79.6%

52.5%

81.4%

72.4%

If at least 4 of 5 parameters are fulfilled, 79.6% sensitive and 72.4% specific

In patient with back pain for ≥ 3 months and age at onset < 45 years

Sacroiliitis on imaging*plus

≥1 SpA feature**

OR HLA-A27plus

≥ 2 other SpA features** **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

*Sacroiliitis on imaging

•Active (acute) inflammation on MRI highly suggestive of sacroi-liitis associated with SpA

or

•Definite radiographic sacroiliitis according to modified New York criteria

Sensitivity 82.9%, Specificity 84.4%Imaging arm alone: Sensitivity 66.2%, Specificity 97.3%



www.avidscience.com

The concept of Assessment of SpondyloArthritis in-ternational Society (ASAS) Classification Criteria devel-oped 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, en-thesitis, and dactylitis. Some patients have a combination of axial and peripheral disease.

Axial SpA is the preferred term that reflects the ex-panded 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 Clas-sification 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 fea-ture. The clinical arm is fulfilled by the presence of HLA-B27 plus ≥2 other clinical SpA features. Patients with nor-mal 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 manifesta-tion, HLA-B27, or sacroiliitis by plain radiographs or MRI or ≥2 other musculoskeletal manifestations or family his-tory 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 com-pared to ESSG and Amor Classification Criteria for Spon-dyloarthritis 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 cri-teria.

Disease Activity Measures for Axial Spondyloarthropathy

Advancements and improvement in classification cri-teria for SpA improves the ability to capture patients espe-cially those with early disease. This is important for inclu-sion of patients in clinical studies especially clinical trials. With the advent on new therapies available such as TNF-α



www.avidscience.com

antagonists [32,33] and IL-17 antagonists [34] and evolv-ing therapies such as those that block IL-17 and IL-12/23 [20], it is important to be able to measure disease activ-ity 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 internation-al Society (ASAS) Classification Criteria for Peripheral

Spondyloarthritis [45].Arthritis or Enthesitis or Dactylitis.

Table 7: Comparison of sensitivity and specificity of ESSG, Amor, and ASAS Classification Criteria for Spondyloar-

thropathy [44,45].

Early efforts to develop measures of disease activity include the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [52], Bath Ankylosing Spondylitis Func-tional 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 symp-toms during the past week. There are 5 parameters in-cluding 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 de-rived 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

Criteria Axial SpA

(N=649)

Sensitivity Specificity

Peripheral SpA

(n=266)

Sensitivity Specificity

Axial and Peripheral SpA

(n=975)

Sensitivity SpecificityASAS Axial SpA

ASAS Peripheral SpA

ESSG Criteria

Modified ESSG (with MRI)

Amor Criteria

Modified Amor (with MRI)

82.9%

---

72.4%

85.1%

69.3%

82.9%

84.4%

---

66.3%

65.1%

77.9%

77.5%

---

77.8%

55.1%

62.5%

35.2%

39.8%

---

82.9%

81.1%

81.1%

97.8%

97.8%

79.5%

66.7%

79.1%

55.6%

67.5%

83.3%

72.0%

68.8%

86.7%

86.7%

Plus ≥ 1 of the following (or) Plus ≥ 2 of the remaining•Psoriasis

•Inflammatory bowel disease

•Preceding infection

•HLA-B27

•Uveitis

•Sacroiliitis on ima-ging

(radiographs or MRI)

•Arthritis

•Enthesitis

•Dactylitis

•Inflammatory back pain in past

•Positive family histo-ry of SpA

Sensitivity 77.8%, Specificity 82.9%



www.avidscience.com

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 (Modi-fied 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 de-velop 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 de-veloped initially using data from clinical trials of NSAIDs

in AS [59]. The ASAS20 Response Criteria includes 4 do-mains: 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 improve-ment 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 Re-mission Criteria. The ASAS5/6 Response Criteria include the 4 domains in the ASAS20 Response Criteria plus 2 ad-ditional 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 prac-tice. 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-



www.avidscience.com

ical trials of TNF-α antagonists and an IL-17A monoclo-nal 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) (Jen-kinson 1994, van der Heijde 2008) [54,55].

The scores for each item in the BASDAI and BASFI are gener-ated by the patient marking a visual analog scale (0-10) for each

item.

The BASMI is determined by physical exam.

In 2009, ASAS developed a new measure of disease activity for AS that is a continuous measure and can meas-ure 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 in-cluding back pain, duration of morning stiffness, patient global assessment, peripheral joint pain and swelling, and acute phase reactants, the CRP and ESR [61]. Four differ-ent formulas were tested, validated, and all performed bet-ter 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 vali-dated in other studies but has not generally been used in

BASDAI

During past week Score/10

BASFI

During past month Score/10

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 discom-fort 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)

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)

BASDMI

Score/2 or 10Lumbar Flexion (modified Schober’s)

Lumbar Side Flexion

Tragus to Wall

Cervical Rotation

Intermalleolar Distance



www.avidscience.com

clinical trials or clinical practice [62,63].

Table 9: Assessment in SpondyloArthritis international Society (ASAS) Criteria for Improvement: ASAS20, 40,

5/6, Partial Remission [59,60].

Table 10: Assessment in SpondyloArthritis international Society (ASAS) Disease Activity Score for use in Ankylos-

ing Spondylitis (ASDAS) [61-63].

Biomarkers in Axial Spondyloar-thropathy

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 dis-ease 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 cor-related with serum levels of CRP and IL-6 [65].

ConclusionOver 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

ASAS Core set for assessment of disease[57,58]• 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



• 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



• Inflammation: Severity and Duration of Morning Stiffness (Average of items 5 & 6 of the BASDAI)

• Spinal mobility: BASMI

• Acute phase reactants: CRPResponder 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 domainASAS Partial Remission: Responders have values of less than 2 for all 4 ASAS20 domains

Preferred version

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)



www.avidscience.com

the dominant clinical manifestations so for the purposes of classification, SpA can be classified as axial SpA [44]and peripheral SpA [45]. Axial SpA includes radiographic and non-radiographic axial SpA [50,51] which may be different parts of the spectrum of a single disease entity. The utility of MRI of the sacrum and spine to detect in-flammatory lesions consistent with axial SpA when plain radiographs are still normal, has improved diagnosis especially in early disease [24]. This is reflected in the ASAS Classification Criteria for Axial Spondyloarthritis [44] and the ASAS Classification Criteria for Peripheral Spondyloarthritis [45], both of which include sacroiliitis on imaging by radiographs or MRI. This change, among others, increases the sensitivity of these criteria in patients with early disease especially when compared to the Rome and New York Criteria for AS. With the advent of pow-erful biologic agents which have the potential to reduce or inhibit disease progression, it is now very important to identify patients early and institute treatment. In addition, there has been an evolution in measures of disease activ-ity. The ASAS20 Response Criteria has proved useful in clinical trials but as it is a measure of clinical improve-ment and not of disease activity, and therefore, has little utility in clinical practice [59,60]. The ASDAS-CRP [61]addresses this issue as a measure of disease activity which is relatively simple, validated, and appropriate for use in individual patients to assess response to treatment.

References1. Deodhar A, Reveille JD, van den Bosch F, Braun J,

Burgos-Vargas R, et al. The concept of axial spon-dyloarthritis: joint statement of the spondyloar-thritis research and treatment network and the Assessment of SpondyloArthritis international Society in response to the US Food and Drug Ad-ministration’s comments and concerns. Arthritis Rheum. 2014; 66: 2649-2656.

2. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med. 1973; 288: 704-706.

3. Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC. Ankylosing spondylitis and HL-A 27. Lancet. 1973; 1: 904-907.

4. McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet. 1998; 352: 1137-1140.

5. McGonagle D, Stockwin L, Isaacs J, Emery P. An enthesitis based model for the pathogenesis of spondyloarthropathy. additive effects of micro-bial adjuvant and biomechanical factors at disease sites. J Rheumatol. 2001; 28: 2155-2159.

6. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, et al. Estimates of the prevalence of



www.avidscience.com

arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008; 58: 15-25.

7. Reveille JD, Witter JP, Weisman MH. Prevalence of axial spondylarthritis in the United States: es-timates from a cross-sectional survey. Arthritis Care Res (Hoboken). 2012; 64: 905-910.

8. Akkoc N1. Are spondyloarthropathies as com-mon as rheumatoid arthritis worldwide? A review. Curr Rheumatol Rep. 2008; 10: 371-378.

9. Stolwijk C, Boonen A, van Tubergen A, Reveille JD. Epidemiology of spondyloarthritis. Rheum Dis Clin North Am. 2012; 38: 441-76.

10. Braun J, Bollow M, Remlinger G, Eggens U, Rud-waleit M. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Ar-thritis Rheum. 1998; 41: 58-67.

11. A Saraux, F Guillemin, P Guggenbuhl, C Roux, P Fardellone, et al. Prevalence of spondyloarthropa-thies in France: 2001. Ann Rheum Dis. 2005; 64: 1431-1435.

12. Trontzas P, Andrianakos A, Miyakis S, Pantelidou K, Vafiadou E, et al. Seronegative spondyloar-thropathies in Greece: a population-based study of prevalence, clinical pattern, and management.

The ESORDIG study. Clin Rheumatol. 2005; 24: 583-589.

13. De Angelis R, Salaffi F, Grassi W. Prevalence of spondyloarthropathies in an Italian population sample: a regional community-based study. Scand J Rheumatol. 2007; 36: 14-21.

14. Onen F, Akar S, Birlik M, Sari I, Khan MA. Preva-lence of ankylosing spondylitis and related spon-dyloarthritides in an urban area of Izmir, Turkey. J Rheumatol. 2008; 35: 305-309.

15. Dougados M, van der Linden S, Juhlin R, Huit-feldt B, Amor B, et al. The European Spondylar-thropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991; 34: 1218-1227.

16. Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis. Immunol Rev. 2010; 233: 162-180.

17. Reveille JD. Genetics of spondyloarthritis--be-yond the MHC. Nat Rev Rheumatol. 2012; 8: 296-304.

18. Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol. 2014; 57: 2-11.

19. Dougados M, Baeten D. Spondyloarthritis. Lan-cet. 2011; 377: 2127-2137.



www.avidscience.com

20. Yeremenko N, Paramarta JE, Baeten D. The inter-leukin-23/interleukin-17 immune axis as a prom-ising new target in the treatment of spondyloar-thritis. Curr Opin Rheumatol. 2014; 26: 361-370.

21. Maksymowych WP, Landewé R. Imaging in anky-losing spondylitis. Best Pract Res Clin Rheumatol. 2006; 20: 507-519.

22. Bennett AN, Marzo-Ortega H, Emery P, McG-onagle D, Leeds Spondyloarthropathy Group. Diagnosing axial spondyloarthropathy. The new Assessment in SpondyloArthritis international Society criteria: MRI entering centre stage. Ann Rheum Dis. 2009; 68: 765-767.

23. Weber U, Hodler J, Jurik AG, Pfirrmann CW, Ru-fibach K, et al. Assessment of active spinal inflam-matory changes in patients with axial spondy-loarthritis: validation of whole body MRI against conventional MRI. Ann Rheum Dis. 2010; 69: 648-653.

24. Braun J, Baraliakos X. Imaging of axial spondy-loarthritis including ankylosing spondylitis. Ann Rheum Dis. 2011; 70 Suppl 1: i97-103.

25. Althoff CE, Sieper J, Song IH, Haibel H, Weiß A, et al. Active inflammation and structural change in early active axial spondyloarthritis as detected

by whole-body MRI. Ann Rheum Dis. 2013; 72: 967-973.

26. Devauchelle-Pensec V, D’Agostino MA, Marion J, Lapierre M, Jousse-Joulin S, et al. Computed tomography scanning facilitates the diagnosis of sacroiliitis in patients with suspected spondylar-thritis: results of a prospective multicenter French cohort study. Arthritis Rheum. 2012; 64: 1412-1419.

27. D’Agostino MA, Aegerter P, Bechara K, Salliot C, Judet O, et al. How to diagnose spondyloarthritis early? Accuracy of peripheral enthesitis detection by power Doppler ultrasonography. Ann Rheum Dis. 2011; 70: 1433-1440.

28. Spadaro A, Iagnocco A, Perrotta FM, Modesti M, Scarno A. Clinical and ultrasonography assess-ment of peripheral enthesitis in ankylosing spon-dylitis. Rheumatology (Oxford). 2011; 50: 2080-2086.

29. Gandjbakhch F, Terslev L, Joshua F, Wakefield RJ, Naredo E. Ultrasound in the evaluation of enthesitis: status and perspectives. Arthritis Res Ther. 2011; 13: R188.

30. Mandl P, Navarro-Compán V, Terslev L, Aegerter P, van der Heijde D, et al. EULAR recommenda-tions for the use of imaging in the diagnosis and



www.avidscience.com

management of spondyloarthritis in clinical prac-tice. Ann Rheum Dis. 2015; 74: 1327-1339.

31. Eshed I, Hermann K-GA. New imaging modali-ties in spondyloarthropathies. Curr Opin Rheu-matol. 2015; 27: 333-342.

32. Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis. 2011; 70: 896-904.

33. van der Heijde D, Sieper J, Maksymowych WP, Dougados M, Burgos-Vargas R, et al. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann Rheum Dis. 2011; 70: 905-908.

34. Baeten D, Sieper J, Braun J, Baraliakos X, Dou-gados M, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med. 2015; 373: 2534-2548.

35. Aggarwal R, Ringold S, Khanna D, Neogi T, John-son SR. Distinctions between diagnostic and clas-sification criteria? Arthritis Care Res (Hoboken). 2015; 67: 891-897.

36. Elyan M, Khan MA. Diagnosing ankylosing spon-

dylitis. J Rheumatol Suppl. 2006; 78: 12-23.

37. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int. 2003; 23: 61-66.

38. Dincer U, Cakar E, Kiralp MZ, Dursun H. Diag-nosis delay in patients with ankylosing spondyli-tis: possible reasons and proposals for new diag-nostic criteria. Clin Rheumatol. 2008; 27: 457-462.

39. Kellgren JH. Rome clinical criteria for ankylosing spondylitis. The Epidemiology of Chronic Rheu-matism. Oxford: Balckwell Scientific Publications; 1963: 326-327.

40. Bennett PH, Burch TA. New York clinical criteria for ankylosing spondylitis. Amsterdam: Excerpta Medica Foundation. 1968: 456-457.

41. van der Linden S, Valkenburg HA, Cats A. Evalu-ation of diagnostic criteria for ankylosing spondy-litis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984; 27: 361-368.

42. Amor B, Dougados M, Mijiyawa M. [Criteria of the classification of spondylarthropathies]. Rev Rhum Mal Osteoartic. 1990; 57: 85-89.

43. Collantes-Estevez E, Del Mazo AC, Munoz-Gomariz E. Assessment of 2 systems of spondy-



www.avidscience.com

loarthropathy diagnostic and classification crite-ria (Amor and ESSG) by a Spanish multicenter study. J Rheumatol. 1995; 22: 246-251.

44. Rudwaleit M, van der Heijde D, Landewé R, List-ing J, Akkoc N, et al. The development of As-sessment of SpondyloArthritis international Society classification criteria for axial spondyloar-thritis (part II): validation and final selection. Ann Rheum Dis. 2009; 68: 777-783.

45. Rudwaleit M, D van der Heijde, R Landewé, N Akkoc, J Brandt, et al. The Assessment of Spon-dyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011; 70: 25-31.

46. Moll JM, Wright V. New York clinical criteria for ankylosing spondylitis. A statistical evaluation. Ann Rheum Dis. 1973; 32: 354-363.

47. Calin A, Porta J, Fries JF, Schurman DJ. Clinical history as a screening test for ankylosing spondy-litis. JAMA. 1977; 237: 2613-2614.

48. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondy-litis: a reassessment of the clinical history for ap-plication as classification and diagnostic criteria.

Arthritis Rheum. 2006; 54: 569-578.

49. Sieper J, van der Heijde D, Landewé R, Brandt J, Burgos-Vagas R. New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assess-ment of SpondyloArthritis international Society (ASAS). Ann Rheum Dis. 2009; 68: 784-788.

50. Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early ankylos-ing spondylitis: do we need new criteria? Arthritis Rheum. 2005; 52: 1000-1008.

51. Poddubnyy D, Sieper J. Similarities and differ-ences between nonradiographic and radiographic axial spondyloarthritis: a clinical, epidemiological and therapeutic assessment. Curr Opin Rheuma-tol. 2014; 26: 377-383.

52. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P. A new approach to defining disease status in ankylosing spondylitis: the Bath Anky-losing Spondylitis Disease Activity Index. J Rheu-matol. 1994; 21: 2286-2291.

53. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, et al. A new approach to defining func-tional ability in ankylosing spondylitis: the devel-opment of the Bath Ankylosing Spondylitis Func-tional Index. J Rheumatol. 1994; 21: 2281-2285.



www.avidscience.com

54. Jenkinson TR, Mallorie PA, Whitelock HC, Ken-nedy LG, Garrett SL, et al. Defining spinal mobil-ity in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol. 1994; 21: 1694-1698.

55. van der Heijde D, Landewé R, Feldtkeller E. Pro-posal of a linear definition of the Bath Ankylosing Spondylitis Metrology Index (BASMI) and com-parison with the 2-step and 10-step definitions. Ann Rheum Dis. 2008; 67: 489-493.

56. Fries JF, Spitz P, Kraines RG, Holman HR. Meas-urement of patient outcome in arthritis. Arthritis Rheum. 1980; 23: 137-145.

57. van der Heijde D, Calin A, Dougados M, Khan MA, van der Linden S, et al. Selection of instru-ments in the core set for DC-ART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis. Progress report of the ASAS Working Group. Assessments in Ankylos-ing Spondylitis. J Rheumatol. 1999; 26: 951-954.

58. J Braun, T Pham, J Sieper, J Davis, S. van der Lin-den, et al. International ASAS consensus state-ment for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis. 2003; 62: 817-824.

59. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M. Ankylosing spondylitis assess-ment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum. 2001; 44: 1876-1886.

60. van der Heijde D, Dougados M, Davis J, Weis-man MH, Maksymowych W, et al. ASsessment in Ankylosing Spondylitis International Work-ing Group/Spondylitis Association of America recommendations for conducting clinical trials in ankylosing spondylitis. Arthritis Rheum. 2005; 52: 386-394.

61. van der Heijde D, Lie E, Kvien TK, Sieper J, Van den Bosch F, et al. ASDAS, a highly discrimina-tory ASAS-endorsed disease activity score in pa-tients with ankylosing spondylitis. Ann Rheum Dis. 2009; 68: 1811-1818.

62. Machado P, Landewé R, Lie E, Kvien TK, Braun J, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for dis-ease activity states and improvement scores. Ann Rheum Dis. 2011; 70: 47-53.

63. Fernández-Espartero C, de Miguel E, Loza E, Tomero E, Gobbo M, et al. Validity of the anky-losing spondylitis disease activity score (ASDAS) in patients with early spondyloarthritis from the Esperanza programme. Ann Rheum Dis. 2014;

38 www.avidscience.com

Clinical Advances in Spondylitis

73: 1350-1355.

64. Maksymowych WP. Biomarkers in axial spondy-loarthritis. Curr Opin Rheumatol. 2015; 27: 343-348.

65. Pedersen SJ, Sørensen IJ, Garnero P, Johansen JS, Madsen OR, et al. ASDAS, BASDAI and dif-ferent treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFalpha inhibitors. Ann Rheum Dis. 2011; 70: 1375-1381.

Documents

Clinical Adances in Spondylitis Clinical Adances in ... › wp-content › uploads › 2016 › 04 › CAS-15-02… · Diagnostic Criteria for AS [40] Modified New York, 1984 Diagnostic