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Eular On-line Course on Rheumatic Diseases module n6 Cecilia Mercieca, Robert Landew, Andrew A Borg

SPONDYLOARTHRITIS: PATHOGENESIS, CLINICAL ASPECTS AND DIAGNOSIS


Cecilia Mercieca, Robert Landew, Andrew A Borg A previous version was co-authored by Maxime Dougados and Robert Landew

Learning objectives:

Discuss the concept of spondyloarthritis (SpA) Describe the pathophysiology of these disorders and the role of genetic and environmental factors Explain the different hypotheses for the role of B27 in the pathogenesis of these disorders Simplify the approach to the diagnosis of SpA Improve assessment of such patients, especially the activity, severity, potential severity and refractory characteristics of the disease Describe the use of the different tools allowing better patient monitoring

1. The concept of spondyloarthritis Spondyloarthritis (SpA) is a heterogeneous group of chronic inter-related inflammatory arthropathies affecting the synovium, entheses and certain extra-articular sites. The SpA group includes reactive arthritis (ReA), psoriatic arthritis (PsA), enteropathic arthritis, juvenile SpA and ankylosing spondylitis (AS), with the latter being the prototype disease. SpA occurs primarily in genetically predisposed individuals, particularly those who are HLA-B27 positive, but additional environmental factors are also thought to play a role. It can be difficult to differentiate these disorders because their clinical features may overlap, and undifferentiated forms of SpA are well recognised. The monitoring and treatment of these diseases is related more closely to the clinical presentation than to the precise diagnosis (box 1). The rheumatic manifestations include inflammation of the spine and sacroiliac joints, peripheral arthritis and enthesitis (inflammation at the entheses, the sites of attachment of tendons, ligaments, fascia or joint capsules to bone). Enthesitis is the distinguishing pathological feature of SpA. The extra- articular manifestations of the disease may be similar whatever the SpA subgroup (eg, acute anterior uveitis) or may be specific to a SpA subgroup such as skin lesions in PsA, gut involvement in inflammatory bowel disease-related arthritis and the oculourethro-synovial triangle in classic ReA.

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Eular On-line Course on Rheumatic Diseases module n6 Cecilia Mercieca, Robert Landew, Andrew A Borg

Box 1 Clinical presentation of Spondyloarthritis Disease subgroups Ankylosing spondylitis Psoriatic arthritis Reactive arthritis Inflammatory bowel disease-related arthritis Juvenile spondyloarthritis Undifferentiated spondyloarthritis

Clinical features Rheumatological manifestations Axial involvement Peripheral arthritis Enthesopathy

Extra articular features Acute anterior uveitis Cardiac involvement (e.g. heart block, aortic insufficiency)

Genetic background Family history HLA-B27 antigen

Specific manifestations Psoriasis Inflammatory bowel disease, etc

Adapted from Dougados M, Hochberg MC. Why is the concept of spondyloarthropathies important? Best Pract Res Clin Rheumatol 2002;16:495505

2. Epidemiology The estimated prevalence of SpA in Caucasian subjects is between 0.5% and 2%. This varies among different ethnic populations, being higher in white and certain Native American subjects and lower in African American and Asian subjects. AS is the most prevalent disease of the SpA. The prevalence of AS parallels that of HLA-B27 gene prevalence. Eight per cent of the healthy white population is HLAB27 positive, while 4% of the healthy African American population is HLA-B27 positive. Ninety-two per cent of the white AS population is HLA-B27 positive, while 50% of the African American AS population is HLA-B27 positive. Sixty per cent of patients with ReA, PsA and enteropathic spondylitis are HLAB27 positive, while 25% of patients with undifferentiated SpA are HLA-B27 positive. The chance of

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Eular On-line Course on Rheumatic Diseases module n6 Cecilia Mercieca, Robert Landew, Andrew A Borg

developing AS if one is HLA-B27 positive is 15%, increasing to 1520% in the case of an affected first degree relative. SpA is commoner in males, with the male-to-female ratio being 3:1. The mean age of onset of symptoms is 26 years and it can present from late adolescence to 40 years of age. There is often significant delay in diagnosis, especially in HLA-B27 negative patients. A shorter time to diagnosis was observed in patients with inflammatory back pain (IBP) or a positive family history because clinical suspicion tended to be higher. 3. Pathogenesis 3.1 Genetics The aetiology of SpA is still largely unknown but is thought to reflect a complex interplay of genetic and environmental factors. The involvement of genetic factors in determining susceptibility to SpA has long been suspected owing to frequent familial clustering of cases. The first genetic factor identified was the tissue antigen HLA-B27. Further genetic studies have led to the discovery of other genes important in disease susceptibility, including various B27 subtypes as well as non-B27 major histocompatibility complex (MHC) and non-MHC genes, although it is not clear how these actually cause the disease. Studies are still in the early phase but potentially might provide further insight into disease pathogenesis and translate into future diagnostic and prognostic tools.

3.1.1 Methodology of genetic studies The genetic analysis of complex, multifactorial diseases such as SpA is difficult due to numerous factors. The model underlying the inheritance of the disease is unknown, although several genes are likely to be involved, which may be different from patient to patient (genetic heterogeneity). Moreover, the molecular variants of a gene (alleles) associated with disease susceptibility may be present in healthy subjects, suggesting that exposure to specific environmental factors is probably required to cause the disease to develop (incomplete penetrance). Discovering genes through family-based or candidate gene methods has not been very successful. Using high-throughput micro-array based single nucleotide polymorphism (SNP) genotyping techniques has made it easier to identify genes associated with SpA more rapidly.

3.1.2 Family and twin studies Twin studies in AS have shown a monozygotic concordance rate of around 70%. The genetic risk determines not only the risk of developing the disease but also the age of onset, clinical disease severity and radiographic severity. Such high heritability is usually associated with monogenic diseases. However, this is unlikely given the high prevalence of AS. In addition, there is clear evidence that other genes are involved. Familial studies show that less than 50% of the genetic risk is secondary to HLA-B27. First degree relatives have a 516% risk of developing the disease, while only 15% of HLA- B27 individuals develop AS, suggesting that other genes and environmental factors are
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involved. HLA-B27 positive relatives of AS patients have recurrence risks that are 5.616 times greater than in HLA-B27 individuals in the normal population, suggesting that there must be other non-HLA-B27 genes which are responsible. This is further supported by twin studies which have shown greater concordance in monozygotic twins than in HLA-B27 dizygotic twins.

3.1.3 HLA-B27 gene The hypothesis of genetic susceptibility factors involved in AS was first developed during the years 195060 based on familial aggregation studies. In 1973, Brewerton and Schlosstein both reported the association of HLA-B27 with AS. Nevertheless, the precise role of B27 in the pathophysiology of the disease remains unknown. Several lines of evidence recently suggested that HLA-B27 may not behave like other class I molecules: HLA-B27 heavy chains can form homodimers that do not contain the 2-microglobulin light chain (a phenomenon also called HLA-B27 misfolding). Such homodimers could mediate, or be the target for, a pro-inflammatory response. These hypotheses are under investigation.

3.1.4 Non-B27 MHC genes The MHC consists of about 220 genes, many of which have immunoregulatory functions. Several studies have looked at non-B27 MHC genes, but to date none have been able to pinpoint specific genes or genetic variants associated with AS. Studies in this area have been hampered by extensive linkage disequilibrium between loci, lack of sufficient marker density and small sample sizes.

3.1.5 Non-MHC genes Recently two key studies have identified non-MHC genes which are associated with AS. The first study was carried out by the Wellcome Trust Case Consortium (WTCC) and the Australo-AngloAmerican Spondyloarthritis Consortium (TASC). In this study, 14 500 non-synonymous SNPs (ie, SNPs which change the amino acid sequence) identified disease association with IL23R and ERAP1. IL23R has also been found to be linked with inflammatory bowel disease and PsA. This partially explains the frequent coexistence of these diseases. The second study carried out by TASC is a complete genome-wide association study. In addition to confirming the above, new associations with gene deserts (regions of the genome lacking proteinencoding genes) at chromosomes 2p15 and 21q22 and genes IL1R2 and ANTXR2 were discovered. Strong evidence to support association with the disease has also been demonstrated for the TNFSF15 and TNFR1 genes and a region on chromosome 16q including the TRADD gene.

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Box 2 Bacteria that trigger reactive arthritis


Chlamydia trachomatis Shigella flexneri Salmonella spp Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter fetus jejuni Clostridium difficile Intravesical injection of bacilli CalmetteGurin (BCG) to treat bladder cancer Chlamydia pneumoniae (unconfirmed)

Adapted from Smith JA, Marker-Hermann E, Colbert RA. Pathogenesis of ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol 2006;20:57192.

3.2 Infections B27-Tg rats housed in a probiotic (non-germ free) environment develop an SpA-like disease. In contrast, when raised under entirely germ-free conditions, B27-Tg rats do not develop disease. Interestingly, colonisation of the gastrointestinal tract with normal gut flora, in particular Bacteroides spp., is sufficient to trigger inflammation. B27-Tg rats develop an SpA-like illness and the severity of the clinical disease correlates with HLAB27 expression. Several gastrointestinal or genitourinary pathogens have been strongly implicated as triggers of HLAB27- associated ReA in humans, including Campylobacter spp., Chlamydia spp., Salmonella spp. and Shigella spp. (box 2). DNA from these organisms has been found by polymerase chain reaction in synovial cell and fluid samples. Salmonella, yersinia and shigella lipopolysaccharide have also been found in the joints of patients with ReA. The presence of bacterial products in the joints provides a potential link between gut infection and joint inflammation. However, despite being strongly implicated in ReA, the requirement for gut pathogens and gut inflammation in AS is less clear. 3.3 Inammation The commonest sites of inflammation in AS include the sacroiliac joints, entheses, vertebral bodies adjacent to intervertebral discs, peripheral joint synovium, gastrointestinal tract and the eye. As many of these lesions are poorly accessible, information on histopathology is limited. In early sacroiliitis, synovitis with myxoid-appearing bone marrow and subsequent formation of pannus and granulation tissue is seen. Destroyed bone is eventually replaced and endochondral ossification results in bony ankylosis. Histologically, there is infiltration of T cells (CD4+ and CD8+) and CD68+ macrophages,

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proliferation of fibroblasts, and neovascularisation as well as TNF and transforming growth factor mRNA over-expression. The synovitis of SpA displays features of other types of inflammatory arthritis, such as increased vascularity and endothelial cell activation, with increased expression of adhesion molecules and chemotactic factors. Relevant differences include a tendency towards greater vascularity, greater CD4+ T cell and CD20+ B cell infiltration and few lymphoid aggregates. While the total numbers of CD68+ macrophages appear to be similar or slightly lower in SpA, macrophages expressing CD163 are increasingly reported. CD163 is the haemoglobin scavenger receptor and may define a population that produces more pro-inflammatory TNF and less IL10, which could promote a Th1 response. These macrophages can also release soluble CD163 that may inhibit T cell proliferation and activation. A recent study in a TNF over-expressing mouse model suggests mesenchymal stromal cells as the main target that are activated by TNF signalling. These mice spontaneously develop an inflammatory disease characterised by Crohn-like arthritis, sacroiliitis, peripheral arthritis and enteritis. Enthesitis is a hallmark of SpA and cartilage is one of the major targets of inflammation. Inflammatory lesions are characterised by soft tissue inflammation and bone marrow infiltration with CD8 and CD4 T cells, B cells, macrophages and osteoclasts. This is commoner at peripheral sites subject to biomechanical stresses and rich in fibrocartilage containing type II collagen and aggrecan proteoglycan such as at the insertion of the Achilles tendon into the calcaneum. In the early phase of enthesitis, CD68+ and macrophages (1 month to 1 year of disease) seem to predominate, while abundant lymphocytes tend to be found in established disease. 4. Clinical features 4.1 Rheumatological manifestations 4.1.1 Inammatory back pain IBP is the first manifestation in 75% of patients. Classically, the pain starts in the lumbar region or at the lumbosacral junction. It is typically a dull pain of insidious onset, becoming persistent after a few months. It is inflammatory the pain worsens with inactivity and improves with exercise and nonsteroidal anti- inflammatory drugs (NSAIDs). Morning stiffness is often prolonged (>30 min) and nocturnal pain may awaken patients from sleep. Sacroiliitis or spondylitis may be the dominant clinical problem or may complicate the course of any of the SpA. If there is progression to ankylosis, the inflammatory pain usually lessens but is replaced by important functional impairment. Symptoms may be mild with intermittent flares and remission. An acute onset of pain, worsening symptoms with activity and radicular pain are more suggestive of a mechanical or degenerative cause, but both pathologies may occur in the same patient. Three different sets of criteria with similar sensitivities and specificities have been proposed (boxes 35). IBP is the one of the main symptoms in SpA, but its value in diagnosis/classification and screening in primary care has still not been validated. About 5% of patients presenting with chronic back pain have SpA, and IBP has long been a central criterion in the classification of AS and SpA. The sensitivity and
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specificity of IBP criteria is directly related to the pre-test probability of the patient having the disease and the stringency of the IBP criteria used. This is important, as the prevalence of IBP is much higher in rheumatology practice (2550%) compared to that in the primary care setting (less than 5%), where the IBP criteria are probably less useful. Another important observation is that not all patients with axial SpA have IBP. These observations have led to the removal of IBP as the first entry criterion in the new classification criteria for axial SpA.

Box 3 Calin inflammatory back pain criteria


At least four of the following: Insidious onset Onset before the age of 40 years At least 3 months duration Morning stiffness ~30 min Improvement with exercise If four out of five criteria are fulfilled, sensitivity is 95% and specificity is 85%.
Calin A, Porta J, Fries JF, et al. Clinical history as a screening test for ankylosing spondylitis. JAMA 1977;237:26134.

Box 4 Berlin inflammatory back pain criteria


At least two of the following: Morning stiffness 30 min Improvement with exercise but not with rest Awakening because of back pain during the second part of the night Alternating buttock pain If two out of four criteria are fulfilled, sensitivity is 70% and specificity is 81%. If three out of four criteria are fulfilled, sensitivity is 33% and specificity is 98%.
Rudwaleit M, Metter A, Listing J, et al. Inammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classication and diagnostic criteria. Arthritis Rheum 2006;54:56978.

Box 5 Expert criteria for inflammatory back pain


Improvement with exercise Pain at night Insidious onset Age at onset < 40 years No improvement with rest

The criteria are fullled if at least four out of ve parameters are present.
Seiper J, van der Heijde D, Landew R, et al. New criteria for inammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS). Ann Rheum Dis 2009;68:7848.

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4.1.2 Ankylosis One of the major concerns of patients with spondylitis is progression towards ankylosis, which results from ossification of the ligaments and of the costovertebral and sternocostal joints. The first sign of an abnormal posture is loss of lumbar lordosis, followed by thoracic kyphosis and, in severe cases, forward stooping of the neck. Spinal movement is restricted in all planes. The restriction in motion may not be proportionate to the degree of ankylosis because of secondary muscle spasms. It is important to detect these abnormal features as early as possible, so that physiotherapy or other appropriate treatments can be initiated. In patients with restricted chest wall motion, airflow measurements are normal, but vital capacity is decreased and functional residual capacity is increased. Respiratory failure can occur in severe cases. However, ankylosis in the thoracic and lumbar spine is not necessarily linked to severe physical limitations unless there is hip involvement, in which case bending forwards is a major problem. Ankylosis at the cervical level has major physical consequences, for example in driving, as patients cannot turn their head to view cars alongside them.

4.1.3 Fracture Despite the fact that SpA is associated with new bone formation at sites of inflammation, spinal osteoporosis is commonly seen in longstanding SpA, resulting in increased fracture risk. This contributes to the high prevalence of fractures which often occur after very minimal trauma to the rigid, ankylosed spine (figure 1). One needs to have a high index of suspicion for the possibility of fracture in SpA patients who present with acute onset of back or neck pain, especially if this follows trauma. Plain radiography is poorly sensitive and CT or preferably MRI may be needed to make the diagnosis. Spinal osteoporosis is partly due to the lack of mobility as a consequence of the disease, as well as a result of pro-inflammatory cytokines. Assessment of biochemical markers of bone metabolism have shown diminished bone formation and enhanced bone resorption. Osteoporotic fractures of the thoracic spine contribute to thoracic kyphosis and increased occiput-to-wall distance. Neurological involvement may rarely result following atlanto-axial subluxation.

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Figure 1. Vertebral fracture in AS.

4.1.4 Peripheral arthritis Peripheral arthritis is typically asymmetric, oligoarticular and involves the lower limbs. Upper limb involvement is typically associated with PsA. A bilateral symmetrical polyarticular presentation is possible, which differs from rheumatoid arthritis in that the distal interphalangeal joints are often affected.

4.1.5 Dactylitis (sausage digit) Dactylitis is very characteristic of SpA, although not entirely specific. It is not as common in AS but is more typical of ReA, PsA or undifferentiated SpA. Unlike synovitis, the swelling is not confined to a joint but involves the whole digit. It is a combination of synovitis, enthesitis, tenosynovitis and soft tissue swelling (figure 2).

4.1.6 Anterior chest wall pain and axial joint involvement (hips and shoulders) Anterior chest wall pain occurs in about 15% of patients and is usually the result of sternoclavicular, manubriosternal or sternocostal arthritis. As stated above, this can lead to reduced chest expansion. Arthritis of the hips and shoulders often occurs early in the first 10 years of the disease and affects a third of patients. Hip involvement is commonly bilateral. It is important to check for hip and shoulder joint involvement, as there may be limited range of movement and flexion deformities. Hip involvement often leads to severe destruction and disability. Total hip replacement might be needed

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at an earlier stage in patients with SpA who usually also have a reduced range of spinal movement resulting in a severe functional disability (virtually complete loss of forward flexion).

Figure 2. Sausage-like digit (dactylitis). Source: www.images.cri-net.com

4.1.7 Enthesitis Painful inflammation of entheses (the sites of attachment of tendons, ligaments, fascia or joint capsules to bone) is the distinguishing pathological feature of SpA. The most typical enthesitis is heel pain (posterior or inferior) related to inflammation of the Achilles tendon or the plantar fascia insertion. Pain appears in the morning as soon as the patient sets foot on the floor and improves with ambulation. Heel enthesitis is not painful during sleep but can be very disabling and resistant to standard anti- rheumatic treatment. Other clinical signs are tenderness of the iliac crest, anterior tibial tuberosity or anterior chest wall. Enthesitis is best visualised by MRI (figure 3) or ultrasonography. It is only detected on radiography after the ossification process has occurred (figure 4). Achilles tendon swelling can be better observed in the standing position from behind. Evaluation of an enthesopathy can be undertaken in various ways, traditionally using enthesitis scoring systems such as the Mandel Enthesitis Index (MEI), Stoke Enthesitis Index (SEI), University of San Francisco Enthesitis Score, Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) or Berlin Enthesitis Score. Dougados et al suggest that these scoring systems can be criticised because they are time consuming and have poor inter-observer reliability and face validity. Other suggested that screening tests should include MRI, an ultrasound enthesitis score or more conventional symptomatic outcome measures such as patient global assessment, pain and functional impairment.

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Figure 3. Heel enthesitis (MRI findings).

Figure 4. Heel enthesitis (ossification).

4.2 Extra-articular features 4.2.1 Uveitis (iritis or iridocyclitis) Acute anterior uveitis is the most common extra-articular manifestation of AS, occurring in about 20 30% of patients, with 2540% of these patients experiencing more than one episode (figure 5). The incidence is higher in HLA-B27 positive patients. It is important to detect and treat acute anterior

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uveitis rapidly as visual loss may be irreversible. The condition typically presents with unilateral eye pain, redness, photophobia and increased lacrimation (figure 5). Patients with these signs require urgent examination by an ophthalmologist, and may need specialised treatment (eg, retro-orbital injections of corticosteroids in severe cases). With treatment, attacks usually resolve after 23 months. The main complication is the occurrence of synechiae. Uveitis that develops with PsA or enteropathic SpA tends to be more chronic and bilateral and often involves posterior elements.

Figure 5. Acute anterior uveitis.

4.2.2 Cardiac manifestations Cardiac features are rare but may be severe. Heart block is the most frequent manifestation. Aortic insufficiency secondary to an aseptic endocarditis can also be a severe cardiac manifestation of the disease.

4.2.3 Pulmonary involvement Restrictive lung disease may occur in end-stage disease, as a result of costovertebral and costosternal fusion and limited chest expansion. Apical fibrosis may occur in severe disease and this may become colonised with bacteria or fungi such as Aspergillus.

4.2.4 Renal involvement IgA nepropathy has been reported in AS. Amyloidosis is a very rare complication in severe longstanding disease.

4.2.5 Gastrointestinal involvement Inflammatory lesions in the gut are common and can cause diarrhoea, which is usually accompanied by blood and mucus. Loss of weight is common. Inflammatory bowel disease may or may not have

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already been diagnosed in these patients. Colonoscopic mucosal biopsy shows that subclinical inflammatory lesions are seen in 2070% of patients with AS who have no gastrointestinal symptoms or clinically obvious inflammatory bowel disease. Follow-up studies of such patients indicate that 6% will develop inflammatory bowel disease. About 2835% of patients with enteropathic arthritis have axial disease: 1020% have sacroiliitis alone, 712% have spondylitis and 10% have the classic features of SpA. The axial radiology is similar to that of AS characterised by symmetrical bilateral sacroiliitis. The onset of axial involvement often precedes that of bowel disease, and axial symptoms do not fluctuate with bowel disease activity.

4.2.6 Dermatological manifestations Dermatological manifestations are common but are usually related to a specific disorder such as psoriasis or ReA. Psoriasis is seen in 2040% of patients with SpA. Nail lesions are a common feature in patients with rheumatological manifestations. 5. Laboratory features No laboratory tests are diagnostic of SpA. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in 40% of patients. Increased CRP is one of the features of SpA used in the Assessment of SpondyloArthritis international Society (ASAS) classification for axial SpA, but must be present with other features. A mild normochromic normocytic anaemia of chronic disease may be present. Alkaline phosphatase may be elevated but this does not correlate with disease activity. HLA-B27 is present in 92% of patients with AS. However, HLA-B27 by itself is not diagnostic since it is found in up to 8% of healthy individuals; it is therefore more helpful in populations with lower HLAB27 prevalence. Determining HLA-B27 status is not mandatory in clinical assessment but is especially helpful for classifying patients who have negative imaging. With the new ASAS classification criteria for axial SpA, a patient with a 3-month history of back pain starting before 45 years of age is classified as having SpA if HLA-B27 is positive and two other SpA features are present. Diagnosis of SpA is unlikely in case of negative imaging and a negative HLA-B27. 6. Imaging 6.1 Plain radiographs Plain radiographs of the spine, sacroiliac joints and peripheral joints can reveal various structural changes. However, they are unhelpful in early non-radiographic disease because radiographic structural changes reflect the consequences of inflammation rather than active inflammation. Radiographic sacroiliitis is the hallmark of AS and takes several years to become visible on plain radiographs. The earliest visible changes include blurring of the cortical margins of the subchondral bone, erosions and sclerosis (figure 6). As erosion progresses, the joint space appears wider and
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then fibrous until bony ankylosing obliterates the joint. Joint changes usually become symmetrical during the course of the disease. Radiographic sacroiliitis can be graded according to the New York grading system as follows: grade I, suspicious; grade II, evidence of erosion and sclerosis; grade III, erosions, sclerosis and early ankylosis; and, finally, grade IV, total ankylosis. Despite the common use of this description, it has to be emphasised that the term sacroiliitis is inappropriate. Sacroiliitis suggests that x-ray examinations can demonstrate an inflammatory aspect of the sacroiliac joints; however, the observed features are the result of a destructive process. Spinal x-rays typically show squaring of the vertebrae secondary to erosions of the superior and inferior margins of these bodies (figure 7). Vertebral enthesitis may cause sclerosis of the upper and lower vertebral bodies which appears as shiny corners (Romanus lesions). Annulus fibrosus ossification leads to syndesmophyte formation and over time bridging of these syndesmophytes results in a bamboo spine (figure 8). AS and enteropathic arthritis typically exhibit bilateral symmetric arthritis and continuous syndesmophytes, while ReA and PsA characteristically exhibit asymmetric sacroiliitis and discontinuous spondylitis. Radiographs of other areas such as the heel or hip might show evidence of enthesitis.

Figure 6. Radiological sacroiliitis in ankylosing spondylitis.

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Figure 7. (A) Radiological lumbar spinal ankylosis; (B) normal spine

Figure 8. Syndesmophytes.

6.2 Magnetic resonance imaging MRI is able to detect inflammatory lesions long before definite lesions are visible on plain radiographs. The ASAS criteria for axial SpA include MRI as one of the major criteria. When clinical suspicion of early SpA is high but standard radiography of the sacroiliac joints is normal or shows only equivocal changes, MRI produces excellent radiation-free evidence of sacroiliitis and enthesitis (figure 9). CT scan is also limited to detecting only structural changes. T2-weighted fat suppressed fast spin-echo

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and STIR sequences are recognised as the imaging sequences of choice for bone marrow assessment. Recently the ASAS/OMERACT MRI working group have proposed a definition of sacroiliitis on MRI. This definition should be applied for the imaging feature active sacroiliitis by MRI of the ASAS classification criteria for axial SpA. According to this definition the following findings are required: Active inflammatory lesions of the sacroiliac joints are required. Bone marrow oedema (BMO) (on STIR) or osteitis (on T1 post Gd) must be clearly located in typical anatomical areas (subchondral or peri-articular bone marrow). In case of a solitary BMO lesion, this should be present on at least two consecutive slices The presence of synovitis, enthesitis or capsulitis without concomitant BMO/osteitis is not sufficient for diagnosis.

In a recent study, BMO was also found in patients with mechanical low back pain, but moderate or severe lesions were only found in IBP. This highlights the need for experience in interpreting MRI of the sacroiliac joints. Also, further study is needed as regards specifying the size and severity of the lesions in order to improve the specificity of MRI.

Figure 9. Sacroiliitis (MRI findings).

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6.3 Other imaging modalities In a recent systemic review, bone scintigraphy sensitivity was found to be 5055%, while the specificity was not higher than 80% for the detection of acute sacroiliitis. Bone scintigraphy is too unspecific to be of use in SpA. No standardisation of ultrasound technique and findings is currently available. CT scan is also limited to detectingonly structural changes. 7. Classification The new validated classification criteria for axial SpA (box 6) are a step forward in the SpA arena. It is now possible to diagnose early non-radiographic axial SpA as well as established SpA. Nonradiographic sacroiliitis implies that there are no radiographic changes at present, but they may develop with time. The earlier European Spondyloarthropathy Study Group (ESSG) (box 7) and the Amor criteria (box 8) incorporate axial, peripheral as well as extra-articular features, allowing the diagnosis of SpA to be made even in the absence of radiographic sacroiliitis. The main difference between the two sets of criteria is based on their format. The ESSG criteria can only classify patients with either axial disease and/or a peripheral articular involvement, while the Amor criteria can also classify patients without axial or articular peripheral articular involvement. However, when these criteria were used for patients without sacroiliitis on plain radiography, their disease was referred to as undifferentiated SpA without differentiation between axial and peripheral SpA. These criteria were both created before MRI was available. MRI is an invaluable tool in early diagnosis as it can detect active inflammation in the spine and sacroiliac joints that is not visible on plain radiography. Early diagnosis enables the institution of treatment before permanent structural damage occurs and possibly alters the disease course. The classification criteria for axial SpA have helped to increase recognition of the axial SpA concept. The term axial SpA encompasses a disease spectrum ranging from clinical non-radiographic disease to more established disease. The most significant change in the criteria is the inclusion of MRI as a main defining criterion. On the other hand, a negative MRI scan does not exclude a diagnosis of SpA; diagnosis of axial SpA can still be made on clinical grounds. In case of a negative MRI or lack of radiographic evidence, the presence of HLA-B27 plus two other SpA features is needed. Another important difference of the new ASAS criteria is that IBP is no longer a compulsory criterion. For diagnosis one must have back pain for at least 3 months starting before 45 years of age, while IBP counts as an extra parameter. It is important to point out that criteria are designed primarily for classification and research purposes. There are no diagnostic criteria for SpA, so in daily clinical practice one has to adopt a more flexible approach. A proposed clinical diagnostic tree is shown in figure 10. Classification criteria for peripheral SpA are being developed.

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Box 6
1 SpA feature* plus sacroiliitis** *SpA features Inflammatory Spinal Pain Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohns/colitis Good response to NSAIDs Family history of SpA HLA-B27 Elevated CRP
**A patient is considered to have axial SpA if they have 1 SpA feature plus sacroiliitis* or HLA-B27 plus 2 other SpA features. Source: Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68(Suppl II):ii144. * Inammation highly compatible with sacroiliitis on MRI or denite radiographic sacroiliitis according to the modied New York criteria. ASAS, Assessment of SpondyloArthritis international Society; CRP, C-reactive protein; NSAIDs, nonsteroidal anti-inammatory drugs; SpA, spondyloarthritis.

or

HLA-B27 plus 2 other SpA features

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Box 7 European Spondyloarthropathies Study Group (ESSG) spondyloarthropathy classification criteria


Inflammatory spinal pain

Or

Synovitisasymmetrical or predominantly in the lower limbs and one or more of the following And one or more of the following: Family historyfirst- or second-degree relative with AS, psoriasis, acute iritis, reactive arthritis or inflammatory bowel disease Inflammatory bowel disease Past or present alternating buttock pain Past or present spontaneous pain or tenderness on examination of the site of insertion of the Achilles tendon or plantar fascia (enthesitis) Episode of diarrhoea occurring <1 month before the onset of arthritis Non-gonococcal urethritis or cervicitis occurring <1 month before the onset of arthritis Bilateral grade 24 sacroiliitis or unilateral grade 3 or 4 sacroiliitis

Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classication of spondylarthropathy. Arthritis Rheum 1991;34:121830.

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Box 8 AMOR spondyloarthropathy classification criteria


Clinical symptoms or past history of
Lumbar/ dorsal pain at night or morning stiffness of lumbar or dorsal area-score 1 Asymmetrical oligoarthritisscore 2 Buttock pain (if alternate buttock pain)score 1(2) Dactylitisscore 2 Heel pain or other well-defined enthesopathyscore 2 Acute anterior uveitisscore 2 Non-gonococcal urethritis/ cervicitis up to 1 month before onset of arthritisscore 1 Acute diarrhoea up to 1 month before onset of arthritisscore 1 Psoriasis, balanitis, or inflammatory bowel disease (IBD)score 1

Radiological findings
Sacroiliitis (bilateral grade 2 or unilateral grade 3)score 2

Genetic background
Presence of HLA-B27 antigen and/or family history of AS, reactive arthritis, uveitis, psoriasis or IBDscore 2

Response to treatment
Clear-cut improvement within 48 h after use of non-steroidal anti-inflammatory or rapid relapse of pain after their discontinuationscore 2

A patient is considered to have SpA if the sum of the points is 6 or more. A total point count of 5 or more classifies for probable SpA. Amor B, Dougados M, Mijiyawa M. [Criteria of the classication of spondylarthropathies]. Rev Rheum Mal Osteoartic 1990;57:859.

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Figure 10. Diagnostic criteria for ankylosing spondylitis (tree decision). AS, ankylosing spondylitis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; NSAIDs, non-steroidal antiinammatory drugs; SpA, spondyloarthritis. Reprinted with permission from Rudwaleit M, van der Heijde D, Khan MA, et al. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:53543.

8. Concept of spondyloarthritis in clinical practice Recognition of the SpA concept is of great importance in daily practice as it: (a) permits earlier diagnosis; (b) improves patient education; and (c) allows better patient monitoring and treatment.

8.1 Earlier diagnosis Early diagnosis is essential because it has been shown that the burden of early disease is substantial and comparable to that of later stages. The advancements in MRI technology, the efficacy of anti-TNF blockers together with the new classification criteria for axial SpA have made early diagnosis and treatment an achievable goal.

8.2 Patient education Patient education is crucial for the successful management of patients with SpA. Once the diagnosis is made, the patient should be given a clear description of the nature of the disease, including an

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explanation of the various potential clinical symptoms and presentations as well as the possible progression of the target symptom. To clarify this approach, take the example of a young patient presenting with inflammatory low back pain: The patient has to be informed clearly about the differences between back pain due to SpA and mechanical back pain. The most common misconceptions are that (a) NSAIDs have a higher toxicity than efficacy and (b) physiotherapy has no effect on the long-term outcome of back pain. Information about the possible occurrence of spinal ankylosis and abnormal postures will lead to better compliance with proposed treatments, such as NSAIDs and physiotherapy, and will give the patient a better understanding of the benefits of regular follow-up. The patient must be informed about the possibility of the occurrence of other clinical symptoms of SpA. For example, the risk of developing acute anterior uveitis in which case an early ophthalmic review would be required, has to be clearly explained.

8.3 Patient monitoring and treatment Monitoring is based on the clinical presentation which can be a combination of axial arthritis, peripheral arthritis, enthesopathy and extra-articular disease. The monitoring tools used for evaluating the severity of axial involvement are similar whatever the subgroup of SpA (eg, AS, PsA, inflammatory bowel disease-related arthritis). Similarly, treatment is based on the clinical presentation rather than on the specific disease subtype. For example, methotrexate is considered to be useful in patients with peripheral arthritis but not in patients with axial involvement whatever the underlying specific disorder. 9. Different diseases belonging to spondyloarthritis SpA can present with a wide spectrum of clinical features. Certain features occur more commonly in some subtypes of SpA. Table 1 shows typical patterns of SpA subtypes. However, there is overlap of symptoms and so it is possible for any of the principal clinical features to be present in any of the distinct diseases.

9.1 Ankylosing spondylitis AS is the prototype of the SpA. It is characterised by the presence of axial symptoms resulting in both spinal mobility limitation and radiological evidence of sacroiliitis. Nevertheless, other manifestations can be seen, in particular, entheisitis (4060%) and/or acute anterior uveitis (3050%). The modified New York criteria (box 9) have been widely accepted both in clinical practice and in clinical trials to classify patients with AS. Although they work well in established disease, they are very limited in early disease. In addition, they focus mainly on the spine and sacroiliac joints and do not include any extra-articular features. A prospective study indicated that the sensitivity of the modified New York criteria increased with disease duration (sensitivity 0% for a disease duration of 2 years vs
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60.2% for a disease duration of >10 years). The delay before detecting radiological sacroiliitis might explain these results. Although the modified New York criteria are sensitive, they cannot detect mild, undifferentiated or early forms of the disease.

Table 1. Prevalence of clinical features/disease in SpA Clinical features/diseases Axial arthritis Peripheral arthritis Enthesitis Extra articular features: Uveitis Psoriasis Diarrhoea Conjunctivitis, urethritis Aortic insufficiency AS Psoriatic Enteropathic Reactive Juvenile- Undifferentiated arthritis arthritis arthritis onset SpA SpA ++ ++ ++ + + +++ + + + + + + + + +

+++ + +

++

+ +++

+ +++

+++ + + + + + +

Box 9 Modified New York criteria for AS.


Diagnosis
Clinical criteria Low back pain and stiffness for more than 3 months which improves with exercise but is not relieved by rest Limitation of motion of the lumbar spine in both the sagittal and the frontal planes Limitation of chest expansion relative to normal value, corrected for age and sex

Radiological criterion Sacroiliitis grade >2 bilaterally or sacroiliitis grade 34 unilaterally

Grading
Definite AS if the radiological criterion is present with at least one clinical criterion Probable AS if: Three clinical criteria are present The radiological criterion is present without any signs or symptoms fulfilling the clinical criteria
van der Linden J, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modication of the New York criteria. Arthritis Rheum 1984;24:3618.

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9.2 Psoriatic arthritis Psoriasis is a common skin disease among Caucasian subjects (13% prevalence), but uncommon in some other ethnic groups, such as Afro-Caribbean and Native American populations (00.3%). It affects men and women equally. About 10% of patients have associated PsA. Psoriasis usually antedates the appearance of arthritis, but the onset is simultaneous in 20% of patients and in up to 15% the arthritis may precede the onset or diagnosis of psoriasis. The arthritis usually starts between 30 and 50 years of age, but can also begin in childhood. In most patients, exacerbations and remissions of skin and joint involvement occur with little or no apparent relationship. Peripheral joint involvement may be polyarticular or oligoarticular. The typical pattern of joint disease is an asymmetrical distribution with distal interphalangeal involvement and dactylitis. About 5% present with predominant spondylitis. A few patients present with a mutilating type of disease affecting the distal interphalangeal joints, called arthritis mutilans. PsA is a chronic erosive disease and treatments are similar to those used in rheumatoid arthritis. The CASPAR (Classification Criteria for Psoriatic Arthritis) criteria were developed by an international study group and have a sensitivity of 91% and a specificity of 99% (box 10). Radiologically, PsA is characterised by juxta-articular new bone formation, absence of peri-articular osteopenia and relative preservation of the joint space. SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome has been associated by some with PsA. It is a specific dermatological entity (pustulosis, acneform skin rash) associated with synovitis of the anterior chest wall and sacroiliac joints, spondylodiscitis, enthesopathy, aseptic osteomyelitis and/or hyperostosis.

Box 10 CASPAR (Classification Criteria for Psoriatic Arthritis) for PsA Current psoriasis score 2 A history of psoriasis (in the absence of current psoriasis) - score 1 A family history of psoriasis in first or second degree relative (in the absence of current psoriasis and history of psoriasis) score 1 Dactylitis score 1 Juxtaarticular new-bone formation score 1 Rheumatoid factor negativity score 1 Nail dystrophy score 1

The patient is considered to have psoriatic arthritis if the sum of the points is 3 or more.
Taylor W, Gladman D, Helliwell P, et al. Classication criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:266573.

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9.3 Enteropathic arthritis Enteropathic arthritis describes the occurrence of inflammatory arthritis in patients with ulcerative colitis or Crohns disease. The prevalence of arthritis in inflammatory bowel disease ranges from 17% to 20%, with a higher prevalence in Crohns disease. The most common manifestation of enteropathic arthritis is inflammation of the knee and ankle joints. Axial involvement and enthesitis may also be found. The peripheral arthritis is usually transient, migratory and non-deforming. The inflammatory episodes are generally self-limiting, often subsiding within 6 weeks, but recurrences are common. In some cases, the arthritis may become chronic and destructive. Intestinal symptoms usually antedate or coincide with joint manifestations, but arthritis may precede the intestinal symptoms by years.

9.4 Reactive arthritis ReA describes an episode of aseptic peripheral arthritis that occurs within 1 month of a primary infection elsewhere in the body, usually a genitourinary infection with Chlamydia trachomatis or enteritis due to Gram-negative enterobacteria such as Shigella, Salmonella, Yersinia or Campylobacter species. Genitourinary tract infection with C trachomatis is the most commonly recognised initiator of ReA in developed countries, whereas infections with enterobacteria are the most common triggers in developing parts of the world. In about 25% of cases, however, the triggering organism is unknown. ReA is typically an acute, asymmetric oligoarthritis and is often associated with one or more characteristic extra-articular features such as ocular inflammation (conjunctivitis or acute iritis), enthesitis, mucocutaneous lesions, urethritis and, on rare occasions, carditis. Conjunctivitis occurs in one-third of patients, usually at the same time as arthritis flares, and acute anterior uveitis may occur at some time in about 5% of patients. The triad of arthritis, conjunctivitis and urethritis is called classic ReA. However, most patients with ReA do not present with this triad. The average duration of arthritis is 45 months, but two-thirds of patients have mild musculoskeletal symptoms that persist for more than 1 year. Recurrent attacks are more common in patients with chlamydia- induced ReA. About 15 30% of patients develop chronic or recurrent peripheral arthritis, sacroiliitis or spondylitis. Most patients with chronic ReA have a positive family history for SpA or are HLA-B27 positive.

9.5 Juvenile-onset spondyloarthritis Juvenile-onset SpA usually manifest initially as peripheral arthritis or enthesitis in children aged 812 years, but onset at younger or older ages has been reported. There is a striking predominance of male subjects, particularly in the prepubertal stage. Juvenile-onset SpA clinically resembles adult SpA. Nonetheless, there are a few differences. Oligoarthritis affecting the knee, ankle and/or mid-foot is the typical initial presentation and dactylitis is commoner in children. Systemic manifestations such as fever and weight loss occur more often in children and enthesitis is prominent early on in the disease course.
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The disease pattern often changes throughout childhood, adolescence and adulthood (eg, from monoarthritis to a more complex form of disease leading to axial, peripheral and extra-articular manifestations). There are undifferentiated and differentiated forms of juvenile-onset SpA, which can be classified according to the International Association for Rheumatology criteria in the enthesitis-related arthritis subgroup. The adult Amor and ESSG criteria have been validated in children and may also be used. Prognosis seems to be less favourable in juvenile-onset SpA than in adults. Potentially structural damage at some sites (particularly the feet, hips and spine) may lead to long-term functional impairment. Nearly 60% of patients have moderate-to-severe limitations 10 years after disease onset. The probability of remission is only 17% after a disease duration of 5 years.

9.6 Undifferentiated SpA Undifferentiated SpA is frequently under-diagnosed and includes isolated clinical syndromes, such as HLA-B27- associated seronegative oligoarthritis or polyarthritis, mostly of the lower limbs. This arthritis has no recognisable preceding bacterial infectious trigger, and is not associated with inflammatory bowel disease or psoriasis. Patients with undifferentiated SpA may have dactylitis with a sausage-like appearance of the affected finger or toe. They may also experience enthesitis, especially at the heel. Some patients may present with an episode of acute anterior uveitis or have a syndrome of aortic insufficiency plus heart block. The cardiac syndrome or acute iritis may occur in patients who never develop signs of arthritis and may sometimes accompany or precede the onset of SpA. 10. Assessment/monitoring For both assessment and monitoring, one has to consider systematically the four potential clinical presentations: axial involvement, peripheral arthritis, enthesopathy and extra-articular features.

10.1 Assessment When assessing a patient, especially in the initial review, the following questions need to be addressed: Does the patient have the disease? What is the disease activity? What is the disease severity? Can we predict the development of severe disease? Is the disease refractory?

10.1.1 Does the patient have the disease? The concept of diagnostic and classification criteria has already been discussed. Nonetheless, it is important to emphasise that at the individual level, such a question might be difficult to answer. In

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other words, no set of criteria has 100% sensitivity and 100% specificity. Difficult situations arise when there are no clear objective signs or symptoms and the diagnosis is based on subjective symptoms, for example IBP, heel pain and chest pain. Before considering a potentially toxic, expensive treatment such as anti-TNF agents, it is strongly recommended that other possible causes are excluded and objective evidence and appropriate investigations are carried out.

10.1.2 What is the disease activity? Disease activity is related to the degree of inflammation. The ASAS has issued recommendations regarding the use of different assessment tools covering the various domains of disease activity (table 2).

Table 2. ASAS recommendations (adapted from van der Heijde D et al. J Rheumatol 1999;26:9514). Domain Physical function* Pain* Spinal mobility* Patient global assessment* Morning stiffness* Fatigue* Peripheral joints and entheses Acute phase reactants Spine radiographs Instrument BASFI or Dougados Functional Index VAS/NRS past week in spine, at night, due to AS and VAS/NRS past week, in spine due to AS Chest expansion and modified Schober and occiput-to-wall distance and lateral spinal flexion VAS/NRS past week Duration of morning stiffness in spine past week VAS/NRS past week Number of swollen joints (44 joint count). Validated enthesis indexes ESR Anteroposterior + lateral lumbar and lateral cervical spine and x-ray examination of pelvis to visualise sacroiliac joint and hips) As above

Hip radiographs

Adapted from van der Heijde D, Calin A, Dougados M, et al. Selection of instruments in the core set for DCART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis. Progress report of the ASAS Working Group. Assessments in Ankylosing Spondylitis. J Rheumatol 1999;26:9514. * Included in core set for DC-ART, SMARDs/physical therapy and clinical record keeping; included in core set for DC-ART and clinical record keeping; included in core set for DC-ART. AS, ankylosing spondylitis; ASAS, Assessment of SpondyloArthritis international Society; BASFI, Bath AS Functional Index; DC-ART, disease-controlling anti-rheumatic therapy; ESR, erythrocyte sedimentation rate; NRS, numerical rating scale; SMARDs, symptom-modifying anti-rheumatic drugs; VAS, visual analogue scale.

Depending on the clinical pattern of the disease, appropriate assessment tools are needed. Table 3 summarises the different clinical patterns.

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Table 3. Evaluation of activity of different clinical patterns of SpA. Axial involvement Night pain Morning stiffness CRP Pain Functional impairment MRI Peripheral arthritis Night pain Morning stiffness Swollen joint count CRP Pain Tender joint count Functional impairment US MRI Enthesopathy Pain Functional impairment Extra articular features Acute anterior uveitis

Enthesopathy index

Psoriasis IBD

US MRI bone scan

CRP, C-reactive protein; IBD, inflammatory bowel disease; MRI, magnetic resonance imaging; US, ultrasonography.

In axial involvement, the degree of both night time pain and spinal pain is measured using either a visual analogue scale (VAS) or a numerical rating scale. Morning stiffness should be evaluated both in terms of duration and severity. Functional impairment is evaluated in clinical trials using the Bath AS Functional Index (BASFI; box 11). All the above tools are patient reported and considered subjective. When using VAS scales, a value over 40 on a scale from 0 to 100 is usually considered as reflecting active disease.

Box 11 Bath AS Functional Index: evaluation of functional impairment


Please indicate your level of ability with each of the following activities during the past week (difculty is assessed on a 10-point scale) Putting on your socks or tights without help or aid (e.g. sock aids) Bending forward from the waist to pick up a pen from the floor without an aid Reaching up to a high shelf without help or aids (e.g. helping hand) Getting up out of an armless dining room chair without using your hands or any other help Getting up off the floor without help from lying on your back Standing unsupported for 10 min without discomfort Climbing 1215 steps without using a handrail or walking aid (one foot each step) Looking over your shoulder without turning your body Doing physically demanding activities (e.g. physiotherapy exercises, gardening or sports) Doing a full days activities whether it be at home or at work

The main question in daily practice is whether it is mandatory to employ objective methods to evaluate such activity before considering a new treatment such as anti-TNF. The only non-subjective instruments reflecting disease activity are serum CRP (raised in up to 40% of patients) and the presence of inflammatory lesions on MRI at the spine and/or sacroiliac joints.

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In peripheral arthritis, disease activity evaluation is similar to that used in rheumatoid arthritis for example, number of tender joints, number of swollen joints, CRP, etc. There is no consensual definition of a peripheral active disease. However, the presence of at least three swollen joints is usually considered to reflect active disease, in particular when associated with an increased CRP.

10.1.3 General evaluation Besides the different instruments facilitating activity assessment of the different clinical presentations, a single instrument (eg, a composite index) has been proposed to allow a general evaluation. Such an instrument (the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); box 12) is simple to use since it comprises only six questions related to: o o o o o fatigue axial involvement peripheral articular involvement enthesopathy morning stiffness (two questions).

Using a scale of 0100, a composite score above 4 is considered as the threshold above which a disease can be considered as active. More recently, another composite index taking into account not only some questions in the BASDAI but also the biological markers of inflammation (either CRP or ESR) has been proposed (box 13). The Ankylosing Spondylitis Disease Activity Score (ASDAS) has been extensively validated. It has been shown to be reliable, discriminative and sensitive, performing equally as well as BASDAI and in some circumstances better. However, cut-offs for disease activity (low/moderate/high) and improvement have not yet been defined and usefulness in daily practice remains to be further investigated.

Box 12 Bath Ankylosing Disease Activity Index: evaluation of disease activity


How would you describe the overall level of fatigue/tiredness you have experienced? How would you describe the overall level of AS neck, back or hip pain you have had? How would you describe the overall level of pain/swelling in joints other than the neck, back or hips you have had? How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure? How would you describe the overall level of morning stiffness you have had from the time you wake up? How long does your morning stiffness last from the time you wake up?

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Box 13 Evaluation of the activity of the disease ASDAS CRP/ESR ASDASCRP*


0.21xTotal Back Pain + 0.110xPatient Global + 0.073xPeripheral Pain/Swelling 0.058xDuration + of Morning Stiffness + 0.579xLn (CRP+1)

ASDASESR*
0.113xPatient Global + 0.293xESR + 0.086xPeripheral Pain/Swelling 0.069xDuration + of Morning Stiffness + 0.079xTotal Back Pain

Lukas C, Landew R, Sieper J et al. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:1824. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

10.1.4 What is the disease severity? Disease severity refers to the concept of irreversible structural damage. Such severity can be assessed using different approaches. Severity can be assessed in terms of death, job loss, functional impairment, limited range of motion, hip involvement and radiological damage. Here, we focus on the last four measures.

10.1.5 Functional impairment Functional impairment can be related to both the activity and the severity of the disease. Several available instruments (BASFI, Health Assessment Questionnaire, WOMAC, etc) can be used depending on the clinical presentation of SpA.

10.1.6 Range of motion The most commonly used instrument in clinical trials is currently a composite index combining information from five different tools: cervical rotation (figure 11), tragus-to-wall distance (figure 12), spinal lateral flexion (figure 13), lumbar flexion (modified Schobers test) (figure 14) and intermalleolar distance (figure 15). Table 4 shows details of this composite index the Bath Ankylosing Spondylitis Mobility Index (BASMI).

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Figure 11. Cervical rotation.

Figure 12. Tragus-to-wall distance.

Figure 13. Spinal lateral flexion.

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Figure 14. Lumbar flexion (modified Schobers test).

Figure15. Intermalleolar distance.

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Table 4. Bath Ankylosing Spondylitis Mobility Index (BASMI)*,**: evaluation of spinal mobility
If: Then score = 0 Lateral lumbar flexion (cm) Tragusto-wall distance (cm) Lumbar flexion (modified Schober) (cm) Intermalleolar distance (cm) Cervical rotation angle () 85 76.6-85 68.176.5 59.6-68 51.159.5 42.6-51 34.142.5 25.6-34 17.125.5 8.6-17 8.5 120 110119.9 100109.9 90-99.9 80-89.9 70-79.9 60-69.9 50-59.9 40-49.9 3039.9 30 7 6.4-7.0 5.7-6.3 5.0-5.6 4.3-4.9 3.6-4.2 2.9-3.5 2.2-2.8 1.5-2.1 0.8-1.4 0.7 10 10-12.9 13-15.9 16-18.9 19-21.9 22-24.9 25-27.9 28-30.9 31-33.9 3436.9 37 20 1 18-20 2 15.917.9 3 13.815.8 4 11.713.7 5 9.611.6 6 7.5-9.5 7 5.4-7.4 8 3.3-5.3 9 1.2-3.2 10 1.2

Jenkinson JR, Mallorie PA, Whitelock HC, et al. Defining spinal mobility in Ankylosing Spondylitis (AS): The Bath AS metrology index. J Rheumatol 1994;21:196498; van der Heijde D, Landew R, Feldtkeller E. Proposal of a linear definition of the Bath Ankylosing Spondylitis Metrology Index (BASMI) and comparison with the 2step and 10-step definitions. Ann Rheum Dis 2008;67:48993.

10.1.7 Evaluation of range of motion in daily practice To understand the usefulness of the physical examination, the natural history of the disease has to be kept in mind. Moreover, the different instruments have to be split into two categories: Those instruments evaluating loss of motion (stiffness), such as lumbar flexion and chest expansion Those evaluating abnormal postures, such as the tragus-to-wall distance.

Abnormal postures have to be carefully checked in order to provide the best physical therapy. Once the loss of lumbar lordosis has appeared, thoracic kyphosis and a fixed flexed posture of the cervical spine may follow. The most disabling abnormal posture is the loss of the horizontal view, for which a surgical spinal intervention (vertebral osteotomy) can be considered.

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10.1.8 Hip involvement Hip involvement is closely related to the severity of spinal ossification and is responsible for significant functional impairment. The prevalence after 10 years of disease is around 1015% in Western European countries, but up to 4050% in other parts of the world such as North Africa. It is typically bilateral. The inter-malleolar distance of the BASMI reflects the degree of hip involvement.

10.1.9 Spinal radiographic severity scoring system A spinal radiographic severity scoring system has been proposed using a 15 Likert scale (table 5). This scoring system is rarely used but may be of interest when conducting clinical studies.

Table 5. Staging severity scoring system: spinal radiographic severity in AS Stage I II Description Grade II or higher bilateral radiographic sacroiliitis Minor radiographic evidence of spinal involvement in 1 spinal segment (<3 vertebrae, which equals <15% of the spine) III Moderate radiographic evidence of spinal involvement in 2 spinal segments (412 vertebrae, which equals 1550% of the spine) IV Radiographic evidence of spinal involvement in 3 spinal segments (1319 vertebrae, which equals 5080% of the spine) V Widespread (>80%) fusion of the spine (>20 vertebrae)

Braun J, van der Heijde D, Dougados M, et al. Staging of patients with ankylosing spondylitis: a preliminary proposal. Ann Rheum Dis 2002;61(Suppl 3):923.

10.1.10 Can we predict the development of severe disease? Information about the potential severity of the disease has become more important. As in rheumatoid arthritis, there is a trend to treat patients efficiently as early as possible and before irreversible structural damage has occurred. This prognostic assessment is important to guide treatment strategies. Candidate predictors for potentially severe disease are shown in box 13. The negative predictive value is more reliable than the positive predictive value. In other words, the absence of any of the variables listed in box 14 is highly predictive of a good prognosis. Ongoing long-term follow-up of patients presenting with recent IBP in different European cohorts will hopefully increase our knowledge in this area in the near future.

10.1.11 Is the disease refractory? This question is of great importance when considering treatments such as anti-TNF blockers. The most common situation is when a patient is described as refractory to NSAIDs. Because of patients variability in their response to NSAIDs, the current recommendation is to define a patient as

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refractory to NSAIDs only when active disease persists despite the intake of at least two courses of NSAIDs taken at an optimal dosage for at least 23 weeks.

Box 14 Candidate predictors for potentially severe disease.


Presence of the following parameters during the first 2 years: Hip involvement Erythrocyte sedimentation rate >30 mm/1st h Refractory to NSAIDs Reduction in lumbar spine movement Dactylitis Monoarthritis/oligoarthritis Age at onset before16 years Diarrhoea Urethritis Psoriasis Inflammatory bowel disease

Amor B, Santos RS, Nahal R et al. Predictive factors for the longterm outcome of spondyloarthropathies. J Rheumatol 1994;21:18837.

11. Monitoring The two main domains which have to be monitored both in daily practice and in clinical trials are disease activity and severity. The monitoring tools are the same as the assessment tools.

11.1 Monitoring disease activity A change of at least 50% in the BASDAI is usually considered as reflecting a clinically relevant improvement. ASAS has proposed two composite indices for monitoring disease activity in clinical trials: One set of responder criteria (ASAS20; box 15) One set of remission criteria (box 16)

Such sets of criteria have been developed via databases evaluating symptomatic drugs (eg, NSAIDs); recently, ASAS has proposed a new set of criteria for evaluating potential diseasemodifying drugs, including two other domains (spinal mobility and biological inflammation; box 17).

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Box 15 ASAS20 responder criteria set


Improvement of at least 20% and absolute improvement of at least 10 on a 0100 scale in at least three of the following domains: Patient global=VAS (0100) Pain=VAS global, past 2 days (0100) Function=BASFI (0100) Inflammation First choicetwo last questions of the BASDAI Second choicemorning stiffness duration with a maximum of 120 mm or a 0100 scale

Absence of deterioration (of at least 20% and absolute deterioration of at least 10 on a 0100 scale) in the remaining domain.
Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing spondylitis assessment group preliminary denition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 2001;44:187686. ASAS, Assessment of Spo ndyloArthritis international Society; BASDAI, Bath AS Disease Activity Index; BASFI, Bath AS Functional Index; VAS, visual analogue scale.

Box 16 ASAS remission criteria set


A value below 20 on a 0100 scale in each of the four domains: Patient global=VAS (0100) Pain=VAS global, past 2 days (0100) Function=BASFI (0100) Inflammation First choicetwo last questions of the BASDAI Second choicemorning stiffness duration with a maximum of 120 mm on a 0100 scale

Absence of deterioration (of at least 20% and absolute deterioration of at least 10 or a 0100 scale) in the remaining domain.
Anderson JJ, et al. Arthritis Rheum 2001;44:187686. BASDAI, Bath AS Disease Activity Index; BASFI, Bath AS Functional Index; VAS, visual analogue scale.

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Box 17 ASAS 5/6 improvement criteria


Improvement of at least 20% and absolute improvement of at least 10 on a 0100 scale in at least four (or five) of the following domains: Patient global Pain Function Morning stiffness Spinal mobility C-reactive protein

Brandt J, Listing J, Sieper J, et al. Development and preselection of criteria for short term improvement after anti-TNF treatment in ankylosing spondylitis. Ann Rheum Dis 2004;63:143844. ASAS, Assessment of SpondyloArthritis international Society; DMARD, disease-modifying anti-rheumatic drug.

11.2 Monitoring disease severity The main measure for monitoring the severity of disease is radiological evaluation of the spine. For this purpose, several scoring systems evaluating not the destructive process but the constructive one (syndesmophyte count) have been proposed. The modified Stoke Ankylosing Spondylitis Spine Score (figure 16) is most frequently used in clinical trials. Figure 16. Radiological spinal scoring system in ankylosing spondylitis (AS) (modied Stoke AS Spine Score). Reprinted with permission from Wanders AJ, Landew RB, Spoorenberg A, et al. What is the most
appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials lter. Arthritis Rheum 2004;50:262232.

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Summary points

Spondyloarthritis (SpA) is a heterogeneous family of disorders characterised by axial inammatory pain, peripheral arthritis and enthesitis. There may be associated extra-articular features such as chronic inammatory bowel disease, psoriasis, urethritis and a tendency to anterior uveitis. Subjects with the HLA-B27 tissue antigen have an increased risk of developing SpA. Genetic epidemiological studies suggest the existence of other predisposing genes, such as the IL23R, ERAP1, IL1R2, ANTXR2, TNF-SF15, 2p15 and 21q22 genes. Apart from the genetic factors, environmental factors, in particular infections, predispose to the occurrence or inuence the severity of the disease. The rate of withdrawal from the labour force is three times higher in patients with ankylosing spondylitis (AS) than in the general population. The initial symptom of AS is typically a dull inammatory lower back pain of insidious onset, becoming persistent after a few months. However, a diagnosis of SpA can made in the absence of inammatory back pain (IBP).

Arthritis of the peripheral joints is mostly oligoarticular, asymmetrical, transient and migratory, with involvement of both small and large joints, predominantly of the lower limbs. Acute anterior uveitis is the most common extra-articular manifestation, with 2540% of patients experiencing one or more episodes. It requires urgent ophthalmological referral since it can lead to permanent visual loss.

There are no specic diagnostic tests for SpA. The radiographic hallmarks of AS are sacroiliitis (identied by blurring of the cortical margins of the subchondral bone), erosions and sclerosis. MRI is able to detect inammatory lesions long before denite lesions are visible on plain radiographs. A negative MRI does not exclude a diagnosis of SpA. The new Assessment of SpondyloArthritis international Society (ASAS) criteria for axial SpA have made it possible to diagnose early non-radiographic axial SpA as well as established SpA. Using the new ASAS criteria, diagnosis of axial SpA can still be based on clinical grounds. This requires the presence of HLA-B27 plus two other SpA features. Another important difference is that IBP is no longer a compulsory criterion.

The ASAS working group has proposed a core set of tools for assessing disease activity and severity in order to facilitate treatment and record keeping. These consist of patient reported outcome measures as well as clinical and radiological measurements.

The domains of pain, patient global assessment of disease activity, morning stiffness, fatigue, spinal mobility and physical function are included in all core sets.

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12. Key references

Australo-Anglo-American Spondyloarthritis Consortium (TASC). Genomewide association study of ankylosing spondylitis identifies multiple non-MHC susceptibility loci. Nat Genet 2010;42:1237. Lukas C, Landew R, Sieper J, et al. Development of an ASAS- endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:1824. Marzo-Ortega H, McGonagle D, OConnor P, et al. Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence. Ann Rheum Dis 2009;68:17217. Rudwaleit M, Jurik AG, Hermann KG, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis 2009;68:15207. Rudwaleit M, Landew R, van der Heijde D, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis 2009;68:7706. Rudwaleit M, van der Heijde D, Khan MA, et al. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:53543. Rudwaleit M, van der Heijde D, Landew R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:77783. Sims AM, Barnardo M, Herzberg I, et al. Non-B27 MHC associations of ankylosing spondylitis. Genes Immun 2007;8:11523. Song IH, Carrasco-Fernndez J, Rudwaleit M, et al. The diagnostic value of scintigraphy in assessing sacroiliitis in ankylosing spondylitis: a systematic literature research. Ann Rheum Dis 2008;67:153540. Wanders AJ, Landew RB, Spoorenberg A, et al. What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter. Arthritis Rheum 2004;50:262232.

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