Ankylosing Spondylitis: A Contemporary Perspective on Diagnosis and Treatment

Mark Mansour,* Gurtej S. Cheema, Stanley M. Naguwa, Adam Greenspan, Andrea T. Borchers, Carl L. Keen, and M. Eric Gershwin#

Objectives: In recent years, great progress has been made in the development of diagnostic tools, therapeutic approaches, and validated outcome measures in the understanding of the pathogenesis of ankylosing spondylitis (AS). The purpose of this review was to summarize these developments. Methods: We performed a PubMed search for the period 1978 to 2005, using the keyword, ankylosing spondylitis, resulting in a total of 4878 publications, including 778 reviews. Articles were then selected based on their discussion of recent diagnostic tools and new treatment approaches in the pathogenesis of AS, leading to a nal total of 104 articles. Results: In recent years, there have been 2 major developments in the management of AS that make earlier diagnosis possible and offer the hope of alleviating pain and preventing structural changes that result in loss of function. These developments include the use of magnetic resonance imaging to visualize the inammatory changes in the sacroiliac joint and the axial spine, and the demonstration that tumor necrosis factor blocking agents are highly efcacious in reducing spinal inammation and possibly in slowing radiographic progression. Conclusions: There have been major advances in both the diagnostic tools and the therapeutic regimens available for patients with AS. 2007 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 36:210-223 Keywords: seronegative spondyloarthritis, computed tomography, TNF blocking agents, sacroiliitis, HLA B27

he prototypic seronegative spondyloarthropathy (SpA) is ankylosing spondylitis (AS); other forms include reactive arthritis (Reiter syndrome), psoriatic arthritis, enteropathic arthritis, and undifferentiated SpA. AS is a chronic inammatory rheumatic disease involving primarily the sacroiliac joint and the axial skeleton, but also peripheral joints and entheses. It can be

*Postdoctoral Fellow, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA. Assistant Clinical Professor of Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA. Clinical Professor of Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA. Professor of Radiology, University of California, Davis, CA. Visiting Postdoctoral Fellow, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA. Professor and Chair, Department of Nutrition, University of California, Davis, CA. #Professor and Chief, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA. Address reprint requests to: M. Eric Gershwin, MD, Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ucdavis.edu

present as primary AS or can be secondary to other SpAs. If patients present with AS before the age of 16 years, they are classied as having juvenile AS or enthesitis-related arthritis, a subtype of juvenile idiopathic arthritis (1). Even though the prevalence of axial SpA is 5% among patients with chronic back pain (2), it is frequently overlooked as a possible diagnosis especially in young patients. Until recently, even if AS was considered a possibility, a decade or more frequently passed before the diagnosis could be considered denite. Furthermore, disease-modifying treatments were essentially unavailable. In recent years, great progress has been made in the development of diagnostic tools, therapeutic approaches, and validated outcome measures in the understanding of the pathogenesis of AS. The purpose of this review was to summarize these developments. METHODS We performed a PubMed search using the terms ankylosing spondylitis in the period of 1978 to 2005, restricted to the English language. This yielded a total of

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0049-0172/07/$-see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2006.08.003

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Abbreviations AS ASAS BASDAI BASFI 2m CD CT DISH DMARD ER ESR EULAR FDA HLA IFN IL MHC MRI NSAIDs RA RCT SpA SSZ TNF ankylosing spondylitis assessment in AS Bath AS Disease Activity Index Bath AS Functional Index 2-microglobulin cluster of differentiation computed tomography diffuse idiopathic skeletal hyperostosis disease-modifying antirheumatic drug endoplasmic reticulum erythrocyte sedimentation rate European League Against Rheumatism Food and Drug Administration human leukocyte antigen interferon interleukin major histocompatibility complex magnetic resonance imaging nonsteroidal antiinammatory drugs rheumatoid arthritis randomized controlled trial spondyloarthropathy sulfasalazine tumor necrosis factor

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the disease of 63 to 75% compared with 12.5% in dizygotic twins (8). This suggests a major genetic component in the pathogenesis of the disease. A strong association between HLA-B27 and susceptibility to AS and other SpAs has been recognized for decades and is illustrated by the fact that 90% of AS patients of European ancestry are HLA-B27-positive, and concordance rates in HLAB27-positive dizygotic twins are signicantly higher than in dizygotic twins overall (27% versus 12.5%) (8). A key role for HLA-B27 is further suggested by the fact that rats transgenic for HLA-27 develop a progressive inammatory arthritis whose clinical and histological features resemble those of the inammatory SpAs (9). Pathogenic Immunologic Mechanisms of HLA-B27 There are at least 25 alleles or subtypes of HLA-B27 that encode 23 different products: HLA-B*2701 to 2723. These alleles are thought to have evolved from the most widespread subtype, B*2705 (10), which is clearly associated with AS risk, as demonstrated by its presence in 90% of B-27-positive patients of northern European extraction (11). Other common subtypes that confer susceptibility to AS and other SpAs are B*2701, B*2702, B*2704, B*2705, and B*2707. In contrast, B*2706 and B*2709, found in Southeast Asia and Sardinia, respectively, do not exhibit disease associations (10). Several mechanisms for the pathogenic role of HLAB27 in AS and other SpAs have been proposed and involve its classical function as a restriction element, molecular mimicry, a role of HLA-B27 as an autoantigen, and some unique features in the intracellular processing of the HLA-B27 heavy chains giving rise to their homodimerization. It has been hypothesized that the pathogenetic role of HLA-B27 involves the presentation of a unique peptide of microbial or self-origin. In particular, it has been postulated that microbial infections can lead to loss of self-tolerance when antibodies or T-cells elicited by the infectious agents cross-react with a host protein because it shares extensive sequence homology with the microbial molecule. In support of such molecular mimicry, homology has been demonstrated between various bacterial or viral peptides and peptides derived from human proteins (12-14). In addition, certain self-peptides not only share sequence homology with bacterial antigens, but are also natural ligands of HLA-B27 (12,15). The differential association of HLA-B27 alleles with AS suggests that disease-associated and nonassociated subtypes differ in their peptide repertoire and/or the mode of peptide presentation. Indeed, even though the major disease-associated and nonassociated subtypes differ by only a single residue within the peptide-binding groove, their peptide and cytotoxic T-lymphocyte repertoires do not completely overlap (14,15). In addition, even when AS-associated and nonassociated subtypes bind the same peptide, the mode of presentation can dif-

4878 publications, including 778 reviews. From this list, and based on the abstract, a total of 427 articles were chosen that appear to highlight recent progress in the pathogenesis of AS as well as in the use of diagnostic tools and therapeutic approaches. In addition, we also reviewed the data in these 104 articles regarding the associations of AS with epidemiology and genetics. The clinical characteristics of patients as well as diagnostic technological advances were also compiled. Our nal emphasis was on the treatment of AS. RESULTS Epidemiology Historically, AS was thought to be a disease that almost exclusively affected young men. More recent studies suggest a male-to-female ratio of about 2 or 3 to 1, although there can be considerable geographical and ethnic variation. Disease onset generally occurs in late adolescence or early adulthood, most frequently in the third decade of life. For white populations, prevalence estimates range between 0.1 and 1.4% (3-6). Human leukocyte antigen (HLA)-B27 is strongly linked to disease susceptibility, and there is a close correlation between the frequency of several subtypes of this allele in a population and the prevalence of AS. Pathogenesis Genetics A positive family history of AS can be found in 15 to 20% of cases (7). Monozygotic twins have a concordance for

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fer dramatically. For example, striking differences in the mode of peptide presentation were demonstrated for the self-peptide pVIPR from vasoactive intestinal peptide type 1 receptor and the viral peptide pLMP2 from latent membrane protein 2 of EpsteinBarr virus (16,17). Importantly, these peptides share 6 of 9 amino acid residues, but exhibit extensive structural similarity only when presented by B*2705, indicating that molecular mimicry is restricted to the disease-associated allele at least in this case (16). Similarly, it was recently shown that another selfpeptide with homology with enterobacterial antigens was recognized by HLA-B27-restricted cluster of differentiation (CD)8 T-cells from AS patients, but not by those of healthy controls (15). In contrast, other HLA-B27:peptide complexes are structurally, thermodynamically, and functionally equivalent and are, therefore, unlikely to play a role in the pathogenesis of AS (18). Of note, although major histocompatibility complex (MHC) class I generally is a restriction element for CD8 T-cells, the existence of MHC class I restricted CD4 T-cells has been demonstrated. It was recently reported that AS patients possessed CD4 T-cells that reacted with HLA-B27 if it was expressed in cell lines with defective antigen-processing pathways (19). Several lines of evidence suggested that altered forms of B27, rather than the usual heterotrimeric complex consisting of a heavy chain associated with 2-microglobulin (2m) and a peptide, were recognized by these CD4 T-lymphocytes. These ndings may be of pathogenetic relevance if microbial infections are capable of altering antigen processing, as has been shown for some viruses, or of otherwise inducing the expression of altered forms of B27. HLA-B27 heavy chains have some highly unusual characteristics in terms of their folding and complex formation with 2m in the endoplasmic reticulum (ER), the cellular compartment in which proteins that are destined for the cell surface or the extracellular space are processed and, in some cases, assembled into larger complexes. Due to their unique B-pocket in the peptide-binding groove, folding of HLA-B27 heavy chains was found to be much slower than folding of other HLA alleles, resulting in their misfolding and degradation even in cells with an intact antigen-processing pathway (20). It has been suggested that the degradation pathway could become overwhelmed and that the resulting accumulation of misfolded protein in the ER could trigger a stress response. Although this would lead to activation of the transcription factor NF-B and, consequently, stimulate the production of proinammatory cytokines, it remains unclear how this would contribute to the pathogenesis of AS. Impaired folding of HLA-B27 heavy chains also results in the formation of 2 types of homodimers, 1 of which is not associated with 2m, but can be detected on the cell surface of HLA-B27-transfected T2 cells and appears to be capable of peptide binding (21,22). It is thought that the homodimerization would require unwinding of the 1 helix, which might then resemble the -chain helix of an

MHC class II molecule. This provides a possible explanation for the ndings discussed above, suggesting that HLA-B27-reactive CD4 T-cells from AS patients recognized homodimeric B27 (19). There is increasing evidence that HLA-B27 itself could be a source of antigenic peptides. Several such peptides share sequence homology with bacterial antigens and to be natural ligands of HLA-B27 (12,15) and also of HLA-A2, which was able to cross-present these peptides to CD4 T-cells (23). Based on molecular modeling studies, it has even been proposed that 2m-free, peptidefree heavy chains of HLA-B27 can undergo rotation of the backbone in such a way that residues 169 to 181 (which correspond to a known B27 ligand) can occupy its own binding groove (24). While B-27 has been shown to be unequivocally linked to AS and other inammatory SpAs, AS can occur in the absence of HLA-B27. Only about 10% of HLA-B27positive subjects (who constitute 8% of the general population) develop the disease (25), and even identical twins who are HLA-B27-positive can be discordant for disease incidence as well as severity (8,26). This clearly indicates that HLA-B27 is neither sufcient nor absolutely necessary for the occurrence of AS. Instead, it is becoming increasingly evident that AS is a polygenetic disease, in which HLA-B27 accounts for a minority of the overall genetic susceptibility to AS (25). Other genes have been implicated in either increasing disease susceptibility or modifying the clinical expression of AS. Candidates include other MHC genes such as HLA-B60, HLADRB1, and HLA-DR8, and tumor necrosis factor (TNF), as well as non-MHC genes such as interleukin (IL)-10, IL-1 receptor (IL-1R), and CYP2D6. In genome-wide searches, chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q have been linked to increased genetic susceptibility (25). To date, however, none of these associations have been consistently seen in different populations. Although the genetic component of AS is strong, development of AS obviously depends on a complex interplay of genetic and environmental factors. The involvement of bacterial infections in the pathogenesis of reactive arthritis is well documented, and a variety of infectious agents, including Shigella, Yersinia, and particularly Klebsiella, have been implicated as triggering agents or sources of cross-reactive peptides in AS. However, a pathogenic role for microbial infections in the pathogenesis of AS has not been shown conclusively. In contrast, it was recently reported that the magnitude of cellular and humoral immune responses to Klebsiella pneumoniae, Yersinia enterocolitica, Chlamydia trachomatis, and Salmonella typhimurium did not differ signicantly between AS patients, unaffected family members, and unrelated healthy controls (27). This argues against a central role for these arthritogenic organisms in the pathogenesis of AS. Subclinical ileal inammation is seen in over 50% of patients with SpA, including those with AS and, conversely, almost 40% of patients with inammatory bowel

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disease exhibit articular manifestations similar to those seen in SpA (13,28). In addition, rats transgenic for HLAB27 do not develop arthritis if raised in germ-free environments, but do so on reintroduction of commensal ora. Although this suggests that gut bacteria could act as triggering agents in AS, their role remains speculative. Enthesitis is a typical feature of AS and typically involves the brocartilaginous rather than the brous entheses (29). It also affects structures that are not classically considered entheses but share many of their structural and functional characteristics as well as the presence of brocartilage (29). In addition, they are all exposed to large amounts of shear stress and microtrauma. This has led to the hypothesis that the immune response in AS is targeted against brocartilage-rich entheses and enthesis-like structures, and that mechanical stresses, possibly in conjunction with bacteria or their products, trigger inammatory and pathological changes in genetically susceptible subjects (29). Since entheseal brocartilage is avascular, such pathological changes would be necessary to expose brocartilaginous antigens to circulating lymphocytes. Like cartilage, brocartilage in entheses and enthesislike structures contains the proteoglycan aggrecan. Immunization of mice with this protein or its hyaluronic acid binding G1 globular domain induces spondylitis and discitis (30). It was recently shown that 62% of AS patients possessed circulating CD4 T-cells that specically recognized the G1 domain of aggrecan, and the percentage was even higher when synovial T-cells were investigated (31). Aggrecan is also present within the intervertebral disc; the anterior uveal tract exhibits immunoreactivity with antibodies to aggrecan, and smooth muscle cells in arterial tissue produce the proteoglycan versican, which also contains a globular G1 domain that binds to hyaluronic acid (30). Thus, the tissue distribution of the G1 domain of aggrecan and related proteoglycans seems to provide an explanation for the tissue tropism of AS manifestations, ie, the fact that such apparently diverse tissues as the axial skeleton, heart, and eyes are affected. This explanation does not contradict the above hypothesis involving shear stress in brocartilaginous structures since these are features of all the tissues that express aggrecan or versican (29). The nding that HLA-B27 can interact with both CD8 and CD4 T-cells raises the possibility that both T-cell subsets are involved in the pathogenesis of AS. The results of the few available immunohistological studies on affected tissues in AS patients suggest that CD8 T-cells predominate in the cellular inltrate of entheses (32) and possibly also of synovial membranes (33), whereas CD4 T-cells are the major cell type in sacroiliac biopsy specimens (34). Oligoclonal expansion of CD8 T-cells, indicative of antigen-specic stimulation of this T-cell subset, was found to be much more extensive in HLA-B27positive AS patients compared with their healthy monozygotic twins and unrelated healthy HLA-B27-pos-

itive subjects (35). It could not be established whether these expanded T-cells were HLA-B27 restricted. Importantly, however, oligoclonal expansion was also seen in the CD4 T-cell subset of AS patients, but was completely absent in unaffected twins. In addition, animal models of SpAs suggest a more important role for CD4 T-cells in disease pathogenesis. As in almost any autoimmune disease, data on cytokine proles in AS patients are rather conicting (36). High levels of circulating IL-6 and normal concentrations of IL-1 have been detected in several groups of AS patients. While some investigators reported increased serum concentrations of TNF- in AS patients compared with healthy controls, others were unable to detect signicant differences. Data on serum IL-10 and interferon (IFN)- levels are contradictory. Somewhat more consistently, intracellular production of Th1 cytokines (IFN-, IL-2, TNF-) was decreased in peripheral and gut mucosal Tcells of AS patients compared with healthy controls. Of note, in computer tomography (CT)-guided sacroiliac joint biopsy samples from 5 AS patients, high levels of TNF- mRNA were detected in the inltrates (34). As will be discussed further below, a role for TNF- in the pathogenesis of AS is clearly indicated by the efcacy of anti-TNF agents in the treatment of this disease. Clinical Features Inammatory low back pain is the most typical presenting symptom of AS (37). Symptoms may be mild initially, and patients have difculty pinpointing the exact date when their pain started. In fact, up to 10% of subjects with radiographic evidence of AS may be unaware of their disease because symptoms are either absent or very mild (38). The presentation of back pain is not an uncommon occurrence in the general population, making it important to differentiate inammatory from noninammatory causes of back pain. Inammatory back pain is characterized by stiffness and pain that is worse in the morning or after long periods of inactivity and is improved with exercise. Patients commonly complain of difculty sleeping or pain that is not relieved with rest or lying down (39). In addition to lumbosacral pain, patients often report pain in the gluteal region, which most likely represents sacroiliac involvement. Sacroiliitis may cause piriformis muscle spasm, which results in compression of the sciatic nerve and subsequent radiation of pain to the lower extremities (40). AS is not limited to the lumbar-sacral spine. Approximately 70% of patients complain of neck pain. In a study of 571 AS patients, radiographic evidence of cervical spine involvement was seen in more than half of the patients (41). The risk of cervical spine involvement was found to be a function of disease duration, with 20% affected after 5 years and 70% affected after 20 years. It was also associated with severity of hip and lumbar involvement and a history of iritis, but not with age of onset or gender. Cervical spine disease usually presents as neck pain and stiff-

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ness; however, torticollis has been reported. Cervical xation in mild exion causes the head to protrude forward and makes it difcult for patients to look straight ahead. A compensatory exion of the knees results in the classic posture of the patient with advanced AS. Peripheral arthritis can be the earliest symptom in a substantial portion (20%) of AS patients (37,42) and develops at some point during the course of the disease in up to 60% of patients (6,42), although it becomes persistent in only about half of those affected; the pattern is commonly asymmetrical and mono- or oligoarticular. In addition to hips and shoulders, the large joints of the lower limbs are most frequently affected, although involvement of elbow, wrist, and hand is not uncommon (37,42,43). Radiographs or magnetic resonance imaging (MRI) of the affected joints show joint space narrowing, erosions with new bone formation, and synovitis (44-46). Peripheral articular joint involvement is associated with increased disease activity (43,47) and deterioration in quality of life (43). An association with worse functional outcome has also been reported (43,48), but this is not a consistent nding (47,49). A recent study in Korean patients even suggests that patients with peripheral joint disease have less severe spinal disease than those without appendicular involvement (42). Bony ankylosis and osteoarthritis can result in severe limitation of motion and substantial to complete loss of function particularly in the hip (50), but also in the knee and shoulder joints (51). Approximately 8 to 15% of AS patients with long-term follow-up have to undergo total joint arthroplasty (48,49). Enthesitis is a hallmark of AS and may involve synovial (including hip and shoulder) or cartilaginous joints, syndesmoses, and extra-articular entheses. Entheses of the lower limbs are affected more frequently than those of the upper limbs and the most common site of enthesitis is the heel (37,52). Heel enthesitis is thought to involve inammation at the site of attachment of the plantar fascia, resulting in erosions of the calcaneus, followed by a periosteal reaction with formation of bone spurs. The Achilles tendon insertion is another common site that can become inamed resulting in heel pain. Note, however, that some other enthesopathies may be underdiagnosed. The results of a recent MRI study in AS patients suggest that synovitis of the knee and possibly of other peripheral joints is always accompanied by enthesitis, although clinically detectable in only a minority of cases (53). It had been assumed that the shoulder pain of AS patients was attributable to synovitis, bursitis, or structural damage. A recent MRI study, however, found synovitis of the glenohumeral joint in only 12% of AS patients compared with 3% of controls (46). However, erosions of the greater tuberosity were seen in 65% of AS shoulders and only 14% of control shoulders. Importantly, these were the same patients in whom clinical evaluation indicated the presence of rotator cuff tendonitis. Together, these ndings suggest that

enthesitis is the primary lesion in AS, underlying many of the skeletal manifestations of the disease. Extra-Articular Manifestations Nonspecic signs and symptoms such as fever, fatigue, and weight loss can arise at any time during the course of AS. Extra-articular manifestations, such as uveitis and cardiovascular, pulmonary, and lung disease, can be the earliest manifestations of disease, but most often occur at later stages. Acute anterior uveitis (iritis) is an inammation of the anterior portion of the eye leading to scarring and blurring of vision if not treated appropriately. It is seen in up to 40% of patients with AS (48,49,54) and is signicantly more common in HLA-B27-positive than in HLA-B27-negative patients (54). Patients typically present with ocular pain, redness, and photophobia. Uveitis can be the rst indication of AS and other HLA-B27associated diseases in a substantial portion (almost 20%) of patients (55). Cardiovascular disease can be seen in 10 to 40% of patients with AS, and its incidence rises with increasing disease duration (56). Cardiovascular complications include aortitis and aortic insufciency, which can result in heart failure and death. In addition, conduction disturbances including audiovisual block and bundle branch block, as well as myocardial involvement resulting in compromise of left ventricular function, have been described in AS patients. While no specic recommendations exist regarding the use of echocardiography to screen for cardiac disease in these patients, a signicant proportion of patients with AS will have echocardiographic evidence of aortic root involvement before the clinical onset of aortic regurgitation. Pulmonary involvement in AS patients is related to both mechanical and brotic changes. Decreased total lung capacity is thought to be secondary to kyphosis and decreased chest expansion. In 17 AS patients, 11 of whom had had AS for 10 years, high-resolution chest CT demonstrated airway disease in 14 (82%), interstitial abnormalities in 11 (65%), and emphysema in 6 (35%). These changes were not evident on plain radiographs (57). Very similar ndings were reported in a study of patients whose disease duration was 10 years (58). Renal manifestations are relatively rare in AS, but include such severe conditions as secondary renal amyloidosis, IgA nephropathy, mesangioproliferative glomerulonephritis, and membranous nephropathy. Secondary renal amyloidosis (62%) is the most common renal manifestation (59) and occurs in 1 to 2% of AS patients (48). IgA nephropathy constitutes 30% of renal manifestations in AS. Elevated serum IgA levels are a common nding and may be attributable to impaired IgA catabolism, as suggested by the observation that expression of the Fc receptor (CD89) on blood monocytes and neutrophils was signicantly lower in AS patients compared with controls (60).

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Diagnosis The diagnosis of AS is based on clinical features and physical examination ndings as well as radiologic evidence of disease. The modied New York diagnostic criteria are in almost universal use (Table 1) (61). For the assessment of the clinical diagnostic criteria, the modied Schober test is used to measure anterior spinal exion, and lateral spine motion is assessed using lateral bending of the lumbosacral spine with the occiput to the wall. Chest expansion is measured at the 4th intercostal space. Palpation or percussion of the sacroiliac joints may elicit pain, but this does not reliably indicate the presence of sacroiliitis. Placing stress on the sacroiliac joints with the Flexion, Abduction, and External Rotation maneuver and the Gaenslen test can illustrate sacroiliac joint dysfunction and may also produce pain. Examination and review of the eyes and the cardiovascular and pulmonary systems may uncover extra-articular disease. The use of radiographs in the assessment of sacroiliitis is instrumental in the diagnosis of AS. Sacroiliitis is the most frequent and earliest radiographic manifestation of AS (62) (Fig. 1). Radiographic grading of sacroiliitis consists of 5 grades, ranging from 0 normal to IV complete ankylosis (Table 2). Due to oblique orientation of the normal sacroiliac joints, the entire joint may not be visible on standard anteroposterior radiographs of the pelvis. An oblique angled or Ferguson view overcomes this problem (62) but there is no evidence that this approach is actually superior to the standard one (63). Osteitis and subsequent erosions of the anterior superior and inferior surfaces cause the classic nding of squaring of the vertebral bodies (64) (Fig. 2). Measuring the vertebral concavity is helpful in monitoring the course of the illness over time. Ossication of the spinal ligaments that bridge the intervertebral discs results in the characteristic bony protuberances called syndesmophytes, giving in advanced disease the appearance of a bamboo spine (Fig. 3). Hip joints are also frequently affected (Fig. 4). Interpretation of sacroiliac radiographs is difcult and open to interpretational variation, especially in the early
Table 1 Modied New York Criteria (61) 1. Radiological criterion Bilateral sacroiliitis grade II or unilateral sacroiliitis grade III to IV 2. Clinical criteria (a) Low back pain and stiffness of at least 3 months duration improved by exercise and not relieved by rest (b) Limitation of motion of the lumbar spine in both the sagittal and the frontal planes (c) Limitation of chest expansion relative to values normal for age and sex
Denite AS is diagnosed if the radiological criterion plus 2 of the 3 clinical criteria are present.

Figure 1 Sacroiliitis. (A) Conventional radiograph of the pelvis of a 32-year-old man with stage II/III ankylosing spondylitis shows bilateral sacroiliitis. (B) In another patient, a 50year-old man with advanced disease, both sacroiliac joints are fused. Inammatory arthritis affects also the right hip joint (arrow).

stages of disease (62). In direct comparisons with conventional radiography, newer techniques such as CT and MRI demonstrate considerably higher sensitivity in identifying sacroiliitis in the early stages of AS (65,66) (Fig. 5). CT appears to be superior to MRI for the visualization of chronic changes (63). On the other hand, MRI is the only technique that can image acute and chronic lesions simultaneously (63) and it seems to perform better than CT in revealing early cartilage changes and bone marrow edema (66). A further advantage of MRI is that it does not involve radiation exposure. In addition, recent MRI studies provide evidence that the most frequent and severe lesions in AS patients affect the thoracic spine (67). Large parts of the thoracic and lumbar spine cannot be adequately visualized radiographically. Therefore, the ability to image

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Table 2 Radiographic Grading of Sacroiliitis (61) Grade 0 I II III IV Appraisal Normalnormal width, sharp joint margins Suspicious Sclerosis, some erosions Severe erosions, pseudodilatation of the joint space, partial ankylosis Complete ankylosis

Ankylosing spondylitis

this spinal region constitutes another important advantage of MRI. MRI of peripheral joints may also help in the early diagnosis of SA. It was recently reported that intense entheseal bone marrow edema particularly in the acromion at the deltoid origin was a highly specic nding, present in 41% of AS shoulders and none of the control shoulders (46). When MRI was used in SpA and rheumatoid arthritis (RA) patients with recent onset knee effusion, perientheseal edema was detected in the knees of all 10 SpA patients and entheseal bone marrow edema in 6 of 10 SA patients, but in none of the RA patients (53). The latter study also reported the co-occurrence of synovitis and enthesitis in all AS patients, compared with none of the RA patients. The specicity for AS of both the co-occurrence of synovitis and enthesitis and the presence of bone marrow edema in affected joints could have important diagnostic implications in patients presenting only with peripheral arthritis. In addition to its role in the early diagnosis of AS, MRI is rapidly developing into a valuable tool for the assessment of changes in spinal inammation and acute and chronic lesions due to treatment (68-70). Nonetheless, conventional radiography remains the method of choice for making the diagnosis of AS since the high cost and limited availability of MRI and CT restrict their use in the routine evaluation of the sacroiliac joints. These tests should be reserved for patients with normal or equivocal radiographs for whom clinical suspicion of AS is high. There are no laboratory ndings that are diagnostic of AS. As in most disease states involving systemic inammation, acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein) may be elevated, but their concentrations show little correlation with disease activity. Rheumatoid factor and antinuclear antibodies are absent. Alkaline phosphatase levels may be elevated in severe disease. Serum IgA levels are raised in many AS patients. Traditionally, testing for HLA-B27 has been discouraged since it is not diagnostic of the disease. However, the high prevalence of this antigen in AS makes the use of HLA-B27 useful as an adjunct in diagnosis, especially in cases where the physician has a strong suspicion that AS is present (71). In ethnic groups such as African and Japanese patients where the presence of HLA-B27 is low, the positive-predictive value of a positive HLA-B27 result in conjunction with inammatory back pain is extremely high (71).

It is not uncommon that 8 or more years pass between the rst symptoms of AS and its denitive diagnosis (48,54). This is partly due to the fact that unequivocal radiographic evidence of sacroiliitis, as required by the modied New York criteria, often can be seen only years after the rst symptoms of disease. Another contributing factor is the low awareness of the disease among general practitioners. Since delay in diagnosis entails a delay of treatment and truly disease-modifying therapies have become available, early diagnosis is of utmost importance. It has been proposed that an early diagnosis of axial SpA (AS and undifferentiated SpA with predominant axial involvement) can be made with a high degree of condence even in patients who lack radiographic evidence of sacroiliitis (2). In such cases, the diagnosis is based on a probability of axial SpA of 90%, with this probability being derived from the presence of inammatory back pain in combination with at least 2 or 3 clinical, laboratory, or imaging features that are highly characteristic of SpA. Examples of such features are a positive family history, enthesitis, anterior uveitis, good response to nonsteroidal

Figure 2 Early vertebral changes. Lateral radiograph of the lumbar spine in a 28-year-old man shows squaring of the vertebral bodies secondary to small osseous erosions at the corners (so-called shiny corners). Note the syndesmophyte formation at the anterior L4 to 5 disk space (arrow).

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Figure 3 Advanced vertebral changes. (A) Lateral radiograph of the cervical spine in a 50-year-old man shows anterior syndesmophytes bridging the vertebral bodies, and posterior fusion of the apophyseal joints. (B) Conventional tomography of the thoracic spine shows syndesmophytes to better advantage, producing a bamboo-spine appearance. Note preservation of the intervertebral disks. (C) Anteroposterior and (D) lateral radiographs of the lumbosacral spine show similar changes as in the cervical and thoracic segments. Note complete fusion of the sacroiliac joints.

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Table 3 Causes of Sacroiliitis (104)

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Spondyloarthropathies AS Reiter syndrome Psoriatic arthritis SAPHO (synovitis acne pustolosis hyperostosis osteitis) syndrome Intestinal bypass arthritis Infectious Pyogenic infections Tuberculosis Brucellosis Whipple disease Others Hyperparathyroidism Paraplegia Sarcoidosis Ulcerative colitis Crohns disease

Figure 4 Complete ankylosis of the right hip joint in a 48year-old man with ankylosing spondylitis.

antiinammatory drugs (NSAIDs), positivity for HLAB27 (in patients of European descent), and MRI abnormalities. It will be of great interest to determine whether this approach proves useful in clinical settings. A recent review of the literature suggests that the combined presence of inammatory back pain and HLA-B27 positivity constituted the best measures to help primary care physicians in deciding to refer patients to a rheumatologist for AS (72). Differential Diagnosis The differential diagnosis of lower back pain in young patients includes mechanical and nonmechanical causes. Mechanical causes comprise sprains and strains, compression or traumatic fracture, spondylosis, and alignment disorders (kyphosis, scoliosis, and spondylolisthesis).

Nonmechanical causes include the other SpAs, RA, osteoarthritis of the spine, herniated disc, infection, and malignancy. Lower back pain can also be due to referred pain from pelvic, renal, or gastrointestinal disease, and aortic aneurysm. When sacroiliitis can be conrmed through imaging, the differential diagnosis becomes limited (Table 3). Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier disease may mimic AS in that syndesmophytes and enthesopathy are present in both diseases. However, DISH usually presents later in life and has larger and horizontally rather than vertically oriented osteophytes, and there is no evidence of sacroiliitis (62). In addition, DISH is not associated with HLA-B27 (73). Treatment The goals of therapy are divided into the 4 following major categories: (1) patient education in the natural history of the disease, treatment options, and the patients role in disease modifying behavior; (2) relief of pain and stiffness; (3) maintenance of spinal and overall mobility and prevention of disability through physical therapy and pharmacological disease modifying agents; and (4) recognition and management of articular and extra-articular complications. In some patients, physicotherapeutic and pharmacologic approaches may be insufcient for pain relief and maintenance of mobility. In such cases, surgical correction of spinal deformity and total joint arthroplasties for hip, knee, or shoulder abnormalities may provide durable pain relief and some functional improvement (74). The International Assessment in AS (ASAS) group has established a group of core domains for the assessment of disease and response to treatment (75). These domains are functional assessment, pain, stiffness, spinal mobility, patients global assessment, peripheral joints and entheses, acute phase reactants, fatigue, and radiographs. The ASAS20 has been validated for the assessment of short-

Figure 5 Axial CT section shows bilateral sacroiliitis in a 34-year-old man.

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term improvement and is dened as an improvement of 20% or a positive change of at least 10 units on a 100-mm visual analog scale in at least 3 of the 4 ASAS domains, patients global assessment, spinal pain, function according to the Bath AS Functional Index (BASFI), and morning stiffness. The remaining domain must not worsen by 20% or show a negative change of at least 10 units on a 100-mm scale (76). The BASFI is a validated instrument for the assessment of physical function (77). The ASAS group together with the European League against Rheumatism (EULAR) recently developed evidence-based recommendations for the management of AS (78). These recommendations emphasize that the optimal management of AS patients requires a combination of nonpharmacological and pharmacological treatments and stress the importance of patient education, regular exercise and/or physical therapy, and possibly social support groups. Home exercise programs, supervised group therapy, and spa-exercise therapy have all been shown to be effective in improving function based on the BASFI, even if the evidence is of moderate quality only (79). First-line therapy to control pain and inammation in AS consists of NSAIDs. In patients with increased risk of gastrointestinal problems, selective cyclooxygenase-2 inhibitors (coxibs) should be considered. Of note, in a recent 2-year randomized controlled trial (RCT) comparing continuous and on-demand treatment with celecoxib or another NSAID in 215 symptomatic AS patients, a strategy of continuous use resulted in a reduction of radiographic progression without increasing toxicity substantially (80). Importantly, this is the rst time that NSAIDs have been reported to slow radiographic progression. The most common side effects were hypertension, dyspepsia, and abdominal pain. With growing evidence that coxib and possibly even noncoxib NSAIDs are associated with signicant cardiovascular toxicity, both gastrointestinal risk and cardiovascular risk need to be considered in choosing an NSAID. Intra- or peri-articular corticosteroid injections are indicated for relieving the pain of sacroiliitis (74). There are no clinical studies on their efcacy in peripheral arthritis and enthesitis. There is no evidence supporting the use of systemic corticosteroids. Recurrences of uveitis are common during the course of AS. Treatment usually begins with topical corticosteroids; periocular corticosteroid injections are necessary in some patients, and resistant cases may require systemic corticosteroids. Sulfasalazine (SSZ) may be of benet in preventing recurrences of uveitis (81). Despite their success in treating other inammatory diseases such as RA, disease-modifying antirheumatic drugs (DMARDs), including methotrexate and SSZ, have not shown efcacy in treating the axial manifestations of AS. However, SSZ may be benecial in treating peripheral joint disease in reducing ESR and easing morning stiffness.

As mentioned previously, TNF- is a proinammatory cytokine found at elevated concentrations in the serum of AS patients (36) and whose mRNA is detectable in high levels in sacroiliac biopsy samples (34). Currently available anti-TNF therapies include iniximab, etanercept, and adalimimab, of which only iniximab and etanercept have undergone RCTs. Results are available from 4 RCTs in AS patients treated with subcutaneous etanercept at a dose of 25 mg twice a week (82-85) and from 2 RCTs with iniximab given intravenously at a dose of 5 mg/kg at 0, 2, and 6 weeks in 1 case (86) and at 0, 2, 6, 12, and 18 weeks in the other (87). The response to both agents is rapid, with improvement seen as early as 2 weeks after initiation of therapy. Overall, the response rate according to either an ASAS20 response or a 50% disease repression as assessed via the Bath AS Disease Activity Index (BASDAI) was around 60% in the etanercept trials and between 51 and 53% in the iniximab trials compared with response rates between 9 and 28% in the placebo groups. A major clinical response to TNF- inhibitors, as dened by a 50% improvement in the BASDAI, was associated with shorter disease duration, younger age, and lower BASFI scores (88). Lower BASFI scores also predicted a better ASAS20 response in another analysis, as did higher levels of C-reactive protein and a greater degree of back pain (89). Since these ndings come from groups of patients with high disease activity at the beginning of anti-TNF treatment, it remains to be established whether these factors can also predict treatment response in AS patients in general. The clinical response is maintained for at least 2 years in the case of etanercept (90) and 3 years in the case of iniximab (68,91). Of note, discontinuation even after 3 years of continuous treatment leads to relapse in virtually all patients (mean time to relapse 17.5 weeks) (92). However, resumption of iniximab or etanercept therapy was safe and resulted in achievement of the same clinical response as seen before cessation of treatment (92,93). Both etanercept and iniximab caused regression of spinal inammation, and this effect was not lost after up to 2 years of treatment (68-70,94). Progression of structural damage was not prevented by treatment with anti-TNF agents, but appeared to have been slowed, in patients with denite radiographic changes at baseline (69,70). Furthermore, treatment of AS patients with TNF- inhibitors is associated with a signicant decrease in the number of anterior uveitis ares (95). Etanercept and iniximab have been approved for the treatment of AS by the FDA and also in Europe, and recommendations regarding the use of these TNF- inhibitors in the treatment of AS have been set by the ASAS group (96). These recommendations include the following: (1) initiation only after a denitive diagnosis of AS (using modied New York criteria); (2) active disease for at least 4 weeks based on clinical symptoms, acute phase reactants, and imaging; (3) refractory disease dened by failure of at least 2 NSAIDs during a 3-month period, failure of at least 1 intra-articular steroid injections, if

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appropriate, and failure of SSZ in patients with predominately peripheral arthritis; and (4) application of the usual precautions and contraindications for biologic therapy (96). We would like to emphasize that, unlike in RA, failure of 1 or more DMARDs is not a requirement in AS since DMARDs are not effective in treating axial disease. While TNF- inhibitors have shown great promise, their expense and their potential toxicities, including reactivation of tuberculosis (which makes screening for Mycobacterium tuberculosis a standard prerequisite) and overwhelming infection, have tempered optimism. However, when carefully monitored and used in patients that meet certain criteria, their benet is indisputable. When medical therapy fails, surgical intervention is an option for some patients. Hip replacement is the most common surgery and may be the only option in patients with xed exion deformities of the hip to relieve pain and increase mobility. Surgical treatment of the spine is indicated in cases of severe instability, pain, vertebral fracture, and for those patients with such a degree of spinal exion that their range of vision is extremely limited. Cauda equina syndrome resulting from spinal instability is a surgical emergency that requires rapid surgical intervention. DISCUSSION As discussed above, the treatment of AS has dramatically improved. In addition, the diagnostic tools as well as medical therapy have changed dramatically in the past decade. A prospective study of 150 war veterans with AS, begun in 1947, indicated that the prognosis for AS patients overall was good, with only 10 to 20% of patients becoming signicantly disabled (97). Most patients were able to maintain full-time employment with adequate treatment and lifestyle modications. Few other data are available on the outcome and prognosis in AS, and older studies suffer from the lack of validated outcome measures. Such tools are now available, including the BASDAI (98), the BASFI (77), and several instruments for assessing radiographic damage (99,100). Recent ndings on patients seen in tertiary referral centers and, hence, from the more severe end of the disease spectrum, suggest that disease activity remains relatively constant for extended follow-up periods, whereas functional impairment steadily increases (49). There appears to be general agreement that hip involvement is an important prognostic factor for worse functional and radiographic outcomes, while other predictors such as peripheral joint involvement, early restriction of spinal mobility, male gender, younger age at onset, elevated ESR, and iritis have been less consistently identied (49,101,102). Unfortunately, AS patients still face a signicantly increased risk of mortality, most commonly due to cardiovascular and cerebrovascular disease (103). Finally, we note that the issue of premature cardiovascular disease in inammatory arthritis is not unique to AS and reects an important issue that rheumatologists

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