Version May 2024
INTRODUCTION — Axial spondyloarthritis (axSpA) is a potentially disabling inflammatory arthritis of the spine, usually presenting as chronic back pain, almost always before the age of 45. It is often associated with one or more of several articular and periarticular extraspinal features, including synovitis, enthesitis, and dactylitis. It may also be associated with several nonarticular features; these include uveitis, psoriasis, and inflammatory bowel disease (IBD). Patients frequently carry the gene for human leukocyte antigen (HLA) B27, and patients with active inflammatory disease may have evidence of an elevated acute phase response [1]. However, axSpA is a syndrome with an evolving definition encompassing a spectrum of features and without highly characteristic biomarkers such as those found in rheumatoid arthritis and diabetes [2].
Patients with axSpA can be classified as having either of two subtypes of axSpA: ankylosing spondylitis (AS, also termed radiographic axSpA) or nonradiographic axSpA (nr-axSpA) [3]. Patients with AS exhibit radiographic abnormalities consistent with sacroiliitis, but such findings are absent or minimal on plain radiography in nr-axSpA. Instead, in patients with nr-axSpA, the diagnosis is supported by evidence of active inflammation of the sacroiliac (SI) joints on magnetic resonance imaging (MRI), by a combination of other findings, or both. Such subclassification might be rather arbitrary, and many experts understand axSpA as a continuum rather than having two separate distinct entities [4]. In clinical practice, a distinction between these two forms of axSpA in an individual patient has limited impact on disease burden and management and may not be relevant [5], although the classification may be of value for epidemiologic and other investigative purposes [6]. (See 'Nomenclature and classification' below.)
The clinical manifestations of axSpA will be reviewed here. The pathogenesis, diagnostic evaluation, and treatment of this disorder in adults are discussed separately, as is spondyloarthritis (SpA) in children. (See "Pathogenesis of spondyloarthritis" and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Spondyloarthritis in children".)
NOMENCLATURE AND CLASSIFICATION — A 2009 classification study divided axial spondyloarthritis (axSpA) into ankylosing spondylitis (AS, also termed radiographic axSpA) and nonradiographic axSpA (nr-axSpA). Historically, spondyloarthritis (SpA, also termed spondyloarthropathy) has been regarded as a family of arthritides that includes AS; undifferentiated SpA; reactive arthritis; psoriatic arthritis; juvenile SpA; and arthritis and spondylitis associated with inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis [7]. Traditionally, AS has been regarded as the prototype of SpA, and the majority of publications prior to 2009 on SpA focused on AS. (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Reactive arthritis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Spondyloarthritis in children" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)
The term "axial spondyloarthritis" (axSpA) became standard nomenclature in 2009, based upon a multinational study of SpA by the Assessment of SpondyloArthritis International Society (ASAS), classifying SpA broadly into two groups [8,9]:
●SpA with predominantly axial involvement is designated as "axial spondyloarthritis" (axSpA), which comprises AS (radiographic axial spondyloarthritis), with typical features of sacroiliitis on plain radiography, and axSpA without definite radiographic changes of sacroiliitis. The latter condition is termed "nonradiographic axial spondyloarthritis" (nr-axSpA). The two are probably a continuum of a disease [4,6,10].
Several studies have shown that approximately 10 to 40 percent of patients with nr-axSpA will develop radiographic sacroiliitis of AS within 2 to 10 years [11]. The risk factors for progression are male sex, being positive for human leukocyte antigen (HLA) B27, showing signs of inflammation on MRI of the sacroiliac (SI) joints, having elevated C-reactive protein (CRP), and history of smoking [5].
●SpA with predominantly peripheral involvement is designated as "peripheral SpA," with symptoms mainly of peripheral arthritis, peripheral enthesitis, and/or dactylitis. Axial symptoms may occur but do not have a chronic character. (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults".)
All classification criteria, including the 2009/2011 ASAS classification of SpA, the 1984 Modified New York Criteria for AS, the 1990 Amor criteria for SpA, and the 1991 European Spondyloarthritis Study Group (ESSG) criteria for SpA, have been developed for use in research such as epidemiologic studies and therapeutic trials (table 1) [12,13]. All criteria have disadvantages that limit their use as diagnostic tools in practice. Diagnosis is typically made based upon the clinician's judgment about the combination of symptoms, physical signs, and laboratory and imaging findings present in an individual patient [14]. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
EPIDEMIOLOGY
●Prevalence – The estimates of the prevalence of ankylosing spondylitis (AS) in various countries range from 0.7 to 49 per 10,000 (0.007 to 0.49 percent). The mean prevalences of AS per 10,000 in North America, Europe, Asia, Latin America, and Africa were 31.9, 23.8, 16.7, 10.2, and 7.4, respectively [15]. There is a paucity of information regarding the prevalence of nonradiographic axial spondyloarthritis (nr-axSpA) [4].
The prevalence of AS among working adults with chronic (greater than three months) low back pain was 4.6 percent in one study [16]. In another group with chronic back pain, the prevalence of either AS or undifferentiated spondyloarthritis (SpA) with axial involvement was 5 percent [17]. (See "Overview of the clinical manifestations and classification of spondyloarthritis".)
There is a heterogeneity in the prevalence reported for axSpA because this depends upon the ethnic group studied, the selection of subjects for evaluation, and the criteria for classification. In general, there is a clear correlation between the prevalence of AS in a given population and the prevalence of human leukocyte antigen (HLA) B27 in that group, with the prevalence of AS being approximately 5 to 6 percent among people who are HLA-B27 positive [18]. In the United States, the prevalence of HLA-B27 varies among different ethnic communities; in a 2009 national survey, the prevalence rates of HLA-B27 in non-Hispanic White Americans, Mexican Americans, and non-Hispanic Black Americans were 7.5, 4.6, and 1.1 percent, respectively [19].
As an example of population data, in the 2009 to 2010 National Health and Nutrition Examination Survey (NHANES) of the general population in the United States, the prevalence of axSpA was 1.4 percent, and the prevalence of AS was 0.55 percent, while the frequency of chronic low back pain in this cohort of 5103 United States adults aged 20 to 69 was 19.4 percent [18]. Similarly, the prevalence of AS in the United States in the 1971 to 1975 NHANES I study of 6913 subjects 25 to 74 years of age was estimated at 0.2 to 0.5 percent [20].
●Risk factors – The risk of AS is increased among relatives of an affected patient. Reported risks of AS in one report were as follows: monozygotic twins – 63 percent; first-degree relatives – 8.2 percent; second-degree relatives – 1.0 percent; third-degree relatives – 0.7 percent; parent-child – 7.9 percent [21]. Some of these numbers might be overestimates. In general, AS risk is increased approximately 20-fold in parents, siblings, and children of a proband patient with AS. Having more than one relative confers a higher risk [22]. Among siblings, AS occurred almost exclusively among HLA-B27-positive individuals [23].
AS is believed to be more common among men, although this may depend on how the disease is identified and defined. The Rochester Epidemiology Project (a population-based cohort of newly diagnosed patients) estimated that the age-adjusted incidence of AS is four times greater in men compared with women (11.7 versus 2.9 per 100,000 person-years) [24]. Similarly, in a meta-analysis of eight studies comprising 2236 patients with AS, 70.4 percent of the patients were male [25]. However, a cohort study of 728,556 United States military personnel indicates that men and women have an approximately equal incidence of AS (26.5 versus 27.2 per 100,000 person-years) [26]. The higher incidence of AS in this study may be partially explained by the use of clinical, rather than radiographic, criteria to diagnose AS.
Sex may not influence the risk of nr-axSpA. The same meta-analysis of eight studies identified 1242 patients with nr-axSpA [25]. In this study, only 46.5 percent of patients with nr-axSpA were male [25]. Male sex has been identified as a risk factor, among others, of radiographic progression in patients with axSpA, which could explain the higher rate of AS among men observed by studies that use radiographic criteria to establish this diagnosis [27].
MUSCULOSKELETAL SYMPTOMS AND FINDINGS — Axial spondyloarthritis (axSpA) is characterized by involvement of the spine and sacroiliac (SI) joints, peripheral joints, entheses, and digits, although extraskeletal organs may also be affected. Spinal and SI involvement typically results in inflammatory back pain. The spinal involvement is more extensive in ankylosing spondylitis (AS) and may result in complications, including fracture and neurologic compromise in a very small number of patients (see 'Fractures' below and 'Neurologic manifestations' below). The major musculoskeletal features include:
●SI joints and spinal involvement
●Hip and shoulder involvement
●Peripheral arthritis (in joints other than the hip and shoulder)
●Costovertebral, manubriosternal, sternoclavicular, and costochondral inflammation
●Inflammation of extraspinal entheses
●Dactylitis
The prevalences of peripheral arthritis, enthesitis, and dactylitis vary depending upon the ancestry of the individual [28].
Low back pain and neck pain — Almost all patients with axSpA report back pain, which frequently but not invariably has characteristics suggesting an inflammatory etiology. Several criteria sets are available that define inflammatory back pain, which all perform similarly and can be used in daily practice [29-31]. According to the Assessment of SpondyloArthritis International Society (ASAS) criteria, "inflammatory back pain" typically exhibits at least four of the following five features [29]:
●Age of onset <40 years
●Insidious onset
●Improvement with exercise
●No improvement with rest
●Pain at night (with improvement upon arising)
Other criteria sets for defining inflammatory back pain are the Calin and Berlin criteria, which also include morning stiffness [30,31].
Traditionally, back pain that does not fulfill the criteria for inflammatory low back pain is designated as "mechanical low back pain." Neither back pain nor inflammatory back pain is specific for axSpA. In a United States population survey, 19.2 percent of the subjects reported chronic axial pain, with 5 to 6 percent having inflammatory back pain. However, only 0.9 to 1.4 percent of all the subjects in this survey had axSpA [32].
Neck pain can be a presenting symptom early in the disease and becomes one of the principal problems caused by the disease in nearly one-half of the axSpA patients with established disease and radiographic features [33].
Impaired spinal mobility in advanced disease — Structural abnormalities of the vertebrae are much more severe in advanced AS compared with nonradiographic axSpA (nr-axSpA) [10]. In AS, the process of progressive spinal fusion may lead to extreme impairment of spinal mobility and also of chest expansion. In a 1948 to 1980 follow-up study of 51 patients, moderate and severe spinal deformity was present at the final year of observation in 15 and 18 percent, respectively; severe restriction of spinal mobility was found in 41 percent [34].
Examination techniques for assessment of the degree of deformity and for deformities and limitations in spinal mobility as well as chest expansion are discussed in detail separately. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Physical examination'.)
Postural abnormalities in advanced disease — Postural abnormalities, especially hyperkyphosis (hunchback), become apparent as early as within the first 10 years of disease in some AS patients. Hyperkyphosis is caused by wedging of the thoracic vertebrae [35]. The typical stooped posture of an AS patient with advanced disease is caused by a combination of flexion deformity of the neck, thoracic hyperkyphosis, loss of normal lumbar lordosis, and flexion deformities of the hips (picture 1) [36]. This phenomenon is, however, observed only in a minority of patients.
Buttock pain — Buttock pain, especially alternating between the two sides but sometimes only one-sided, may be indicative of SI joint involvement. In a study of 101 patients with AS and 112 with mechanical low back pain, alternating buttock pain was present in 37 percent of patients with AS and only 12 percent of patients with mechanical low back pain [30]. In another study that examined axSpA collectively, the prevalence of alternate buttock pain was 24 percent and discriminated axSpA from other low back pain better than both-sided or one-sided buttock pain [37].
Hip pain — Hip involvement, resulting in hip joint pain, is present in approximately 20 to 25 percent of patients with AS, approximately 10 percent of those with nr-axSpA [38-40], and is associated with higher degrees of disability and a worse prognosis. The typical symptom is groin pain, but, as with other disorders of the hip joint, pain may be referred to the medial thigh or even the knee. Flexion deformities of the hips may develop. Hip involvement may be more severe in patients with early onset of AS, axial, and entheseal disease, and such patients may be more likely to eventually require hip replacement surgery [38].
Peripheral arthritis — Peripheral arthritis is seen in approximately 30 percent of patients with axSpA [25,28]. Joints that may be affected are the ankles, hips, knees, shoulders, and the sternoclavicular joints. Extremely few AS patients voluntarily report temporomandibular joint (TMJ) pain. When specifically evaluated, as many as half of AS patients have at least one TMJ symptom and have some tomographic changes [41].
Enthesitis — The enthesis is the region of attachment of tendons and ligaments to bone; enthesitis, inflammation of the enthesis, is a classic feature of axSpA. Enthesitis manifests as pain, stiffness, and tenderness of insertions, usually without much swelling, although swelling may be a prominent feature at the Achilles tendon attachment (picture 2). In a meta-analysis of eight studies, the pooled prevalences of a history of enthesitis were 35 percent in nr-axSpA and 29 percent in AS [25].
Extraspinal areas other than the attachment of Achilles tendon that may be involved by enthesitis in patients with axSpA include the calcaneal attachment of the plantar fascia, the heel, the patellae, the shoulders, the costochondral junctions, the manubriosternal and sternoclavicular joints, and along the superior iliac crest. Tenderness at these and other entheseal sites is suggestive of enthesitis.
Dactylitis — Dactylitis (sausage digits) is characterized by diffuse swelling of toes or fingers (picture 3A-B). A history of dactylitis is present in approximately only 6 percent of patients with AS and a similar proportion of patients with nr-axSpA [3,28,42].
EXTRAARTICULAR MANIFESTATIONS — In axial spondyloarthritis (axSpA), some coexisting diseases are so strongly associated with the articular disease that they seem to be part of the index disease "SpA" itself. These coexisting diseases, especially acute anterior uveitis, psoriasis, and inflammatory bowel disease (IBD), are therefore referred to as "extraarticular manifestations" (EAMs) rather than being described as comorbidities.
Some experts make a distinction between EAMs related to the concept of SpA and EAMs not related to the concept of SpA [43]. EAMs related to the concept of SpA are those that commonly occur in patients with axSpA (typically in 10 to 50 percent of patients), involve clinically evident inflammation, and can occur at any point during disease evolution. Sometimes the activity of the EAM may fluctuate with the axial or peripheral joint symptoms. Acute anterior uveitis, psoriasis, and IBD are conditions considered SpA-related EAMs.
EAMs that are not considered related to the concept of SpA are rare (1 percent of patients) compared with related EAMs, are typically subclinical, occur in patients with longstanding disease, and are unrelated to the activity of joint or spine symptoms [43]. Conditions frequently considered as non-SpA-related EAMs are those affecting the heart, kidneys, and lungs.
Besides EAMs, comorbidities of the disease may also occur, for example, cardiovascular disease related to longstanding inflammation.
Patients with axSpA also complain of constitutional symptoms. In particular, fatigue is a common problem in axSpA [44,45]. Poor sleep is common and is thought to be related in part to pain caused by active disease.
Acute anterior uveitis — Unilateral uveitis is a common EAM of both ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA) [25,46-48]. The frequency of uveitis in patients with SpA is approximately 25 to 35 percent, but accurate estimates are difficult because the occurrence of uveitis is associated with longer disease duration and the presence of human leukocyte antigen (HLA)-B27 [48,49]. The incidence rate is over 20 times greater in patients compared with population-based controls (8.9 versus 0.42 per 1000 patient-years) [49].
Uveitis typically presents as acute unilateral pain, photophobia, and blurring of vision [50]. Uveitis may be the first problem to require medical evaluation and should alert clinicians to the possibility of SpA. Approximately 50 percent of patients with acute recurrent unilateral anterior uveitis have a form of SpA [51]. The activity and severity of the eye disease are not correlated with the activity and severity of the articular disease.
Recurrence is common despite the effectiveness of local therapy but seldom leads to permanent impairment of vision. In one study of 148 patients with HLA-B27-associated uveitis performed before the availability of tumor necrosis factor (TNF) inhibitors, the median duration of an attack was six weeks, and there were a median number of three recurrences for patients with more than 12 months of follow-up [52]. Cataracts and glaucoma can also occur. They are associated with posterior synechiae, increased intraocular pressure, and cystoid macular edema. The evaluation and management of uveitis are discussed in detail separately. (See "Uveitis: Etiology, clinical manifestations, and diagnosis" and "Uveitis: Treatment", section on 'Noninfectious uveitis'.)
Inflammatory bowel disease — Ileal and colonic mucosal inflammation, which are frequently asymptomatic, can be detected by histologic examination in approximately 50 percent of patients with nr-axSpA and AS [53-55]. A minority of those with histologic inflammation develop clinically apparent IBD, whether Crohn disease or ulcerative colitis, with overt IBD found in approximately 6.4 percent of patients with nr-axSpA and 4.1 percent of those with AS [25].
On the other hand, back and joint pain is common in patients with IBD, and at least one-third of patients with IBD show some features of SpA, including axSpA and peripheral SpA with changes in the sacroiliac joints visible on imaging [56-59]. However, in a prospective study only 10 percent of the IBD patients with chronic back pain or peripheral joint complaints eventually received a diagnosis of SpA from a rheumatologist [60]. The association between HLA-B27 and AS is weaker in the presence of established IBD, compared with AS [61]. However, the clinical presentation is very similar.
Peripheral and axial arthritis associated with IBD is discussed in more detail separately. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)
Psoriasis — Psoriasis is present in up to approximately 10 percent of patients with nr-axSpA and AS [25,48,62]. Patients with concomitant psoriasis have more frequent peripheral joint involvement and possibly a more severe axSpA disease course compared with axSpA patients without psoriasis [63,64]. Similar to IBD, the association between HLA-B27 and AS is weaker in the presence of established psoriasis compared with AS alone [64].
Peripheral and axial arthritis associated with psoriasis (psoriatic arthritis) is discussed in more detail separately. (See "Clinical manifestations and diagnosis of psoriatic arthritis".)
SEX DIFFERENCES IN DISEASE PATTERN — Increasingly, studies have shown that axial spondyloarthritis (axSpA) runs a different disease course in women compared with men [65]. In women, more cervical involvement of the spine and more peripheral involvement (arthritis, enthesitis, dactylitis) is seen, and women have a higher prevalence of inflammatory bowel disease (IBD) and psoriasis. In contrast to men, women tend to have less structural damage in the sacroiliac (SI) joint and spine. Additionally, progression of radiographic abnormalities is greater in men. Men experience more limitations in chest expansion and thoracic kyphosis. Inflammatory back pain is more often reported by men as a first symptom of axSpA.
COMORBIDITIES — In general, the prevalences of comorbidities are higher in those patients with axial spondyloarthritis (axSpA) who have higher disease activity and functional impairment, more severe pain, and poorer quality of life [66]. In addition to the major comorbidities described here, including osteopenia, poor psychosocial status, cardiovascular disease, and pulmonary disease, other less common comorbidities have also been described [67]. (See 'Osteopenia' below and 'Psychosocial status' below and 'Cardiovascular disease' below and 'Pulmonary disease' below.)
Osteopenia — Osteoporosis and reduced bone mass are common in patients with spondyloarthritis (SpA), even in young males with short disease duration [68]. Low bone mineral density (BMD) and bone loss are evident within the first 10 years of disease [69-71], and, in more than half of patients with longstanding and persistently active disease, BMD is decreased at both the spine and the hip [72,73]. In a multinational study of 3984 patients with SpA, osteoporosis was the most common comorbidity identified (13 percent) [74].
However, with advanced ankylosing spondylitis (AS), dual photon absorptiometry (DEXA) measurement of BMD of the spine may provide falsely high values because of the superimposed effect of syndesmophytes and periosteal bone formation [75]. However, estimation of bone density in the presence of syndesmophytes may be facilitated by dual-energy quantitative computed tomography (CT) scanning of the spine; using this technique, it has been shown that patients with syndesmophytes have lower bone mass than those without this finding [76]. Osteopenia or frank osteoporosis may predispose to fracture, especially in the spine. (See 'Fractures' below.)
Psychosocial status — AxSpA can adversely affect psychologic health and socioeconomic status in addition to causing pain and disability. Taken together, these factors influence the patient's overall quality of life, and they are collectively responsible for the intensity of pain, fatigue, and sleep disturbance [77-80]. A sense of helplessness (a feeling of an inability to actively cope with the disease) was an important contextual factor identified in both longitudinal and cross-sectional studies that affected health-related quality of life and functional measures [81-83]. A 2020 meta-analysis of four studies indicates that the odds ratio (OR) of depression in is almost twice as likely in patients with axSpA compared with controls (pooled OR of 1.8) [66].
In small studies, symptoms of pain and fatigue in patients with AS were associated on MRI and on functional MRI with structural differences in certain regions in white and gray matter of the brain, compared with controls, as well as abnormal cross-network functional connectivity [84-86]. A 2020 systematic literature review showed that overall one in six patients with axSpA satisfy the criteria for fibromyalgia [87].
Cardiovascular disease — AS is associated with an increased risk of cardiovascular diseases, including hypertension, heart failure, acute coronary syndromes (ACS), strokes, venous thromboembolism, conduction abnormalities, and, rarely, disease of the aortic root and of the aortic valve. Although cardiovascular involvement has been examined in patients with AS in several studies [88-90] and evaluated in patients with SpA in general [66,74], it has not been examined specifically in patients with nr-axSpA.
The estimated frequencies of aortic regurgitation and conduction disturbances are both increased but vary considerably, ranging from 6 to 10 percent for aortic regurgitation and from 3 to 33 percent for conduction disturbances [91-95]. In patients with AS, even without clinical evidence of heart disease, the aortic roots are less elastic than in healthy controls, based upon measurement of aortic distensibility [96]. This probably reflects a sclerosing inflammatory process involving the aortic root (aortitis), the aortic valve cusps, and the interventricular septum. The ultimate consequences are cusp retraction, aortic regurgitation, and conduction abnormalities [95,96].
Most but not all studies show increases in ischemic heart disease compared with the general population. The increased risk has been attributed to the systemic inflammation and increased prevalence of traditional cardiovascular risk factors. Differences between studies may reflect the particular populations studied and both differences and flaws in study design [88-90].
Pulmonary disease — In a minority of AS patients after longstanding disease, pulmonary compromise occurs due to restrictive changes caused by the musculoskeletal disease and changes in the lungs themselves, including interstitial, nodular, and parenchymal abnormalities [97]. Pulmonary involvement has been studied in patients with AS but not examined in nr-axSpA. (See "Chest wall diseases and restrictive physiology", section on 'Ankylosing spondylitis'.)
●Restrictive pulmonary disease is related largely to diminished chest wall and spinal mobility. In one study in which pulmonary function tests (PFTs) were compared between patients with AS and matched controls, 18 percent of patients with AS but none of the controls showed a restrictive pattern [98]. Vital capacity was decreased and functional residual capacity was increased in AS.
●A small percentage of AS patients, with estimates ranging from 1.3 to 15 percent, have evidence of other pulmonary changes such as apical pulmonary fibrosis by plain radiography [99-102]. The apical fibrosis is usually asymptomatic and associated with a long duration of disease.
●Abnormalities in AS detected on a high-resolution CT are much more common than findings on plain radiography. These include a mosaic pattern, subpleural nodules, and parenchymal bands and may be present even early in the disease [101,102].
●Fibrotic disease and cigarette smoking may be risk factors for spontaneous pneumothorax, a complication that is otherwise rare in AS [103].
The causes of these intrinsic pulmonary abnormalities are unknown. There is a lack of evidence for alveolitis, as bronchoalveolar lavage is generally unremarkable [100]. However, in one report, transbronchial biopsies revealed interstitial fibrosis of variable degree in 5 out of 12 patients, indicating that the radiologic appearance of apical fibrosis may actually reflect a more generalized process [100].
COMPLICATIONS
Fractures
●Vertebral fractures – Vertebral fragility fractures from trauma are at least twice as common in ankylosing spondylitis (AS) compared with non-AS controls [104,105]. Estimates of the lifetime incidence of clinical vertebral fracture in patients with AS range from 4 to 18 percent [106]. Patients with ankylosed spines can develop vertebral fractures with minimal (and sometimes not recollected) trauma [107,108]. The increased risk of vertebral fracture is thought to be due to a combination of low bone mineral density (BMD) and spinal rigidity.
The lower cervical spine is the most commonly involved area. Of the three major types of fracture (extension, flexion, and compression), the one most common in AS is an extension fracture [109]. CT and MRI are more sensitive and specific techniques for detecting these fractures than plain radiography, which may appear normal despite the presence of a fracture (image 1) [110]. Additionally, hyperkyphosis of the spine is common in patients with longstanding AS, and many of these patients have anterior wedging of the thoracic vertebrae as well as the intervertebral discs [35,111].
●Non-vertebral fractures – Whether AS is also associated with an increased risk of non-vertebral fractures is less clear. In a study of 758 patients with AS, the risk of hip and forearm fractures was not significantly increased (odds ratio [OR] 0.77 and 1.21, respectively) [104]. However, a larger study of 5909 patients with AS indicated that AS was associated with hip fractures (adjusted hazard ratio 1.65). This larger study also demonstrated that patients with AS developed hip fractures at a younger age than matched non-AS controls (74 versus 79 years) [112].
Neurologic manifestations — In AS, neurologic symptoms can occur by several different mechanisms, including cord or spinal nerve compression due to fracture of the ankylosed spine or from atlantoaxial subluxation. Delayed diagnosis of fracture is not uncommon because most injuries are from only minor low-energy trauma, and sustained neurologic deficits are common [113]. Additionally, and unrelated to spinal fractures, subclinical neuropathy, myelopathy, and myopathy are common but rarely symptomatic [114].
●Spinal cord injury – Spinal cord injury is 11 times more common in AS than in the general population and affects the cervical spine, including the lower cervical spine, more often than the thoracic and lumbar spine [115]. Approximately 50 to 65 percent of spinal fractures are associated with neurologic complications, although the initial complaints are often subtle and might be missed without a high index of suspicion [113,116]. The morbidity of spinal injury is very high, causing paraparesis or tetraparesis in some patients [106].
●Atlantoaxial subluxation – Clinically significant spontaneous subluxation of the atlantoaxial joint (C1-C2) may occur in patients with AS; it can lead to spinal cord compression if it is not recognized and stabilized. As an example, in one study of 103 patients, anterior or posterior atlantoaxial subluxation was observed in 21 and 2 percent of individuals, respectively [117,118]. In a two-year follow-up, progression of anterior subluxation was observed in approximately 50 percent. In other reports, clinically significant spontaneous subluxation occurred in approximately 2 percent of individuals. This problem is managed in a fashion similar to that in rheumatoid arthritis (RA). (See "Cervical subluxation in rheumatoid arthritis".)
●Cauda equina syndrome – The cauda equina syndrome is a rare complication in patients with AS, typically reported in patients with longstanding disease who have marked ankylosis of the spine [106,119,120]. The symptoms are those of damage to the lumbosacral nerve roots, probably caused by arachnoiditis. Patients usually complain of abnormalities in cutaneous sensation, problems with bladder and bowel control, and impotence. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)
Renal disease — Renal disease is very uncommon in axial spondyloarthritis (axSpA), but nonspecific glomerulopathy, immunoglobulin A (IgA) nephropathy, and renal amyloidosis may be seen in AS [121-123]. In a cohort of 681 patients diagnosed with AS in 2008/2009, abnormal findings on urinalysis were seen in 8 percent, including proteinuria and/or hematuria. Patients with proteinuria exceeding 1000 mg per day underwent renal biopsy. The biopsies showed nonspecific glomerulopathy (three patients), IgA nephropathy (two patients), and amyloidosis (one patient) [121]. This spectrum of renal diseases is in agreement with an earlier literature review [122]. Renal amyloidosis is rare [121,124,125]. (See "Clinical manifestations and diagnosis of analgesic nephropathy" and "IgA nephropathy: Clinical features and diagnosis" and "Renal amyloidosis".)
Pregnancy outcomes — There are conflicting data regarding the impact of axSpA on pregnancy outcomes. A review of 21 studies assessing pregnancy and AS demonstrated an increased risk of prematurity (OR 1.99, 95% CI 1.30-3.05) and small-for-gestational-age births (OR 2.41, 95% CI 1.22-4.77) for pregnancies in patients with AS [126]. Similarly, a retrospective analysis of 2479 women enrolled in The Danish Medical Birth Registry with a diagnosis of spondyloarthritis (SpA) between 1997 and 2016 also demonstrated that women with SpA carried a higher chance of preterm birth and elective cesarean delivery [127].
More optimistic results were demonstrated by a nationwide cohort study in Sweden, which examined the outcomes of 1580 births in women with axSpA between 2007 and 2020 [128,129]. In this study, axSpA was not associated with an increased risk preterm birth, preeclampsia, elective cesarean delivery, or serious infant infection. During the 13-year study period, the risks of preterm birth, infant infection, and cesarean delivery decreased by 0.5 percent annually.
Similarly, the European Network of Pregnancy Registries in Rheumatology, which evaluated pregnancy outcomes in 304 females with axSpA starting in 2015, also suggests that the risk of pregnancy complications is comparable among women with axSpA versus the general population [130]. In this study, the rates of preeclampsia, preterm birth, and low birth weight were either comparable or less than in the general European population. Preconception counseling, tight management of pregnancies, and a tailored treatment approach may have contributed to these good outcomes.
Whether these improved outcomes can be attributed to more widespread use of tumor necrosis factor (TNF) inhibitors is not clear. In the Swedish cohort study, the use of TNF inhibitors increased from 10 to 40 percent over the study period; in the European registry study, 67 percent of women did not receive TNF inhibitors during pregnancy.
Only limited data examine the impact of pregnancy on disease activity in patients with axSpA. In the review cited above, it was found that 25 to 80 percent of patients experienced a disease flare during pregnancy, and 30 to 100 percent experienced a disease flare after delivery [126].
LABORATORY FINDINGS — Laboratory findings in axial spondyloarthritis (axSpA) are generally nonspecific. An elevated acute phase response may be present, including an elevated erythrocyte sedimentation rate (ESR) and elevated C-reactive protein (CRP), in approximately 50 to 70 percent of patients with active ankylosing spondylitis (AS), but such changes are less frequent in patients with nonradiographic axSpA (nr-axSpA) at approximately 30 percent [131]. Thus, a normal ESR and CRP do not exclude axSpA [3,42,132]. A normochromic normocytic anemia is occasionally seen, most typically in patients with very active disease [132,133]. (See "Acute phase reactants" and "Anemia of chronic disease/anemia of inflammation".)
The level of serum bone-specific alkaline phosphatase may be elevated in severe axSpA [134]; one study found that mildly elevated serum alkaline phosphatase levels were present in 13 percent of patients with axSpA and associated with high disease activity, greater structural damage in the sacroiliac (SI) joints and spine, and lower bone mineral density (BMD) [135]. Serum levels of IgA are also commonly elevated above the normal range [136,137].
Synovial fluid findings are typical of inflammatory arthritis, with an increased white blood cell count that is dominated by polymorphonuclear leukocytes. (See "Synovial fluid analysis".)
Human leukocyte antigen (HLA) B27 is present, but not invariably so, in most patients with axSpA. In a pooled analysis of eight cohorts (from seven European countries and Turkey), the prevalences of HLA-B27 in nr-axSpA and AS were 77 and 78 percent, respectively [25]. (See 'Epidemiology' above.)
MUSCULOSKELETAL IMAGING — A number of imaging abnormalities, particularly those affecting the sacroiliac (SI) joints and spine, are characteristic of axial spondyloarthritis (axSpA), including changes that may be evident on conventional radiographs and by MRI. Such findings are reviewed here, while the selection of diagnostic imaging studies and the utility of particular studies and findings for the diagnosis of axSpA are presented in detail separately. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Imaging studies'.)
Sacroiliac joints and pelvis — An abnormal appearance of the SI joint(s) using an appropriate imaging technique is a hallmark of axSpA. Definite changes on radiography are characteristic of ankylosing spondylitis (AS), while patients with nonradiographic axSpA (nr-axSpA) by definition exhibit normal or minimally abnormal radiography of the SI joints but may have abnormal MRI findings of the joints that support the diagnosis of axSpA.
Radiographic findings of the SI joints range from subtle joint-space narrowing and sclerosis to erosive change and may eventually result in bony ankylosis (fusion). Radiography and MRI are the principal techniques used to assess the SI joints; additional methods that have been used to detect abnormalities include CT and scintigraphy. CT, especially low-dose CT, can demonstrate erosions in some patients in whom the radiographic findings are uncertain. Scintigraphy can show abnormal increased uptake, but such findings are not specific for sacroiliitis.
Radiography — Plain radiographic findings of axSpA can be recognized on a standard anteroposterior (AP) plain radiograph of the pelvis; the SI joint abnormalities can include erosions, ankylosis, changes in joint width, or sclerosis. In the first few years of axSpA, the radiographic changes in the SI joints can be quite subtle, but up to approximately 20 to 30 percent of patients may exhibit some abnormalities on SI joint radiographs [138-141].
Normal SI joints have well-defined thin white subchondral bony margins. In AS, erosions begin on the iliac side of the SI joint where cartilage is thinner than on the sacral side. SI joint abnormalities can include erosions (with loss of the white line), ankylosis, changes in joint width, and sclerosis [138]. As disease becomes more advanced the most obvious abnormalities are fusion and large erosions. Larger erosions are seen as irregular bony margins, usually associated with widening of the joint space. In advanced disease of the joint, when an SI joint is fused, the joint space disappears, so that the bone is continuous between the sacrum and the ilium. On the radiograph, the joint space becomes a thin, narrow line. In nr-axSpA, the radiographic appearances of the sacroiliac joints are normal or suspicious (but not definite).
The SI joint abnormalities are typically graded from 0 (normal) to 4 (total ankylosis) to identify the nature and severity of involvement, and such grading is used to determine the degree of confidence that the changes seen reflect sacroiliitis [142-144]. The level of change that defines AS that is employed in the modified New York criteria used for inclusion in clinical trials requires bilateral grade 2 or unilateral grade 3 changes. Minor abnormalities can be seen on plain radiographs in patients with nr-axSpA. The findings that characterize each grade are:
●Grade 0: Normal (image 2 and image 3)
●Grade 1: Suspicious (but not definite) changes (image 4)
●Grade 2: Minimal abnormality – Small localized areas with erosions or sclerosis, without alteration in the joint width (image 5A-B)
●Grade 3: Unequivocal abnormality – Moderate or advanced sacroiliitis with one or more of the following: erosions, sclerosis, joint-space widening, narrowing, or partial ankylosis (image 6A-B and image 5B)
●Grade 4: Total ankylosis of joints (image 7A-B)
A number of publications have reviewed and given illustrations of the imaging features of normal and abnormal sacroiliac joints [145]. Other examples of the various grades are available in the slide library of the Assessment of SpondyloArthritis International Society (ASAS). Scoring of the grades is reader-dependent to some degree [144]. Hence, scoring of the same SI joint might vary between readers, especially with grades 0, 1, and 2.
The use of sacroiliac joint grading for the identification of sacroiliitis and the diagnosis of axSpA is described in detail separately. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Plain radiography'.)
MRI of sacroiliac joints — MRI, unlike radiography, can reveal inflammatory changes, fatty changes, and subtle structural abnormalities. Such findings are especially important in nr-axSpA because the radiographs in nr-axSpA, by definition, are normal or equivocal. However, not all patients with nr-axSpA have abnormal MRI findings, and false-positive findings may occur in healthy individuals without axSpA [146].
Findings of active sacroiliitis, which are usually evident without contrast enhancement and best seen on semicoronal views parallel to the long axes of the SI joints, have been defined by the ASAS [147,148]; they include active inflammatory lesions of the SI joints, which appear as "bone marrow edema" (BME) on short tau inversion recovery (STIR) or on T2-weighted images with fat suppression. Typical locations of BME in patients with axSpA include subchondral or periarticular bone marrow (image 8 and image 9). The lesions are of high intensity on T2 and give a dark signal in the T1-weighted images. Similar lesions appearing as bright signals on T1-weighted images after gadolinium contrast administration are referred to as "osteitis” and are considered equivalent. However, MRI contrast use is not required for evaluation of the SI joints in patients with suspected axial SpA. It is rare for MRI of definite sacroiliitis to show only one lesion.
BME in the SI joints is not entirely axSpA-specific. The presence of BME on MRI, even of high intensity, has been observed in up to 23 percent of patients with mechanical back pain and 7 percent of healthy volunteers [149-152].
Structural abnormalities (eg, erosions, bony ankylosis, fat metaplasia, or sclerosis) (image 10) may also be seen but can be nonspecific as well, as are other inflammatory lesions such as synovitis, enthesitis, or capsulitis, which may also be present [153,154].
CT of the sacroiliac joints — High-resolution CT scans can demonstrate structural changes of the SI joints, such as erosion, more clearly than plain radiograph [155]. Hence, CT is more sensitive than radiography for detecting erosion [156]. CT is not generally recommended to establish the diagnosis of sacroiliitis. There is no standardization as yet as to the equipment or interpretations applicable to SpA. However, it may be useful in clinical practice if radiographs are ambiguous and especially if structural changes are suspected or if MRI cannot be performed [157]. If a CT is considered, a low-radiation CT of the SI joint should be ordered, which is normally sufficient [156]. Limitations of CT include the inability to assess the activity of inflammation.
Radiographic progression of sacroiliitis — Several studies have explored the rates and predictors of radiographic progression in SI joints in SpA [11]. Studies involving patients fulfilling the ASAS criteria showed a progression from nr-axSpA to AS of approximately 1 to 5 percent per year. A positive MRI for active sacroiliitis, human leukocyte antigen (HLA) B27 positivity, smoking, male sex, and an elevated C-reactive protein (CRP) were important predictors for progression. Sequential studies of either plain radiographs or MRI are not used in clinical practice, although they have been performed for research purposes.
Spine
Radiography of the spine — A series of plain (conventional) radiographic changes characteristic of AS can develop progressively over the course of disease; these are best seen on the lateral view [139]:
●Squaring of the vertebral bodies due to anterior and posterior inflammation and bone erosion and deposition is a relatively early radiographic sign of spinal involvement in AS (image 11) [158].
●Changes that are more easily distinguished and found at later stages of AS include syndesmophytes and ankylosis of the facet joints (image 12 and image 13). When syndesmophytes from a lower and an upper vertebra join together, they become a bridge. Syndesmophytes may very infrequently (fewer than 5 percent) be present in the absence of radiographic sacroiliitis [159].
●The signature abnormality that is most easily recognizable is the bamboo spine in late AS (image 14).
Unlike in AS, syndesmophytes of the spine are rare in patients with nr-axSpA [160].
Anterior atlantoaxial (C1-C2) subluxation of can also be visualized by use of radiographs; lateral views in flexion and extension may be necessary to demonstrate subluxation and whether or not it reduces in extension (see 'Neurologic manifestations' above). This finding has been reported in 14.1 percent of a cohort of 819 patients with AS [118]. Other findings of AS that may be apparent on radiographs of the spine are discovertebral (Andersson) lesions and acute fractures [161].
MRI of the spine — MRI of the lumbar spine may show changes other than those visible on plain radiographs and infrequently even in the absence of SI joint inflammation [8]; spinal changes in the absence of significant SI joint inflammation were more frequent in a study population of patients with clinically active, longstanding nr-axSpA [162]. The spinal lesions of anterior/posterior spondylitis appear either as BME (bright signal on STIR or T2-weighted sequences with fat suppression) or areas of fatty deposition (bright signal in T1-weighted sequences) (image 15) [163]. These lesions commonly localize to the anterior or posterior vertebral corners on sagittal views of the spine but can also be found in posterior vertebral elements. The finding of a single or only a few vertebral lesions is relatively nonspecific [153].
Radiographic progression of spinal changes — Radiographic involvement of the vertebrae is much more prominent in AS compared with nr-axSpA [10]. The endpoint of radiographic progression of the AS spine is total fusion in the form of a "bamboo spine." The evolution of these changes has been described in a prospective longitudinal study of 211 Western European AS patients followed over 12 years [164,165]. The initial radiographic abnormalities were erosions and sclerosis at vertebral corners. These were followed by the appearance of syndesmophytes. Bridging of syndesmophytes across vertebrae led to fusion (image 16). Taking all patients together, there was a linear overall progression of these changes over time. However, there was a great deal of variability among patients. Over the period of 12 years, approximately a quarter of the patients did not show any progression. By contrast, another quarter showed clinically important progression, such as having multiple new erosions, squaring or sclerosis, or new syndesmophytes over two years. One-half of the patients fell between these extremes, having one or a few new erosions, squaring or sclerosis, or up to two new syndesmophytes over two years. The factors that correlated with faster progression were male sex, preexisting radiographic damage, positive testing for HLA-B27, and a history of smoking.
The endpoint of spinal fusion was evaluated in a separate study of 769 United States patients, which found complete spinal fusion in 28 percent of patients with AS for more than 30 years and 43 percent of those with AS for more than 40 years [139].
Radiographic changes in the lumbar spine are associated with functional impairment in the second and third decades of disease. Functional impairment in the third and fourth decades is associated with cervical spine changes. By the fifth decade, comorbid conditions usually associated with that age group become more important than radiographic changes [166].
Hips — Radiographic involvement of the hip is sometimes observed in patients with AS and may result in a destructive joint changes (image 17 and image 18 and image 19). Characteristic features of hip involvement in AS include circumferential cartilage space narrowing, axial migration of the femoral head, protrusion deformity, and a ring of osteophytes [167]. Additional changes typical but not diagnostic of AS that may also be seen on radiography of the pelvis include erosions and osteitis at the ischial tuberosities, iliac crests, symphysis pubis, femoral trochanters, and hips. Radiographs from these sites typically show destructive changes without much new bone formation [139]. The severity of radiographic hip involvement correlates with more severe spinal disease [168].
Peripheral arthritis — Radiographs of peripheral joints in patients with axSpA and peripheral SpA are often unremarkable and do not show the same type of erosions seen in rheumatoid arthritis (RA). An exception is in patients with psoriatic arthritis, in whom both osteoproliferative and osteodestructive lesions may be seen. Peripheral joint changes in SpA are described separately. (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults", section on 'Imaging' and "Clinical manifestations and diagnosis of psoriatic arthritis".)
Enthesitis — The combined use of B-mode and power Doppler ultrasound (PDUS) can demonstrate changes consistent with peripheral enthesitis in patients with SpA, including findings of hypoechogenicity, increased thickness of the tendon insertion, calcifications, enthesophytes (bone spurs), and Doppler activity (image 20A-B) [169,170]. Enthesitis can also be seen using MRI, showing both soft tissue changes and intraosseous inflammation [171]. Abnormalities that can be seen include the presence of BME, soft tissue edema, changes in tendon thickness, erosions or enthesophytes in the adjacent bones, and fluid around tendons or adjacent to the bursa [172].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Ankylosing spondylitis (The Basics)")
●Beyond the Basics topics (see "Patient education: Axial spondyloarthritis, including ankylosing spondylitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Nomenclature and classification – Axial spondyloarthritis (axSpA) consists of ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), which are characterized by symptoms of spinal inflammation and other features shared with spondyloarthritis (SpA) in general (table 1). AS can potentially lead to disabling spinal fusion and hyperkyphosis (picture 1). (See 'Nomenclature and classification' above and 'Musculoskeletal symptoms and findings' above and 'Musculoskeletal imaging' above.)
●Epidemiology – Estimates of the prevalence of axSpA in the United States are 1.0 to 1.4 percent. Globally, the prevalence varies depending upon the ethnic group and with the prevalence of human leukocyte antigen (HLA) B27. The prevalence of AS is approximately 5 to 6 percent among people who are HLA-B27-positive. (See 'Epidemiology' above.)
●Musculoskeletal symptoms – The predominant symptom of axSpA is chronic back pain, which is frequently inflammatory in character. Inflammatory low back pain is characterized by age of onset <40 years, insidious onset, association with morning stiffness, improvement with exercise but not with rest, and pain at night. AxSpA patients may also have peripheral arthritis, enthesitis (picture 2), and dactylitis (picture 3A-B). (See 'Musculoskeletal symptoms and findings' above.)
●Extraarticular manifestations – Extraarticular manifestations may include anterior uveitis, psoriasis, and symptomatic as well as asymptomatic inflammatory bowel disease (IBD). Additional comorbidities include, for example, cardiovascular diseases. Complications may also occur. In AS, there is a significantly increased risk of vertebral fractures (image 1) from low-impact trauma related to spinal rigidity and low bone mineral density (BMD). (See 'Extraarticular manifestations' above.)
●Laboratory findings – Laboratory findings are generally nonspecific and may include the presence of HLA-B27. An elevated acute phase response may be present, including an elevated erythrocyte sedimentation rate (ESR) and elevated C-reactive protein (CRP), but a normal ESR and CRP do not exclude axSpA or active disease. (See 'Laboratory findings' above.)
●Musculoskeletal imaging – Definite changes on plain (conventional) radiography are characteristic of AS (image 7A), while patients with nr-axSpA by definition exhibit normal or minimally abnormal radiography of the SI joints but may have abnormal MRI findings (eg, bone marrow edema [BME] (image 8)) of the joints that support the diagnosis of axSpA. Radiographic findings of the sacroiliac (SI) joints range from subtle joint-space narrowing and sclerosis to erosive change and may eventually result in bony ankylosis (fusion). Radiographic changes may also occur in the spine, particularly in patients with AS (image 12). (See 'Musculoskeletal imaging' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Yu, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
