Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Ankylosing spondylitis (AS) is a chronic, multisystem inflammatory disorder primarily involving the sacroiliac (SI) joints and the axial skeleton. Other clinical manifestations include peripheral arthritis, enthesitis, and extra-articular organ involvement.[15, 16, 17, 18] AS has been designated by various names, including rheumatoid spondylitis in the American literature, spondyloarthrite rhizomegalique in the French literature, and the eponyms Marie-Strümpell disease and von Bechterew disease.

AS is the prototype of the spondyloarthropathies, a family of related disorders that also includes non-radioraphic axial spondyloarthritis (nr-axSpA),  reactive arthritis (ReA), psoriatic arthritis (PsA), inflammatory bowel disease–associated spondyloarthropathy (IBD-SpA), undifferentiated spondyloarthropathy (USpA), and possibly Whipple disease and Behçet disease (see the image below). The spondyloarthropathies are linked by common genetics (the human leukocyte antigen [HLA] class-I gene HLA-B27) and a common pathology (enthesitis).

AS is classified as a spondyloarthropathy. The disorder is often found in association with other spondyloarthropathies, including ReA, PsA, ulcerative colitis (UC), and Crohn disease. Patients often have a family history of either AS or another spondyloarthropathy.

The etiology of AS is not understood completely; however, a strong genetic predisposition exists.[19, 6] A direct relationship between AS and the HLA-B27 gene has been determined.[20, 21, 22, 23] The precise role of HLA-B27 in precipitating AS remains unknown; however, one hypothesis is molecular mimicry in which HLA-B27 preferentially presents a bacterial (arthritogenic) antigen that induces an immune response to a self-antigen and autoimmunity.

The diagnosis of AS is generally made by combining clinical criteria of inflammatory back pain and enthesitis or arthritis with radiological findings. Early diagnosis is important because early medical and physical therapy may improve functional outcome. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, physical therapy, and surgical.

The spondyloarthropathies are chronic inflammatory diseases that most commonly involve the SI joints and the axial skeleton, with hip and shoulder joints less frequently affected. Peripheral joints and entheses and certain extra-articular organs, including the eyes, skin, and cardiovascular system, may be involved to a lesser degree.

The primary pathology of the spondyloarthropathies is enthesitis with chronic inflammation, including CD4+ and CD8+ T lymphocytes and macrophages. Cytokines, particularly tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), are also important in the inflammatory process by leading to inflammation, fibrosis, and ossification at sites of enthesitis.[24, 25, 26] The IL-23/IL-17 axis is also important in the spondyloarthropathies including the induction of Th17 cells and the production of the proinflammatory cytokine IL-17.[27, 28] In addition, TNF-α and IL-17 have been targeted therapeutically for the treatment of axial spondylarthritis.

The initial presentation of AS generally relates to the SI joints; involvement of the SI joints is required to establish the diagnosis. SI joint involvement is followed by involvement of the discovertebral, apophyseal, costovertebral, and costotransverse joints and the paravertebral ligaments.

Early lesions include subchondral granulation tissue that erodes the joint and is replaced gradually by fibrocartilage and then ossification. This occurs in ligamentous and capsular attachment sites to bone and is called enthesitis.[29]

In the spine, this initial process occurs at the junction of the vertebrae and the annulus fibrosus of the intervertebral discs. The outer fibers of the discs eventually undergo ossification to form syndesmophytes. The condition progresses to the characteristic bamboo spine appearance.

Extra-articular involvement can include acute anterior uveitis and aortitis. Anterior uveitis occurs in 25-30% of patients and generally is acute and unilateral. Symptoms include pain, lacrimation, photophobia, and blurred vision. Cardiac involvement, including aortic insufficiency and conduction defects, is generally a late finding and is rare.[30]

Pulmonary involvement is secondary to inflammation of the costovertebral and costotransverse joints, which limits chest wall range of motion (ROM). Pulmonary fibrosis is generally an asymptomatic incidental radiographic finding. Neurologic deficits are secondary to spinal fracture or cauda equina syndrome resulting from spinal stenosis. Spinal fracture is most common in the cervical spine.

The etiology of AS is unknown, but a combination of genetic and environmental factors works in concert to produce clinical disease.[31]

Genetic predisposition

The strong association of AS with HLA-B27 is direct evidence of the importance of genetic predisposition (see Table 1 below).[20, 21, 22, 32, 33, 34, 35] Of the various genotypic subtypes of HLA-B27, HLA-B*2705 has the strongest association with the spondyloarthropathies. HLA-B*2702, *2703, *2704, and *2707 are also associated with AS.[36] People who are homozygous for HLA-B27 are at a greater risk for AS than those who are heterozygous.[37]

AS is more common in persons with a family history of AS or another seronegative spondyloarthropathy. The concordance rate in identical twins is 60% or less. HLA-B27–restricted CD8+ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis.[38] An epistatic interaction between HLA-B60 and HLA-B27 increases the risk of developing AS.[39]

Table 1. Association of Spondyloarthropathies With HLA-B27 (Open Table in a new window)

The shared amino acid sequence between the antigen-binding region of several HLA-B27 genotypic subtypes, especially HLA-B*2705, and nitrogenase from Klebsiella pneumoniae supports molecular mimicry as a possible mechanism for the induction of spondyloarthropathies in genetically susceptible hosts via an environmental stimulus, including bacteria in the GI tract.[40] The specifics of this relationship remain unclear.

Several other genes have been studied with respect to their potential involvement in the development of AS (see Table 2 below).

Table 2. Genetics of Ankylosing Spondylitis (Open Table in a new window)

 ARTS1 is also associated with AS. This gene encodes the endoplasmic reticulum aminopeptidase, which cleaves cytokine receptors for IL-6, TNF-α, and IL-1 from the cell surface and is important in antigen presentation by class 1 major histocompatibility complex (MHC) molecules.[41, 34, 35]

IL23R, which encodes the receptor for IL-23, is also associated with AS.[41, 42, 43, 44, 34, 35] IL-23 promotes survival of Th17 CD4+ T cells. Th17 cells play an important role in inflammatory responses by producing various proinflammatory cytokines (eg, IL-17, IL-6, and TNF-α) and recruiting other inflammatory cells (eg, neutrophils) in inflammatory and infectious diseases. Thus, they may play an important role cells in the pathogenesis of AS and other spondyloarthropathies.[45]

The interleukin (IL)-1 gene cluster is an important locus associated with susceptibility to AS.[46, 47] CYP 2D6 and ANKH genes are probably associated with AS.[33]

Numerous genes have been excluded in the etiology of ankylosing spondylitis, such as the following[33] :

• TGF-β
• MMP3
• IL-10
• IL-6
• Immunoglobulin (Ig) allotypes
• TCR
• TLR4
• NOD2/CARD15
• CD14
• NFbBIL1
• PTPN22

Immunologic mechanisms

Another possible mechanism in the induction of AS is presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with AS have subclinical GI tract inflammation and elevated IgA antibodies directed against Klebsiella. The bacteria may invade the GI tract of a genetically susceptible host, leading to chronic inflammation and increased permeability. Over time, bacterial antigens containing arthritogenic peptides enter the organism via the bloodstream.

Localization of pathology to certain types of connective tissues (eg, entheses) may be explained by affinity of bacterial antigens to these specific sites. Biomechanical stress, such as that which occurs at entheses in the spine and feet, may predispose to clinical enthesitis at these sites.

The spondyloarthropathies are the only known autoimmune diseases linked to an HLA class-I rather than HLA class-II genes. The cytotoxic CD8+ T-cell response appears to be important; it would respond to antigen presented by HLA class-I molecules on the surface of cells. The association of spondyloarthropathies (eg, ReA) with HIV infection in certain areas of the world supports the relative importance of the CD8+ cytotoxic T-cell responses compared with the CD4+ helper cells in these conditions.

Environmental factors

AS does not develop in every person who is HLA-B27 positive; thus, it is clear that environmental factors are important. Even first-degree relatives who are HLA-B27 positive do not uniformly develop the disease. In fact, only 15-20% of such individuals develop the disease.

HLA-B27–positive transgenic rats develop an illness similar to a spondyloarthropathy, with manifestations that include sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular inflammation, cardiac inflammation, and inflammation of the gastrointestinal and male genitourinary tracts.[48] The severity of the clinical disease correlates with the number of copies of HLA-B27 expressed in the transgenic animal.

HLA-B27–positive transgenic rats that are raised in a germ-free environment do not develop clinical disease. Once introduced into a regular environment (ie, non–germ-free) and exposed to bacteria, the rats develop clinical manifestations of spondyloarthropathy.[49, 50]

Patients with AS may experience exacerbations after trauma. However, no scientific studies support trauma as a cause of AS.

AS is the most common of the classic spondyloarthropathies. Prevalence varies with the prevalence of the HLA-B27 gene in a given population, which increases with distance from the equator. In general, AS is more common in whites than in nonwhites. It occurs in 0.1-1% of the general population,[51, 52, 53] with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa.[36, 54, 55]

Approximately 1-2% of all people who are positive for HLA-B27 develop AS. This increases to 15-20% if they have a first-degree relative with HLA-B27 positive AS.[6, 31]

Prevalence data for nr-axSpA and USpA are scarce, although this disorder appears to be at least as common as AS, if not more so.[51] The actual prevalence may be as high as 1-2% of the general population. The prevalence of nr-axSpA geographically and among different sexes and ethnic groups is probably similar to AS but specific data are limited, as it is also associated with HLA-B27.

Age-related demographics

The age of onset of AS is usually from the late teens to age 40 years. Approximately 10%-20% of all patients experience symptom onset before age 16 years; in such patients, the disease is referred to as juvenile-onset AS. Onset of AS in persons older than 50 years is unusual, although a diagnosis of mild or asymptomatic disease may be made at a later age.[56]   Uncommonly, patients may not come to medical attention until they have advanced disease.

Diagnosis is often significantly delayed, usually for several years after the onset of inflammatory rheumatic symptoms. In a study of German and Austrian patients with AS, the age of onset of disease symptoms was 25 years in HLA-B27–positive and 28 years in HLA-B27–negative patients, with a delay in diagnosis of 8.5 years in HLA-B27–positive and 11.4 years in HLA-B27–negative patients.[57]

In a study of Turkish patients with AS, the age of onset of disease symptoms was 23 years, with a delay in diagnosis of 5.3 years in HLA-B27–positive patients and 9.2 years in HLA-B27–negative patients.[58] Patients with inflammatory back pain or a positive family history of AS had a shorter diagnostic delay.

USpA is generally found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.[59]

Sex-related demographics

According to radiographic survey studies, prevalence rates of AS are approximately equal in men and women. However, men have more severe radiographic changes in the spine and hips than women,[60] and clinical AS is more common in men than in women, with a male-to-female ratio of approximately 3:1.[6, 56] Females may have milder or subclinical disease. The male-to-female ratio for USpA is 1:3.[59]

Race-related demographics

The prevalence of AS parallels the prevalence of HLA-B27 in the general population. The prevalence of HLA-B27 and AS is higher in whites and certain Native Americans than in African Americans, Asians, and other non-white ethnic groups.[36, 33]  However, a study of racial differences in AS among patients in the United States found that African Americans have high disease activity and co-morbidities compared with whites.[61] AS is least prevalent in sub-Saharan Africa. The less common juvenile-onset version of AS is more common among Native Americans, Mexicans, and persons in developing countries.

USpA is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.[59]

 

The outcome in patients with spondyloarthropathies, including AS, is generally better compared with that in patients with a disease such as rheumatoid arthritis. Patients often require long-term anti-inflammatory therapy. Morbidity can occur from spinal and peripheral joint involvement or, rarely, extra-articular manifestations. Indicators of poor prognosis include the following:

• Peripheral joint involvement
• Young age of onset
• Elevated erythrocyte sedimentation rate (ESR)
• Poor response to nonsteroidal anti-inflammatory drugs (NSAIDs)

At the onset of the disease, symptoms are generally unilateral and intermittent. As the disease progresses, pain and stiffness generally become more severe and more constant. Adequate exercise can improve symptoms and ROM.

Some patients have few, if any, symptoms. A significant portion of AS patients develop chronic progressive disease and develop disability due to spinal inflammation leading to fusion, often with thoracic kyphosis or erosive disease involving peripheral joints, especially the hips and shoulders. Patients with spinal fusion are prone to spinal fractures that may result in neurologic deficits. Most functional loss in AS occurs during the first 10 years of illness.[62]

Severe physical disability is not common among patients with AS. Problems with mobility occur in approximately 47% of patients. Disability is related to the duration of the disease, peripheral arthritis, cervical spine involvement, younger age at onset of symptoms, and coexisting illnesses. Disability has been demonstrated to improve with prolonged periods of exercise or surgical correction of peripheral joint and cervical spine involvement.

Most patients remain fully functional and continue working after the onset of symptoms.[63, 64, 65, 66, 67, 68] Vocational counseling has been demonstrated to decrease the risk of employment disability by more than 60%.[69] Although most patients are able to continue to work, as many as 37% change occupations to less physically demanding jobs as symptoms progress.

In rare cases, patients with severe long-standing AS develop significant extra-articular manifestations such as cardiovascular disease, including cardiac conduction defects and aortic regurgitation; pulmonary fibrosis; neurologic sequelae (eg, cauda equina syndrome); or amyloidosis. Patients with severe long-standing AS have a greater risk of mortality than the general population.[62] Death is more likely in the presence of either extra-articular manifestations or coexisting diseases.[70, 71]

Emotional problems related to the disease are reported in 20% of patients. Depression is more common among women, and contributing factors include the level of pain and functional disability involved.

In some patients, nr-axSpA progresses to AS over time, but that does not happen in all cases. USpA appears to carry a good-to-excellent prognosis, although some patients have chronic symptoms associated with functional disability. Erosive arthritis is very uncommon. Uveitis occasionally occurs and may be recurrent or chronic. Patients who develop sacroiliitis and spondylitis, by definition, have AS.[72, 59]

Patient education is essential in disease management. Teach patients about the long-term nature of the illness and the use and toxicities of medications. Inform patients that proper exercise programs are useful in reducing symptoms and increasing ROM. For patient education information, see the Ankylosing Spondylitis Directory.

Because of the joint involvement in the chest wall and the potential for pulmonary complications, include smoking cessation in recommendations. One 2011 study found that a history of smoking was associated with higher disease activity and decreased function in AS.[73]

Genetic counseling is useful in assisting patients with questions regarding the risk of family members developing AS or other seronegative spondyloarthropathies. Various patient support groups are available to assist in the education of these patients (eg, Spondylitis Association of America support groups).

Key components of the patient history that suggest ankylosing spondylitis (AS) include the following:

• Insidious onset of low back pain
• Onset of symptoms before age 40 years
• Presence of symptoms for more than 3 months
• Symptoms worse in the morning or with inactivity
• Improvement of symptoms with exercise ^[3]

General symptoms

Symptoms of AS include those related to inflammatory back pain, peripheral enthesitis and arthritis, and constitutional and organ-specific extra-articular manifestations. Because AS is a systemic inflammatory disease, systemic features are common.

Chronic pain and stiffness are the most common complaints of patients with AS. More than 70% of patients report daily pain and stiffness.[74]

Fatigue is another common complaint, occurring in approximately 65% of AS patients. Most patients report their fatigue to be moderately severe. Increased levels of fatigue are associated with increased pain and stiffness and decreased functional capacity.[4, 5]

Fever and weight loss may occur during periods of active disease.

Inflammatory back pain

Inflammatory back pain is the most common symptom and the first manifestation in approximately 75% of patients.[75] The pain is typically dull and poorly localized to the gluteal and sacroiliac (SI) areas.

Symptoms associated with inflammatory back pain include insidious onset occurring over months or years, generally with at least 3 months of symptoms before presentation. Most patients have mild chronic disease or intermittent flares with periods of remission. The spinal disease is rarely persistently active.

The pain often begins unilaterally and intermittently, and generally begins in the lumbosacral region (SI joints). However, as the disease progresses, it becomes more persistent and bilateral and progresses more proximally,[5] with ossification of the annulus fibrosus that results in fusion of the spine (bamboo spine).

Patients commonly experience morning stiffness lasting at least 30 minutes, improvement of symptoms with moderate physical activity, and diffuse nonspecific radiation of pain into both buttocks. Patients often experience stiffness and pain that awakens them in the early morning, a distinctive symptom not generally found in patients with mechanical back pain.

Diagnostic criteria for inflammatory back pain have been proposed.[76, 77] When 4 of the 5 following criteria are present, it yields a sensitivity of 79.6% and a specificity of 72.4%[77] :

• Improvement with exercise
• Pain at night
• Insidious onset
• Age of onset less than 40 years
• No improvement with rest

In contrast, acute onset of pain, exacerbation of symptoms with activity, and radicular radiation of pain suggest a mechanical or degenerative process such as disc disease.

Peripheral enthesitis and arthritis

Peripheral musculoskeletal involvement occurs in 30-50% of all patients. Peripheral enthesitis is the basic pathologic process, involving inflammation at the site of insertion of ligaments and tendons on to bone. This often progresses from erosion and osteitis to ossification, resulting in telltale radiological signs of periosteal new bone formation.

The following sites are commonly involved:

• Achilles tendon insertion
• Insertion of the plantar fascia on the calcaneus or the metatarsal heads
• Base of the fifth metatarsal head
• Tibial tuberosity
• Superior and inferior poles of the patella
• Iliac crest

Other sites of involvement include the following:

• Greater trochanter
• Ischial tuberosity
• Costochondral junctions
• Distal scapula
• Lateral epicondyle
• Distal ulna

Enthesopathic lesions tend to be quite painful (eg, the plantar fascia when getting out of bed), especially in the morning. Some of the peripheral arthritis occurs at sites in which the major component is local enthesitis, as suggested by magnetic resonance imaging (MRI).

Joint involvement tends to occur most commonly in the hips, shoulders, and joints of the chest wall, including the acromioclavicular and sternoclavicular joints, and often occurs in the first 10 years of disease. Involvement of the hips and shoulders may result in joint damage with radiographic changes. Involvement of the hips and shoulder joints is more common in persons with juvenile-onset AS than in adults with AS.  In addition, involvement of the tarsal joints occurs more comonly in juvenile-onset AS; it is sometimes called ankylosing tarsitis.

Other peripheral joints are involved less frequently and to a milder degree, usually as an asymmetric oligoarthritis predominantly involving the lower extremities. Involvement of the temporomandibular joint (TMJ) occurs in approximately 10% of patients. Patients may complain of decreased range of motion (ROM) or jaw pain. Involvement of the costovertebral and costotransverse joints can lead to decreased ROM and restriction in respiration. Patients may complain of difficulty breathing or chest tightness.

Chronic involvement of the spine eventually can lead to decreases in ROM and fusion of the vertebral bodies. Involvement of the cervical and upper thoracic spine can lead to fusion of the neck in a stooped forward-flexed position (kyphosis) (see the images below). This position can significantly limit the patient’s ability to ambulate and look straight ahead.

Articular manifestations

Focus the physical examination on active and passive ROM of the axial and peripheral joints. Tenderness in the SI joints is common. Peripheral enthesitis is often identified by tenderness and swelling of tendons and ligamentous insertions.[6]

Spine

Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of advanced-stage AS. Earlier in the course of the disease, indirect evidence of sacroiliitis and spondylitis may be observed, including tenderness of the SI (elicited by either direct pressure or indirect compression) or a limited spinal ROM. Some patients may have a deformity of the spine, most commonly with a loss of lumbar lordosis and accentuated thoracic kyphosis.

The ROM of the lumbar spine can be assessed using various methods, of which the Schober test is the most popular. (This test is not specific for AS.)

Perform the Schober test by marking a 10-cm length of the lumbar spine (with the patient in the erect position), starting at the fifth lumbar spinous process. Instruct the patient to flex his or her spine maximally. Remeasure the distance between the marks. Normal flexion increases the distance by at least 5 cm.

Loss of chest expansion (< 3-cm difference between minimum and maximum chest diameter) is usually found only in patients with late-stage disease. It is generally not helpful in diagnosis.

Peripheral entheses and joints

Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender to palpation and may be associated with swelling of the tendon or ligament insertion.

The most common and characteristic peripheral sites of enthesitis are the insertion of the Achilles tendon on the calcaneus and the insertion of the plantar fascia on the calcaneus. Certain anatomic areas may be more prone to enthesitis because of biomechanical stress. Carefully examine patients for tenderness upon palpation.

Enthesitis and synovitis account for some of the peripheral joint involvement. Peripheral joint disease occurs in 33% of patients, most commonly in the hips. Hip involvement usually occurs in the first 10 years of the disease course and is typically bilateral.

Other joints may be involved, including the following:

• Shoulder girdle (glenohumeral, acromioclavicular, and sternoclavicular joints)
• Costovertebral joints
• Costosternal junctions
• Manubriosternal joints
• Symphysis pubis
• Temporomandibular joint

Peripheral joints are uncommonly involved. When they are involved it is in an asymmetric oligoarticular pattern.

Dactylitis (sausage digit) is very uncommon in patients with AS. Isolated small-joint involvement of the hands, feet, or dactylitis strongly suggests reactive arthritis (ReA), psoriatic arthritis (PsA), or undifferentiated spondyloarthropathy (USpA).

Destructive arthritis may affect the hips or shoulder girdle, which may result in limited range of motion and flexion deformities.

Extra-articular manifestations

Screen for extra-articular manifestations of AS by performing specific examinations (eg, ophthalmologic, cardiac, gastrointestinal [GI]). Such manifestations may include the following:

• Uveitis
• Cardiovascular disease
• Pulmonary disease
• Renal disease
• Neurologic disease
• GI disease

Uveitis

Uveitis (also called iritis or iridocyclitis) is the most common extra-articular manifestation of AS, occurring in 20-30% of patients.[78, 79] Of all patients with acute anterior uveitis, 30-50% have or will develop AS. The incidence is much higher in individuals who are HLA-B27 positive (84-90%). Patients with uveitis may also have or may develop other spondyloarthropathies, including ReA (5-10%), USpA (2-5%), and PsA (< 1%), although this is less common. Isolated inflammatory bowel disease (IBD) is also associated with uveitis.

The uveitis associated with AS is usually acute in presentation and unilateral, and symptoms include a painful red eye with photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely including posterior elements. Attacks usually resolve over 2-3 months with treatment, and residual visual impairment is unlikely unless treatment is inadequate or delayed. Recurrences are common.

The uveitis that develops in ReA is similar to the uveitis that develops in AS, whereas the uveitis that develops in PsA and in spondyloarthropathy associated with IBD tends to be more chronic and bilateral and often involves posterior elements.

Cardiovascular involvement

Clinically significant cardiovascular involvement occurs in fewer than 10% of AS patients, typically those with severe long-standing disease. However, subclinical disease can be detected in many patients and may occur as an isolated clinical entity in association with HLA-B27.

Aortitis of the ascending aorta may lead to distortion of the aortic ring, resulting in aortic valve insufficiency. Mitral valve insufficiency rarely occurs. Fibrosis of the conduction system may result in various degrees of atrioventricular block, including complete heart block.

Pulmonary involvement

Restrictive lung disease may occur in patients with late-stage AS, with costovertebral and costosternal involvement that limits chest expansion. Bilateral apical pulmonary fibrosis rarely occurs in the setting of severe disease. These lesions may cavitate and become colonized by bacteria or fungi (eg, Aspergillus), resulting in cough, dyspnea, and hemoptysis.

Renal involvement

Amyloidosis is a very rare complication of AS in patients with severe, active, and long-standing disease. These patients generally have active spondylitis, active peripheral joint involvement, a higher erythrocyte sedimentation rate (ESR), and an increased C-reactive protein (CRP) level. This may result in renal dysfunction with proteinuria and renal insufficiency or failure. Immunoglobulin A (IgA) nephropathy has been reported in association with AS.

Neurologic involvement

Neurologic complications may occur secondary to fractures of a fused spine, which may be very difficult to detect with standard radiography. Patients are also prone to atlantoaxial subluxation, which may result in cervical myelopathy. Cauda equina syndrome may also occur in patients with severe long-standing AS.

Gastrointestinal involvement

Asymptomatic inflammation of the proximal colon and terminal ileum has been observed in as many as 60% of patients with AS and USpA. Patients with established AS only rarely develop Crohn disease or ulcerative colitis.

Metabolic bone disease

Although AS is associated with new bone formation at sites of spinal and peripheral enthesitis, osteopenia and osteoporosis have been documented in patients with long-standing spondylitis, resulting in an increased risk of fracture. Patients with AS who have severe spondylitis and who present with acute exacerbations of back or neck pain should be re-evaluated for possible fracture, especially in the setting of trauma. Standard radiography may not be revealing; computed tomography (CT) or MRI may be required to aid in diagnosis.

Heterotopic bone formation may occur after total hip replacement.

Juvenile ankylosing spondylitis

Juvenile AS is clinically similar to adult AS.[80, 81] In approximately 10-20% of all cases, symptom onset occurs before age 16 years. The male-to-female ratio of 3:1 is similar to that of adults.

Enthesitis is prominent early in the course of the disease, while spinal symptoms and limitation of motion may not be present until several years later. Peripheral arthritis, especially in the lower extremities, and dactylitis are more common in children than in adults. Systemic manifestations (eg, fever, weight loss, anemia, leukocytosis) occur at disease onset in children more frequently than in adults.

Initial radiography findings of the sacroiliac regions and spine are often normal or difficult to interpret in children. These factors make a definitive diagnosis of AS difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of a spondyloarthropathy.

Some children exhibit a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) that is clinically similar to USpA. These children often develop AS over time, with typical radiographic changes, usually by early adulthood. A variant, ankylosing tarsitis, is described in children who present with enthesitis in the tarsal region. This can lead to ossification, which results in a characteristic radiographic appearance. When tarsal inflammation is part of the clinical picture in a child or adult, strongly consider one of the spondyloarthropathies.

Undifferentiated spondyloarthropathy

USpA has features consistent with the spondyloarthropathies, but affected patients do not fulfill criteria for any specific spondyloarthropathy.[72, 82]

USpA may represent an early phase or incomplete form of AS or another spondyloarthropathy. In fact, several studies of USpA included many patients who probably should have been diagnosed with AS, ReA, or IBD-associated spondyloarthropathy, which made the clinical description very ambiguous. However, subsequent data suggest that these patients may represent a distinct disease entity on the basis of demographic and clinical criteria.

Although no specific criteria are identified, using modified Amor criteria can be helpful in confirming a clinical diagnosis of USpA (see Table 3 below).[59, 83, 7]

Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria (Open Table in a new window)

The age of onset for USpA extends over a very wide range, with the peak onset at approximately age 50 years. The male-to-female ratio is 1:3. The onset is usually insidious, and, even after years of active disease, sacroiliitis and spondylitis are either absent or appear very mild on routine radiography.

Clinical manifestations of undifferentiated spondyloarthropathy include inflammatory back pain, buttock pain, enthesitis, peripheral arthritis, dactylitis, and fatigue (see Table 4 below). Extra-articular manifestations are uncommon, occurring in fewer than 10% of patients, and include acute anterior uveitis (1-2%), oral ulcers, rash, nonspecific IBD, pleuritis, and pericarditis.

Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy (Open Table in a new window)

Findings of laboratory studies are generally unremarkable except for the presence of an elevated ESR or CRP level. HLA-B27 antigen is positive only in approximately 20-25% of patients.

These factors, especially the late age of onset, female predominance, and low HLA-B27 positivity, suggest that USpA is distinct from AS and the other classic spondyloarthropathies.

In addition, when these patients are observed over long periods, they rarely develop clinical manifestations or radiographic changes that result in a change of diagnosis. Occasionally, radiographs show evidence of periosteal new bone formation at sites of enthesitis, especially at the insertion of the Achilles tendon or plantar fascia on the calcaneus, or early syndesmophytes on the lumbar spine without bridging.

Although most patients with USpA (>75%) have chronic, active disease and require long-term therapy for ongoing symptoms, some patients have mild and intermittent symptoms that require intermittent symptomatic therapy. These episodes may last from 1-2 weeks to several months, with long asymptomatic periods that do not require therapy.

Most patients respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). The majority maintain good function without progressive disease or clinically significant radiographic changes. A small minority of patients do not respond well to or tolerate NSAIDs. In these patients, treatment progression is similar to that in AS patients, including the use of sulfasalazine, methotrexate, and tumor necrosis factor alpha (TNF-α) antagonists, although no well-designed clinical trials have been conducted on the treatment of USpA.

Complications

Complications may occur from spinal and articular disease or extra-articular manifestations. The most common complications of AS include pain, stiffness, and limited functional disability. All of these complications can be reduced through a proper treatment plan consisting of medications, exercise, and education. Patients with AS often have additional coexisting diseases, including other spondyloarthropathies. IBD is also more common in these individuals.

A small minority of patients develop spinal fusion, which may result in severe kyphosis and limited motion of the spine, including the cervical region. The fused spine is more susceptible to fracture, even with relatively minor trauma. Occasionally, the hip and shoulder joints develop severe arthritis, requiring total joint replacement.

Extra-articular manifestations (eg, recurrent uveitis, cardiovascular involvement, pulmonary involvement, amyloidosis) rarely result in significant morbidity or mortality.

Fracture

The most serious complication related to AS is a vertebral fracture. Vertebral fractures associated with AS are most common in the cervical spine and are usually the result of a minor fall. For a patient with advanced AS, minor trauma is capable of producing an unstable spinal injury with the risk of neurologic injury or death.

Vertebral fractures are more likely to produce spinal instability in an individual with AS than in an individual without AS, because in advanced AS, the fracture occurs as in a long-bone fracture. The fracture disrupts not only the bony elements but also the ligamentous supports that have become ossified. Without the ligamentous support, the spine becomes grossly unstable, and this instability can lead to severe neurologic injury, including paralysis and death.

Proper diagnosis of a vertebral fracture is often delayed because the patient does not realize the need to seek medical help, because the physician fails to consider the possibility of a vertebral fracture after minor trauma, or because the fracture is difficult to visualize on radiography.

In some cases, radiographic diagnosis is made difficult by the presence of osteopenia and spinal deformity. Additionally, immobility of the glenohumeral joint can interfere with the ability to obtain an adequate “swimmer’s view” to visualize the lower cervical spine. In many cases, CT scans are required for assessment of the spine. The possibility of fractures in the transverse plane suggests the need for sagittal reformatting of the images. If visualization is still inadequate, MRI and bone scans may be helpful.

Spondylodiscitis

Spondylodiscitis (also referred to as Andersson lesion) is a destructive discovertebral lesion with an estimated symptomatic prevalence of 1-10% in patients with AS.[84, 85] The prevalence in asymptomatic patients is unknown.

The etiology of spondylodiscitis is debatable. Some authors argue that these lesions are the result of mechanical factors, whereas others believe that the inflammation caused by AS is the source. Each of these possible etiologies is likely capable of producing similar lesions.

Spondylodiscitis can occur at any time, regardless of the severity of AS. Patients generally present with acute-onset localized pain. Pain is exacerbated with movement and is alleviated with rest. These symptoms can be easily differentiated from the normal pain pattern of AS, which is insidious in onset and relieved with motion.

Radiologic evidence of spondylodiscitis varies with the disease progression but can include the following[84, 86] :

• Destructive foci throughout the discovertebral junction
• Bony sclerosis on both sides of the affected disc level
• Widening or narrowing of the disc space
• Osteolysis of the vertebral bodies

Plain radiographs are not always sufficient to identify spondylodiscitis. CT scans, MRI, and bone scans are often helpful in confirming the diagnosis.

The prognosis is generally good with conservative therapy, including rest, administration of NSAIDs, and physical therapy. Surgical treatment is indicated only in cases where there is evidence of spinal instability or neurologic injury.

Radiographic studies are most helpful in establishing a diagnosis of ankylosing spondylitis (AS).[90] Computed tomography (CT) and magnetic resonance imaging (MRI) may be useful in selected patients but, for reasons of expense, are not typically part of routine evaluation. For full discussion, see Imaging in Ankylosing Spondylitis.

European League Against Rheumatism (EULAR) guidelines for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice, issued in April 2015, recommend conventional radiography of the sacroiliac (SI) joints as the first imaging method to diagnose sacroiliitis as part of axial spondyloarthritis in the majority of cases. Magnetic resonance imaging (MRI) of the SI joints is an alternative in certain cases, such as young patients and those with short duration of symptoms.[91]

EULAR also recommends MRI of the SI joints for patients in whom clinical features and conventional radiography findings are not diagnostic, but axial spondyloarthritis is still suspected. On MRI, findings to consider include both active inflammatory lesions (primarily bone marrow edema) and structural lesions (eg, bone erosion, new bone formation, sclerosis and fat infiltration).[91]

EULAR does not generally recommend imaging modalities other than conventional radiography and MRI for diagnosing axial spondyloarthropathy. CT may provide additional information on structural damage if conventional radiography is negative and MRI cannot be performed. Scintigraphy and ultrasound (US) are not recommended for diagnosis of sacroiliitis as part of axial spondyloarthropathy.

EULAR recommends initial conventional radiography of the lumbar and cervical spine to detect syndesmophytes in patients with AS. MRI may also be used to predict development of new radiographic syndesmophytes.[91]

Power Doppler ultrasonography can be used to document active enthesitis. In addition, this technology may be useful to assess changes in inflammatory activity at entheses during institution of new therapies.[10]

The diagnosis of AS is not dependent on laboratory data; no laboratory tests are specific for AS. Biopsy and histologic analysis are not indicated for individuals with AS.

Approximately 15% of patients with AS present with a normochromic normocytic anemia of chronic disease. The erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP) level is elevated in approximately 75% of patients and may correlate with disease activity in some, but not all, patients; these values may also be used as markers of response to treatment.[92, 93]

Alkaline phosphatase (ALP) is elevated in 50% of patients; this indicates active ossification but does not correlate with disease activity. Creatine kinase (CK) is occasionally elevated but is not associated with muscle weakness. The serum immunoglobulin A (IgA) level may be elevated, correlating with elevated acute-phase reactants.

Of white patients with AS, 92% are HLA-B27 positive; the percentage is lower in patients of other ethnic backgrounds. Determining HLA-B27 status is not a necessary part of the clinical evaluation and is not required to establish the diagnosis. However, in patients suspected of having a spondyloarthropathy, determining HLA-B27 status may help support the diagnosis, especially in populations with a low prevalence of HLA-B27.

Radiographic evidence of inflammatory changes both in the sacroiliac (SI) joints and in the spine are useful in the diagnosis and ongoing evaluation of the disease process.[9] This disease generally begins in the distal portions of the spine and progresses more proximally with time in a continuous fashion.

Involvement of the SI joint is a requirement for the diagnosis of AS. Sacroiliitis is an inflammatory condition leading to bony erosions and sclerosis of the joints (see the image below).

The sacroiliitis seen in AS is usually bilateral, symmetric, and gradually progresses over years. The lesions progress from blurring of the subchondral bone plate to irregular erosions of the margins of the SI joints (pseudo-widening) to sclerosis, narrowing, and finally fusion. Erosions of the subchondral bone of the SI joint are generally seen earlier in the lower portion of the joint (because this portion is lined by synovium) and on the iliac side (because of the thinner cartilage covering this side of the joint).

The radiographic signs of AS are due to enthesitis, particularly of the annulus fibrosus. Early radiographic signs include squaring of the vertebral bodies caused by erosions of the superior and inferior margins of the vertebral bodies, resulting in loss of the normal concave contour of the anterior surface of the vertebral bodies (see the images below). The inflammatory lesions at vertebral entheses may result in sclerosis of the superior and inferior margins of the vertebral bodies, called shiny corners (Romanus lesion).

Ossification of the annulus fibrosus leads to the radiographic appearance of syndesmophytes, which in AS are typically marginal. Over time, the development of continuous (bridging) syndesmophytes may result in complete fusion (bamboo spine), which is essentially fused (see the images below).

 

Spinal disease associated with inflammatory bowel disease (IBD) is similar to AS with bilateral symmetric sacroiliitis and gradually ascending spondylitis and marginal syndesmophytes. On the other hand, reactive arthritis (ReA) and psoriatic arthritis (PsA) typically exhibit asymmetric sacroiliitis and discontinuous spondylitis with nonmarginal syndesmophytes.

Radiographs of other areas may show evidence of enthesitis with osteitis or arthropathy. Radiographs of the pelvis may show ossification of various entheses, such as the iliac crest, ischial tuberosity, and femoral trochanter, which is termed whiskering. Occasionally, the symphysis pubis develops erosive changes (osteitis pubis).

Peripheral entheses may develop radiographic changes, including erosion, periosteal new bone formation, and finally, ossification, especially in the feet at the insertion of the Achilles tendon and the plantar fascia on the calcaneus.

Peripheral joint involvement is most common in the hips and shoulders and may result in uniform joint space narrowing, cystic or erosive changes, deformation, and subchondral sclerosis without osteopenia (see the image below). Heterotopic bone formation may occur after total joint replacement, especially in the hip. Ultimately, peripheral joints may undergo ankylosis. See the radiographs below for an example.

Patients with AS are vulnerable to cervical spine fractures. Long-standing pain may mask the symptoms of a fracture. On radiographs, the distorted anatomy, ossified ligaments, and artifacts may obscure the fracture.

A retrospective case series of 32 patients with AS and cervical spine fractures revealed that in 19 patients (59.4%), a fracture was not identified on plain radiographs.[94] Only 5 patients (15.6%) presented immediately after the injury. Of the 15 patients (46.9%) who were initially neurologically intact, 3 patients had neurologic deterioration before admission. Early diagnosis with appropriate radiologic investigations may prevent possible long-term neurologic cord damage.

Patients with a fused spine are prone to fractures, which may be hard to diagnose with standard radiography. CT scanning or MRI may be required to document the presence of a fracture in patients with late-stage spinal disease (see the images below). Patients with a history of AS who report any recent trauma or an increased level of back or neck pain should be fully evaluated for the possibility of a vertebral fracture and subsequent spinal instability (see the image below).

MRI or CT scanning of the SI joints, spine, and peripheral joints may reveal evidence of early sacroiliitis, erosions, and enthesitis that are not apparent on standard radiographs.[11, 12] MRI using fat-saturating techniques such as short tau inversion recovery (STIR) or MRI with gadolinium is sensitive for inflammatory lesions of enthesitis.[95, 96] The so-called MR corner sign, characterized by inflammatory lesions at the corners of vertebral bodies, is common in the thoracolumbar region of the spine in patients with AS.[97]

Investigations of patients with AS using serial MRI over time has shown a link between inflammatory lesions and the later development of syndesmophytes.[98] MRI can be used as an adjunct to evaluate the inflammatory changes and to assess neural compromise (see the image below). However, MRI and CT are not part of the routine evaluation of AS patients, because of their relatively high cost.

In patients with inflammatory back pain who have normal plain radiographs, MRI imaging of the pelvis (sacroiliac joints) may be very useful to confirm a diagnosis of axial SpA. This is illustrated in the images below, which are of a patient with nr-axSpA who presented with inflammatory back pain and had an excellent response to NSAIDs.

Patients who develop bowel or bladder dysfunction should be evaluated immediately with MRI to assess for possible cauda equina syndrome secondary to spinal stenosis. Cauda equina syndrome is a surgical emergency necessitating decompression within 48 hours to prevent permanent loss of function.

Computerized tomography (CT) can be used to assess bony changes in patients with AS.  It is not routinely used because of its cost and radiation exposure.

Histopathologic evaluation is not generally part of the diagnostic workup in patients with ankylosing spondylitis.

The basic pathologic lesion is inflammation at the enthesis (enthesitis), which occurs at the site of insertion of ligaments and tendons into bone. The histologic picture is that of chronic inflammation with CD4+ and CD8+ T lymphocytes and macrophages. Early AS lesions include subchondral granulation tissue that erodes the joint. Over time, fibrosis and ossification occur, which can be seen radiographically as periostitis and ossification at sites of enthesitis, particularly the SI joints, spine, and heels.

No definite disease-modifying treatment exists for individuals with ankylosing spondylitis (AS) although biologic agents show evidence of such activity. Early diagnosis is important. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, surgical, and physical therapy.

No drugs have been proved to modify the course of the disease, although tumor necrosis factor-α (TNF-α) inhibitors (TNHi) and IL-17 inhibitors (IL-17i) appear to have potential as disease-modifying agents.[99] Symptoms are generally not affected by pregnancy or childbirth. Medical management of AS, including medications, must be adjusted during pregnancy in accordance with the specific pregnancy profiles of the medications.

Inpatient care is generally not necessary for patients with AS. The exceptions to this include patients with coexisting or extra-articular disease and those requiring surgery.

Extra-articular manifestations, which may necessitate specialist referral for appropriate care, include the following:

• Acute anterior uveitis
• Aortitis
• Conduction defects
• Pulmonary fibrosis
• Amyloidosis
• Neurologic deficits, including cauda equina
• Associated inflammatory bowel disease

Disease progress and response to therapy can be monitored by following laboratory values, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level.

Surgical treatment is geared toward resolution of the complications related to AS; it is occasionally used for repairing damaged peripheral joints and rarely used to correct spinal deformities as it involves significant morbidity. Patients with fusion of the spine secondary to AS who report a change in position of the spine should be treated cautiously and should be considered to have sustained a spinal fracture. Surgical intervention may be necessary to stabilize the fracture and prevent neurologic deficit.[100, 101]

Outpatient care should be aimed toward providing adequate pain control and maximizing motion and functional ability. Such care includes pain medication, exercise programs, recreational therapy, and vocational therapy. Regular exercise helps reduce the symptoms and may slow the progress of the disease. Generally, no dietary restrictions are implemented for patients with AS; however, patients with coexisting diseases, such as inflammatory bowel disease (IBD), have dietary restrictions.

Peripheral spondyloarthritis

Pharmacologic treatment for peripheral spondyloarthritis includes the following:

• Nonsteroidal anti-inflammatory drugs
• Corticosteroid injections
• Sulfasalazine
• TNFi (infliximab, etanercept, adalimumab, certolizumab, golimumab)
• IL-17i (secukinumab, ixekizumab)

In a study of adult patients with recent-onset peripheral spondyloarthritis (symptom duration < 12 weeks), early use of the TNFi golimumab resulted in sustained clinical remission in 49 of 60 patients (82%). Most patients (n=30) fulfilled criteria for sustained clinical remission by week 24. On follow-up at least 18 months after drug withdrawal, 26 of the 49 patients (53%) were still in drug-free remission.[102, 103] Similar data have been seen with all the TNFi and IL-17i.  IL-12/23i are effective in the peripheral arthritis and enthesitis of PsA but do not seem to be effective in axial disease such as is seen in AS.

Nonradiographic axial spondyloarthritis

In 2019, the US Food and Drug Administration (FDA) approved certolizumab for treatment of nonradiographic axial spondyloarthritis (nr-axSpA) with objective inflammation. Certolizumab is the first therapy approved for nr-axSpA. Approval was based on data from the phase 3 C-AXSPAND study, which favored certolizumab over placebo at both week 12 and week 52. At week 52, major improvement in the Ankylosing Spondylitis Disease Activity Score (ASDAS) had occurred in 42% of patients receiving certolizumab, compared with 7% of those receiving placebo.[104] IL-17i, secukinumab and ixekizumab, are also FDA approved for the treatment of nr-axSpA.[105, 106] Other TNFi and IL-17i have had similar results in patients with nr-axSpA.

Agents used in the treatment of AS include the following:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Sulfasalazine
• Tumor necrosis factor–alpha inhibitors (TNFi)
• Interleukin-17A (IL-17A) inhibitors
• Corticosteroids
• Janus kinase (JAK) inhibitors
• Miscellaneous agents

Nonsteroidal anti-inflammatory drugs

NSAIDs improve the symptoms of the disease by reducing pain and decreasing inflammation. Numerous choices are available, and they are separated into different families of agents.[107] If one NSAID is ineffective, another from a different family may provide relief.

Efficacy and adverse effect profiles differ among agents and families. Indomethacin may be more effective than other NSAIDs, although this potential advantage has not been proved. Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as nonselective NSAIDs.[108]

Sieper et al, in a randomized, double-blind, controlled study comparing two dosages of celecoxib (200 mg once daily and 200 mg twice daily) to diclofenac (75 mg twice daily), noted that both dosages of celecoxib were comparable to the diclofenac dosage with respect to global pain intensity.[109] However, with respect to changes in disease activity, functional and mobility capacities, and adverse events, once-daily celecoxib was not as effective in reducing certain inflammation-associated parameters as twice-daily celecoxib and diclofenac were.

Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in AS.[108] Common toxicities involve the gastrointestinal (GI) tract (nausea, dyspepsia, ulceration, bleeding), the kidneys, and the central nervous system.

Sulfasalazine

Sulfasalazine is useful in AS patients who do not respond to or who have contraindications to NSAIDs, as well as in those with coexisting inflammatory bowel disease. In particular, it is often given to treat peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine reduces spinal stiffness, peripheral arthritis, and the erythrocyte sedimentation rate (ESR), but there is no evidence that it improves spinal mobility, enthesitis, or physical function.[110, 111, 112] In a randomized, double-blind study, treatment with sulfasalazine resulted in significantly lesser improvement when compared to treatment with the TNFi etanercept.[113] Sulfasalazine toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely).

Tumor necrosis factor–alpha inhibitors

TNF is a cytokine with two identified forms, which have similar biologic properties. TNF-α (cachectin) is produced predominantly by macrophages, and TNF-β (lymphotoxin) is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to AS.[114, 107]

Agents that inhibit TNF-α have proved very effective in the treatment of AS.[115] These TNFi have a fairly rapid onset of action (2 weeks), and have been shown to reduce the inflammatory activity of spinal disease as assessed with magnetic resonance imaging (MRI).[116]

The European League Against Rheumatism notes that extensive MRI inflammatory activity, particularly in the spine, might be used as a predictor of good clinical response to TNFi treatment in patients with AS. Thus, MRI might aid in the decision of initiating TNFi, in addition to clinical examination and C-reactive protein (CRP) testing.[91]

TNFi are indicated after NSAID therapy has failed (two different NSAIDs for one month each).[99] The following TNFi have been approved by the US Food and Drug Administration (FDA) as therapies for AS:

• Etanercept ^{[117, 118]}
• Infliximab ^{[119, 120, 121]}
• Adalimumab ^[122]
• Golimumab ^[123]
• Certolizumab pegol ^{[124, 125]}  

TNFi are also approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Other approved indications include the following:

• Psoriasis (etanercept, infliximab, adalimumab, certolizumab pegol)
• Juvenile idiopathic arthritis (etanercept, adalimumab)
• Crohn disease (infliximab, adalimumab, certolizumab pegol)
• Non-infectious uveitis (adalimumab)

Toxicities associated with TNFi include injection-site and infusion reactions. Increased risks of bacterial infections, reactivation of latent tuberculosis, and certain fungal infections (eg, histoplasmosis, coccidioidomycosis) have been observed.

There is some concern regarding an increased risk of malignancy in patients receiving TNFi. The most attention has been focused on lymphoma and non-melanotic skin cancers in patients with rheumatoid arthritis, although this has been difficult to document in such patients and has not been described in patients with AS. In rare cases, cytopenias have been associated with TNFi use.

Patients with rheumatoid arthritis who have recently started TNFi may be at increased risk for new-onset congestive heart failure even in the absence of any obvious risk factors for the disease. These agents should not be initiated in patients with uncompensated congestive heart failure.

Patients should be screened for latent tuberculosis, hepatitis B, and HIV infection before beginning TNFi therapy.[126] Although these agents should not be used in patients with active hepatitis B, they appear to be safe in patients with chronic hepatitis C. Rarely, autoimmune syndromes (eg, a lupuslike illness) have been noted in patients receiving TNFi. More commonly, a positive antinuclear antibody (ANA) test result, in the absence of clinical disease, may occur during treatment.

Demyelinating syndromes have rarely been documented in patients receiving TNFi, though no direct link has been proved. These agents should not be used in patients with multiple sclerosis or other demyelinating diseases. New-onset psoriatic skin lesions have been documented after the initiation of TNFi.

In a prospective study of 334 patients with AS, response to treatment with TNFi was associated with a 50% reduction in the risk of radiographic progression of AS. However, nearly 4 years of treatment were necessary for the benefit to become apparent. Moreover, in patients who first began TNFi treatment 10 or more years after disease onset, AS progression was twice as likely as it was in patients who started treatment earlier.[127, 128]

Interleukin-17A inhibitors

IL-17A is a proinflammatory cytokine that is involved in normal inflammatory and immune responses and also plays a key role in the pathogenesis of AS. Two human IgG monoclonal antibodies that target IL-17A are approved for use in AS and active non-radiographic axial spondyloarthritis: secukinumab and ixekizumab.

Secukinumab

Secukinumab (Cosentyx), a human IgG1 monoclonal antibody that selectively binds to and neutralizes IL-17A, was approved by the FDA for adults with active AS in 2016. In 2020, approval was expanded to include non-radiographic axial spondyloarthritis (nr-axSpA).

Approval of secukinumab for AS was based on 2 phase III trials (MEASURE 1 and 2). In MEASURE 1 (n=371), the Assessment of Spondyloarthritis International Society (ASAS20) response rates at week 16 for secukinumab (at a dose of 150 mg subcutaneously) versus placebo were 61% versus 29%, respectively (P < 0.001 for both comparisons with placebo). In MEASURE 2 (n=219), those rates were 61% and 28%, respectively (P < 0.001). The significant improvements were sustained through 52 weeks.[129]

The approval of secukinumab for nr-axSpA was based on outcomes from the PREVENT phase III study (n = 555) in adults with active nr-axSpA who were biologic-treatment naïve or had an inadequate response or intolerance to an anti–TNF-α therapy. Of the 481 patients who completed 52 weeks of treatment, ASAS40 in TNFi-naïve patients was significantly higher with a loading dose (41.5%) at week 16 and without a loading dose (39.8%) at week 52 compared with placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05).[105]

Ixekizumab 

Ixekizumab (Taltz), a humanized monoclonal IgG4 antibody, also targets IL-17A. In 2019, ixekizumab was approved by the FDA for adults with active AS. In 2020, approval was expanded to include nr-axSpA. Approval was based on two phase III trials (COAST-V and COAST-W) that included 657 adults with active AS. In COAST-V, which included patients who had not been treated with biological DMARDs, at week 16, significantly more patients achieved improvement with ixekizumab than with placebo or adalimumab.[130]  In the COAST-W trial, patients with active AS with a previous inadequate response or intolerance to TNF inhibitors showed a statistical improvement at 16 weeks with ixekizumab, compared with placebo (30.6% versus 12.5%; P=0.003%).[131]

Approval of ixekizumab for active nr-axSpA with objective signs of inflammation was based on the COAST-X phase III trial. The primary endpoint,  the proportion of patients achieving ASAS40 at 52 weeks, was achieved in 30% of patients treated with ixekizumab versus 13% for placebo (P = 0.0045).[106]

Corticosteroids

Oral corticosteroids are occasionally helpful in controlling AS symptoms. However, they should be used only for short-term management; long-term management carries a high risk of adverse effects. No evidence has shown that corticosteroids alter the outcome of the disease, and these agents are known to increase the tendency toward spinal osteoporosis.

Local corticosteroid injections are useful for symptomatic sacroiliitis, peripheral enthesitis, and arthritis, although the response is not typically as rapid as in patients with rheumatoid arthritis. 

Janus kinase inhibitors

JAKs are intracellular tyrosine kinases that affect a range of intracellular activity, including the production of inflammatory cytokines. The JAK family contains four JAKs: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Two JAK inhibitors, upadacitinib (Rinvoq) and tofacitinib (Xeljanz), are approved by the FDA for treatment of active AS in adults who have an inadequate response or are intolerant to one or more TNFi. Both are available as extended-release tablets.

Upadacitinib

Upadacitinib, a JAK1-selective inhibitor, was approved by the FDA for use in AS in April 2022. Approval was based on data from the phase III SELECT-AXIS 2 and the phase II/III SELECT-AXIS 1 clinical trials. SELECT-AXIS 2 evaluated upadacitinib in patients who had an inadequate response (IR) or intolerance to 1 or 2 biologic DMARDs (bDMARDs) and in patients with active non-radiographic axial spondyloarthritis (Nr-axSpA). At 14 weeks, significantly more patients from SELECT-AXIS 2 reached an Assessment of SpondyloArthritis international Society 40 (ASAS40) response versus placebo, the primary endpoint (45% versus 23%; P < 0.0001 in Nr-axSpA patients and 45% versus 18%; P < 0.0001 in bDMARD-IR patients).[132]   

In SELECT-AXIS 1, which comprised patients who had an IR or intolerance to at least 2 NSAIDs, the percentage of participants achieving the primary efficacy end point of ASAS40 at 14 weeks was significantly greater with upadacitinib than with placebo (52% vs 26%; P = 0.003).[133] At week 14, patients in the placebo arm were switched to upadacitinib, and all patients continued in the open-label study extension and received upadacitinib up to week 104. At week 64, similar proportions of patients in either group (continuous upadacitinib or placebo-to-upadacitinib) achieved ASAS40 or ASDAS and showed low disease activity.[134]  

Tofacitinib

Tofacitinib, which inhibits JAK1 and JAK3, was approved by the FDA for use in AS in December 2021. Approval was based on data from a phase III, randomized, double-blind, placebo-controlled trial in patients who had an inadequate response or intolerance to 1 or more TNFi. At 16 weeks, the percentage of patients achieving an ASAS20 was significantly higher with tofacitinib than with placebo (56.4% vs 29.4%; P < 0.0001). Additionally, the ASAS40 response was significantly greater with tofacitinib vs placebo (40.6% versus 12.5%; P < 0.0001).[135]  

Other agents

Anecdotal reports suggest that other medications may be helpful in the treatment of AS, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Methotrexate is of questionable benefit in AS; various studies have shown conflicting results.[136] At present, it is reserved for patients with symptoms that are not adequately controlled with NSAIDs or sulfasalazine.

Leflunomide was evaluated in a randomized, double-blind, placebo-controlled study in active AS but was not found to be effective.[137] Bisphosphonates may modestly affect clinical disease activity in AS. Anakinra, a recombinant human IL-1 receptor antagonist, may be effective in treatment-resistant AS. 

Guidelines on treatment for ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) have been issued by the American College of Rheumatology.[138]

In adults with active AS:

• Strongly recommend treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) over no treatment with NSAIDs
• Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs
• No recommendation for any particular NSAID as the preferred choice
• Strongly recommend against treatment with systemic glucocorticoids

In adults with active AS despite treatment with NSAIDs:

• Conditionally recommend treatment with sulfasalazine, methotrexate, or tofacitinib over no treatment with those medications; sulfasalazine or methotrexate should be considered only in patients with prominent peripheral arthritis or when a tumor necrosis factor inhibitor (TNFi) is not available. 
• Conditionally recommend treatment with a TNFi over treatment with tofacitinib
• Strongly recommend treatment with a TNFi over no treatment with TNFi
• No recommendation for any particular TNFi as the preferred choice
• Strongly recommend treatment with secukinumab or ixekizumab over no treatment with those agents;
• Conditionally recommend treatment with a TNFi over treatment with secukinumab or ixekizumab 
• Conditionally recommend treatment with secukinumab or ixekizumab over treatment with tofacitinib
• In patients who have contraindications to TNFis, conditionally recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine, methotrexate, or tofacitinib 
• In patients with primary nonresponse to TNFi therapy, conditionally recommend treatment with secukinumab or ixekizumab over treatment with a different TNFi
• In patients with secondary nonresponse to TNFi therapy, conditionally recommend treatment with a different TNFi over treatment with a non-TNFi biologic
• In patients whose AS does not respond to treatment with the first TNFi used, strongly recommend against switching to treatment with a biosimilar of the first TNFi
•  In patients whose AS does not respond to treatment with the first TNFi used, conditionally recommend against the addition of sulfasalazine or methotrexate in favor of treatment with a new biologic
• In adults with AS and isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
• In adults with AS with stable axial disease and active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids; however, peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided
• In adults with AS with stable axial disease and active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
• Strongly recommend treatment with physical therapy over no treatment with physical therapy
• Conditionally recommend active physical therapy interventions (supervised exercise) over passive physical therapy interventions (massage, ultrasound, heat)
• Conditionally recommend land-based physical therapy interventions over aquatic therapy interventions

In adults with stable AS:

• Conditionally recommend on-demand treatment with NSAIDs over continuous treatment with NSAIDs
• In patients receiving treatment with TNFi and NSAIDs, conditionally recommend continuing treatment with TNFi alone versus continuing both treatments
• In patients receiving treatment with TNFi and a conventional synthetic antirheumatic drug, conditionally recommend continuing treatment with TNFi alone over continuing both treatments
• In patients receiving treatment with a biologic, conditionally recommend against discontinuing it
• In patients receiving treatment with a biologic, conditionally recommend against tapering of the biologic dose as a standard approach
• In patients receiving treatment with an originator TNFi, strongly recommend continuing treatment with the originator TNFi over mandated switching to its biosimilar
• Strongly recommend treatment with physical therapy over no treatment with physical therapy

In adults with active or stable AS:

• Conditionally recommend against co-treatment with a TNFi and low-dose methotrexate
• Conditionally recommend advising unsupervised back exercises
• Conditionally recommend evaluation and counseling regarding falls
• Conditionally recommend participation in formal group or individual self-management education
• In patients with spinal fusion or advanced spinal osteoporosis,strongly recommend against treatment with spinal manipulation
• In patients with advanced hip arthritis, strongly recommend treatment with total hip arthroplasty over no surgery
• In patients with severe kyphosis, conditionally recommend against elective spinal osteotomy

In adults with AS-related comorbidities:

• In patients with acute iritis, strongly recommend treatment by an ophthalmologist to decrease the severity, duration, or complications of episodes
• In patients with recurrent iritis, conditionally recommend prescription of topical glucocorticoids over no prescription for prompt at-home use in the event of eye symptoms, to decrease the severity or duration of iritis episodes
• In patients with recurrent iritis,conditionally recommend treatment with TNFi monoclonal antibodies over treatment with other biologics
• In patients with inflammatory bowel disease, do not recommend any particular NSAID as the preferred choice to decrease the risk of worsening of inflammatory bowel disease symptoms
• In patients with inflammatory bowel disease, conditionally recommend treatment with TNFi monoclonal antibodies over treatment with other biologics

Assessment of disease activity, imaging, and screening:

• Conditionally recommend the monitoring of a validated AS disease activity measure at regular intervals
• Conditionally recommend regular-interval monitoring of C-reactive protein (CRP) concentrations or erythrocyte sedimentation rate (ESR) over usual care without regular CRP or ESR monitoring
• In adults with active AS, conditionally recommend against using a treat-to-target strategy using a target Ankylosing Spondylitis Disease Activity Score (ASDAS) of < 1.3 (or 2.1) over a treatment strategy based on physician assessment
• Conditionally recommend screening for osteopenia/osteoporosis with dual-energy x-ray absorptiometry (DXA) scan over no screening
• In adults with syndesmophytes or spinal fusion, conditionally recommend screening for osteoporosis/osteopenia with DXA scan of the spine as well as the hips, compared with DXA scan solely of the hip or other non-spine sites
• Strongly recommend against screening for cardiac conduction defects with electrocardiograms
• Strongly recommend against screening for valvular heart disease with echocardiograms
• In adults with AS of unclear activity while on a biologic, conditionally recommend obtaining a spinal or pelvis MRI to assess activity
• In adults with stable AS, conditionally recommend against obtaining a spinal or pelvis MRI to confirm inactivity
• In adults with active or stable AS on any treatment, conditionally recommend against obtaining repeat spine radiographs at a scheduled interval (eg, every 2 years) as a standard approach

In adults with active nonradiographic axial spondyloarthritis (SpA):

• Strongly recommend treatment with NSAIDs over no treatment with NSAIDs
• Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs
• Do not recommend any particular NSAID as the preferred choice

In adults with active nonradiographic axial SpA despite treatment with NSAIDs​:

• Conditionally recommend treatment with sulfasalazine, methotrexate, or tofacitinib over no treatment with these medications
• Strongly recommend treatment with TNFi over no treatment with TNFi
• Do not recommend any particular TNFi as the preferred choice
• Conditionally recommend treatment with TNFi over treatment with tofacitinib
• Conditionally recommend treatment with secukinumab or ixekizumab over no treatment with secukinumab or ixekizumab
• Conditionally recommend treatment with TNFi over treatment with secukinumab or ixekizumab
• Conditionally recommend treatment with secukinumab or ixekizumab over treatment with tofacitinib
• In patients who have contraindications to TNFi, conditionally recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine, methotrexate, or tofacitinib
• In adults with active nonradiographic axial SpA and primary nonresponse to the first TNFi used, conditionally recommend switching to secukinumab or ixekizumab over switching to a different TNFi.
• In adults with active nonradiographic axial SpA and secondary nonresponse to the first TNFi used, conditionally recommend switching to a different TNFi over switching to a non-TNFi biologic.
• In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, strongly recommend against switching to the biosimilar of the first TNFi.
• In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, conditionally recommend against the addition of sulfasalazine or methotrexate in favor of treatment with a different biologic.

Other recommendations for adults with nonradiographic axial SpA:

• Strongly recommend against treatment with systemic glucocorticoids
• In patients with isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with local glucocorticoids over no treatment with local glucocorticoids
• In patients with active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoid; however, peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided
• In patients with active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
• Strongly recommend treatment with physical therapy over no treatment with physical therapy
• Conditionally recommend active physical therapy interventions (supervised exercise) over passive physical therapy interventions (massage, ultrasound, heat)
• Conditionally recommend land-based physical therapy interventions over aquatic therapy interventions

In adults with stable nonradiographic axial spondyloarthritis (SpA):

• Conditionally recommend on-demand treatment with NSAIDs over continuous treatment with NSAIDs
• In adults receiving treatment with TNFi and NSAIDs, conditionally recommend continuing treatment with TNFi alone over continuing both medications
• In patients receiving treatment with TNFi and a conventional synthetic antirheumatic drug, conditionally recommend continuing treatment with the TNFi alone over continuing treatment with both medications
• In patients receiving treatment with a biologic, conditionally recommend against discontinuing it
• In patients receiving treatment with a biologic, conditionally recommend against tapering of the biologic dose as a standard approach
• In patients receiving treatment with an originator TNFi, strongly recommend continuation of treatment with the originator TNFi over mandated switching to its biosimilar

In adults with active or stable nonradiographic axial SpA:

• Conditionally recommend against co-treatment with a TNFi and low-dose methotrexate

Assessment of disease activity and imaging:

• Conditionally recommend monitoring of a validated AS disease activity measure at regular intervals
• Conditionally recommend regular monitoring of the CRP concentrations or ESR over usual care without regular CRP or ESR monitoring
• In adults with active nonradiographic axial SpA, conditionally recommend against using a treat-to-target strategy using a target of ASDAS < 1.3 (or 2.1) over a treatment strategy based on physician assessment
• In adults with nonradiographic axial SpA of unclear activity while on a biologic, conditionally recommend obtaining a pelvis MRI to assess activity
• In adults with stable nonradiographic axial SpA, conditionally recommend against obtaining a spinal or pelvis MRI to confirm inactivity
• In adults with active or stable nonradiographic axial SpA on any treatment, conditionally recommend against obtaining repeat spine radiographs at a scheduled interval (eg, every 2 years) as a standard approach

Guidelines issued by an international task force on treating axial and peripheral spondyloarthritis to target include the following recommendations[139] :

• The treatment target should be clinical remission/inactive disease of musculoskeletal (arthritis, dactylitis, enthesitis, axial disease) and extra-articular manifestations.
• The treatment target should be individualized on the basis of current clinical manifestations, and the treatment modality should be considered when defining the time required to reach the target.
• Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant disease activity; low or minimal disease activity may be an alternative treatment target .
• Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants.
• Validated measures of musculoskeletal disease activity and assessment of cutaneous and/or other relevant extra-articular manifestations should be used in clinical practice to define the target and to guide treatment decisions; the frequency of the measurements depends on the level of disease activity.
• In axial spondyloarthritis, the Ankylosing Spondylitis Disease Activity Score (ASDAS) is a preferred measure.
• The choice of the target and of the disease activity measure should take comorbidities, patient factors, and drug-related risks into account.
• In addition to clinical and laboratory measures, imaging results may be considered in clinical management.
• Once the target is achieved, it should ideally be maintained throughout the course of the disease. 
• The patient should be appropriately informed and involved in the discussions about the treatment target and the risks and benefits of the strategy planned to reach this target.

Joint guidelines on axial SpA (axSpA) issued by the Assessment of SpondyloArthritis international Society (ASAS) and the European League Against Rheumatism (EULAR) update and aggregate previous ASAS-EULAR guidelines on AS and ASAS guidelines on management of axSpA with TNFi into a single set of recommendations.[99]

The ASAS-EULAR guidelines begin with the following five overarching principles:

1. AxSpA is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.
2. The primary goal of treating the patient with axSpA is to maximize long-term health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, and preservation/normalization of function and social participation.
3. The optimal management of patients with axSpA requires a combination of non-pharmacological and pharmacological treatment modalities.
4. Treatment of axSpA should aim at the best care and must be based on a shared decision between the patient and the rheumatologist.
5. AxSpA incurs high individual, medical, and societal costs, all of which should be considered in its management by the treating rheumatologist.

The ASAS recommendations are as follows:

• The treatment of patients with axSpA should be individualized according to the current signs and symptoms of the disease (axial, peripheral, extra-articular manifestations) and the patient characteristics, including comorbidities and psychosocial factors.
• Disease monitoring of patients with axSpA should include patient-reported outcomes, clinical findings, laboratory tests and imaging, all with the appropriate instruments and relevant to the clinical presentation. The frequency of monitoring should be decided on an individual basis, depending on symptoms, severity and treatment.
• Treatment should be guided according to a predefined treatment target.
• Patients should be educated about axSpA and encouraged to exercise on a regular basis and stop smoking; physical therapy should be considered.
• Patients suffering from pain and stiffness should use an NSAID as first-line drug treatment up to the maximum dose, taking risks and benefits into account. For patients who respond well to NSAIDs and whose symptoms recur after stopping the NSAID or reducing the dose, continuous use is advised.
• Analgesics, such as acetaminophen and opioid-(like) drugs, might be considered for residual pain after previously recommended treatments have failed, are contraindicated, and/or are poorly tolerated.
• Glucocorticoid injections directed to the local site of musculoskeletal inflammation may be considered. Patients with axial disease should not receive long-term treatment with systemic glucocorticoids.
• Patients with purely axial disease should normally not be treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); sulfasalazine may be considered in patients with peripheral arthritis.
• Biologic DMARDs (bDMARDs) should be considered in patients with persistently high disease activity despite conventional treatments; current practice is to start with TNFi therapy.
• If TNFi therapy fails, switching to another TNFi or an anti–interleukin-17 (IL-17) therapy should be considered.
• If a patient is in sustained remission, tapering of a bDMARD can be considered.
• Total hip arthroplasty should be considered in patients with refractory pain or disability and radiographic evidence of structural damage, independent of age; spinal corrective osteotomy in specialized centers may be considered in patients with severe disabling deformity.
• If a significant change in the course of the disease occurs, causes other than inflammation (eg, a spinal fracture) should be considered and appropriate evaluation, including imaging, should be performed.

Acute anterior uveitis presents as a painful red eye that is associated with photophobia and often recurs. Untreated uveitis may lead to vision loss. Evaluation and treatment of uveitis should be performed under the guidance of an ophthalmologist.

Generally, patients respond well to topical corticosteroids, mydriatics, and artificial tears, with resolution of the attack over 2-3 months. Treatment occasionally requires topical NSAIDs, retrobulbar corticosteroid injections, or immunosuppressive drugs. TNFi may be helpful in selected cases. A study by van Denderen and colleagues reported a significant reduction in the recurrence rate of anterior uveitis in patients with AS who were treated with adalimumab.[140]  Adalimumab is FDA approved for treatment of noninfectious uveitis, including that associated with axial SpA.

Laboratory values, including the ESR and the C-reactive protein (CRP) level, are commonly employed to monitor the progression of the disease and the effectiveness of treatment. Guidelines from the European League Against Rheumatism (EULAR) recommend that conventional radiography of the sacroiliac (SI) joints, spine, or both may be used for long-term monitoring of structural damage, particularly new bone formation. If performed, it should not be repeated more frequently than every second year.[91]

MRI may provide additional information. MRI of the SI joints and/or the spine may be used to assess and monitor disease activity in axial spondyloarthropathy. In general, short tau inversion recovery (STIR) sequences are sufficient to detect inflammation, and the use of contrast medium is not needed.[91]

In addition, numerous tools have been developed to measure AS disease activity, especially in the setting of clinical trials.[141, 142, 143] These tools include the following:

• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) - A questionnaire that assesses fatigue, pain (in the neck, back, and hip), peripheral joint pain and swelling, discomfort, and severity and duration of morning stiffness

• Bath Ankylosing Spondylitis Functional Index (BASFI) - A questionnaire of physical function that evaluates dressing, bending, mobility, standing, stairs, and full-day activities

• Bath Ankylosing Spondylitis Metrology Index (BASMI) - A physical evaluation of range of motion (ROM) of the cervical and lumbar spine

• Assessment in Ankylosing Spondylitis (ASAS) - The ASAS core set of domains (parameters) measures disease activity and includes patient global assessment of disease activity, patient assessment of back pain, BASFI, morning stiffness, synovitis and enthesitis score, ESR, CRP level, and fatigue

The ASAS response criteria are used to assess improvement in AS in clinical trials. Each of four domains is scored by the patient on a visual analog scale ranging from 0 to 10. The four domains are as follows:

• Patient global assessment of disease activity for the past week
• Patient assessment of back over the past week
• Function (BASFI)
• Inflammation (severity and duration of morning stiffness, average of items 5 and 6 in the BASDAI)

An ASAS20 response is defined as an improvement of at least 20% and an absolute improvement of at least 1 unit (on a 0-10 scale) in at least three of four domains, with no worsening of the remaining domain. An ASAS40 response is similar but requires a 40% improvement. An ASAS partial remission is defined as values of less than 2 for all four ASAS20 domains.

ASAS5/6 includes the four domains included in the ASAS20 plus spinal mobility (BASMI) and acute-phase reactants (CRP). An ASAS5/6 response is defined as improvement of at least 20% and an improvement of at least 1 unit in at least five of six domains, with no worsening of the remaining domain.

Surgical interventions for AS include the following:

• Vertebral osteotomy
• Fracture stabilization
• Joint replacement

Vertebral osteotomy

Patients with fusion of the cervical or upper thoracic spine may have significant impairment in line of sight, eating, and psychosocial well-being. These patients may benefit from extension osteotomy of the cervical spine.[13] This procedure is difficult and hazardous and should be performed only by surgeons specializing in spine surgery who have experience with the operation. The risk of major neurologic morbidity is significant; however, if the procedure is successful, it allows the patient to return to a more functional life.

Fracture stabilization

Many patients with advanced disease have fusion of the spine. If these patients report any change in position or movement of the spine, they should be assumed to have a spinal fracture because such an injury is the only way for a fused spine to move. Patients should be treated cautiously until fracture has been ruled out. If spinal fracture is present, surgical stabilization may be necessary.

Joint replacement

Patients with significant involvement of the hips may benefit from total hip arthroplasty[14] ; occasionally, total shoulder replacement may be indicated. These procedures may be very useful for reducing pain and improving function when the hip and shoulder joints become severely damaged. However, patients with AS at increased risk for complications after total hip arthroplasty, as the alteration in biomechanics resulting from spinal rigidity and kyphosis place higher demands on hip joints.[144]

Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by giving NSAIDs (eg, indomethacin) or employing radiation therapy postoperatively. In general, outcomes of total joint replacement in patients have been satisfactory.

Physical therapy is important for maintaining function.[145, 146] A proper exercise program is a crucial component of such therapy. Patients obtain a significant reduction in symptoms after exercising. Referral to physical therapy or to a rehabilitation specialist is useful in assisting patients to develop an appropriate exercise program.  

Water therapy and swimming are excellent activities for maintaining mobility and fitness. In addition, a meta-analysis concluded that aquatic physical therapy can statistically significantly reduce pain and disease activity in patients with AS.[147]

Postural training is also useful. Spinal extension and deep-breathing exercises help maintain spinal mobility, encourage erect posture, and promote chest expansion. Maintaining an erect posture during daily activities and sleeping on a firm mattress with a thin pillow also tend to reduce the tendency toward thoracic kyphosis.

Consultations with the following specialists may be appropriate:

• Rheumatologist - For evaluation and management of ongoing medical treatment of patients with AS; additional coexisting spondyloarthropathies can be assessed

• Ophthalmologist - For patients with symptoms of acute anterior uveitis

• Gastroenterologist - For patients with symptoms suggesting coexisting IBD

• Cardiologist - For patients with cardiac involvement, including aortitis or heart block

• Physical therapist or physical medicine and rehabilitation specialist - Indicated for all patients

• Surgeon (orthopedic, neurologic, or both)

• Support groups - Many patients benefit from various support groups, which can provide further education on the disease process and available treatment options

The goal of pharmacotherapy is to reduce morbidity and to prevent complications—specifically, by reducing the pain and inflammation associated with ankylosing spondylitis (AS).

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for reducing pain secondary to inflammation and systemic symptoms in AS patients. These agents reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness and appear to have a modest disease-modifying effect on spinal disease. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as traditional NSAIDs.

NSAIDs and COX-2 inhibitors may increase the risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. They also increase the risk of serious adverse gastrointestinal (GI) effects, including stomach or intestinal bleeding, ulceration, and perforation, which can also be fatal. Elderly patients are at greater risk for serious GI events.

Indomethacin (Indocin)

Indomethacin is thought to be the most effective NSAID for the treatment of AS, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Ibuprofen (Advil, Motrin)

Ibuprofen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Diclofenac (Voltaren, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors. Liver function test abnormalities occur more often with diclofenac than with other NSAIDs.

Celecoxib (Celebrex, Elyxyb)

Celecoxib is a COX-2 selective inhibitor that is associated with less GI toxicity and does not have any antiplatelet effect.

Class Summary

5-Aminosalicylic acid derivatives inhibit prostaglandin synthesis and reduce the inflammatory response to tissue injury.

Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

Sulfasalazine has been shown to reduce the inflammatory symptoms of AS in controlled studies; its most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).

Class Summary

Immunosuppressants inhibit key factors in the immune system that are responsible for inflammatory responses.

Methotrexate (Trexall, Otrexup, Rasuvo)

Methotrexate has an unknown mechanism of action in AS; it may affect immune function by inhibiting dihydrofolate reductase, interfering with purine synthesis. Effects are observed in the 3-6 weeks following administration. Methotrexate ameliorates symptoms (eg, pain, swelling, stiffness) but there is no evidence that it induces remission. Adjust the dose gradually to obtain a satisfactory response.

Class Summary

Tumor necrosis factor alpha (TNF-α) antagonists are biologic agents and include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. These agents inhibit TNF-α and have been shown to improve symptoms and function in AS patients in clinical trials. All have been approved for the treatment of AS. These agents are also all approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA).

Etanercept (Enbrel, Erelzi, etanercept-szzs)

Etanercept consists of a fusion protein of the extracellular portion of the p75 TNF-α receptor and the Fc portion of immunoglobulin G (IgG). It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous (SC) injection and is available in a prefilled syringe, an autoinjector, or lyophilized powder. It is also approved for rheumatoid arthritis, PsA, psoriasis, and juvenile idiopathic arthritis.

Infliximab (Remicade, Inflectra, infliximab-dyyb, Renflexis, infliximab-abda, Ixifi, infliximab-qbtx)

Infliximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against TNF-α. The variable regions of heavy and light chains are murine in origin, and the constant regions are human. Infliximab inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an intravenous (IV) infusion. It is also approved for rheumatoid arthritis, PsA, psoriasis, and Crohn disease.

Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)

Adalimumab is a human IgG1κ monoclonal antibody directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, Crohn disease, and noninfectious uveitis. The FDA has approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd as biosimilars and not as interchangeable drugs.

Golimumab (Simponi)

Golimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis and PsA.

Certolizumab pegol (Cimzia)

Certolizumab pegol is a recombinant humanized anti-human TNF-α neutralizing antibody. It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous injection and is available as a powder for injection. It is FDA-approved for active ankylosing spondylitis and non-radiographic axial spondyloarthropathy, as well as for Crohn disease, rheumatoid arthritis, and psoriatic arthritis.

Class Summary

Various interleukins play a role in inflammatory processes.

Secukinumab (Cosentyx)

Human IgG1 monoclonal antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin 17A (IL-17A). IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It is indicated for adults with active ankylosing spondylitis and for those with active non-radiographic axial spondyloarthritis with objective signs of inflammation. 

Ixekizumab (Taltz)

Humanized monoclonal IgG4 antibody that targets interleukin-17A (IL-17A) and neutralizes the proinflammatory effects of IL-17A. It is indicated for adults with active ankylosing spondylitis and for those with active non-radiographic axial spondyloarthritis with objective signs of inflammation.

Class Summary

Janus kinase (JAK) inhibitors interfere with the JAK signaling pathways for various cytokines involved in inflammation. Blocking these signals is crucial in treating many inflammatory conditions including AS. 

Upadacitinib (Rinvoq)

A small molecule that interferes with the JAK signaling pathways. This results in decreased activity of pro-inflammatory interleukins, increased lymphocytes, and decreased immunoglobulins. It is indicated for active AS in adults who have had an inadequate response or intolerance to at least 1 TNF blocker.

Tofacitinib (Xeljanz, Xeljanz XR)

A small molecule that is a partial and reversible inhibitor of JAK. By inhibiting JAK, phosphorylation then activation of signal transducers and activators of transcription (STAT) is prevented. The JAK-STAT signaling pathway correlates with hematopoiesis and immune cell function. Inhibition results in a decreased inflammatory response. It is indicated for active AS in adults who have had an inadequate response or intolerance to at least 1 TNF blocker.