Spondylitis (pronounced spon-d-lie-tiss) is the name given to a group of chronic or long lasting diseases also called Spondyloarthritis (spon-dyl-oh-arthritis) or Spondyloarthropathy (spon-d-low-are-throp-ah-thee). These diseases are forms of inflammatory arthritis that primarily affect the spine, although other joints and organs can become involved. The group of diseases in the spondylitis family includes:

Ankylosing Spondylitis (AS) - Ankylosing spondylitis is the primary disease in the spondylitis family of diseases and is a form of chronic arthritis that primarily affects the spine, although other joints can become involved. Occurring primarily in young adults, (age of onset normally before age 35), AS causes inflammation of the spinal joints (vertebrae) that can lead to severe, chronic pain and discomfort.

Undifferentiated Spondyloarthropathy (USpA) - Undifferentiated Spondyloarthropathy (USpA) is a term used to describe symptoms and signs of spondylitis in someone who does not meet the criteria for a definitive diagnosis of AS or related disease. Over time, some people with USpA will develop a well-defined form of spondylitis such as ankylosing spondylitis.

Juvenile Spondyloarthropathy (JSpA) - Juvenile-onset spondyloarthritis (JSpA), also known as Juvenile Spondyloarthropathy, is the medical term for a group of childhood rheumatic diseases, which cause arthritis before the age of 16 and may span through adult life. JSpA typically causes pain and inflammation in the joints in the lower part of the body, for example, the pelvis, hips, knees and ankles.

Psoriatic Arthritis (PsA) - In 5-10% of those with psoriasis, arthritis also appears. In most cases, the psoriasis will precede the arthritis, sometimes by many years. When arthritis symptoms occur with psoriasis, it is called psoriatic arthritis (PsA).

Reactive Arthritis (ReA) - Reactive Arthritis (also known as Reiter's Syndrome) is a form of arthritis that can cause inflammation and pain in the joints, the skin, the eyes, the bladder, the genitals and the mucus membranes. Reactive arthritis is thought to occur as a "reaction" to an infection that started elsewhere in the body, generally in the genitourinary or gastrointestinal tract.

Enteropathic Arthritis - Enteropathic (en-ter-o-path-ic) arthritis is a form of chronic, inflammatory arthritis associated with the occurrence of an inflammatory bowel disease (IBD), the two best-known types of which are ulcerative colitis and Crohn's disease. The most common areas affected by enteropathic arthritis are inflammation of the peripheral (limb) joints, as well as the abdominal pain and possibly bloody diarrhea associated with the IBD component of the disease.

What is ankylosing spondylitis?

Ankylosing spondylitis is a form of chronic inflammation of the spine and the sacroiliac joints. The sacroiliac joints are located in the low back where the sacrum (the bone directly above the tailbone) meets the iliac bones (bones on either side of the upper buttocks). Chronic inflammation in these areas causes pain and stiffness in and around the spine. Over time, chronic inflammation of the spine (spondylitis) can lead to a complete cementing together (fusion) of the vertebrae, a process referred to as ankylosis. Ankylosis leads to loss of mobility of the spine.

Ankylosing spondylitis is also a systemic disease, meaning it can affect other tissues throughout the body. Accordingly, it can cause inflammation in or injury to other joints away from the spine, as well

as to other organs, such as the eyes, heart, lungs, and kidneys. Ankylosing spondylitis shares many features with several other arthritis conditions, such as psoriatic arthritis, reactive arthritis, and arthritis associated with Crohn's disease and ulcerative colitis. Each of these arthritic conditions can cause disease and inflammation in the spine, other joints, eyes, skin, mouth, and various organs. In view of their similarities and tendency to cause inflammation of the spine, these conditions are collectively referred to as "spondyloarthropathies." Ankylosing spondylitis is considered one of the many rheumatic diseases because it can cause symptoms involving muscles and joints.

Ankylosing spondylitis is two to three times more common in males than in females. In women, joints away from the spine are more frequently affected than in men. Ankylosing spondylitis affects all age groups, including children. The most common age of onset of symptoms is in the second and third decades of life.

What causes ankylosing spondylitis?

The tendency to develop ankylosing spondylitis is believed to be genetically inherited, and a majority (nearly 90%) of people with ankylosing spondylitis are born with a gene known as the HLA-B27 gene. Blood tests have been developed to detect the HLA-B27 gene marker and have furthered our understanding of the relationship between HLA-B27 and ankylosing spondylitis. The HLA-B27 gene appears only to increase the tendency of developing ankylosing spondylitis, while some additional factor(s), perhaps environmental, are necessary for the disease to appear or become expressed. For example, while 7% of the United States population have the HLA-B27 gene, only 1% of the population actually has the disease ankylosing spondylitis. In northern Scandinavia (Lapland), 1.8% of the population have ankylosing spondylitis while 24% of the general population have the HLA-B27 gene. Even among HLA-B27-positive individuals, the risk of developing ankylosing spondylitis appears to be further related to heredity. In HLA-B27-positive individuals who have relatives with the disease, the risk of developing ankylosing spondylitis is 12% (six times greater than for those whose relatives do not have ankylosing spondylitis).

Recently, two more genes have been identified that are associated with ankylosing spondylitis. These genes are called ARTS1 and IL23R. These genes seem to play a role in influencing immune function. It is anticipated that by understanding the effects of each of these known genes researchers will make significant progress in discovering a cure for ankylosing spondylitis.

How inflammation occurs and persists in different organs and joints in ankylosing spondylitis is a subject of active research. Each individual tends to have their own unique pattern of presentation and activity of the illness. The initial inflammation may be a result of an activation of the body's immune system, perhaps by a preceding bacterial infection or a combination of infectious microbes. Once activated, the body's immune system becomes unable to turn itself off, even though the initial bacterial infection may have long subsided. Chronic tissue inflammation resulting from the continued activation of the body's own immune system in the absence of active infection is the hallmark of an inflammatory autoimmune disease.

What are ankylosing spondylitis symptoms?

The symptoms of ankylosing spondylitis are related to inflammation of the spine, joints, and other organs. Fatigue is a common symptom associated with active inflammation. Inflammation of the spine causes pain and stiffness in the low back, upper buttock area, neck, and the remainder of the spine. The onset of pain and stiffness is usually gradual and progressively worsens over months. Occasionally, the onset is rapid and intense. The symptoms of pain and stiffness are often worse in the

morning or after prolonged periods of inactivity. The pain and stiffness are often eased by motion, heat, and a warm shower in the morning. Because ankylosing spondylitis often affects adolescents, the onset of low back pain is sometimes incorrectly attributed to athletic injuries in younger patients.

Those who have chronic, severe inflammation of the spine can develop a complete bony fusion of the spine (ankylosis). Once fused, the pain in the spine disappears, but the affected individual has a complete loss of spine mobility. These fused spines are particularly brittle and vulnerable to breakage (fracture) when involved in trauma such as motor-vehicle accidents. A sudden onset of pain and mobility in the spinal area of these patients can indicate bone breakage. The lower neck (cervical spine) is the most common area for such fractures.

Chronic spondylitis and ankylosis cause forward curvature of the upper torso (thoracic spine), which limits breathing capacity. Spondylitis can also affect the areas where ribs attach to the upper spine, further limiting lung capacity. Ankylosing spondylitis can cause inflammation and scarring of the lungs, causing coughing and shortness of breath, especially with exercise and infections. Therefore, breathing difficulty can be a serious complication of ankylosing spondylitis.

People with ankylosing spondylitis can also have arthritis in joints other than the spine. This feature occurs more commonly in women. Patients may notice pain, stiffness, heat, swelling, warmth, and/or redness in joints such as the hips, knees, and ankles. Occasionally, the small joints of the toes can become inflamed or "sausage" shaped. Inflammation can occur in the cartilage around the breast bone (costochondritis) as well as in the tendons where the muscles attach to the bone (tendinitis) and in ligament attachments to bone. Some people with this disease develop Achilles tendinitis, causing pain and stiffness in the back of the heel, especially when pushing off with the foot while walking up stairs. Inflammation of the tissues of the bottom of the foot, plantar fasciitis, occurs more frequently in people with ankylosing spondylitis.

Other areas of the body affected by ankylosing spondylitis include the eyes, heart, and kidneys. Patients with ankylosing spondylitis can develop inflammation of the iris (iritis), the colored portion of the eye. Iritis is characterized by redness and pain in the eye, especially when looking at bright lights. Recurrent attacks of iritis can affect either eye. In addition to the iris, the ciliary body and choroid of the eye can become inflamed; this is referred to as uveitis. Iritis and uveitis can be serious complications of ankylosing spondylitis that can damage the eye and impair vision and may require an eye specialist's (ophthalmologist) urgent care. Special treatments for serious eye inflammation are discussed in the treatment section below. (It should be noted that iritis and inflammation of the spine can occur in other forms of arthritis such as reactive arthritis [formerly known as Reiter's syndrome], psoriatic arthritis, and the arthritis of inflammatory bowel disease.)

A rare complication of ankylosing spondylitis involves scarring of the heart's electrical system, causing an abnormally slow heart rate (referred to as heart block). A heart pacemaker may be necessary in these patients to maintain adequate heart rate and output. In others, the part of the aorta closest to the heart can become inflamed, resulting in leakage of the aortic valve. In this case, patients can develop shortness of breath, dizziness, and heart failure.

Advanced spondylitis can lead to deposits of protein material called amyloid into the kidneys and result in kidney failure. Progressive kidney disease can lead to chronic fatigue and nausea and can require removal of accumulated waste products in the blood by a filtering machine (dialysis).

How is ankylosing spondylitis diagnosed?

The diagnosis of ankylosing spondylitis is based on evaluating the patient's symptoms, a physical examination, X-ray findings, and blood tests. Stiffness, pain, and decreased range of motion of the spine are characteristic of the inflammatory back pain of ankylosing spondylitis. Symptoms include pain and morning stiffness of the spine and sacral areas with or without accompanying inflammation

in other joints, tendons, and organs. Early symptoms of ankylosing spondylitis can be very deceptive, as stiffness and pain in the low back can be seen in many other conditions. It can be particularly subtle in women, who tend to (though not always) have more mild spine involvement. Years can pass before the diagnosis of ankylosing spondylitis is even considered.

The examination can demonstrate signs of inflammation and decreased range of motion of joints. This can be particularly apparent in the spine. Flexibility of the low back and/or neck can be decreased. There may be tenderness of the sacroiliac joints of the upper buttocks. The expansion of the chest with full breathing can be limited because of rigidity of the chest wall. Severely affected people can have a stooped posture. Inflammation of the eyes can be evaluated by the doctor with an ophthalmoscope.

Further clues to the diagnosis are suggested by X-ray abnormalities of the spine and the presence of the genetic marker HLA-B27 identified by a blood test. Other blood tests may provide evidence of inflammation in the body. For example, a blood test called the sedimentation rate is a nonspecific marker for inflammation throughout the body and is often elevated in inflammatory conditions such as ankylosing spondylitis. Urinalysis is often done to look for accompanying abnormalities of the kidney as well as to exclude kidney conditions that may produce back pain that mimics ankylosing spondylitis. Patients are also simultaneously evaluated for symptoms and signs of other related spondyloarthropathies, such as psoriasis, venereal disease, dysentery (reactive arthritis or Reiter's disease), and inflammatory bowel disease (ulcerative colitis or Crohn's disease).

What are treatment options for ankylosing spondylitis?

The treatment of ankylosing spondylitis typically involves the use of medications to reduce inflammation and/or suppress immunity to stop progression of the disease, physical therapy, and exercise. Medications decrease inflammation in the spine and other joints and organs. Physical therapy and exercise help improve posture, spine mobility, and lung capacity.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to decrease pain and stiffness of the spine and other joints. Commonly used NSAIDs include indomethacin (Indocin), tolmetin (Tolectin), sulindac (Clinoril), naproxen (Naprosyn), and diclofenac (Voltaren). Their common side effects include stomach upset, nausea, abdominal pain, diarrhea, and even bleeding ulcers. These medicines are frequently taken with food in order to minimize side effects.

In some people with ankylosing spondylitis, inflammation of joints excluding the spine (such as the hips, knees, or ankles) becomes the major problem. Inflammation in these joints may not respond to NSAIDs alone. For these individuals, the addition of medications that suppress the body's immune system is considered. These medications, such as sulfasalazine (Azulfidine), may bring about long-term reduction of inflammation. An alternative to sulfasalazine that is somewhat more effective is methotrexate (Rheumatrex, Trexall), which can be administered orally or by injection. Frequent blood tests are performed during methotrexate treatment because of its potential for toxicity to the liver, which can even lead to cirrhosis, and toxicity to bone marrow, which can lead to severe anemia.

Recent research has shown that for persistent ankylosing spondylitis with spinal involvement that is unresponsive to anti-inflammatory medications, both sulfasalazine and methotrexate are ineffective. Newer, effective medications for spine disease attack a messenger protein of inflammation called tumor necrosis factor (TNF). These TNF-blocking medications have been shown to be extremely effective for treating ankylosing spondylitis by stopping disease activity, decreasing inflammation, and improving spinal mobility. Examples of these TNF-blockers include etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and golimumab (Simponi).

Several major points about the treatment of ankylosing spondylitis deserve emphasis. There is an early, underdiagnosed stage of spondylitis that occurs before plain X-ray testing can detect classic

changes. Patients who are treated earlier respond better to treatments. Current disease-modifying drugs such as methotrexate, sulfasalazine, and leflunomide (Arava), which can be effective for joint inflammation of joints away from the spine, are not effective for spinal inflammation. If nonsteroidal anti-inflammatory drugs (NSAIDs) are not effective in a patient whose condition is dominated by spinal inflammation (and 50% do respond), then biologic medications that inhibit tumor necrosis factor (TNF inhibitors) are indicated. All TNF inhibitors, including Remicade, Enbrel, Humira, and Simponi are effective in treating ankylosing spondylitis. The improvement that results for TNF inhibition is sustained during years of treatment. If the TNF inhibitors are discontinued, for whatever reason, relapse of disease occurs in virtually all patients within a year. If TNF inhibitor is then resumed, it is typically effective.

Oral or injectable corticosteroids (cortisone) are potent anti-inflammatory agents and can effectively control spondylitis and other inflammations in the body. Unfortunately, corticosteroids can have serious side effects when used on a long-term basis. These side effects include cataracts, thinning of the skin and bones, easy bruising, infections, diabetes, and destruction of large joints, such as the hips.

Physical therapy for ankylosing spondylitis includes instructions and exercises to maintain proper posture. This includes deep breathing for lung expansion and stretching exercises to improve spine and joint mobility. Since ankylosis of the spine tends to cause forward curvature, patients are instructed to maintain erect posture as much as possible and to perform back-extension exercises. Patients are also advised to sleep on a firm mattress and avoid the use of a pillow in order to prevent spine curvature. Ankylosing spondylitis can involve the areas where the ribs attach to the upper spine as well as the vertebral joints, thus limiting breathing capacity. Patients are instructed to maximally expand their chest frequently throughout each day to minimize this limitation.

Exercise programs are customized for each individual. Swimming often is a preferred form of exercise, as it avoids jarring impact of the spine. Ankylosing spondylitis need not limit an individual's involvement in athletics. People can participate in carefully chosen aerobic sports when their disease is inactive. Aerobic exercise is generally encouraged as it promotes full expansion of the breathing muscles and opens the airways of the lungs.

Inflammation and diseases in other organs are treated separately. For example, inflammation of the iris of the eyes (iritis or uveitis) may require cortisone eyedrops (Pred Forte) and high doses of cortisone by mouth. Additionally, atropine eyedrops are often given to relax the muscles of the iris. Sometimes injections of cortisone into the affected eye are necessary when the inflammation is severe. Heart disease in patients with ankylosing spondylitis, such as heart block, may require a pacemaker placement or medications for congestive heart failure.

Cigarette smoking is strongly discouraged in people with ankylosing spondylitis, as it can accelerate lung scarring and seriously aggravate breathing difficulties. Occasionally, those with severe lung disease related to ankylosing spondylitis may require oxygen supplementation and medications to improve breathing.

People with ankylosing spondylitis may need to modify their activities of daily living and adjust features of the workplace. For example, workers can adjust chairs and desks for proper postures. Drivers can use wide rearview mirrors and prism glasses to compensate for the limited motion in the spine.

Finally, orthopedic surgery maybe required when there is severe disease of the hip joints and spine.

What is in the future for patients with ankylosing spondylitis?

Ankylosing spondylitis and each of the spondyloarthropathies are areas of active research. The relationship between infectious agents and the triggering of chronic inflammation is vigorously being

pursued. Factors that perpetuate "autoimmunity" are being identified. The characteristics of the gene marker HLA-B27 are being further defined. In fact, there are now known to be seven different subtypes of HLA-B27.

The impact of the recent discovery of the two additional genes, ARTS1 and IL23R, associated with ankylosing spondylitis (described above under "Causes") cannot be overstated. These genes seem to play a role in influencing immune function. It is anticipated that by understanding the effects of each of these known genes researchers will make significant progress in discovering a cure for ankylosing spondylitis.

As more about the precise mechanisms these genes use to influence the immune system is understood, the discovery of a cure will be possible. Moreover, results of ongoing research will lead to a better understanding and treatment of the entire group of diseases collectively known as spondyloarthropathies.

Ankylosing Spondylitis At A Glance

Ankylosing spondylitis belongs to a group of arthritis conditions which tend to cause chronic inflammation of the spine (spondyloarthropathies).

Ankylosing spondylitis affects males two to three times more commonly than females. Ankylosing spondylitis is a cause of back pain in adolescents and young adults. The tendency to develop ankylosing spondylitis is genetically inherited. The HLA-B27 gene can be detected in the blood of most patients with ankylosing spondylitis. Ankylosing spondylitis can also affect the eyes, heart, lungs, and occasionally the kidneys. The optimal treatment of ankylosing spondylitis involves medications that reduce

inflammation or suppress immunity, physical therapy, and exercise.

Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Introduction

Background

The spondyloarthropathies (SpAs) are a family of related disorders that includes ankylosing spondylitis (AS), reactive arthritis (ReA; also known as Reiter syndrome [RS]), psoriatic arthritis (PsA), spondyloarthropathy associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and, possibly, Whipple disease and Behçet disease. Ankylosing spondylitis, which literally means "inflamed spine growing together," is the prototypical spondyloarthropathy.

Ankylosing spondylitis 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.

The spondyloarthropathies are linked by common genetics (human leukocyte antigen [HLA] class-I gene, HLA-B27) and a common pathology (enthesitis). Ankylosing spondylitis was the first disease to be linked with an HLA gene (1973).[1,2,3 ]The first documented ankylosing spondylitis case was reported in 1691, although it may have been present in ancient Egyptians.

The family of spondyloarthropathies is included in the image below.

Pathophysiology

The spondyloarthropathies are chronic inflammatory diseases that involve the sacroiliac joints, axial skeleton, and, to a lesser degree, peripheral joints and certain extra-articular organs, including the eyes, skin, and cardiovascular system. The etiology is unknown but involves the interaction of genetic and environmental factors.[4 ]

The spondyloarthropathies are associated strongly with HLA-B27, an HLA class-I gene. Several genotypic subtypes of HLA-B27 are associated with the spondyloarthropathies, with HLA-B*2705 having the strongest association. HLA-B*2702, *2703, *2704, and *2707 are also associated with ankylosing spondylitis.[5 ] HLA-B27 –restricted CD8+ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis.[6 ]

The shared amino acid sequence between the antigen-binding region of 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 gastrointestinal tract.[7 ]

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 fibrosis and ossification at sites of enthesitis.[8 ]

Animal models of spondyloarthropathy have been developed using transgenic technology. Transgenic rats expressing human HLA-B27 and β2 -microglobulin 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.[9 ]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, suggesting an important interaction between genetic and environmental factors.[10,11 ]

Frequency

International

Ankylosing spondylitis is the most prevalent of the classic spondyloarthropathies. Prevalence varies with the prevalence of the HLA-B27 gene, which increases with distance from the equator. Ankylosing spondylitis is more common in whites than in nonwhites. Prevalence is 0.1-1% of the general population,[12,13,14 ]with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa.[5,15 ]Approximately 1-2% of all people who are positive for HLA-B27 develop ankylosing spondylitis. This increases to 15-20% if they have a first-degree relative with ankylosing spondylitis.[16,4 ]Prevalence data for undifferentiated spondyloarthropathy are scarce, although this disorder appears to be at least as common as ankylosing spondylitis, if not more so.[12 ]Its actual prevalence may be as high as 1-2% of the general population.

Mortality/Morbidity

The outcome in patients with spondyloarthropathies, including ankylosing spondylitis, is generally good compared with a disease such as rheumatoid arthritis. Some patients have few, if any, symptoms. A significant portion of 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 ankylosing spondylitis occurs during the first 10 years of illness.[17 ]

In rare cases, patients with severe long-standing ankylosing spondylitis 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 ankylosing spondylitis have a greater risk of mortality than the general population.[17 ]

Undifferentiated spondyloarthropathy 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 ankylosing spondylitis.[18,19 ]

Race

The prevalence of ankylosing spondylitis parallels the prevalence of HLA-B27 in the general population. The prevalence of HLA-B27 and ankylosing spondylitis is higher in whites and certain Native Americans than in African Americans, Asians, and other nonwhite ethnic groups.[5,20 ]

Undifferentiated spondyloarthropathy is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.[19 ]

Sex

Ankylosing spondylitis, in general, is diagnosed more frequently in males. However, females may have milder or subclinical disease.

The male-to-female ratio of ankylosing spondylitis is 3:1.[16,21 ]

The male-to-female ratio of undifferentiated spondyloarthropathy is 1:3.[19 ]

Age

The age of onset of ankylosing spondylitis is usually from the late teens to age 40 years. Approximately 10%-20% of all patients have onset of symptoms before age 16 years. Onset in persons older than 50 years is unusual, although diagnosis of mild or asymptomatic disease may be made at a later age.[21 ]

There is often a significant delay in diagnosis, usually occurring several years after the onset of inflammatory rheumatic symptoms. In a study of German and Austrian patients with ankylosing spondylitis, 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.[22 ]In a study of Turkish patients with ankylosing spondylitis, 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. Patients with inflammatory back pain or a positive family history of ankylosing spondylitis had a shorter diagnostic delay.[23 ]

Undifferentiated spondyloarthropathy is generally found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.[19 ]

Clinical

History

General symptomso Symptoms include those related to inflammatory back pain, peripheral enthesitis,

arthropathy, and constitutional and organ-specific extra-articular manifestations.o Because ankylosing spondylitis is a systemic inflammatory disease, systemic features

are common.o Morning stiffness is characteristic, and fatigue is common.o Fever and weight loss may occur during periods of active disease.

Inflammatory back paino This is the most common symptom and the first manifestation in approximately 75%

of patients.[24 ]

o Symptoms associated with an inflammatory process include insidious onset occurring over months or years, generally with at least 3 months of symptoms before presentation. Symptoms include 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. New criteria to define inflammatory back pain have been proposed; when 2 of the 4 criteria are present, they yield a sensitivity of 70.3% and specificity of 81.2%.[25 ]These criteria include the following:

Morning stiffness that lasts more than 30 minutes Improvement of back pain with exercise but not rest Nocturnal back pain during second half of the night only Alternating buttock pain

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

o The spinal disease starts in the sacroiliac joints (bilateral lumbosacral region). Most patients have mild chronic disease or intermittent flares with periods of remission. The spinal disease is rarely persistently active. Progression occurs from the lumbosacral region proximally, with ossification of the annulus fibrosus that results in fusion of the spine (bamboo spine).

Peripheral enthesitis and arthropathyo Peripheral musculoskeletal involvement occurs in 30-50% of all patients.

o 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.

o Sites commonly involved are the Achilles tendon insertion, the insertion of the plantar fascia on the calcaneus or the metatarsal heads, the base of the fifth metatarsal head, the tibial tuberosity, the superior and inferior poles of the patella, and the iliac crest. Other sites of involvement include the greater trochanter, ischial tuberosity, costochondral junctions, distal scapula, lateral epicondyle, and distal ulna.

o Enthesopathic lesions tend to be quite painful (eg, the plantar fascia when getting out of bed), especially in the morning.

o Some of the peripheral arthritis occurs at sites in which the major component is local enthesitis as suggested by MRI.

o 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. Other peripheral joints are involved less frequently and to a milder degree, usually as an asymmetric oligoarthritis predominantly involving the lower extremities. Temporomandibular joints are occasionally involved.

Physical

Articular manifestations[16 ]

Spineo Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of

ankylosing spondylitis at advanced stages.o Earlier in the course of the disease, indirect evidence of sacroiliitis and spondylitis

may be observed, including tenderness of the sacroiliac joints (elicited by either direct pressure or indirect compression) or a limited range of spine motion.

o Some patients may have a deformity of the spine, most commonly with a loss of lumbar lordosis and accentuated thoracic kyphosis.

o The range of motion 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 ankylosing spondylitis. Perform the Schober test by marking a 10-cm length of the lumbar spine (with patient in the erect position), starting at the fifth lumbar spinous process. Instruct the patient to maximally flex his or her spine. 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 and is generally not helpful in diagnosis.

Peripheral entheses and jointso Peripheral enthesitis occurs in approximately 33% of patients. These lesions are

painful and tender upon examination and may be associated with swelling of the tendon or ligament insertion.

o 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 due to biomechanical stress. Other areas of involvement are listed in Peripheral enthesitis and arthropathy. Carefully examine patients for tenderness upon palpation.

o 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 shoulder girdle (glenohumeral, acromioclavicular, sternoclavicular joints), costovertebral joints, costosternal junctions, manubriosternal joints, symphysis pubis, and temporal mandibular joints. Other peripheral joints are uncommonly involved and, if so, in an asymmetric oligoarticular pattern.

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

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

Extraarticular manifestations

Uveitis (also called iritis or iridocyclitis)[26,27 ]

o Uveitis is the most common extra-articular manifestation, occurring in 20-30% of patients with ankylosing spondylitis. Of all patients with acute anterior uveitis, 30-50% have or will develop ankylosing spondylitis. The incidence is much higher in individuals who are HLA-B27 positive (84-90%).

o Patients with uveitis may also have or may develop other spondyloarthropathies (SpAs), although less commonly, including reactive arthritis (5-10%), undifferentiated spondyloarthropathy (2-5%), and psoriatic arthritis (<1%). Isolated inflammatory bowel disease (IBD) is also associated with uveitis.

o The uveitis associated with ankylosing spondylitis is usually acute in presentation and unilateral, with symptoms that include a painful red eye with photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely involving posterior elements. Attacks usually resolve over 2-3 months with treatment and without residual visual impairment unless treatment is inadequate or delayed. Recurrences are common.

o Uveitis that develops in reactive arthritis is similar to the uveitis that develops in ankylosing spondylitis, while uveitis that develops in psoriatic arthritis and spondyloarthropathy associated with IBD tends to be more chronic and bilateral and often involves posterior elements.

Cardiovascular involvemento Cardiovascular involvement of clinical significance occurs in fewer than 10% of

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.

o Aortitis of the ascending aorta may lead to distortion of the aortic ring, resulting in aortic valve insufficiency.

o Mitral valve insufficiency rarely occurs.o Fibrosis of the conduction system may result in various degrees of atrioventricular

block, including complete heart block. Pulmonary involvement

o Restrictive lung disease may occur in patients with late-stage ankylosing spondylitis, with costovertebral and costosternal involvement causing limited chest expansion.

o 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 involvemento Amyloidosis is a very rare complication of ankylosing spondylitis in patients with

severe, active, and long-standing disease. These patients generally have active spondylitis, active peripheral joint involvement, and an elevated erythrocyte

sedimentation rate (ESR) and C-reactive protein level. This may result in renal dysfunction with proteinuria and renal insufficiency or failure.

o Immunoglobulin A (IgA) nephropathy has been reported in association with ankylosing spondylitis.

Neurologic involvemento Neurologic complications may occur secondarily to fractures of a fused spine, which

may be very difficult to detect with standard radiography.o Patients are also prone to atlantoaxial subluxation, which may result in cervical

myelopathy.o Cauda equina syndrome may also occur in patients with severe long-standing disease.

Gastrointestinal involvemento Asymptomatic inflammation of the proximal colon and terminal ileum has been

observed in as many as 60% of patients with ankylosing spondylitis and undifferentiated spondyloarthropathy.

o Patients with established ankylosing spondylitis only rarely develop Crohn disease or ulcerative colitis.

Metabolic bone diseaseo Although ankylosing spondylitis 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. Reevaluate patients with ankylosing spondylitis who have severe spondylitis and who present with acute exacerbations of back or neck pain for possible fracture, especially in the setting of trauma. Standard radiography may not be revealing; CT scanning or MRI may be required to aid in diagnosis.

o Heterotopic bone formation may occur after total hip replacement. Ankylosing spondylitis in women[28 ]

o Clinical ankylosing spondylitis is more common in men than in women, with a male-to-female ratio of approximately 3:1.

o Based on radiographic survey studies, prevalence rates of ankylosing spondylitis are approximately equal in men and women.

o Studies of clinical manifestations of ankylosing spondylitis in men and women show similar clinical manifestations, although men have more severe radiographic changes in the spine and hips than women.

Juvenile ankylosing spondylitis[29,30 ]

o Juvenile ankylosing spondylitis is clinically similar to adult ankylosing spondylitis.o In approximately 10-20% of all cases, symptom onset occurs before age 16 years.o The male-to-female ratio of 3:1 is similar to that of adults.o 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.o Peripheral arthritis, especially in the lower extremities, and dactylitis are more

common in children than in adults.o Systemic manifestations (eg, fever, weight loss, anemia, leukocytosis) occur at

disease onset in children more frequently than in adults.o 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 ankylosing spondylitis difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of a spondyloarthropathy.

Researchers describe a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) in children that is clinically similar to undifferentiated spondyloarthropathy. These children often develop ankylosing spondylitis 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[18,31 ]

o Undifferentiated spondyloarthropathy is a syndrome with features consistent with the spondyloarthropathies, but affected patients do not fulfill criteria for any specific spondyloarthropathy. Criteria are outlined in Table 2 at the end of this section.

o Undifferentiated spondyloarthropathy may represent an early phase or incomplete form of ankylosing spondylitis or another spondyloarthropathy. In fact, several studies of undifferentiated spondyloarthropathy included many patients who probably should have been diagnosed with ankylosing spondylitis, reactive arthritis, or IBD-associated spondyloarthropathy, which made the clinical description very ambiguous. However, more recent data suggest that these patients may represent a distinct disease entity based on demographic and clinical criteria.

o Although no specific criteria are identified, using modified Amor criteria can be helpful in confirming a clinical diagnosis.[19 ]

Distinguishing features of undifferentiated spondyloarthropathy[19 ]

o The age of onset has a very wide range, with the peak onset at approximately age 50 years.

o The male-to-female ratio is 1:3.o 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.o Clinical manifestations of undifferentiated spondyloarthropathy include inflammatory

back pain (90%), buttock pain (80%), enthesitis (85%), peripheral arthritis (35%), dactylitis (17%), and fatigue (55%).

o Extraarticular 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.

o Findings of laboratory studies are generally unremarkable except for the presence of an elevated ESR or C-reactive protein level (36%). 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 Undifferentiated spondyloarthropathy is distinct from ankylosing spondylitis 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 (outlined in Table 3, at the end of this section). 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 undifferentiated spondyloarthropathy have chronic, active disease and require long-term therapy, 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 with undifferentiated spondyloarthropathy (>75%) require long-term therapy for ongoing symptomatic disease. Most patients respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). Most patients maintain good function without progressive disease or clinically significant radiographic changes. A small minority of patients does not respond well to or tolerate NSAIDs. In these patients, treatment progression is similar to patients with ankylosing spondylitis, including the use of sulfasalazine, methotrexate, and TNF-α antagonists, although no well-designed clinical trials have been conducted on the treatment of undifferentiated spondyloarthropathy.

Table 2. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria[32,33 ]

Inclusion Criteria Exclusion Criteria

Inflammatory back pain 1 point Diagnosis of specific

spondyloarthropathy

Unilateral buttock pain 1 point Sacroiliitis on radiograph >grade 2

Alternating buttock pain 2 points Precipitating genitourinary/GI infection

Enthesitis 2 points Psoriasis

Peripheral arthritis 2 points Keratoderma blennorrhagicum

Dactylitis (sausage digit) 2 points IBD (Crohn disease or ulcerative colitis)

Acute anterior uveitis 2 points Positive rheumatoid factor

HLA-B27 –positive or family history of spondyloarthropathy

2 points Positive antinuclear antibody, titer >1:80

Good response to nonsteroidal anti-inflammatory drugs

2 points

Diagnosis of spondyloarthropathy with 6 or more points

Table 3. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy

Clinical Feature of Undifferentiated Spondyloarthropathy Frequency

Inflammatory back pain 90%

Buttock pain 80%

Enthesitis 75%

Peripheral arthritis 40%

Dactylitis (sausage digits) 20%

Acute anterior uveitis 1-2%

Fatigue 55%

Elevated ESR 32%

HLA-B27 –positive 25%

Causes

The cause of ankylosing spondylitis is unknown, but a combination of genetic and environmental factors works in concert to produce clinical disease.

Genetic predisposition[34,20,35,36 ]

o The strong association of ankylosing spondylitis with HLA-B27 is direct evidence of the importance of genetic predisposition.[1,2,3 ]The shared amino acid sequence between several HLA-B27 genotypic subtypes and K pneumoniae nitrogenase, especially HLA-B*2705, suggests a link between these enteric bacteria and the induction of ankylosing spondylitis, but this has yet to be proven.[7 ]People who are homozygous for HLA-B27 are at a greater risk for ankylosing spondylitis than those who are heterozygous.[37 ]

o The shared amino acid sequence of the HLA-B27 molecule is located in the antigen-binding region. Thus, molecular mimicry may be the mechanism by which an environmental trigger (eg, Klebsiella) initiates immunologic and then pathologic changes in a genetically predisposed individual.

o The interleukin (IL)–1 gene cluster is an important locus associated with susceptibility to ankylosing spondylitis.[38,39 ]

o CYP 2D6 gene is weakly associated with ankylosing spondylitis.[20 ]

o ARTS1 gene is also associated with ankylosing spondylitis. 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 MHC molecules.[40,35,36 ]

o The IL23R gene, which encodes the receptor for IL-23, is also associated with ankylosing spondylitis.[40,41,42,43,35,36 ]IL-23 promotes survival of TH17 CD4+ T cells. TH17 cells play an important role in inflammatory responses by producing various proinflammatory cytokines, including IL-17, IL-6, and TNF-α, and recruiting other inflammatory cells, especially neutrophils, in inflammatory and infectious diseases. This genetic link may indicate an important role for TH17 cells in that pathogenesis of ankylosing spondylitis and other spondyloarthropathies.[44 ]

o Genes possibly associated with ankylosing spondylitis include ANKH and HLA-DRB1.[20 ]

o Numerous genes have been excluded in the etiology of ankylosing spondylitis, including TGF- β, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFbBIL1, and PTPN22, among others.[20 ]

Immunologic mechanismso Another possible mechanism in the induction of ankylosing spondylitis is

presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with ankylosing spondylitis have subclinical gastrointestinal tract inflammation and elevated IgA antibodies directed against Klebsiella. The bacteria may invade the gastrointestinal 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 blood stream.

o 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.

o The spondyloarthropathies are the only known autoimmune diseases linked to a class-I and not a class-II HLA marker. 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, reactive arthritis) with HIV infection in certain areas of the world supports the relative importance of the CD8+ cytotoxic T-cell responses compared to the CD4+ helper cells in these conditions.

Environmental factorso Ankylosing spondylitis does not develop in every person who is HLA-B27 –positive,

indicating that environmental factors are important.o 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.o 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.[9 ]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.[10,11 ]

Differential Diagnoses

Lumbar Disc DiseaseLumbar SpondylosisPsoriatic ArthritisReactive Arthritis

Other Problems to Be Considered

Inflammatory bowel disease (IBD)–associated spondyloarthropathy (SpA)Juvenile idiopathic arthritisDiffuse idiopathic skeletal hyperostosis

Workup

Laboratory Studies

No laboratory tests are specific for ankylosing spondylitis. The diagnosis is made by combining clinical criteria of inflammatory back pain and enthesitis

or arthritis with radiological findings. Two sets of criteria, which are sensitive and specific, are available for diagnosis of spondyloarthropathies (SpAs) in general: (1) the European Spondyloarthropathy Study Group (ESSG) criteria (see Table 5, below) and (2) the Amor criteria (see Table 2, in the Physical section). New York and Rome criteria (see Table 6, below) are used widely for the diagnosis of ankylosing spondylitis.

Approximately 15% of patients present with a normochromic normocytic anemia of chronic disease.

The ESR or C-reactive protein level is elevated in 75% of patients and may correlate with disease activity in some, but not all, patients.

Alkaline phosphatase is elevated in 50% of patients, which 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 IgA level may be elevated, correlating with elevated acute-phase reactants. HLA-B27

o Ninety-two percent of white patients with ankylosing spondylitis are HLA-B27 –positive. This is less prevalent in patients of other ethnic backgrounds.

o Determining HLA-B27 status is not a necessary part of the clinical evaluation.

o 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.

Diagnostic criteria for spondyloarthropathy and ankylosing spondylitis 

Table 5. Spondyloarthropathy Criteria[ 45, 33 ]

ESSG Criteria Amor Criteria*

Inflammatory spinal pain or synovitis and one of the following:

Inflammatory back pain 1 point

Alternating buttock pain Unilateral buttock pain 1 point

Enthesitis Alternating buttock pain 2 points

Sacroiliitis Enthesitis 2 points

Inflammatory bowel disease (IBD) Peripheral arthritis 2 points

Positive family history of spondyloarthropathy Dactylitis (sausage digit) 2 points

Acute anterior uveitis 2 points

HLA-B27 –positive or family history of spondyloarthropathy

2 points

Good response to NSAIDs 2 points

 *Diagnosis of spondyloarthropathy with 6 or more points

Table 6. Criteria for Diagnosis of Ankylosing Spondylitis[16 ]

New York Criteria (1984) Rome Criteria (1961)

Low back pain with inflammatory characteristics

Limitation of lumbar spine motion in sagittal and frontal planes

Decreased chest expansion Bilateral sacroiliitis grade 2 or higher Unilateral sacroiliitis grade 3 or higher

Low back pain and stiffness for >3 months that is not relieved by rest

Pain and stiffness in the thoracic region Limited motion in the lumbar spine Limited chest expansion History of uveitis

Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria

Diagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2 or higher

Imaging Studies

Standard radiography[46 ]

o Radiographic studies are most helpful in establishing a diagnosis.o In ankylosing spondylitis, sacroiliitis is usually bilateral, symmetric, and gradually

progressive over years. The lesions progress from blurring of the subchondral bone plate to irregular erosions of the margins of the sacroiliac joints (pseudowidening) to sclerosis, narrowing, and finally fusion. Erosions of the subchondral bone of the sacroiliac joint are generally seen earlier in the lower portion of the joint (because this portion is lined by synovium) and on the iliac side (due to the thinner cartilage covering this side of the joint).

o The spondylitis of ankylosing spondylitis starts in the lumbar or thoracolumbar spine and progresses proximally in a continuous fashion.

o The radiographic signs of ankylosing spondylitis 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 these bodies, resulting in loss of the normal concave contour of the anterior surface of the vertebral bodies. 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 ankylosing spondylitis, are typically marginal. Over time, development of continuous (bridging) syndesmophytes may result in a bamboo spine, which is essentially fused.

o Spinal disease associated with IBD is similar to ankylosing spondylitis 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.

o Radiographs of other areas may show evidence of enthesitis with osteitis or arthropathy.

o 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).

o 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.

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

Magnetic resonance imaging[47 ]and computed tomography scanning[48 ]

o MRI or CT scanning of the sacroiliac and peripheral joints may reveal evidence of early sacroiliitis, erosions, and enthesitis that are not apparent on standard radiographs. MRI using fat-saturating techniques such as short tau inversion recovery (STIR) or MRI with gadolinium are sensitive for inflammatory lesions of enthesitis.[49,50 ]The "MR corner sign," which characterized by inflammatory lesions at the corners of vertebral bodies, was common in the thoracolumbar region of the spine in patients with ankylosing spondylitis.[51 ]Investigations of patients with ankylosing

spondylitis using serial MRI over time has shown a link between inflammatory lesions and the later development of syndesmophytes.[52 ]However, MRI and CT scanning is not part of the routine evaluation of patients because of the expense of these studies.

o Because of the insensitivity of standard radiography in the clinical setting of acute back pain in advanced ankylosing spondylitis, an MRI and a CT scan may be useful in diagnosis of a spinal fracture in patients with late-stage spinal disease.

Histologic Findings

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. Over time, fibrosis and ossification occur, which can be seen radiographically as periostitis and ossification at sites of enthesitis, particularly the sacroiliac joints, spine, and heels.

Treatment

Medical Care

Treatment of ankylosing spondylitis is divided into medical care, physical therapy, and surgical care. Patient education is important in the management of any chronic disease so that the patient is familiar with the symptoms, course, and treatment of the disease. No drugs have been proven to modify the course of the disease, although TNF-α antagonists have potential as disease-modifying agents.[53 ]

Nonsteroidal anti-inflammatory drugso NSAIDs improve the symptoms of the disease. Indomethacin may be more effective

than other NSAIDs, although this has not been proven.o Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear

to be as effective as nonselective NSAIDs.[54 ]

o Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in ankylosing spondylitis.[54 ]Common toxicities involve the gastrointestinal (nausea, dyspepsia, ulceration, bleeding), renal, and central nervous systems.

Sulfasalazineo Sulfasalazine is often used in the treatment of ankylosing spondylitis and other

spondyloarthropathies (SpAs), especially for peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine has been shown to be effective in ankylosing spondylitis, particularly in reducing spinal stiffness, peripheral arthritis, and the ESR, but no evidence shows that spinal mobility, enthesitis, or physical function is benefited.[55,56,57 ]

o Toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely). TNF-α antagonists

o The TNF-α antagonists have been shown to be effective in the treatment of ankylosing spondylitis.[58 ]Etanercept,[59,60 ]infliximab,[61 ]adalimumab,[62 ]and golimumab[63 ]are FDA-approved therapies for the treatment of ankylosing spondylitis and are indicated after NSAID therapy has failed.[53 ]These agents are also approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Some of these agents are approved for psoriasis (etanercept, infliximab, adalimumab), juvenile idiopathic arthritis (etanercept, adalimumab), and Crohn disease (infliximab, adalimumab).

TNF-α antagonists are very effective, with a fairly rapid onset of action (2 wk), and have been shown to reduce inflammatory activity of spinal disease as assessed with MRI.[64 ]

o Toxicities associated with TNF-α antagonists include injection-site and infusion reactions. An increased risk of bacterial infections, reactivation of latent tuberculosis, and certain fungal infections (eg, histoplasmosis, coccidioidomycosis) has been observed.

o There is a concern of an increased risk of malignancy in patients receiving these agents, with most interest regarding lymphoma and nonmelanotic 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 ankylosing spondylitis. In rare cases, cytopenias have been associated with TNF-α antagonists.

o Patients with rheumatoid arthritis who have recently started TNF-α antagonists may be at an increased risk of new onset congestive heart failure despite no obvious risk factors for the disease. These agents should not be initiated in patients with uncompensated congestive heart failure.

o TNF-α antagonists should not be used in patients with active hepatitis B infection but appear to be safe in patients with chronic hepatitis C infections. Rare cases of autoimmune syndromes, such as a lupuslike illness, have been noted in patients receiving TNF-α antagonists. More commonly, a positive ANA may occur during treatment without clinical disease.

o Demyelinating syndromes have rarely been documented in patients receiving TNF-α antagonists, although no direct link has been proven. These agents should not be used in patients with multiple sclerosis or other demyelinating diseases.

o Cases of new onset psoriatic skin lesions have been documented after initiation of TNF-α antagonists.

o Patients should be screened for latent tuberculosis, hepatitis B, and HIV infection before beginning therapy.[65 ]

Other medicationso Anecdotal reports suggest that other medications are helpful in the treatment of

ankylosing spondylitis, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine.

o Methotrexate is of questionable benefit in ankylosing spondylitis, as various studies have shown conflicting results.[66 ]

o Leflunomide was evaluated in a randomized, double-blind, placebo-controlled study in active ankylosing spondylitis but was not found to be effective.[67 ]

o Bisphosphonates may modestly affect clinical disease activity in ankylosing spondylitis.

o Anakinra, a recombinant human IL-1 receptor antagonist, may be effective in treatment-resistant ankylosing spondylitis.

Corticosteroidso Oral corticosteroids are occasionally helpful in controlling symptoms; however, use

them only for short-term management. No evidence has shown that corticosteroids alter the outcome of the disease, and they increase the tendency toward spinal osteoporosis.

o 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.

Treatment of extra-articular manifestationso Treat extra-articular manifestations as dictated by the clinical setting.o Acute anterior uveitis presents as a painful red eye that is associated with

photophobia and often recurs. Untreated uveitis may lead to vision loss.o 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. TNF-α antagonists may be helpful in selected cases.

Evaluation of disease activity and treatment response

Numerous tools have been developed to measure the disease activity of ankylosing spondylitis, especially in the setting of clinical trials.[68,69,70 ]

The Assessment in Ankylosing Spondylitis (ASAS) core set of domains (parameters) is used to measure disease activity. It includes the patient global assessment of disease activity, patient assessment of back pain, Bath Ankylosing Spondylitis Functional Index (BASFI), morning stiffness, synovitis and enthesitis score, ESR and CRP, and fatigue.

The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a questionnaire that is used to assess fatigue; neck, back, and hip pain; peripheral joint pain and swelling; discomfort; and severity and duration of morning stiffness.

The BASFI is a questionnaire of physical function used to evaluate dressing, bending, mobility, standing, stairs, and full-day activities.

Bath Ankylosing Spondylitis Metrology Index (BASMI) is a physical evaluation of range of motion of the cervical and lumbar spine.

The ASAS response criteria are used to assess improvement in ankylosing spondylitis in clinical trials.

o Each of 4 domains is scored by the patient, using a visual analog scale (0-10). 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 3 of 4 domains, with no worsening of the remaining domain. The 4 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)

o An ASAS40 response is similar but requires a 40% improvement.o An ASAS partial remission is defined as values of less than 2 for all 4 ASAS20

domains.o ASAS5/6 includes the 4 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 5 of 6 domains, with no worsening of the remaining domain.

Surgical Care

Surgery is occasionally useful to correct spinal deformities or to repair damaged peripheral joints.

Vertebral osteotomy may be performed to correct spinal deformities, but significant morbidity is related to neurologic complications of this procedure. This procedure should be performed only by surgeons specializing in spine surgery who have experience with this procedure, as the risk of major neurologic morbidity is significant.

Patients may need total hip replacement and, occasionally, total shoulder replacement. These procedures may be very useful to reduce pain and to improve function when the hip and shoulder joints become severely damaged. Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by using postoperative NSAIDs (eg, indomethacin). In general, outcomes of total joint replacement in patients have been satisfactory.

Consultations

Rheumatologist Physical medicine and rehabilitation specialist Orthopedic surgeon Neurosurgeon

Diet

No special diet is required.

Activity

Physical therapy[71,72 ]

o Physical therapy, including an exercise program and postural training, is important to maintain function.

o 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.

o Water therapy and swimming are excellent activities to maintain mobility and fitness.

Medication

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Nonsteroidal anti-inflammatory drugs

NSAIDs (eg, indomethacin, ibuprofen, naproxen) are useful to reduce pain secondary to inflammation and systemic symptoms (eg, fatigue, morning stiffness). Sulfasalazine is also useful in improving symptoms, most notably peripheral arthritis. NSAIDs reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness. NSAIDs appear to have modest disease-modifying effect on spinal disease. 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, MI, and stroke, which can be fatal. They also increase the risk of serious adverse GI effects, including stomach or intestinal bleeding, ulceration, and perforation, which can be fatal. Elderly patients are at greater risk for serious GI events.

Indomethacin (Indocin, Indochron)

Thought to be the most effective NSAID for the treatment of ankylosing spondylitis, although no scientific evidence supports this claim. For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Dosing

Adult

100-150 mg/d PO divided bid/tid

Pediatric

1.5-3 mg/kg/d PO divided bid/tid

Interactions

Coadministration with ACE inhibitors, angiotensin-II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; coadministration with warfarin may increase PT due to displacement of warfarin from plasma proteins and may aggravate bleeding tendency due to antiplatelet effect of NSAIDs; may decrease the effect of diuretics

Contraindications

Documented hypersensitivity; history of peptic ulcer disease (unless prophylaxis is adequate); renal insufficiency, anticoagulation, and coagulopathy; caution should be used in patients with cardiovascular disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Black box warning for GI hemorrhage and serious thrombotic sequelaeMost common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; patients with diabetes mellitus should have close monitoring of renal function

Ibuprofen (Ibuprin, Motrin)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in decrease of prostaglandin synthesis.

Dosing

Adult

600-800 mg PO tid/qid

Pediatric

30-40 mg/kg/d PO divided tid/qid

Interactions

Coadministration with ACE inhibitors, angiotensin-II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; coadministration with warfarin may increase PT due to displacement of warfarin from plasma proteins and may aggravate bleeding tendency due to antiplatelet effect of NSAIDs; may decrease the effect of diuretics

Contraindications

Documented hypersensitivity; history of peptic ulcer disease (unless prophylaxis is adequate); renal insufficiency, anticoagulation, and coagulopathy; caution should be used in patients with cardiovascular disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Black box warning for GI hemorrhage and serious thrombotic sequelaeMost common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; patients with diabetes mellitus should have close monitoring of renal function

Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Dosing

Adult

500 mg PO bid/tid

Pediatric

10-20 mg/kg/d PO divided bid/tid

Interactions

Coadministration with ACE inhibitors, angiotensin-II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; coadministration with warfarin may increase PT due to displacement of warfarin from plasma proteins and may aggravate bleeding tendency due to antiplatelet effect of NSAIDs; may decrease the effect of diuretics

Contraindications

Documented hypersensitivity; history of peptic ulcer disease (unless prophylaxis is adequate); renal insufficiency, anticoagulation, and coagulopathy; caution should be used in patients with cardiovascular disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Black box warning for GI hemorrhage and serious thrombotic sequelaeMost common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; patients with diabetes mellitus should have close monitoring of renal function

Sulfasalazine (Azulfidine, EN-tabs)

Shown to reduce inflammatory symptoms of ankylosing spondylitis in controlled studies; most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).

Dosing

Adult

2000-3000 mg/d PO divided bid/tid

Pediatric

40-60 mg/kg/d PO divided bid/tid

Interactions

Absorption may be reduced by coadministration of oral iron

Contraindications

Documented hypersensitivity; porphyria (may precipitate acute exacerbations)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Most common toxicities include nausea, diarrhea, and hypersensitivity; caution in renal or hepatic impairment, blood dyscrasias, or urinary obstruction; rarely, patients may develop blood dyscrasias, especially leukopenia, which may progress to agranulocytosis or hepatotoxicity

TNF antagonists

The TNF-α antagonists are biologic agents and include etanercept (fusion protein of the extracellular portion of the p75 TNF-α receptor and Fc portion of IgG), infliximab (chimeric anti–TNF-α monoclonal antibody [mab]), and adalimumab (humanized TNF-α mab). These agents inhibit TNF-α and have been shown to improve symptoms and function in patients with ankylosing spondylitis in clinical trials. All have been approved for the treatment of ankylosing spondylitis. These agents are also all approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA).

Etanercept (Enbrel)

Consists of a fusion protein of the extracellular portion of the p75 TNF-α receptor and Fc portion of IgG. Inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. Given as a subcutaneous injection. Available as prefilled syringe, autoinjector, or lyophilized powder. Also approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, and juvenile idiopathic arthritis.

Dosing

Adult

25 mg SC 2 times/wk or 50 mg SC qwk

Pediatric

0.4 mg/kg SC 2 times/wk 0.8 mg SC qwk

Interactions

None reported

Contraindications

Active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse events include injection-site reactions, occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo); respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely occur (association not clear); TNF--α antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting etanercept; isoniazid prophylaxis recommended if PPD results are positive); may cause reactivation of hepatitis B infection

Infliximab (Remicade)

Chimeric IgG1 κ mab directed against TNF-α. Variable region of heavy and light chains are murine in origin, constant regions are human. Inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. Given as an intravenous infusion. Also approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, and Crohn disease.

Dosing

Adult

5 mg/kg IV at weeks 0, 2, and 6, then q6wk depending on clinical response; dose may be increased to 10 mg/kg/dose if needed

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Severe infusion reactions such as hypotension and dyspnea; active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse events include infusion reactions (eg, rash, hypotension, and shortness of breath), occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo); respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely occur; TNF-α antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting infliximab; isoniazid prophylaxis is necessary if PPD results are positive); may cause reactivation of hepatitis B infection

Adalimumab (Humira)

Human IgG1 k mab directed against TNF-a. Inhibits TNF-a, reducing inflammation and symptoms of ankylosing spondylitis. Given as a subcutaneous injection. Available as prefilled syringe or autoinjector. Also approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, and Crohn disease.

Dosing

Adult

40 mg SC q2wk, may be increased to qwk

Pediatric

Not established

Interactions

Methotrexate reduces adalimumab clearance

Contraindications

Active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Similar to other TNF-a antagonists; adverse events include injection-site reactions, occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo; respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely occur; TNF-a antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting etanercept; isoniazid prophylaxis necessary if PPD results are positive); may cause reactivation of hepatitis B infection

Golimumab (Simponi)

Human IgG1 k mab directed against TNF-a. Inhibits TNF-a, reducing inflammation and symptoms of ankylosing spondylitis. Given as a subcutaneous injection. Available as prefilled syringe or autoinjector. Also approved for rheumatoid arthritis and psoriatic arthritis.

Dosing

Adult

50 mg SC monthly with or without methotrexate or other nonbiological DMARD

Pediatric

Not established

Interactions

None reported

Contraindications

Active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Similar to other TNF-a antagonists; adverse events include injection-site reactions, occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo; respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely

occur; TNF-a antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting etanercept; isoniazid prophylaxis necessary if PPD results are positive); may cause reactivation of hepatitis B infection

Follow-up

Complications

Complications may occur from spinal and articular disease or extra-articular manifestations. 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 arthropathy, requiring total joint replacement.

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

Prognosis

Ankylosing spondylitis and undifferentiated spondyloarthropathy (USpA) generally carry a good prognosis.

Patients often require long-term anti-inflammatory therapy. Morbidity can occur related to spinal and peripheral joint involvement or, rarely, extra-articular manifestations.

Poor prognostic indicators include peripheral joint involvement, young age of onset, elevated ESR, and poor response to NSAIDs.

The risk of mortality is increased in patients with ankylosing spondylitis who have severe long-standing disease and significant extra-articular manifestations.

Patient Education

Teach patients about the long-term nature of the illness, the use and toxicities of medications, and the importance of a well-balanced exercise program.

Because of the joint involvement in the chest wall and the potential for pulmonary complications, include smoking cessation in recommendations.