Ankylosing spondylitis (AS) is a common clinical subtype of spondyloarthritis (SpA). It is a chronic inflammatory disease primarily involving the axial joints and can present with extra-articular manifestations. In severe cases, it can result in spinal deformity and ankylosis.
Pathogenesis
Both genetic and environmental factors play important roles in the development of AS. The disease shows a strong familial aggregation and is closely associated with HLA-B27. The prevalence of HLA-B27 positivity varies significantly across different populations and regions. AS may also be linked to infections by urogenital pathogens such as Chlamydia trachomatis or certain intestinal pathogens, including Shigella, Salmonella, and Yersinia enterocolitica. These pathogens trigger inflammatory and immune responses in the host, leading to tissue damage that contributes to the initiation and progression of AS.
Pathology
The fundamental pathological feature of AS is enthesitis, which refers to nonspecific inflammation, fibrosis, and even ossification occurring at sites where tendons, ligaments, and joint capsules attach to bone. Early changes are characterized by lymphocyte and plasma cell infiltration, causing erosion at attachment sites and bone marrow edema. Granulation tissue formation follows, and the affected areas ultimately undergo calcification and new bone formation. This process recurs, leading to repeated cycles of inflammation and repair, which eventually result in squared vertebrae, ligament calcification, and a characteristic "bamboo spine" appearance.
Sacroiliitis is the earliest pathological manifestation in AS patients. It can present with synovitis, cartilage degeneration, destruction of subchondral bone plates, granulation tissue proliferation, and fibrosis. Over time, the joint space disappears, resulting in joint fusion and bony ankylosis. Peripheral joint involvement is mainly characterized by nonspecific synovitis. Extra-articular pathological changes include inflammation of fibrous connective tissue in the iris, ciliary body, aortic root, aortic valve, atrioventricular (AV) node, and pulmonary interstitium.
Clinical Manifestations
Symptoms
AS generally causes mild systemic symptoms. However, a small proportion of severe cases may present with fever, anemia, fatigue, weight loss, or poor appetite.
Axial Joint Involvement
Axial joint involvement often begins with inflammatory lower back pain, which may wake patients at night or cause morning stiffness in the lower back. Symptoms may include unilateral, bilateral, or alternating pain in the buttocks and groin that radiates to the lower limbs. Symptoms tend to worsen during periods of inactivity or rest and improve with movement. There is typically a good response to non-steroidal anti-inflammatory drugs (NSAIDs).
As the disease progresses, ankylosis may occur in the spine, beginning in the lumbar spine and ascending. This can lead to loss of lumbar lordosis, kyphotic deformity, restricted cervical mobility, and decreased chest expansion capacity.
Peripheral Joint Involvement
Peripheral joint involvement often presents as asymmetric arthritis primarily affecting the lower limb’s large joints, including the knees, hips, ankles, and shoulders. The elbows and wrists are less commonly involved. Joint damage is rare when flares and remissions alternate.
Hip joint involvement is seen in 25–35% of AS patients, often within the first five years of disease onset. It typically presents as unilateral groin or hip pain and restriction in activities such as flexion, rotation, adduction, or abduction. Pain worsens with weight-bearing positions, and the disability rate is high.
Enthesitis
Enthesitis most commonly affects areas such as the heel and the soles of the feet but may also involve the knee joints, costosternal joints, spinal processes, iliac crest, greater trochanter, and ischial tuberosity. This often manifests as localized swelling. Enthesitis of the fingers or toes may lead to diffuse joint swelling, giving a “sausage digit” appearance.
Extra-Articular Manifestations
About 30% of patients develop ocular symptoms during the disease course. The most typical manifestation is acute anterior uveitis, which is often unilateral but may alternate between both eyes. Symptoms include eye pain, redness, photophobia, tearing, and blurred vision. Anterior uveitis is generally self-limiting and is not closely associated with the disease activity of AS.
Other less common extra-articular manifestations include aortic regurgitation, cardiac conduction block, pulmonary fibrosis, renal amyloidosis, and IgA nephropathy.
Physical Signs
Common physical signs include:
- Tenderness over the sacroiliac joints.
- Positive Patrick’s (FABER) test.
- Reduced range of motion in spinal forward flexion, backward extension, lateral bending, and rotation.
- Decreased chest wall expansion.
- Increased occiput-to-wall distance and finger-to-floor distance (>0).
Auxiliary Examinations
Laboratory Tests
During the active phase of ankylosing spondylitis (AS), an elevated erythrocyte sedimentation rate (ESR) and increased serum C-reactive protein (CRP) levels may be observed. Over 90% of patients test positive for HLA-B27, which increases the likelihood of the diagnosis, although a negative result does not exclude AS. Rheumatoid factor (RF) and antinuclear antibodies (ANA) are usually negative.
Imaging Studies
X-ray
X-ray evaluation of the sacroiliac joints serves as an important basis for diagnosing AS. Key findings include blurring of the sacroiliac joint margins, erosion of adjacent bone, periarticular sclerosis, and narrowing or eventual obliteration of the joint space as the disease progresses. Based on the New York criteria, the radiographic findings of sacroiliitis can be categorized into five grades:
- Grade 0: Normal.
- Grade I: Suspicious.
- Grade II: Mild abnormalities, such as localized erosion or sclerosis, with blurred joint margins, but the joint space remains normal.
- Grade III: Moderate abnormalities, including erosion, sclerosis, joint space widening or narrowing, or partial ankylosis.
- Grade IV: Severe abnormalities, characterized by complete joint ankylosis.
Pelvic X-rays are routinely performed in clinical settings. Apart from observing the sacroiliac joints, they provide information on lesions in the hip joint, ischium, and pubic symphysis.
Spinal X-rays may show osteoporosis and squaring of vertebral bodies, blurred facet joint margins, calcification of paravertebral ligaments, and the formation of bony bridges. In the advanced stage of the disease, the spine may exhibit a characteristic "bamboo spine" appearance.
CT Scans
CT imaging, with higher resolution and less interference from overlapping structures, can detect subtle bone erosion, sclerosis, and structural changes in the sacroiliac joints, offering greater sensitivity compared to conventional X-rays.
MRI Scans
MRI of the sacroiliac joints and spine can reveal early inflammatory changes in axial joints in AS. T2-weighted fat-suppressed images highlight inflammatory features such as bone marrow edema, while T1-weighted images detect structural changes such as fat deposition, bone erosion, ligament ossification, or bony bridge formation. However, the specificity of bone marrow edema on MRI is low, as similar findings can occur in physiological conditions, infections, or metabolic diseases, requiring careful differentiation.
Diagnosis
The 1984 revised New York criteria are currently used for clinical diagnosis of AS. These criteria include the following:
Clinical Criteria:
- Chronic low back pain with morning stiffness lasting more than three months, improving with activity but not relieved by rest.
- Limited lumbar spine movement in both forward flexion and lateral bending.
- Chest expansion less than the normal range for age and sex.
Radiographic Criteria:
- Bilateral sacroiliitis of grade II to IV, or unilateral sacroiliitis of grade III to IV.
Diagnostic Interpretation:
- Confirmed AS: Radiographic criteria are met along with at least one clinical criterion.
- Probable AS: Either all three clinical criteria are met or the radiographic criteria are fulfilled without any clinical criteria.
Differential Diagnosis
AS requires differentiation from several conditions, including intervertebral disc herniation, infections of the spine or sacroiliac joints, diffuse idiopathic skeletal hyperostosis, osteitis condensans ilii, rheumatoid arthritis, osteoarthritis, and synovitis-acne-pustulosis-hyperostosis-osteomyelitis (SAPHO) syndrome.
Treatment
The primary therapeutic goals in AS are the control of inflammation and symptoms, the prevention or delay of progressive joint damage, the maximum restoration of physical function, the avoidance of long-term joint deformities, and the overall improvement of quality of life. Both pharmacological and non-pharmacological approaches are integral components of treatment.
Non-Pharmacological Treatment
Non-pharmacological management includes patient education, regular exercise, and physical therapy. Patients are advised to sleep on a firm mattress and maintain a good posture using a low pillow in the supine position. Smoking cessation is highly recommended. Regular physical exercise, particularly targeting the spine, chest, and hips, is most effective, though care is needed to avoid excessive load-bearing and strenuous activities.
Swimming, as a non-weight-bearing exercise, provides greater benefits for pain relief, social functioning, and mental health when compared to land-based exercises. Additional interventions, such as ultrasound therapy, magnetic therapy, thermotherapy, and electrotherapy, may help alleviate joint swelling and pain, and selective use can be considered.
Pharmacological Treatment
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
NSAIDs are considered the frontline pharmacological treatment for ankylosing spondylitis (AS). They can rapidly relieve lower back pain and morning stiffness and reduce joint swelling and pain. The choice of NSAIDs should be individualized, with a specific NSAID prescribed at the maximum recommended dose for 2-4 weeks. If there is insufficient efficacy, switching to another class of NSAIDs may be considered. The concurrent use of multiple NSAIDs is not recommended. For patients with a high risk of gastrointestinal complications, selective COX-2 inhibitors may be utilized.
Conventional Disease-Modifying Anti-Rheumatic Drugs (DMARDs)
Conventional DMARDs, such as methotrexate and sulfasalazine, may be considered for patients with peripheral joint involvement. However, these drugs have not been proven effective in treating axial manifestations of AS.
Biological Agents
Biological agents may be considered for patients whose disease remains active despite NSAID treatment. Commonly used options include tumor necrosis factor-alpha (TNF-α) inhibitors and interleukin-17 (IL-17) inhibitors. Different types of TNF-α inhibitors exhibit similar efficacy in treating AS. For AS patients with recurrent uveitis or comorbid inflammatory bowel disease, monoclonal antibody-based TNF-α inhibitors are often prioritized.
Janus Kinase (JAK) Inhibitors
JAK inhibitors, such as tofacitinib and upadacitinib, alleviate enthesitis and dactylitis by inhibiting intracellular JAK-STAT signaling pathways. These are suitable for patients who do not respond to or cannot tolerate TNF-α inhibitors or IL-17 inhibitors.
Glucocorticoids
For acute uveitis or localized muscle and joint inflammation, the local injection of glucocorticoids may be considered. However, evidence-based research does not support systemic glucocorticoid therapy for axial joint disease in AS.
Surgical Treatment
Surgical interventions may be considered in AS patients with significant functional limitations or deformities that severely impact quality of life. These situations include severe thoracic kyphosis, progressive thoracic kyphotic deformities with loss of horizontal gaze ability, persistent and severe hip pain, or hip joint ankylosis in a non-functional position. In cases where adequate pharmacological treatment fails to sufficiently alleviate symptoms, patients may consider corrective surgery for the cervical or thoracolumbar spine or total hip replacement.
Prognosis
AS exhibits significant heterogeneity. Some patients experience recurrent flare-ups with continuous disease progression, while others maintain long-term disease stability. Prompt and appropriate treatment may reduce the risk of spinal and joint deformity. Early onset of the disease, hip joint involvement, HLA-B27 positivity, an elevated erythrocyte sedimentation rate, and persistently high C-reactive protein levels are associated with poor prognosis. Additionally, poor outcomes are observed in patients who smoke, experience delayed diagnosis, or receive inadequate treatment.