Overview
Definition
Ankylosing spondylitis (AS) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton.
Mnemonic
To remember the seronegative arthropathies, use the mnemonic “PAIR.”
- Psoriatic arthritis
- Ankylosing spondylitis
- Inflammatory bowel disease–associated arthritis
- Reactive arthritis
Epidemiology
- Incidence: 0.4–14 per 100,000 people per year
- Highest prevalence in northern European countries
- Age at onset: 20–30 years
- 3 times more common in men
- 10–20 times more common in 1st-degree relatives of those with ankylosing spondylitits
Etiology
- Exact cause unknown
- Strong association with HLA-B27
- Possible triggers:
- Klebsiella infection
- Trauma
Pathophysiology
Pathogenesis of ankylosing spondylitis:
Inflammation induces the formation of syndesmophytes and the fusion of the intervertebral discs and vertebral bodies.
Pathogenesis of ankylosing spondylitis:
Erosion of the iliac side of sacroiliac joints is the earliest radiologic sign of ankylosing spondylitis.
Proposed mechanism of inflammation
- Innate immunity is triggered:
- Possibly from GI microbes invading the systemic circulation
- Due to disruption of the gut mucosal barrier
- Cytokines and interleukins (ILs) are released:
- IL-17 and IL-23
- Tumor necrosis factor alpha (TNF-alpha)
- Transforming growth factor beta (TGF-beta)
- Development of enthesitis (inflammation at the site of ligament or tendon insertion into bone):
- Micro-injury from mechanical stress may make entheses susceptible to inflammation.
- Joints are infiltrated with macrophages and with CD4 and CD8 T cells.
- Main joints involved:
- Sacroiliac (SI) joints
- Paravertebral joints
Axioskeletal changes
- Chronic inflammation of the ligaments and the annulus fibrosus of the intervertebral disc → erosion of bone and destruction of articular tissues
- Erosion → fibrocartilage regeneration → fibrosis and ossification → syndesmophyte formation
- Syndesmophytes bridge together → vertebral fusion
Clinical Presentation
Articular manifestations
- Pain:
- Lower back and neck
- Progressive
- Often nocturnal
- Varies in intensity
- Present for > 3 months
- Paraspinal muscle spasm
- Morning stiffness:
- Improves with activity or exercise
- Worsened by inactivity
- Diminished range of motion of the spine
- Oligoarthritis (50% of patients):
- Asymmetrical involvement of ≤ 4 peripheral joints
- Pain, warmth, swelling, and stiffness
Extra-articular manifestations
- General:
- Fatigue
- Weakness
- Low-grade fever
- Anorexia
- Weight loss
- Periarticular:
- Enthesitis
- Plantar fasciitis
- Costochondral junctions
- Tendinitis
- Achilles
- Patellar
- Dactylitis (sausage fingers)
- Enthesitis
- Ocular:
- Anterior uveitis
- Conjunctivitis
- Cardiac:
- Aortitis
- Aortic valve insufficiency
- Conduction abnormalities
- Due to fibrosis of the conduction system
- Varying degrees of atrioventricular block may result.
- Pericarditis
- Pulmonary
- Restrictive lung disease
- Nontuberculous apical fibrosis
- Can result in cavitation
- Secondary bacterial or fungal (Aspergillus) infections
- Cutaneous:
- Psoriasis
- Painless oral ulcerations
- GI:
- Asymptomatic ileal and colonic inflammation
- Inflammatory bowel disease
- Renal:
- Immunoglobulin A (IgA) nephropathy
- Renal amyloidosis
- Genitourinary: prostatitis
- Neurologic:
- Radiculitis
- Cauda equina syndrome
Anterior uveitis is a common extra-articular manifestation of ankylosing spondylitis.
Image: “Anterior uveitis” by Christopher J. Gilani et al. License: CC BY 4.0Dactylitis of the 3rd digit in ankylosing spondylitis
Image: “Involvement of the feet in patients with SpA” by Department of Rheumatology, Hospital General de México, Faculty of Medicine, Universidad Nacional Autónoma de México, Dr, Balmis 148, Colonia Doctores, México, DF 06720, Mexico. License: CC BY 2.0, cropped by Lecturio.
Physical examination
- Spine:
- Cervical and upper thoracic vertebrae:
- Accentuated thoracic kyphosis
- Stooped, forward-flexed position (when fused)
- Distance between chin and sternum with flexed head > 2 cm
- Lumbar vertebrae:
- Reduced range of motion (Schober’s test)
- Loss of lumbar lordosis
- Cervical and upper thoracic vertebrae:
- Sacroiliac joint:
- Localized tenderness
- Mennell’s sign
- FABER (Flexion, Abduction, and External Rotation) test
- Tenderness at the following points:
- Achilles tendon insertion
- Insertion of the plantar fascia on the calcaneus or the metatarsal heads
- Base of the 5th metatarsal head
- Tibial tuberosity
- Superior and inferior poles of the patella
- Iliac crest
- Reduced chest expansion (< 4 cm) on deep inspiration
Diagnosis
Physical examination tests
- Schober’s test:
- Tests limitation of lumbar movement
- Procedure:
- Place a mark 5 cm below and 10 cm above the L5 spinous process.
- Have the patient touch the toes.
- If distance does not increase by > 5 cm, the patient has reduced lumbar flexion.
- FABER test:
- Also known as Patrick’s test
- Nonspecific test that detects joint dysfunction in the sacroiliac joint
- Procedure:
- The patient’s leg is flexed at the hip, abducted, and placed in a figure-4 position.
- Force is applied to the ipsilateral knee.
- Test is deemed positive if it reproduces pain in the ipsilateral sacroiliac joint.
- Mennell’s sign:
- Helps determine whether pain is coming from the hip, lumbar spine, or sacroiliac joint
- Procedure:
- Performed with the patient facedown
- Passive hyperextension of the upper leg
- This procedure provokes pain in the sacroiliac joint, hip, or lumbar spine depending on where the physician fixates (places the hand) on the spine or hip.
- Chin–brow vertical angle (CBVA)
- An assessment for kyphotic deformity
- Procedure:
- Measures the angle between a vertical line and a line connecting the brow to the chin while the patient is standing
- Any degree greater than zero is abnormal.
The Schober test: a photograph of a patient demonstrating the Schober test for spinal mobility. After the marks are placed 10 cm and 5 cm away from the spinal process of L5, the patient is asked to bend over. If distance does not increase by > 5 cm, the patient has reduced lumbar flexion indicative of ankylosing spondylitis.
Image: “Schober test” by Kamil Eyvazov et al. License: CC BY 4.0The FABER test:
Image: “FABER” by Orthopaedic Research Unit, Aarhus University Hospital, Denmark. License: CC BY 2.5
This test may be used to detect hip, lumbar, or sacroiliac joint pathology. These signs are often positive in ankylosing spondylitis.The Mennell sign:
Image by Lecturio.
From left to right: testing of the sacroiliac joint, hip joint, and lumbar spine. This test may be used in the evaluation for ankylosing spondylitis.Chin–brow vertical angle:
Image by Lecturio.
Left: patient with a normal back
Right: patient with ankylosing spondylitis
Imaging
- Radiography:
- Diagnostic and assesses severity of the disease
- Should be performed in all patients in whom AS is suspected
- Bilateral sacroiliitis:
- Subchondral erosions (“pseudo-widening” of the SI joint)
- Subchondral sclerosis
- SI joint narrowing
- Fusion of the SI joint (end-stage)
- Spine findings:
- Small erosions with reactive sclerosis
- Squaring of vertebrae
- Ligament calcifications
- Evolving syndesmophytes
- Bridging syndesmophytes (“bamboo spine”)
- MRI:
- Aids in early detection
- May reveal inflammatory changes not seen on radiographs
Lateral lumbar spine radiograph in ankylosing spondylitis:
Image: “Lateral Lumbar Spine X-Ray” by Glitzy Queen. License: Public Domain
This image demonstrates squaring of the vertebrae with a “bamboo stick” appearance due to bridging syndesmophytes.MRI of the sacroiliac joint in ankylosing spondylitis:
Image: “Active sacroiliitis” by Nele Herregods et al. License: CC BY 4.0, cropped by Lecturio.
The arrows point to enhancement of the right sacroiliac joint, indicating sacroiliitis.MRI of the sacroiliac joints in ankylosing spondylitis:
Image: “Magnetic resonance imaging” by Rheumatology Department, Hassan II University Hospital, Fez, Morocco. License: CC BY 2.0
This image shows bilateral sacroiliitis with a hyperintense signal on T2 (arrow) at the SI joint.Sagittal MRIs in ankylosing spondylitis:
Image: “Confirmed AS” by Weber et al. License: CC BY 2.0
These images show inflammatory lesions in the thoracic and lumbar spine (arrows). Inflammatory lesions of the spinous process are also shown at L4 (curved arrows).Radiograph of the pelvis in ankylosing spondylitis:
Image: “Figure 3” by Manoj and Ragunathan. License: CC BY 2.0
This image demonstrates advanced sacroiliitis with fusion of the SI joints.
Laboratory Tests
- Nonspecific
- ↑ CRP
- ↑ Erythrocyte sedimentation rate (ESR)
- Mildly ↑ alkaline phosphatase
- Negative rheumatoid factor (RF)
- Negative ANA test
- Genetic testing for HLA-B27:
- May be considered if clinical evaluation and radiography are inconclusive
- Positive in approximately 90% of Caucasian patients with AS
- Not required for diagnosis
Management and Complications
Management requires a multidisciplinary approach to reduce pain, increase range of motion, decrease inflammation, and improve quality of life.
Conservative measures
- Lifestyle changes:
- Urge smoking cessation.
- Encourage regular physical activity.
- Physical therapy:
- Crucial for maintaining mobility
- Exercises for:
- Mobilization of the vertebral joints and muscle stability
- Maintenance of adequate posture and range of motion
- Depression and anxiety screening
- Psychosocial support
Medical management
- Initial therapy:
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- 70% of patients achieve clinical improvement.
- 2nd line:
- TNF inihibitors
- Etanercept, adalimumab, golimumab, infliximab
- Used in patients in whom NSAID therapy fails
- IL-17 inhibitors
- Secukinumab or ixekizumab
- Alternative to TNF inhibitors
- Disease-modifying antirheumatic drugs (DMARDs)
- Sulfasalazine or methotrexate
- Used for persistent peripheral arthritis
- TNF inihibitors
Surgical interventions
- Indications:
- Severe deformities resulting in functional impairment
- Severe pain causing diminished quality of life
- Acute fracture
- Neurologic deficits
- Options:
- Spinal fusion
- Osteotomy
- Total hip arthroplasty
Complications
- In addition to the manifestations of this disease, patients may develop:
- Osteoporosis
- Most frequent complication
- Predisposes patients to fractures
- Vertebral fracture
- Most serious complication
- Cervical spine fractures can lead to paralysis or death.
- Respiratory compromise
- Osteoporosis
- Adverse effects on the patient’s quality of life:
- Sleep disturbances
- Disability
- Diminished psychologic health (depression)
Prognosis
- Ankylosing spondylitis is a chronic disease.
- Most patients retain complete functionality.
- Indicators of a poor prognosis:
- Younger age at onset
- Peripheral arthritis
- ↑ Inflammatory markers
- Poor response to NSAIDs
- Severe and long-standing AS is associated with ↑ risk of mortality.
Differential Diagnosis
- Lumbar spinal stenosis: narrowing of the lumbar spinal canal resulting in compression of nerve rootlets. This condition is more common in older patients. Patients may experience chronic back, buttock, and thigh pain that is relieved by flexing the back. Neurologic signs and symptoms, including paresthesias, weakness, and diminished reflexes, are also prominent. The diagnosis is based on clinical evaluation and MRI. Management includes physical therapy, analgesics, and surgery for severe cases.
- Psoriatic arthritis: a seronegative spondyloarthropathy that occurs in patients with psoriasis. This asymmetric, inflammatory arthritis involves small and large joints, including the distal interphalangeal joints and the sacroiliac spine. Enthesopathy and dactylitis are also seen. The diagnosis is clinical, and the condition should be suspected in patients with psoriasis. Management includes DMARDs and biologic agents.
- Reactive arthritis: a seronegative spondyloarthropathy that is often precipitated by a GI or genitourinary infection. Patients may present with asymmetric arthritis, typically of the lower extremities. This arthritis can be associated with fever, tendinitis, enthesitis, mucocutaneous ulcers, and conjunctivitis. The diagnosis is clinical. Treatment includes NSAIDs, DMARDs, and treatment of the underlying infection.
- Rheumatoid arthritis (RA): a seropositive autoimmune disease resulting in joint inflammation and destruction. This arthritis is typically symmetric, and patients will frequently have tender inflammation in the joints of the hands and feet (although any peripheral joints can be involved). The axial skeleton is less commonly included. The diagnosis is made with the presence of positive RF and anti–cyclic citrullinated peptide (anti-CCP) laboratory studies. Management includes NSAIDs, DMARDs, corticosteroids, immunosuppressive medications, biologics, and TNF inhibitors.
- Fibromyalgia: a nonarticular disorder of unknown etiology that causes generalized pain, including the muscles, points of tendon insertion (which can mimic enthesitis), and soft tissues. Associated symptoms include fatigue, muscle stiffness, cognitive disturbances, depression, and anxiety. The diagnosis is based on clinical criteria. Imaging and laboratory testing will be unrevealing. Management includes exercise, nonopioid analgesics, and efforts to improve sleep and stress.
- Diffuse idiopathic skeletal hyperostosis: a noninflammatory disease causing ossification of spinal ligaments and entheses. Patients may be asymptomatic or may have progressive back and neck pain with reduced range of motion (particularly of the thoracic spine). The diagnosis is made with imaging, which may show the changes of AS. However, the SI joints are usually spared, and there may be extra-axial joint involvement. Management involves analgesics and physical therapy for pain relief.
References
- Sieper, J., Rudwaleit, M., Baraliakos, X., Brandt, J., Braun, J., Burgos-Vargas, R. van der Heijde, D. (2009). The assessment of SpondyloArthritis international society (ASAS) handbook: A guide to assess spondyloarthritis. Ann Rheum Dis, 68, ii1. DOI:10.1136/ard.2008.104018
- Khan M. A. (1978). Race-related differences in HLA association with ankylosing spondylitis and Reiter’s disease in American blacks and whites. Journal of the National Medical Association, 70(1), 41–42.
- Raychaudhuri, S. P., & Deodhar, A. (2014). The classification and diagnostic criteria of ankylosing spondylitis. Journal of Autoimmunity, 48-49, 128–133. https://doi-org.ezproxy.unbosque.edu.co/10.1016/j.jaut.2014.01.015
- Patterson, James W., MD, F.A.C.P., F.A.A.D. (2021). The psoriasiform reaction pattern. In Patterson, James W., MD, FACP, FAAD (Ed.), Weedon’s skin pathology (pp. 99-120.e11). https://www.clinicalkey.es/#!/content/3-s2.0-B9780702075827000058
- Taurog, J. D. (2018). The spondyloarthritides. In J. L. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo & J. Loscalzo (Eds.), Harrison’s principles of internal medicine, 20th ed. New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1156606812
- Wenker KJ, Quint JM. Ankylosing Spondylitis. (2020) StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK470173/
- Brent, L.H., Patel, A., and Patel, R. (2021). Ankylosing spondylitis and undifferentiated spondyloarthropathy. In Diamond, H.S. (Ed.), Medscape. Retrieved February 4, 2021, from https://emedicine.medscape.com/article/332945-overview
- Kontzias, A. (2020). Ankylosing spondylitis. [online] MSD Manual Professional Version. Retrieved February 4, 2021, from https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/ankylosing-spondylitis
- Yu, D.T., and van Tubergen, A. (2020). Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults. In Romain, P.L. (Ed.), UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults
- Yu, D.T., and van Tubergen, A. (2020). Pathogenesis of spondyloarthritis. In Romain, P.L. (Ed.), Uptodate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/pathogenesis-of-spondyloarthritis
- Yu, D.T., and van Tubergen, A. (2020). Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults. In Romain, P.L. (Ed.), UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/diagnosis-and-differential-diagnosis-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults
- Yu, D.T., and van Tubergen, A. (2020). Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults. In Romain, P.L. (Ed.), UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/treatment-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults