Medication Summary
The goal of pharmacotherapy is to reduce morbidity and to prevent complications—specifically, by reducing the pain and inflammation associated with ankylosing spondylitis (AS).
Nonsteroidal Anti-inflammatory Drugs
Class Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for reducing pain secondary to inflammation and systemic symptoms in AS patients. These agents reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness and appear to have a modest disease-modifying effect on spinal disease. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as traditional NSAIDs.
NSAIDs and COX-2 inhibitors may increase the risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. They also increase the risk of serious adverse gastrointestinal (GI) effects, including stomach or intestinal bleeding, ulceration, and perforation, which can also be fatal. Elderly patients are at greater risk for serious GI events.
Indomethacin (Indocin)
Indomethacin is thought to be the most effective NSAID for the treatment of AS, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.
Ibuprofen (Advil, Motrin)
Ibuprofen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.
Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)
Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.
Diclofenac (Voltaren, Zipsor, Cambia)
Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors. Liver function test abnormalities occur more often with diclofenac than with other NSAIDs.
Celecoxib (Celebrex, Elyxyb)
Celecoxib is a COX-2 selective inhibitor that is associated with less GI toxicity and does not have any antiplatelet effect.
5-Aminosalicylic Acid Derivatives
Class Summary
5-Aminosalicylic acid derivatives inhibit prostaglandin synthesis and reduce the inflammatory response to tissue injury.
Sulfasalazine (Azulfidine, Azulfidine EN-tabs)
Sulfasalazine has been shown to reduce the inflammatory symptoms of AS in controlled studies; its most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).
Immunosuppressants
Class Summary
Immunosuppressants inhibit key factors in the immune system that are responsible for inflammatory responses.
Methotrexate (Trexall, Otrexup, Rasuvo)
Methotrexate has an unknown mechanism of action in AS; it may affect immune function by inhibiting dihydrofolate reductase, interfering with purine synthesis. Effects are observed in the 3-6 weeks following administration. Methotrexate ameliorates symptoms (eg, pain, swelling, stiffness) but there is no evidence that it induces remission. Adjust the dose gradually to obtain a satisfactory response.
DMARDs, TNF Inhibitors
Class Summary
Tumor necrosis factor alpha (TNF-α) antagonists are biologic agents and include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. These agents inhibit TNF-α and have been shown to improve symptoms and function in AS patients in clinical trials. All have been approved for the treatment of AS. These agents are also all approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA).
Etanercept (Enbrel, Erelzi, etanercept-szzs)
Etanercept consists of a fusion protein of the extracellular portion of the p75 TNF-α receptor and the Fc portion of immunoglobulin G (IgG). It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous (SC) injection and is available in a prefilled syringe, an autoinjector, or lyophilized powder. It is also approved for rheumatoid arthritis, PsA, psoriasis, and juvenile idiopathic arthritis.
Infliximab (Remicade, Inflectra, infliximab-dyyb, Renflexis, infliximab-abda, Ixifi, infliximab-qbtx)
Infliximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against TNF-α. The variable regions of heavy and light chains are murine in origin, and the constant regions are human. Infliximab inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an intravenous (IV) infusion. It is also approved for rheumatoid arthritis, PsA, psoriasis, and Crohn disease.
Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)
Adalimumab is a human IgG1κ monoclonal antibody directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, Crohn disease, and noninfectious uveitis. The FDA has approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd as biosimilars and not as interchangeable drugs.
Golimumab (Simponi)
Golimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis and PsA.
Certolizumab pegol (Cimzia)
Certolizumab pegol is a recombinant humanized anti-human TNF-α neutralizing antibody. It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous injection and is available as a powder for injection. It is FDA-approved for active ankylosing spondylitis and non-radiographic axial spondyloarthropathy, as well as for Crohn disease, rheumatoid arthritis, and psoriatic arthritis.
Interleukin-17 Inhibitors
Class Summary
Various interleukins play a role in inflammatory processes.
Secukinumab (Cosentyx)
Human IgG1 monoclonal antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin 17A (IL-17A). IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It is indicated for adults with active ankylosing spondylitis and for those with active non-radiographic axial spondyloarthritis with objective signs of inflammation.
Ixekizumab (Taltz)
Humanized monoclonal IgG4 antibody that targets interleukin-17A (IL-17A) and neutralizes the proinflammatory effects of IL-17A. It is indicated for adults with active ankylosing spondylitis and for those with active non-radiographic axial spondyloarthritis with objective signs of inflammation.
DMARDs, JAK Inhibitors
Class Summary
Janus kinase (JAK) inhibitors interfere with the JAK signaling pathways for various cytokines involved in inflammation. Blocking these signals is crucial in treating many inflammatory conditions including AS.
Upadacitinib (Rinvoq)
A small molecule that interferes with the JAK signaling pathways. This results in decreased activity of pro-inflammatory interleukins, increased lymphocytes, and decreased immunoglobulins. It is indicated for active AS in adults who have had an inadequate response or intolerance to at least 1 TNF blocker.
Tofacitinib (Xeljanz, Xeljanz XR)
A small molecule that is a partial and reversible inhibitor of JAK. By inhibiting JAK, phosphorylation then activation of signal transducers and activators of transcription (STAT) is prevented. The JAK-STAT signaling pathway correlates with hematopoiesis and immune cell function. Inhibition results in a decreased inflammatory response. It is indicated for active AS in adults who have had an inadequate response or intolerance to at least 1 TNF blocker.
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This 15-year-old female patient presented with recent onset of right-sided low back pain. Plain radiography findings were normal.
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MRI of the same patient whose radiography findings were normal (previous image). She underwent further evaluation, including MRI. The MRI (short tau inversion recovery [STIR]) showed increased sinal intensity in the right sacroiliac joint, revealing sacroiliitis. Other laboratory study findings were essentially normal. The patient was started on indomethacin and rapidly improved.
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Patient with ankylosing spondylitis affecting cervical and upper thoracic spine. The patient's spine has been fused in flexed position.
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Posterior view of a patient with ankylosing spondylitis affecting cervical and upper thoracic spine. The patient's spine has been fused in a flexed position.
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Anteroposterior radiograph of spine of a patient with AS. Ossification of annulus fibrosus can be observed at multiple levels, which has led to fusion of spine with abnormal curvature.
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Anteroposterior radiograph of spine of a patient with AS.
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Anteroposterior (left) and lateral (right) radiographs of a patient with AS.
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Radiographs of hand (top) and arm (bottom) of a patient with peripheral involvement of AS. Fusion of joint spaces and deformity can be observed.
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Sagittal MRI of thoracolumbar spine of a patient with AS. Syndesmophytes and anterior corner lesions can be seen.
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Radiograph shows vertebral fracture in a patient with AS.
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This radiograph of the lumbar spine of a patient with end-stage AS shows bridging syndesmophytes, resulting in bamboo spine.
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This radiograph of the cervical spine of a patient with AS shows fusion of the vertebral bodies due to bridging syndesmophytes.
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ASAS Classification Criteria for Axial Spondyloarthropathy.
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ASAS Classification Criteria for Peripheral Spondyloarthropathy.
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Family of spondyloarthropathies and HLA-B27 associated diseases
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Bilateral symmetric sacroiliitis in a patient with AS showing blurring of the margins of the joints and pseudo-widening.
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Bilateral symmetric sacroiliitis in a patient with AS with narrowing and sclerosis of the joints.
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Bilateral sacroiliac joint fusion in a patient with AS.
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Enthesitis at the site of the insertion of the annulus fibrosis on the corners of the vertebral bodies, shiny corner (Romanus) lesions.
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CT scan of the pelvis in a patient with AS showing ankylosis of the sacroiliac joints.
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CT scan of the L-spine in a patient with AS showing bony syndesmophytes.
Tables
- Table 1. Association of Spondyloarthropathies With HLA-B27
- Table 2. Genetics of Ankylosing Spondylitis
- Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria
- Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy
- Table 5. ESSG and Amor Criteria for Diagnosis of Spondyloarthropathy
- Table 6. New York and Rome Criteria for Diagnosis of Ankylosing Spondylitis
Population or Disease Entity |
HLA-B27 –Positive |
Healthy whites |
8% |
Healthy African Americans |
4% |
Ankylosing spondylitis (whites) |
92% |
Ankylosing spondylitis (African Americans) |
50% |
Reactive arthritis |
60-80% |
Psoriasis associated with spondylitis |
60% |
IBD associated with spondylitis |
60% |
Isolated acute anterior uveitis |
50% |
Undifferentiated spondyloarthropathy |
20-25% |
Genes |
Chromosome Location |
Gene Product/Function |
Definitely or probably associated HLA-B27 HLA-B60 ERAP1 (ART1) IL23R IL-1 gene cluster IL-1R2 STAT3 |
6p21.3 6p21.3 5q151p31.1 2q12.1 2q11-12 17q21 |
Antigen presentation Antigen presentation ER aminopeptidase 1 IL-23 receptor Modulator of inflammation Decoy receptor for IL-1 Signal transduction for IL-5, 6, 11 |
Probably associated CYP 2D5 ANKH TLR4 KIR (Killer Ig-like receptor) MEFV |
22q13.1 5p15 9q32 19q13.4 16p13.3 |
Metabolism about xenobiotics Ectopic mineralization Pattern recognition receptor forLPS NK cell receptor Pyrin, innate immunity |
Not associated TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc |
Multiple |
Multiple |
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/gastrointestinal infection |
Enthesitis |
2 points |
Psoriasis |
Peripheral arthritis |
2 points |
Keratoderma blennorrhagicum |
Dactylitis (sausage digit) |
2 points |
Inflammatory bowel disease (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 |
||
Clinical or Laboratory Feature |
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% |
ESR = erythrocyte sedimentation rate. |
|
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 |
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. European Spondyloarthropathy Study Group (ESSG); IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug. |
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New York Criteria |
Rome Criteria |
|
|
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 |
