Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
nonsteroidal anti-inflammatory drug + nonpharmacologic therapy
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line drug treatment for patients with ankylosing spondylitis (AS) with pain and stiffness.[109][114]
Inadequate dosing is a common reason for lack of response to NSAIDs. Patients should be challenged with the largest tolerated dose of an NSAID (within its recommended maximum dose), while weighing risks against benefits, before consideration is given to switching to another NSAID.[109] European guidelines recommend at least two courses of NSAIDs at the maximum tolerated dose before moving on to alternative treatments.[109]
Evidence that continuous NSAID use reduces progression of structural damage to the spine compared with on-demand use is conflicting.[137][138][139][140][141] Continuous NSAID treatment is, however, recommended in all patients with active AS on the premise that it provides symptomatic control.[109][114]
Guidelines do not recommend any specific NSAID for the treatment of symptomatic AS.[109][114] One Cochrane review concluded that traditional NSAIDs and cyclo-oxygenase-2 (COX-2) inhibitors are effective for treatment of axSpA.[140]
Both traditional NSAIDs and COX-2 inhibitors have been associated with an increased risk of cardiovascular morbidity.[142] COX-2 inhibitors confer a reduced risk of gastrointestinal toxicity compared with traditional NSAIDs, and coprescription of proton-pump inhibitors can reduce the risk even further. Preparations combining an NSAID with a proton-pump inhibitor are available and have demonstrated equal clinical efficacy to standard preparations.[143][144] The development of acute and chronic renal failure appears to be rare. Younger patients are at lower risk for these complications. The choice of NSAID/COX-2 inhibitor should be adapted to the patient profile, and patients on regular therapy should be monitored regularly.[145]
Guidelines recommend supervised active physical therapy interventions over passive physical interventions (e.g., massage, heat) for patients with active AS.[115][116] Stretching, strengthening, cardiopulmonary, spinal extension, and range of motion exercises are important components of the exercise program.[116][117] Hydrotherapy may improve function and help with pain management.[116][118] Exercise type, frequency, and intensity should be tailored to the individual.[117]
Despite the heterogeneity of physical therapy and exercise programs evaluated in randomized controlled trials, systematic reviews and meta-analyses indicate that these interventions can potentially contribute to improved function, reduced pain, and reduced disease activity in patients with AS.[119][120][121]
[ 
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Patients with AS should be routinely assessed for cardiovascular risk, and modifiable risk factors should be aggressively treated.[126]
Primary options
naproxen: adults: 500 mg orally twice daily, maximum 1250 mg/day
OR
naproxen/esomeprazole: adults: 375/20 mg or 500/20 mg (1 tablet) orally twice daily
OR
indomethacin: adults: 25 mg orally twice daily, maximum, 200 mg/day
OR
ibuprofen: adults: 400-800 mg orally three times daily, maximum 2400 mg/day
OR
diclofenac potassium: adults: 50 mg orally (immediate-release) three times daily
OR
celecoxib: adults: 100 mg orally twice daily, maximum 400 mg/day
tumor necrosis factor (TNF)-alpha inhibitor + physical therapy
Biologic DMARDs should be considered in patients with axial disease activity despite conventional treatment (including NSAIDs and nonpharmacologic treatment).[109][114] For patients with peripheral disease biologic DMARDs may be considered when conventional treatment including local corticosteroid injection or sulfasalazine is ineffective or contraindicated.[109]
Specific risks have been identified for patients treated with biologic DMARDs, including TNF-alpha inhibitors, therefore there are precautions that clinicians should take before initiating treatment. A guideline from the BSR outlines recommendations on precautions for biologic DMARD use.[155] The guideline recommends that baseline screening for patients with AS prior to treatment should include complete blood count; creatinine/calculated glomerular filtration rate; alanine aminotransferase and/or aspartate aminotransferase; albumin; tuberculin skin test or interferon-gamma release assay or both as appropriate; hepatitis B and C serology; chest radiograph.[155] The BSR recommends that treatment with biologic DMARDs should not be initiated in the presence of serious active infections (defined as requiring intravenous antibiotics or hospitalization; not including tuberculosis).[155] For patients at a high risk of infection, biologic DMARDs should be used with caution after discussing risks and benefits. Etanercept should be considered as a first-line biologic therapy in patients at high risk of infection.
Adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab (all TNF-alpha inhibitors) are recommended as first-line treatment after conventional treatment has failed.[109][114] Guidelines recommend monoclonal antibodies over etanercept for the treatment of patients with AS and recurrent uveitis, or with AS and inflammatory bowel disease.[109][114]
Adalimumab is a recombinant monoclonal antibody that binds specifically to TNF and neutralizes the biologic function of TNF. Subsequent to completing a 24-week randomized controlled trial, approximately half of patients with active AS who received open-label adalimumab experienced sustained remission during a 5-year follow-up period.[162] The strongest predictor of remission was achievement of remission at 12 weeks of treatment.[162] Data from nearly 12 years of exposure in clinical trials suggest that risk of serious opportunistic infection and malignancy is reduced in patients prescribed adalimumab for AS compared with those prescribed adalimumab for rheumatoid arthritis.[163]
Certolizumab pegol is a pegylated humanized monoclonal antibody directed against TNF-alpha. In one 52-week study, patients with nonradiographic axial spondyloarthropathy (nr-axSpA) receiving certolizumab pegol were almost seven times more likely to achieve major improvement in the AS Disease Activity Score (ASDAS) compared with placebo.[164]
Sustained response to certolizumab pegol over a 4-year period has been reported in a long-term study of patients with axSpA.[165] Treatment with certolizumab reduced radiographic progression and spinal inflammation.[166] There is some evidence that patients with early axSpA with sustained remission (at 48 weeks) can reduce their dose of certolizumab pegol; treatment should not be discontinued due to the high risk of flare following certolizumab pegol withdrawal.[167]
Etanercept is a human TNF receptor p75 Fc fusion protein. It is a competitive inhibitor of TNF binding to its cell surface receptors.
Long-term etanercept may improve clinical and imaging outcomes in patients with early active axSpA.[168][169] However, results from one small randomized controlled trial indicate that in patients with suspected nr-axSpA with high disease activity, etanercept is no more effective than placebo at 16 weeks.[170]
Golimumab is a human monoclonal antibody that prevents the binding of TNF-alpha to its receptors.
Long-term studies report sustained efficacy of golimumab in the treatment of active AS through 24, 52, and 104 weeks.[173][174][175]
Pooled 5-year safety data from clinical trials of rheumatoid arthritis, psoriatic arthritis, and AS suggest a numerically increased incidence of tuberculosis, opportunistic infection, lymphoma, and demyelination, with a higher dose of golimumab compared with a lower dose of golimumab.[176] The majority of treated patients (67%) participated in rheumatoid arthritis trials.
Infliximab is a chimeric immunoglobulin G1 monoclonal antibody that binds with high affinity to TNF-alpha.
In patients with AS, treatment response with infliximab is sustained over the long term.[177][178][179] In one network meta-analysis, infliximab was demonstrated to be the most effective TNF-alpha inhibitor, with the highest probability of patients achieving ASAS20 response both at 12 and 24 weeks of treatment.[180]
Proactive therapeutic drug monitoring of infliximab (proposed as an alternative to standard therapy to maximize efficacy and safety of biologic agents) did not significantly improve clinical remission rates over 30 weeks in patients with chronic immune-mediated inflammatory diseases including spondyloarthritis.[181]
US guidelines recommend against tapering of biologic agent dose as a standard approach in patients with stable AS disease.[114] European guidance suggests that tapering of a biologic DMARD can be considered in patients in sustained remission.[109] One systematic review reported that patient-tailored dose reduction of TNF-alpha inhibitors successfully preserved a stable low disease activity in with remission rates ranging between 20.2% and 93.7%.[156] However a complete treatment discontinuation is associated with a high risk of flares.[156][157]
Reported adverse effects of TNF-alpha inhibitors (mainly derived from rheumatoid arthritis studies, where many of the increased risks are at least partly attributable to the underlying rheumatologic disorder) include serious infections, the development of malignancies such as lymphoma, worsening of cardiac failure, and a low incidence of demyelinating disease.[206][207][208][209][210][211][212] The risks of adverse events may be lower in patients with AS than in patients with rheumatoid arthritis.[213] Systematic reviews report no significant increase in the risk of infection in patients with AS on TNF-alpha inhibitors.[214][215][216]
TNF-alpha inhibitors are contraindicated in moderate-to-severe heart failure and should be avoided in New York Heart Association class IV cardiac failure, active tuberculosis and other serious infections, and in patients with a history of demyelinating disease or malignancy (particularly melanoma). Before initiation of therapy, evidence of prior hepatitis B virus infection should be sought. Data suggest that patients with hepatitis B surface antigen (HBsAg)-negative and anti-hepatitis B core (HBc)-positive status should be carefully monitored while undergoing treatment with TNF-alpha inhibitors to monitor for potential reactivation of the virus.[217][218] Evidence of active and inactive (latent) tuberculosis infection should also be sought.[217] Pretreatment tuberculosis screening is particularly important in endemic populations.[219]
Baseline chest x-ray and tuberculosis screening are required.[220]
Despite the heterogeneity of physical therapy and exercise programs evaluated in randomized controlled trials, systematic reviews and meta-analyses indicate that these interventions can potentially contribute to improved function, reduced pain, and reduced disease activity in patients with AS.[119][120][121]
[ ]
Primary options
adalimumab: adults: 40 mg subcutaneously every 2 weeks
OR
etanercept: adults: 50 mg subcutaneously once weekly
OR
golimumab: adults: 50 mg subcutaneously once monthly; 2 mg/kg intravenously at 0 and 4 weeks, followed by every 8 weeks thereafter
OR
infliximab: adults: 5 mg/kg intravenously at 0, 2, and 6 weeks, followed by every 6 weeks thereafter
OR
certolizumab pegol: adults: 400 mg subcutaneously at weeks 0, 2, and 4, then 200 mg every 2 weeks or 400 mg every 4 weeks
interleukin-17 inhibitor + physical therapy
If TNF-alpha inhibitor therapy fails, switching to an interleukin (IL)-17 inhibitor (e.g., secukinumab, ixekizumab) should be considered.[109][114] For patients with significant psoriasis, an IL-17 inhibitor are preferred treatment over TNF-alpha-inhibitors.[109]
IL-17 inhibitors have proven efficacy in patients who experience treatment failure with a TNF-alpha inhibitor, but improvements may be greater in TNF-alpha inhibitor naive patients.[109][182]
Specific risks have been identified for patients treated with biologic DMARDs, including IL-17 inhibitors, therefore there are precautions that clinicians should take before initiating treatment. A guideline from the BSR outlines recommendations on precautions for biologic DMARD use.[155] The guideline recommends that baseline screening for patients with AS prior to treatment should include complete blood count; creatinine/calculated glomerular filtration rate; alanine aminotransferase and/or aspartate aminotransferase; albumin; tuberculin skin test or interferon-gamma release assay or both as appropriate; hepatitis B and C serology; chest radiograph.[155] The BSR recommends that treatment with biologic DMARDs should not be initiated in the presence of serious active infections (defined as requiring intravenous antibiotics or hospitalization; not including tuberculosis).[155] For patients at a high risk of infection, biologic DMARDs should be used with caution after discussing risks and benefits.
Guidelines recommend an IL-17 inhibitor for patients with a primary nonresponse (absence of clinically meaningful improvement in disease activity over 3 to 6 months after treatment initiation) to the first TNF-alpha inhibitor.[109][114]
Secukinumab is a fully humanized anti-IL-17A monoclonal antibody. IL-17 is a cytokine produced by T-helper 17 cells that has been increasingly implicated in a variety of autoimmune and inflammatory diseases.
Secukinumab significantly reduces symptoms and signs of AS, as measured by Assessment of SpondyloArthritis International Society criteria.[184][185]
Sustained secukinumab efficacy (signs and symptoms, low rate of radiographic progression) over 4 to 5 years has been reported in patients with AS.[186][187]
Ixekizumab is a recombinant humanized monoclonal antibody that binds with high affinity to IL-17A.
In a phase 3 randomized trial of patients with nr-axSpA, ixekizumab significantly improved signs and symptoms (disease activity, physical function, quality of life, and inflammation) compared with placebo at weeks 16 and 52.[189] In an extension of this trial, patients who completed the initial 52-week phase and were randomized to continued ixekizumab experienced significantly delayed time-to-flare compared with those randomized to placebo.[190]
Ixekizumab is recommended to treat patients who have failed TNF-alpha inhibitor therapy.[109][114]
Ixekizumab is approved in Europe for this indication, but it is not yet included in European guidance for the treatment of AS.[109]
Despite the heterogeneity of physical therapy and exercise programs evaluated in randomized controlled trials, systematic reviews and meta-analyses indicate that these interventions can potentially contribute to improved function, reduced pain, and reduced disease activity in patients with AS.[119][120][121]
[ ]
Primary options
secukinumab: with loading dose: 150 mg subcutaneously at weeks 0, 1, 2, 3, and 4, followed by 150 mg every 4 weeks; without loading dose: 150 mg subcutaneously every 4 weeks
MoreOR
ixekizumab: 160 mg subcutaneously at week 0, followed by 80 mg every 4 weeks
alternative tumor necrosis factor (TNF)-alpha inhibitor + physical therapy
The American College of Rheumatology recommends that adults with secondary nonresponse (recurrence of active disease after sustained clinically meaningful improvement on treatment) to TNF-alpha inhibitor consider a different TNF-alpha inhibitor treatment, before treatment with a non-TNF inhibitor biologic.[114] Evidence suggests a response to a second TNF-alpha inhibitor is possible when the first agent has not worked.[158][159][160][161]
Despite the heterogeneity of physical therapy and exercise programs evaluated in randomized controlled trials, systematic reviews and meta-analyses indicate that these interventions can potentially contribute to improved function, reduced pain, and reduced disease activity in patients with AS.[119][120][121]
[ ]
Janus kinase inhibitor + physical therapy
Janus kinase (JAK) inhibitors (e.g., tofacitinib, upadacitinib) can be considered for patients with AS who are unresponsive or have contraindications to both TNF-alpha inhibitors and IL-17 inhibitors.[109][191][192]
JAK inhibitors have been demonstrated to reduce disease activity, improve physical function, emotional well-being, and social participation in patients with active AS.[193]
Safety data for the use of JAK inhibitors is limited for patients with AS as these treatments are relatively new for this population. There is evidence to suggest that JAK-inhibitor treatment is associated with an increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, opportunistic infections, and serious infections in patients with rheumatoid arthritis.[194]
Despite the heterogeneity of physical therapy and exercise programs evaluated in randomized controlled trials, systematic reviews and meta-analyses indicate that these interventions can potentially contribute to improved function, reduced pain, and reduced disease activity in patients with AS.[119][120][121]
[ ]
Primary options
tofacitinib: 5 mg orally (immediate-release) twice daily; 11 mg orally (extended-release) once daily
OR
upadacitinib: 15 mg orally once daily
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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer
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