Approach

The aims of treatment are to prevent disease progression, maximizing quality of life through control of symptoms and inflammation.[109]​ The ability to predict the likely disease course of ankylosing spondylitis (AS) is limited.

Known predictors of spinal radiographic progression in early spondyloarthropathy are syndesmophytes on baseline radiographs, elevated erythrocyte sedimentation rate or C-reactive protein, and smoking.[110][111]​ It is, therefore, particularly important to consider regular nonsteroidal anti-inflammatory drugs (NSAIDs) and to encourage smoking cessation in patients with these risk factors.[109]​​

With reference to overall patient management, treatment of AS should be:[109]​​

  • Tailored to the individual patient, with their wishes taken into consideration.

  • Targeted at the given symptoms, at the time of consultation.

  • Influenced by the patient's disease activity levels, functional impairment, and degree of mobility impairment, as reflected by assessment with both outcome measures and clinical findings.

Nonpharmacologic and pharmacologic treatments should be combined to provide optimal care.[109]​​

Patients with a diagnosis of AS but without spinal pain and/or stiffness should be reviewed to confirm a definite diagnosis of AS. No specific treatment is necessary other than general advice to keep active and to continue physical therapy exercises; NSAIDs might be considered if there is progressive bone formation over time.

Nonpharmacologic management

Physical therapy

Physical therapy is essential for patients with AS to improve and maintain:[109]​​[112][113][114]

  • Posture

  • Flexibility

  • Mobility

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] [ Cochrane Clinical Answers logo ]

Patient education

Patient education about AS facilitates informed decision-making.[109]​​

The importance of maintaining regular daily stretches and exercise programs needs constant reinforcement. Evidence demonstrates that educational and exercise interventions benefit functional status, disease activity, and quality of life.[122][123][124][125]​​​​​​​

Patient self-help groups and associations have not been studied for their effect on outcomes, but patients may find associations such as the National Axial Spondyloarthritis Society (NASS) beneficial in terms of additional information, support, and group exercise via local branches of the association.

Cardiovascular risk management

The European League Against Rheumatism (EULAR) has published recommendations for cardiovascular risk management in inflammatory arthritis, including AS:[126]

  • Addressing traditional risk factors (including smoking, hypertension, cholesterol, diabetes), as well as optimal treatment of the underlying inflammatory disease.

  • Undertaking cardiovascular disease (CVD) risk assessment at least once every 5 years and following major changes in antirheumatic therapy. Patients at high risk of CVD may be rescreened on a more frequent basis as judged appropriate by the treating clinician.

  • Using the SCORE CVD risk prediction model if no national guideline for CVD risk assessment is available.[127] Total cholesterol and high-density lipoprotein cholesterol should form part of CVD risk assessment and should ideally be measured when disease activity is stable or in remission.

  • Providing advice on diet and smoking cessation.

  • Prescribing NSAIDs in accordance with treatment-specific recommendations.

Patients should receive specific education about the importance of smoking cessation to:[128]

  • Modify their cardiovascular risk

  • Reduce their risk of radiographic progression

  • Where appropriate, optimize individual response to anti-tumor necrosis factor (TNF)-alpha

Compared with the general population men and women with AS have been demonstrated to have an increased risk of death from all causes and cardiovascular causes.[129] This is likely attributable to an excess of CVD, particularly ischemic heart disease.[130][131][132]​ Accelerated atherosclerosis may be due to a combination of an increased prevalence of traditional cardiovascular risk factors, decline in physical activity due to disability, and inflammatory activity, although there is some evidence to suggest that AS may be associated with subclinical atherosclerosis.[131][133]​​[134]​​​[135]​​​

All patients with AS should be routinely assessed for cardiovascular risk; modifiable risk factors should be aggressively treated; and control of the inflammatory disease should be optimized.[136]

Pharmacologic management: pain or stiffness

Treatments for pain or stiffness include NSAIDs, with adjunctive acetaminophen or codeine if required, and possible further treatment with corticosteroid injections.

NSAIDs

NSAIDs are the first-line drug treatment for patients with active 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 the 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]

Adjunctive analgesics

Acetaminophen or codeine may be considered in all patients who find that NSAIDs do not completely control their pain, or if NSAIDs are contraindicated and/or poorly tolerated.[109]​​

Corticosteroid injections

Intra-articular or local-site corticosteroid injections are recommended for localized inflammation (e.g., unilateral sacroiliitis after exclusion of infection, Achilles enthesopathy).[109]​​[114] In some countries, intra-articular or local corticosteroid injection should only be considered when at least two courses of NSAIDs have failed to control symptoms.[109]​​

Local-site corticosteroids are given in addition to NSAIDs and analgesia (and if necessary disease-modifying antirheumatic drugs [DMARDs]) for concomitant peripheral disease.[109]​​[114]

Systemic corticosteroids are not recommended.[109]​​[114] Although, there is some evidence to suggest that the use of high-dose systemic corticosteroids in the short term (≤6 months) is beneficial for patients with AS.[146]​​

Adults with peripheral joint involvement

Sulfasalazine and methotrexate (conventional synthetic DMARDs) may be considered for patients with peripheral disease, but there is no evidence supporting their efficacy for treating axial disease.[109]​​[114] They are given in addition to analgesia for concomitant peripheral disease.

Evidence for sulfasalazine efficacy in patients with peripheral disease is primarily derived from placebo-controlled randomized controlled trials conducted in the 1990s or earlier.[114] One systematic review and meta-analysis noted that none of these trials assessed contemporary outcome measures (i.e., Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Bath Ankylosing Spondylitis Function Index [BASFI], Bath Ankylosing Spondylitis Metrology Index [BASMI], radiographic progression) and concluded that there is 'insufficient evidence to support any benefit of sulfasalazine in reducing pain, disease activity, radiographic progression, or improving physical function and spinal mobility in the treatment of AS'.[147]

There is no confirmed benefit with methotrexate in the treatment of AS.[148][149] However, guidance now advocates its use in peripheral arthritis, as some studies may have used suboptimal doses of methotrexate.[114]

Safety data and precautions to take before biologic DMARD treatment

Biologic DMARDs including TNF-alpha inhibitors, and interleukin (IL)-17 inhibitors are recommended, and have been demonstrated as effective for patients with AS who do not respond to, or have contraindications to conventional treatment such as education, exercise, NSAIDs, and corticosteroid injections or sulfasalazine for patients with peripheral disease.[109][114]​​​​​[150][151][152][153][154] [ Cochrane Clinical Answers logo ]

However, as specific risks have been identified for patients treated with biologic DMARDs there are precautions that clinicians should take before initiating treatment. A guideline from the British Society of Rheumatology (BSR) outlines recommendations on precautions for biologic DMARD use. It recommends that baseline screening for patients with AS prior to treatment should include:[155]

  • 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, and

  • chest radiograph.

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 the risks and benefits. Etanercept should be considered as a first-line biologic therapy in patients at high risk of infection.[155]

Adults with refractory disease: TNF-alpha inhibitors

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]​​

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 (IBD).[109][114]​​​​​​ On initiation of a TNF-alpha inhibitor, NSAIDs are recommended for active AS disease and can be taken continuously until the patient is stable. After this, patients may use NSAIDs on demand.[114]

US guidelines recommend against tapering of biologic agent dose as a standard approach in patients with stable AS disease.[114] International and 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 most studies, 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]

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]

Adalimumab

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

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

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]

Observational data suggest that etanercept may be less effective at preventing anterior uveitis than monoclonal antibodies that target TNF.[171][172]​ Guidelines recommend monoclonal antibodies over etanercept for the treatment of patients with AS and recurrent uveitis, or with AS and IBD.[114]

Golimumab

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

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]

Adults with refractory disease: interleukin-17 inhibitors

If TNF-alpha inhibitor therapy fails, switching to another TNF-alpha inhibitor or an IL-17 inhibitor should be considered.[109]​​[114]

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]​ However, for patients with significant psoriasis, an IL-17 inhibitor are preferred treatment over TNF-alpha-inhibitors.[109]​​

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]​ This group includes secukinumab and ixekizumab.

Interleukin inhibitors (IL-1, IL-6, IL-12/23, IL-17, IL-23) have been associated with an increased risk of serious infections, opportunistic infections, and cancer in patients with rheumatologic disease.[183] Further research is required to determine the comparative contribution of specific interleukin inhibitors in different disease states.

Secukinumab

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]​ Secukinumab has demonstrated a favorable safety profile over long term (up to 4 years) treatment in patients with AS.​[188]

Ixekizumab

Ixekizumab is a recombinant humanized monoclonal antibody that binds with high affinity to IL-17A.

In one 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]​​​​

Adults with refractory disease: janus kinase (JAK) inhibitors

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]

Management of children

The management of children with spondyloarthropathy is dependent on the extent of peripheral arthritis.

Oligoarthritis can often be managed with a combination of NSAIDs and intra-articular corticosteroid injections. Persistent oligoarthritis or polyarthritis is commonly treated with sulfasalazine or methotrexate.[195] The use of methotrexate is based largely on efficacy data from other subtypes of juvenile idiopathic arthritis.[196][197]

Enthesitis (inflammation of the tendon or ligament attachments to bone) may respond to local corticosteroid injections under radiographic guidance.

Adalimumab improved signs and symptoms of juvenile enthesitis-related arthritis at 12 weeks, sustained through 52 weeks, in one small placebo-controlled randomized trial.[198] The safety profile was consistent with previous adalimumab studies.[198]

Etanercept showed sustained efficacy at treating clinical symptoms over 96 weeks, with no major safety issues, in one multicenter open-label study of children with subtypes of juvenile arthritis (including spondyloarthritis).[199]

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