Ankylosing spondylitis (AS) is a chronic inflammatory disease manifested by back pain and progressive spinal stiffness. AS characteristically affects young adults with a peak age of onset between 20 and 30 years. Although classically thought of as a spinal disease, transient acute arthritis of peripheral joints occurs in up to 50 percent of patients. In addition, other organs such as the eyes, lungs, heart, and kidneys can be affected. The assessment, monitoring, prognosis, and treatment of ankylosing spondylitis in adults are presented here. The clinical manifestations and diagnosis of ankylosing spondylitis in adults, and a detailed discussion of the clinical manifestations, approach to diagnosis, pathogenesis, and treatment of SpA in children, are presented separately.

GOALS OF MANAGEMENT

The primary goal of management for patients with ankylosing spondylitis (AS) is to maximize long-term health-related quality of life through the following:

Relief of symptoms – To eliminate symptoms such as pain, stiffness, and fatigue or to reduce them to the minimal possible level
Maintenance of function – To maintain the best possible functional capacity
Prevention of complications of spinal disease – To prevent flexion contractures, especially dorsal kyphosis (hunching over from the spine)
Minimization of extraspinal and extraarticular manifestations and comorbidities – To reduce the impact of AS-associated disorders such as uveitis and aortic valve insufficiency

The authors' recommendations are generally consistent with those jointly developed by the Assessment of SpondyloArthritis international Society (ASAS) and the European League Against Rheumatism (EULAR), and also with those proposed by an international task force [1-3]. This task force advocates a “treat to target” approach to spondyloarthritis management, with an ideal goal of disease remission, and an alternative goal, appropriate particularly for some patients with more longstanding disease, of minimal disease activity [3]. Management of AS is lifelong for each patient, and shared decision-making by patients and their clinicians is important in management.

The symptoms of AS and the rate of progression fluctuate with time and can vary substantially between patients. Functional limitations can result directly from disease activity but also indirectly from the feelings of helplessness and depression, which may be associated with disease activity and which also require recognition and appropriate treatment intervention [4].

ASSESSMENT AND MONITORING

Treatment decisions depend upon an accurate assessment of disease impact. In general, four approaches are required:

Information is elicited in the patient medical history to assess the degree of disease activity, functional disability, and health-related quality of life.
Physical examination is used to detect inflammation, contractures, and limitations in range of motion.
Blood tests are used to assist in assessing disease activity.
Imaging is used to assess skeletal damage and, in some patients, disease activity.

1. Patient medical history

— The medical history is used to assess disease activity, functional disability, and health-related status. The following parameters are recommended:

The patient global assessment on a scale of 0 to 10 or (1 to 10).
The physician global assessment on a scale of 1 (mild) to 4 (severe).
The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) disease activity questionnaire

A) Functional disability and psychological status – In clinical practice, the particular daily activities and quality-of-life parameters to be assessed depend upon the judgement of clinician. In clinical research on ankylosing spondylitis (AS), functional disability and health-related quality of life are numerically scored using the Bath Ankylosing Spondylitis Functional Index (BASFI) and the AS Quality of Life instrument (ASQoL), respectively [5-8]. The BASFI focuses on functional ability, while the ASQoL also addresses social and psychological domains.

Disease activity scores:

A.1) BASDAI — The BASDAI disease activity questionnaire consists of six questions concerning overall symptoms during the week immediately prior to answering the questions, including [9]:

How would you describe the overall level of fatigue/tiredness you have experienced?
How would you describe the overall level of AS neck, back, or hip pain you have had?
How would you describe the overall level of pain/swelling in joints other than neck, back, hips you have had?
How would you describe the level of discomfort you have had from an area tender to touch or pressure?
How would you describe the level of morning stiffness you have had from the time you wake up?
How long does your morning stiffness last from the time you wake up?

Each question is scored on a scale of 0 to 10. Except for the last question, 0 indicates none and 10 indicate very severe. For the last question, 0 is 0 hours, 5 is one hour, and 10 is two or more hours.

To calculate the BASDAI score, the sum of the scores for questions one through four is added to the mean of the sum of the scores for questions five and six; the total is divided by five to calculate the disease activity score. A BASDAI score of at least 4.0 (out of a maximum of 10) indicates severe disease activity. An interactive webpage is available at http://basdai.com/BASDAI.php.

A.2) ASDAS — The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite measure of disease activity. It incorporates information from the level of acute phase reactants and various clinical parameters (a patient global score and several questions also used for the BASDAI) [10]. An ASDAS calculator is available from the Assessment of SpondyloArthritis international Society (ASAS), together with information regarding its use and interpretation [11,12]. The ASDAS has the advantage of categorizing the disease activity as inactive, moderate, high, or very high. It also defines the degree of change in the score that would classify the response to treatment as a clinically important improvement or major improvement.

2. Physical examination

In addition to the general physical examination, the physical examination in AS focuses on three areas:

axial joints, including the hips;
peripheral joints; and
entheses (inflammation of the muscular or tendinous attachments to bone).

Details of the assessment used in research are available (http://www.asas-group.org/ and [13-15]).The parameters below are those used in clinical practice. There is considerable variation among healthy individuals in the ranges of motion of the cervical, thoracic and lower spine. Thus, the threshold values given should be considered as estimates, rather than precise cut-off points between normal and abnormal [16].

Cervical spine – AS may cause forward stooping of the thoracic and cervical spine. The degree of flexion deformity is measured by asking the patient to stand erect with heels and buttocks against a wall and to extend his or her neck, while keeping the chin (mandible) horizontal in an attempt to touch the wall. Almost all normal individuals can touch the wall with the occiput (bony prominence at the back of the head). The distance between the occiput and the wall in a patient with AS reflects the degree of cervical deformity. In addition, the range of flexion, extension, lateral flexion, and rotation are also recorded.
Thoracic spine – The range of motion of the costovertebral joints is measured by the degree of chest expansion. Chest expansion is measured at the level of the fourth intercostal space or just below the breasts in females. The patients are instructed to raise their arms above their heads and to exert a maximal forced expiration followed by a maximal inspiration. Normal expansion is usually 2.5 cm.
Lower spine – Range of motion of the lower spine is tested in the sagittal plane by the Schober test, and in the coronal plane by the extent of lateral spinal flexion.

•Schober test – The Schober test measures the forward flexion of the lumbar spine. The patient stands erect; a mark is placed at the midpoint of a line joining the posterior superior iliac spines (dimples of Venus); another mark is made 10 cm above it in the midline. The patient then bends forward maximally without bending the knees and the distance is measured again. In normal individuals, the difference between the two measurements should exceed 4 cm.
•Lateral spinal flexion – With the patient standing erect with heel and back against a wall and knees and hands extended, the distance between the tip of the middle finger and the floor is measured. The patient is then instructed to bend sideways without bending the knees or lifting the heels. A second measurement is made and the difference between the two is recorded. The final result is the averaged measurements of right and left flexion. Normal is greater than 10 cm.

Hip joint – Hip involvement should be suspected when a patient shows an abnormal gait. It is verified by testing whether there is limitation of flexion, internal and external rotation, or pain at the extremes of these joint motions. Destructive disease at the hip joints in AS can lead to flexion deformities. However, a unilateral flexion deformity is frequently masked by compensatory motion in the spine. To eliminate this problem during physical examination, the patient is asked to lie supine and maximally flex one hip. If there is a flexion deformity of the contralateral hip, the knee of the contralateral limb will be raised and the degree of flexion deformity can be measured by the angle of the contralateral thigh.
Peripheral joint count – This involves a 44-joint count of the number of tender and/or swollen joints, including those of the ankles, feet and the sternoclavicular joints (page II40 in handbook in http://www.asas-group.org/) [17].
Sausage digit (dactylitis) – The number of digits that have sausage appearance should be determined.
Enthesitis count (inflammation of the muscular or tendinous attachments to bone) – At least 18 entheseal sites are assessed during clinical trials (http://www.asas-group.org/). In practice, the minimum should be at the heel, at the sites where the Achilles tendon and the plantar fascia are each attached to the calcaneus.

Extraarticular comorbidities — The methods of monitoring extraarticular involvement, such as uveitis, are based upon standards used for the organs being involved. AS is associated with increased risk of both osteoporosis and cardiovascular disease.

Recommendations for office practice — The following are a suggested set of indicators for minimum evaluation in initial visits and for monitoring disease progression:

Patient self-assessment of pain (1 to 10)
BASDAI and/or ASDAS, depending upon the availability of information on acute phase reactants, as the CRP or ESR value is required for calculating the ASDAS
BASFI or those daily activities that are limited by disease
Physician's global assessment on a scale of 1 (mild) to 4 (severe)
ESR or CRP

The frequency of monitoring depends on the course of symptoms, severity of disease and the therapies being used.

3. Acute phase reactants in the blood

The erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) are useful for monitoring disease activity, if they are elevated at baseline of treatment.

4. Imaging

In research, radiographic damage of the spine is assessed using lateral views of the cervical and lumbar spine, graded vertebra by vertebra, and scored, for example, using the Modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) [18]. In clinical practice, it is useful to examine the anterosuperior and anteroinferior margins of the lumbar vertebrae on a lateral spine radiograph, and to record those with syndesmophytes. In advanced disease, plain radiographs of the spine will reveal "bamboo spine" with virtually complete fusion of the vertebral column. At that stage there is usually fusion of the sacroiliac joints. Because disease progression is slow, unless changes are suspected, it is not necessary to repeat radiographs of the vertebrae more than once every two years.

NONPHARMACOLOGICAL TREATMENT

Patient education, exercise, and medications are all very important in the management of ankylosing spondylitis (AS) [3]. Patient education and support, in addition to that provided by the patient’s clinician, is frequently available from support groups.

Smoking cessation is recommended for everyone who smokes. It is a modifiable risk factor for poor functional outcome in AS [19].
Home exercises are effective, but supervised exercise programs or formal physical therapy can be of greater benefit [20]. Optimally, an initial evaluation and training by a physical therapist should be part of the therapeutic regimen. Exercises include postural training, range of motion stretching, recreational activities, and perhaps hydrotherapy. In addition, pain relief measures such as local heat or cold can be given a trial. At a minimum, patients with AS should participate in an unsupervised home exercise program [21]. Inpatient rehabilitation is rarely needed [22]. Many patients, however, do not exercise on a frequent basis, despite widespread appreciation of the benefits of exercise [23]. Video demonstrations of exercises tailored for ankylosing spondylitis are available for viewing through the National Ankylosing Spondylitis Society in the UK [24].Guide books and audio and video aids on compact disc and digital video disc are available from the Spondylitis Association of America. Even those patients who are doing well clinically with pharmacologic treatment will also benefit from education and exercise [25-28].

PHARMACOLOGIC THERAPY

Pharmacotherapy includes one or more of the following:

nonsteroidal antiinflammatory drugs (NSAIDs),
analgesics,
sulfasalazine (SSZ), and
anti-tumor necrosis factor (TNF) agents.
Systemic glucocorticoids have a limited role, but intraarticular injections may be helpful to some patients.

Nonsteroidal antiinflammatory drugs

NSAIDs should be the first line of treatment for all symptomatic ankylosing spondylitis (AS) patients, unless contraindicated. In many patients, NSAIDs are the only medications required. About 70 to 80 percent of AS patients report substantial relief of their symptoms, including back pain and stiffness, with NSAIDs [29]. This is significantly more than the 15 percent observed in mechanical low back pain. NSAID use also results in decreased pain in peripheral joints [30]. There are two issues related to NSAID therapy in AS:

The choice of NSAID, including the possible role of selective cyclooxygenase (COX)-2 inhibitors – Initial anecdotal evidence suggested that indomethacin is the most effective NSAID [31]. However, multiple studies support the view that other NSAIDs are also effective [32]. Regardless of the NSAID used, the maximum dose is usually required. To assess the usefulness of a particular NSAID, it should be given at a sustained dose on a regular basis for at least four weeks. A table of recommended doses is available [29]. Short-term studies indicate that selective COX-2 inhibitors, such as celecoxib and etoricoxib, are as effective as nonselective NSAIDs [33-36].
Continuous versus on-demand therapy – AS patients who have persistent, active, symptomatic disease should use continuous NSAIDs to control symptoms. This approach is in agreement with the 2010 Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations [1,2]. In addition, a randomized trial and several additional studies have shown that patients who use either continuous daily NSAIDs or high-dose NSAIDs regardless of symptoms may have a lower rate of radiographic progression in the spine [37-40].

As an example, in one trial involving 215 patients, which suggested that continuous daily use of NSAIDs may suppress radiographic progression, patients were randomly assigned to receive either continuous or on-demand NSAID therapy [37]. At two years, the degree of radiographic progression was statistically significantly less (by 73%) in the patients who were treated continuously with NSAIDs. Patients with more active inflammation seem to particularly benefit from continuous NSAID therapy. In one study, continuous NSAID therapy was especially effective in patients with an elevated erythrocyte sedimentation rate (ESR) [39]. In another study, continuous NSAIDs were most effective in patients with high C-reactive protein (CRP) and with the presence of syndesmophytes at baseline [40]. However, the exact clinical meaning of these findings remains to be determined.

Analgesics and Opiods

When used alone, analgesics and opioids are seldom effective during active AS. However, they can be considered for residual pain, or when NSAIDs are contraindicated.

Tumor necrosis factor alpha antagonists

The anti-TNF-alpha agents available in Canada, the United States, and Europe for use in AS are infliximab, etanercept, adalimumab, and golimumab. Concomitant use of an immunomodulatory drug, such as methotrexate (MTX), is not required, as this provides no additional benefit but may increase the cost and the risk of adverse effects [41].

Overall efficacy — A 2007 meta-analysis indicated that all three of the anti-TNF alpha agents then available (adalimumab, etanercept, and infliximab) were similar in efficacy in patients with AS [42]. These medications have not been compared directly with each other, but indirect comparisons were unable to distinguish significant differences. At week 12 of trials, patients treated with the anti-TNF agents were 3.6-fold more likely, compared with those treated with placebo, to achieve 50 percent improvement (using a composite measure, the ASAS50). Approximately 80 percent of patients with AS respond to treatment with one of these agents and approximately one half get at least 50 percent improvement in a composite index, modified from the one adopted by the Ankylosing Spondylitis Assessment Group that includes [43]:

Patient global assessment
Patient assessment of pain
A functional assessment, such as ability to carry out certain activities with which the patient had difficulty prior to treatment
Degree of inflammation as assessed by morning stiffness

The clinical responses are typically rapid. Eighty percent of patients who experienced a 50 percent response according to BASDAI by 12 weeks did so within the first six weeks of treatment. The long-term effects of anti-TNF therapy appear to be durable, with continued efficacy for at least two years in two observational studies, and for five years in a third study [44-46]. Patients who do not respond to or do not tolerate one anti-TNF agent may respond to an alternate anti-TNF agent [47]. Why some patients but not others respond to these interventions is unknown.

Use of anti-TNF therapy may also decrease the frequency of recurrences of uveitis in patients with AS [48]. Despite their efficacy, the indiscriminate use of anti-TNF-alpha drugs is discouraged because of cost concerns and a lack of long-term safety data [49]. A guideline for selecting patients for whom anti-TNF therapy is indicated, dosing (amount and frequency), and monitoring for efficacy and adverse effects has been developed and updated by an international panel of clinicians with expertise in the treatment of AS [50-52]. A summary of guidelines is presented separately.

Effect on radiographic progression — Whether long-term use of anti-TNF agents can halt the radiographic progression of the disease has been uncertain; such effects may not be evident until patients have been followed for several years. In a prospectively followed cohort of 334 patients treated with standard therapies for AS, in whom TNF inhibitors were administered to 201 patients, treatment with a TNF inhibitor was associated with a 50 percent reduction in the odds of radiographic progression (odds ratio 0.52, 95% CI 0.30-0.88) [53]. Such benefit was more evident in patients in whom these agents were begun earlier in the disease course and in whom the follow-up was at least four years. This finding was confirmed in a separate study in which patients with AS who were treated with the TNF inhibitor infliximab showed a similar rate of radiographic progression, during the first four years of follow-up, compared with a historical control group that did not receive a TNF inhibitor, but significantly less progression, compared with the historical controls, from years four to eight [54].

In contrast, analyses of imaging data in patients treated for only two years, comparing patients who received these drugs in several clinical trials with a historical cohort of patients who did not receive TNF inhibitors, failed to demonstrate that treatment with infliximab, adalimumab, etanercept, or golimumab [55] could halt radiologic progression of AS, despite evidence of clinical improvement and reduced spinal inflammation [56-58].

Use of TNF antagonists in early and advanced axial spondyloarthritis — Most studies of anti-tumor necrosis factor (TNF) therapy have recruited patients whose states of disease are neither very early nor very advanced. However, in trials that have evaluated these populations, the highest remission rates are observed with patients with very early disease [59], and patients with advanced disease have also benefited from anti-TNF therapy [60].

Predictors of response — The following parameters are possible predictors of a good response to TNF antagonists [61,62]:

Shorter disease duration, which is the best predictor
Elevated CRP
Young age

Improvement of greater than 50 percent may be seen in up to 80 percent of such patients [63].

Switching to a second TNF antagonist — A large open-label study addressed the effectiveness of switching to adalimumab when patients failed etanercept or infliximab because of either an inadequate response or adverse effect. Such patients were compared with those begun on adalimumab who had never received etanercept or infliximab. After 12 weeks, a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response was observed in 63 percent of patients who had never received TNF antagonists, and 40.8 percent of patients who had been treated with prior TNF antagonists [64]. In general, switching to another TNF antagonist is more useful for patients who have loss of response to the first one.

Stopping TNF antagonists when patients have obtained a major clinical response — The majority of patients will relapse soon after discontinuing the TNF antagonists [63]. It is possible that the dose or interval of treatment can be modified, but this has not been systematically studied.

Improvement in bone density — Some data suggest that use of anti-TNF biologic agents may be associated with improved bone density. Three studies utilizing anti-TNF biologic agents in the treatment of 75 patients with various forms of spondyloarthritis were reviewed [65]; when the changes in bone density from baseline to the end of observation were compared, patients receiving anti-TNF agents had increases in bone mineral density of 3.2 to 3.6 percent at the lumbar spine and 1.8 to 2.0 percent at the hip.

General side effects — Potential adverse effects such as an increased risk of reactivation of latent tuberculosis and the exacerbation or development of demyelinating disease must be considered when using these agents. Infliximab, etanercept, and adalimumab, when used in patients with AS, have been temporally associated with the development of psoriasis, including the palmoplantar pustulosis type [66,67]. Three cases of retropharyngeal abscess were also noted among 107 patients with a variety of spondyloarthritis (incidence of 1.6 per 100 patient years).

Infliximab
Significant benefit has been noted in patients with axial as well as peripheral spondyloarthritis using the chimeric mouse-human monoclonal anti-TNF alpha antibody infliximab [66,68-72]. Infliximab use also resulted in improvement in the synovial histopathology [73]. Decreases in vascularity, thickness of the lining layer, and the degree of infiltration of synovium by neutrophils, macrophages, and T cells were seen; these findings have been confirmed in a subsequent study in two additional cohorts [74].

The largest study of this anti-TNF agent randomly assigned 357 North American and European patients to receive infliximab (5 mg/kg at week 0, 2, 6, 12, and 16) or placebo (The ASSERT trial) [75]. Patients with complete spinal ankylosis were excluded from this study, as were those with a recent infection, active or latent tuberculosis, or immunosuppression due to HIV/AIDS or solid organ transplantation. Patients with other diseases that could be exacerbated by infliximab, including demyelinating disorders and heart failure, were also excluded. MTX and other disease-modifying antirheumatic drugs (DMARDs) were prohibited. The primary outcome assessed at 24 weeks was a change that met ASAS criteria for a 20 percent improvement (ASAS20).

This and other controlled trials of infliximab utilized a 5 mg/kg dose [76,77], which is higher than the usual dose of 3 mg/kg for patients with rheumatoid arthritis. The 5 mg/kg dose appears to remain effective when used for periods of at least three years [46,78,79]. Whether a lower dose would be equally effective is uncertain. When 21 patients were given the 3 mg/kg dose in one of the observational studies cited above [71], infliximab appeared to be effective; however, three patients were given the 5 mg/kg dose after three months of therapy because of inadequate control of symptoms on the lower dose. Some patients who are not controlled with infusions every eight weeks may benefit from a reduced interval between treatments (eg, six weeks) [80].

The time to maximal response may be as long as six weeks, though some patients experience pain relief shortly after the first infusion. Our experience suggests that patients with longstanding disease are less likely to respond to infliximab therapy.

Most initial studies with infliximab in AS were carried out with patients who had definite sacroiliitis by plain radiography. A placebo-controlled randomized trial was carried out in a group of patients in whom the majority did not have plain radiographic sacroiliitis. These were inflammatory back pain patients with positive magnetic resonance imaging (MRI) changes of sacroiliitis and positive testing for HLA-B27. Infliximab was also effective in these patients [81]. In one case report, infliximab was effective in reversing symptoms of cauda equina syndrome [82]. No other interventions have previously been of benefit, but the utility of this approach in other patients has not yet been demonstrated.

MTX, although routinely used in combination with infliximab to treat rheumatoid arthritis, has not been found to be necessary or provide additional beneficial when infliximab is being used to treat AS [83]. The importance of coadministration of MTX on efficacy has not been studied with other TNF-alpha antagonists in AS.

Biosimilar for infliximab — The immunoglobulin (Ig)G1 chimeric human–murine monoclonal antibody, CT-P13 [84,85], was developed as an anti-TNF alpha monoclonal antibody biosimilar to the original (termed “innovator”) infliximab, which had first became commercially available in 1999. A “biosimilar” is defined by the World Health Organization (WHO) as a “biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product” [86]; “similarity” is defined as the “absence of a relevant difference in the parameter of interest.” CT-P13 has an identical amino acid sequence to infliximab and is produced in the same type of cell line; it exhibits highly similar in vitro and in vivo pharmacodynamics, binding specificities and affinities, and other biologic and pharmacologic characteristics [84,85].

CT-P13 has shown equivalent clinical efficacy to the innovator infliximab in a small number of clinical trials, including the PLANETAS (Programme evaluating the autoimmune disease investigational drug CT-P13 in AS patients) trial, a randomized phase 1 trial in patients with AS, which also showed equivalent pharmacokinetic profiles of CT-P13 and infliximab [85]. In this trial, which involved 250 patients with active AS, treatment with CT-P13 demonstrated equivalent efficacy to infliximab up to week 30 (ASAS20 of 71 and 72 percent, odds ratio [OR] 0.91, 95% CI 0.51-1.62; ASAS40 of 52 and 47 percent, OR 1.19, 95% CI 0.70-2.00). Multiple other response measures were also comparable, and there were no differences detected in immunogenicity or safety. The initial trials of CT-P13 were the first clinical trials comparing a biosimilar to an innovator biologic agent for a rheumatic disease [87]. The worldwide availability of this agent is limited and will depend upon regulatory requirements in different regions and local patent laws and patent expiration dates [87].

Etanercept
Several open studies and randomized trials have demonstrated the efficacy of etanercept in AS [88-93]. Limited data suggest that the symptomatic benefits of etanercept are quickly lost after cessation of therapy [94]. As with infliximab, etanercept use also resulted in improvement in synovial pathology in the peripheral joints [95].

The largest trial confirmed the efficacy of etanercept; it was a well-designed, international trial that randomly assigned 277 patients to receive etanercept (25 mg sc twice weekly) or placebo [91]. After 12 weeks of treatment, the proportion of patients achieving improvements of 20, 50, or 70 percent were about 60, 45, and 25 percent, respectively. Seventeen percent of patients achieved partial remission. These were significantly higher than the corresponding placebo values. In a subset of 40 subjects who had serial MRI examinations of the spine, there was a mean 54 percent decrease in T2-weighted signal in those treated with etanercept, suggesting decreased spinal inflammation, while the placebo group had a slight worsening (increase of 13 percent) [96]. Significant improvement was also noted in spinal and chest wall mobility. Hence, these are also useful follow-up parameters for patients receiving anti-TNF therapies. Only injection site reactions were more frequent in the etanercept group. In an unblinded extension of this study, beneficial effects were sustained during nearly two years of continued etanercept treatment [97].

Further support for the efficacy of etanercept in AS was provided by a multicenter randomized trial carried out at 14 European sites; 84 ankylosing spondylitis patients were randomly assigned to etanercept (25 mg SC twice a week) or placebo for 12 weeks [92]. Significant improvement was observed in the etanercept group by week 2, and significantly more patients achieved an ASAS50 at week 12 (48.9 versus 10.3 percent).
The results of the multiple randomized trials summarized above show convincingly that etanercept is effective for patients with ankylosing spondylitis. Weekly dosing with 50 mg appears to result in similar efficacy to 25 mg twice weekly [98,99].

Adalimumab
Adalimumab, a humanized anti-TNF monoclonal antibody, is also far more efficacious than placebo [59,100,101]. This was illustrated in a study that randomly assigned 315 patients in a 2:1 ratio to adalimumab (40 mg every other week by subcutaneous injection) or placebo injections [100]. The study population was predominantly Caucasian, male, and HLA-B27 positive with a mean duration of disease of 10 years. A significantly greater proportion of adalimumab-treated patients achieved the primary efficacy endpoint, an ASAS20 response at the end of 12 weeks (58 versus 21 percent). Patients who did not achieve an ASAS20 after 12 weeks were eligible to receive 40 mg weekly. At week 24 all patients were switched to or continued adalimumab 40 mg every other week in an open-label extension of the trial [45]. Of 61 patients treated weekly, ASAS20 responses were achieved after six weeks and after one year by 23 and 34 percent, respectively. At week 24 patients were switched to or continued adalimumab 40 mg every other week in an open-label extension of the trial [45]. At two years, for patients who were still receiving adalimumab, an ASAS20 was achieved by 64.5 percent. The proportion of these patients who experienced over 50 percent improvement in the BASDAI was 71 percent [45].

Thus, the advantage of adalimumab treatment was maintained for up to 24 weeks in the randomized phase of the study, and subsequently maintained for up to two years of follow-up in the open-label phase of the study.
Adalimumab has also been tested in randomized trials using patients with axial SpA who do not have radiographic signs of sacroiliitis (nr-axSpA). There is a significantly higher ASAS40 response at week 12 using adalimumab compared with placebo [102]. At two years, the frequency of patients with serious adverse events that were possibly drug-related was 5.5 percent. No cases of tuberculosis, heart failure, lupus-like symptoms, or demyelinating disease were reported.

Golimumab
Golimumab is a human anti-TNF alpha monoclonal antibody that is administered by subcutaneous injections once every four weeks. Efficacy for patients with AS appears similar to that of other anti-TNF agents. This was illustrated in a study that randomly assigned 356 patients to golimumab 50 mg, golimumab 100 mg, or placebo injections every four weeks [103]. After 14 weeks ASAS20 responses occurred in 59, 60, and 22 percent of patients in the three groups, respectively. These responses appear to be comparable to those of other TNF antagonists. The recommended dose is 50 mg subcutaneously every four weeks. The precautions and possible side effects are the same as those for the other FDA-approved TNF antagonists.

Certolizumab
An additional TNF inhibitor that is available for use in patients with active axial spondyloarthritis (SpA), including AS, is certolizumab pegol (CZP), a pegylated Fab fragment of a humanized monoclonal antibody directed against TNF-alpha that is administered by subcutaneous injection. In a randomized trial involving 325 patients with active axial SpA, including patients with AS and non-radiographic axial SpA, the patients who received CZP (200 mg every two weeks or 400 mg every four weeks) were significantly more likely to achieve improvement in disease activity compared with patients receiving placebo (ASAS20 58 and 64 versus 38 percent, ASAS40 43 and 49 versus 18 percent) [104]. Benefit was sustained at week 24. The response was similar to that seen with other TNF inhibitors, and no additional safety concerns were identified.

Disease modifying agents (DMARDs)
The only traditional DMARD regarded as potentially useful in AS is sulfasalazine.

Sulfasalazine (SSZ)
We typically use sulfasalazine in patients with peripheral arthritis, such as those with oligoarthritis of the knees and/or ankles, for whom a drug other than an anti-TNF agent is desirable, and prefer it to MTX in this setting. We discontinue sulfasalazine if there is no improvement after a four- to six-month trial at maximum dose. We also consider stopping the agent after a remission has been obtained, with its reinstitution in those who relapse. We do not recommend using sulfasalazine in those with only symptoms or signs of axial disease.

A 2006 meta-analysis that included data from 11 randomized clinical trials of SSZ concluded that it was significantly more effective than placebo in reducing spinal stiffness and in lowering the ESR [105]. However, most of the clinical trials of SSZ have been relatively small. Two of the larger trials involved 89 and 264 patients with AS, respectively [106,107]. In both of these trials, SSZ was more effective for the treatment of peripheral arthritis than for axial disease.

The use of SSZ has declined very considerably since the introduction of the TNF antagonists, which are more effective for both axial and peripheral disease [108,109]. Most experts in the care of patients with spondyloarthropathy recommend SSZ only for AS patients with peripheral arthritis, and many experts do not recommend its use if TNF antagonists are available [52]. In one study, SSZ was less effective in reducing disease activity compared with etanercept, whether or not peripheral joint involvement was present [110].

A typical dose of SSZ used in clinical trials was one 500 mg tablet daily for the first week, increasing by one tablet per day each subsequent week to a total of four to six tablets daily, divided and given twice a day. For those on the higher daily dose, the dose was reduced to four tablets if the higher dose was not tolerated. Approximately 60 percent of the SSZ-treated patients reported side effects, all reversible on withdrawal of the drug. The most common side effects were nausea, dizziness, headache, and rash. There is no guideline as to how patients on SSZ should be monitored for side effects. Leukopenia and neutropenia can develop quite suddenly, with an incidence varying from 1 to 5 percent. We recommend that blood counts be monitored at least every three months, and more frequently in the initial period.

Methotrexate
Some studies have suggested that MTX may be effective in some patients with AS [111,112]. However, a 2006 meta-analysis of the efficacy of MTX in AS found no evidence of benefit in this disease [113]. Additionally, the combination of MTX and infliximab did not increase the efficacy or decrease the risk of adverse effects compared with infliximab alone [83,114,115]. Thus, there is currently a lack of evidence to support the use of MTX in the treatment of AS. Nevertheless, some rheumatologists do prescribe methotrexate for AS patients with peripheral arthritis.

Leflunomide
Limited data suggest that leflunomide is of little or no benefit for patients with AS [116,117].

Glucocorticoids
We suggest not using systemic glucocorticoids on a long-term basis for patients with AS, although very limited data suggest that relatively high doses of prednisolone may have some benefit for very short-term therapy. There is only one small randomized trial of oral glucocorticoid therapy in AS, involving a total of 39 patients [118]. This two-week trial compared the responses of NSAID-resistant patients who were randomly allocated to receive prednisolone (either 50 or 20 mg daily) or placebo. The proportion of patients achieving a 50 percent reduction in the BASDAI did not differ significantly between the groups, although there was a statistically significant greater improvement in the BASDAI score in the patients receiving prednisolone 50 mg but not 20 mg, compared with placebo. Similarly, pain scores in the patients receiving prednisolone 50 mg daily differed significantly from the controls, but not in the patients receiving 20 mg daily. Additional trials would be required to establish whether glucocorticoid therapy has a role in the treatment of AS, especially given the high dose of glucocorticoids required to achieve a significant effect, the small number of patients studied, and the short duration of therapy. In addition, patients with AS generally already have significant loss of bone density, which can be exacerbated by glucocorticoid therapy.

Intraarticular injections, although never evaluated in a well-designed clinical trial to our knowledge, and local injections into painful plantar fasciae can be helpful for peripheral arthritis and plantar fasciitis, respectively. Local injections into the area of Achilles tendon are not recommended as rupture of the tendon may follow glucocorticoid infiltration at this site. Injection of long-acting glucocorticoids into the sacroiliac joints may be beneficial in patients who complain of marked pain at the sacroiliac joints that is unresponsive to systemic medications. Benefit of injection of long-acting glucocorticoid has been found in some but not all studies [119,120]. A double-blind study reported more than 70 percent relief in over 80 percent of injected sacroiliac joints [120]. Relief persisted for as long as six months or more after the injection and no complications were seen.

Other therapies possibly beneficial
Several agents have shown evidence of potential benefit for AS but require further study. These include:

Biologics blocking the IL23-IL17 axis – The IL-23/IL17 axis is being studied as a major axis in the pathogenesis of SpA [121]. The results of two small proof-of-concept investigations suggest that blocking these mediators may be of benefit:

•Secukinumab – Secukinumab is an anti-interleukin (IL)-17A monoclonal antibody that has shown benefit in a randomized proof-of-concept trial in which 24 patients with moderate to severe AS (mean disease duration of 10 years) were assigned to receive secukinumab (10 mg/kg administered intravenously twice, three weeks apart) and 6 patients were assigned to receive placebo [122]. ASAS20 response rates at week six were significantly greater in patients allocated to receive secukinumab (59 versus 24 percent). Much larger trials of a substantially greater duration are required to assess the potential benefit of this approach. Secukinumab and other IL-17 inhibitors are of particular interest in AS because of the potential importance of IL-17 in the pathogenesis of the disease and possible benefit of IL-17 inhibition in patients with psoriatic arthritis.

•Ustekinumab - The other biologic against tested in AS that is directed against the IL23/IL17 axis is ustekinumab. It is an antibody directed against the p40 protein subunit shared by IL12 and IL23. In a 24-week open-label study the drug was administered to 20 patients with active AS, with substantial improvement in disease activity measures at 24 weeks; an ASAS40 was achieved in 65 percent of the patients, and greater than 50 percent improvement in the BASDAI was reported in 55 percent of the patients. Randomized trials are needed [123].

•Pamidronate – Pamidronate, a bisphosphonate, has been evaluated in the treatment of AS, because of some evidence of antiinflammatory activity and its effect on bone turnover [124-127]. Dose-dependent benefit of pamidronate treatment was demonstrated in a trial involving 84 patients with AS with a suboptimal response to NSAID therapy who were randomly assigned to one of two doses of pamidronate (60 mg/month or 10 mg/month), administered intravenously for six months [125]. Other observational studies have reported, at the most, only modest clinical benefit with pamidronate (60 mg/month), and several patients have experienced serious adverse effects with this regimen [126-128]. Additional data from randomized trials would be required before pamidronate could be considered for use in routine clinical practice for the treatment of AS.
•Thalidomide – The potential benefit of thalidomide has been examined in AS because of its immunomodulatory properties, including its effects on TNF [129-131]. A 2002 review of observational studies reported that among more than 50 patients treated with thalidomide, 68 percent improved and 19 percent withdrew from treatment due to lack of efficacy or adverse effects [131]. Randomized trials are needed to better define the role of thalidomide in the treatment of AS, and the seriousness of the potential side effects will need to be considered in determining whether it has a role in therapy.
•Rituximab – Rituximab, a monoclonal antibody that depletes B cells, has undergone preliminary study in 20 patients with active AS, based in part upon previous findings of dense B cell infiltration in subchondral bone of inflamed sacroiliac joints of patients with AS [132]. Significant efficacy at week 24 following initial intravenous administration of rituximab was observed in patients who were naive to TNF inhibitor therapy, but not in those who had already failed to respond to a TNF inhibitor (ASAS20 response 50 versus 30 percent, BASDAI50 response 50 versus 0 percent). Further study, including randomized trials, will be required to determine whether there is a role for rituximab in the treatment of AS.
•Apremilast – Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor with antiinflammatory and immunomodulatory effects, has shown some evidence of benefit in a randomized trial involving 38 patients with symptomatic AS and active disease on MRI [133]. There were trends suggesting greater improvement with apremilast, compared with placebo, in several clinical measures at 12 weeks, but these differences did not achieve statistical significance. The improved measures returned to their baseline values by four weeks following discontinuation of the trial medications. Larger trials of greater duration would be required to determine if this medication will be of benefit to patients with AS.

Other biologic agents probably not beneficial – Inhibitors of interleukin IL-12/23 and other agents have been the subject of investigation, but there is presently a lack of sufficient evidence for the use in AS of any biologics other than the TNF antagonists [1,134,135]. Several agents that have been shown to be effective in patients with rheumatoid arthritis or other forms of inflammatory arthritis have not been found effective in patients with ankylosing spondylitis. These include:

•Abatacept – Abatacept, a biologic agent which blocks T-cell costimulation, has not been found to be useful in AS in a 24-week open-label study involving 30 patients [136].

•Tocilizumab – Tocilizumab, a monoclonal antibody directed against IL-6 receptors, showed no benefit in composite clinical outcomes compared with placebo in a 12-week randomized trial involving 102 patients with AS, despite a decrease in C-reactive protein in the patients receiving tocilizumab [137].

SURGERY

Hip and spine surgery may be beneficial in selected patients with ankylosing spondylitis (AS). Clinicians and anesthetists should be cautioned that such patients may have reduced chest expansion and more rigid cervical spines.

Total hip arthroplasty

Total hip arthroplasty (THA, total hip replacement) is indicated in AS whenever there is severe, persistent pain or severe limitation in mobility and quality of life due to hip involvement. THA is more common in patients with early onset of disease, axial, and entheseal involvement [138]. Although there has been concern that patients with AS undergoing THA at a young, active age will experience a higher incidence of replacement failure compared with older, less active patients, excellent long-term results were found in a group of 340 patients with AS who had undergone initial THA at a mean age of 40 years [139]. The proportions of such hips that did not require revision at 10, 15, and 20 years following operation were 90, 78, and 64 percent, respectively. In another analysis of 181 hips, the survival of the prosthetic joint was 71 percent at 27 years [140]. Currently, the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations are that age not be a factor in decisions regarding THA.

Patients with AS may be at higher risk of developing heterotopic ossification following joint replacement, but this remains an unusual complication [141]. If, however, this complication has occurred following a prior joint arthroplasty, prophylactic therapy has been recommended, such as a nonsteroidal antiinflammatory drug (NSAID) beginning on the day of surgery or radiation therapy (pre- or postoperative).

Spinal surgery

Cervical fusion is indicated for the very small number of patients who develop atlantoaxial subluxation with impairment in neurologic function. This problem is managed in a fashion similar to that in rheumatoid arthritis. Wedge osteotomy is indicated in those patients who develop flexion deformities severe enough to impair the ability to look in a forward direction. Spinal surgeons should be consulted in the event of acute vertebral fractures, which should be suspected in patients who develop unusual neck or back pain, even in the absence of trauma.

PROGNOSIS

Most ankylosing spondylitis (AS) patients with mild disease that is restricted to a small area of involvement are able to maintain almost full functional and employment capacity. However, a minority of patients develop severe skeletal restrictions or life-threatening extra-musculoskeletal complications. A questionnaire survey found that employment is affected in approximately 30 percent of the males with AS. However, the majority of patients can work well into their fifties [142].

Disease activity usually fluctuates in the individual patient, with symptoms usually persisting over decades. Approximately 1 percent of patients develop a stage of "burn-out" of disease activity and enter long-term remission [143].

Prognostic indicators

A number of prognostic indicators were identified before the use of biologics in patients with AS. One study, for example, evaluated 328 patients with spondyloarthritis; seven variables at entry correlated with increased disease severity [144]:

Hip arthritis – odds ratio (OR) 23
Sausage-like finger or toe – OR 8
Poor efficacy of NSAIDs – OR 8
High erythrocyte sedimentation rate (>30 mm/h) – OR 7
Limitation in range of motion of the lumbar spine – OR 7
Oligoarthritis – OR 4
Onset less than 16 years of age – OR 3

A mild outcome was likely if none of these factors was present at entry (sensitivity 93 percent, specificity 78 percent). However, a severe outcome was predictable if the hip were involved or if three factors were present (sensitivity 50 percent), and mild disease could be virtually excluded (specificity 98 percent). Patients with these features should therefore be followed at more frequent intervals.

A number of other factors have been associated with a poor outcome in patients with AS [19,145,146]. These include cigarette smoking, increasing severity of radiographic changes, active disease as assessed by a disease activity index, functional impairment as assessed by a self report, lower educational attainment, presence of other diseases related to spondyloarthritis (eg, psoriasis, inflammatory bowel disease), male sex, a history of uveitis, and occupational activities involving either dynamic flexibility (ability to quickly and repeatedly bend, twist, and stretch) or exposure to whole-body vibration (such as driving a truck or operating heavy equipment). Other predictors of poor outcome are HLA-B27, age, the presence of enthesitis, poor functional ability, and elevated C-reactive protein (CRP) [147].

Elevated CRP levels are associated with increased risk of radiographic progression both in the sacroiliac joints and in the spine [148,149]. Other factors associated with an increased degree of radiographic progression include the baseline severity of radiographic change and cigarette smoking [53,150].

Tumor necrosis factor inhibitors might be more effective in controlling inflammation when used early in the disease course, prior to the development of changes on plain radiographs [63]. Some evidence also suggests that such therapy may prevent or reduce radiographic progression.

Spinal cord injury
Patients with AS suffer an increased rate of spinal fractures. In those with AS, a majority of spinal cord injuries resulted from slips and falls, an event that was rarely the cause of cord damage in those without AS (53 versus 7 percent, respectively).

Cardiovascular risk and mortality
It is uncertain whether patients with AS have significantly higher cardiovascular risk compared with the general population. One longitudinal, population-based study found a significant increase in the risk of ischemic heart disease among young patients (ages 18 to 45) with newly diagnosed AS, compared with controls without AS, during three years of follow-up.[152].

Mortality among patients with AS admitted to the hospital for medical care is about 1.5 times higher than that of the general population [153]. Overall, mortality may be modestly increased. This was illustrated in a review of eight studies on mortality in AS that concluded that there was an increase in mortality rates compared with the general population (standardized mortality ratios ranging from 1.32 to 2.62) [154]. The major causes of death in patients with AS were infections, cancer, and diseases of the respiratory and cardiovascular systems [155]. In contrast to some other chronic rheumatic diseases (eg, rheumatoid arthritis and Sjögren's syndrome) the risk of developing lymphoma does not appear to be significantly increased in patients with AS [156].

SUMMARY AND RECOMMENDATIONS

Treatment of patients with ankylosing spondylitis (AS) must be individualized. The level of disease activity, presence of poor prognostic factors or concomitant illnesses, degree of functional impairment, patient's tolerance of the risk of adverse effects, expectations of treatment, and other psychosocial factors must be considered. The level of disease activity and the extent of improvement can be scored by using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questionnaire and/or the Ankylosing Spondylitis Disease Activity Score (ASDAS).
We recommend use of a nonsteroidal antiinflammatory drug (NSAID) as initial therapy (Grade 1A). Any NSAID may be effective. Regular use for a period of four weeks allows the maximal effect of a given NSAID to be assessed. If some but not satisfactory improvement is noted, the NSAID may be continued indefinitely while other interventions are initiated.
The NSAID can be supplemented by use of an analgesic; occasionally, low-potency opioids may be used.
We recommend an exercise program for all patients (Grade 1B). Individual physical therapy may be needed by some.
We suggest NOT using systemic glucocorticoids (Grade 2C). We suggest intraarticular glucocorticoids for persistent peripheral joint involvement, enthesitis at sites other than the Achilles tendon, and for pain of sacroiliitis (Grade 2B).
Traditional nonbiologic disease-modifying antirheumatic drugs (DMARDs) (eg, sulfasalazine, methotrexate, leflunomide, or penicillamine) are ineffective for those with axial disease.
For patients with axial disease who do not respond to NSAIDs we recommend an anti-tumor necrosis factor (TNF) agent (Grade 1A). If there is failure to one anti-TNF agent, it is possible that an alternate anti-TNF agent can be effective. Prior to initiating anti-TNF therapy, active infection and latent tuberculosis should be excluded.
In patients with predominantly peripheral arthritis who do not respond adequately to NSAIDs and for whom a TNF inhibitor is unavailable or is contraindicated, we recommend sulfasalazine, unless there are contraindications (eg, allergy to sulfonamide antibiotics) to this drug (Grade 1A). Methotrexate is being used by some clinicians as an alternative.
There is a paucity of data to guide therapy if the treatments recommended above are ineffective or contraindicated.
Surgical interventions are used selectively. Total joint replacement may be necessary for those whose joints are already destroyed. Wedge osteotomy of the spine is reserved for those patients with severe spinal deformities, as in patients with neck flexion so pronounced that useful forward vision is difficult or impossible. Fusion of the atlantoaxial joint of the cervical spine is needed if there is significant neck or occipital pain or evidence of neurologic dysfunction due to C1-C2 (atlantoaxial) subluxation, as occurs in patients with rheumatoid arthritis.

Author: David T Yu, MD

Section Editor: Joachim Sieper, MD

Deputy Editor: Paul L Romain, MD

Source: UptoDate
All topics are updated as new evidence becomes available and the peer review process for UptoDate is complete. Literature review current through: Apr 2014. | This topic last updated: Feb 10, 2014.

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June 03, 2014

Assessment and treatment of ankylosing spondylitis in adults