Assessment and treatment of ankylosing spondylitis in adults INTRODUCTION Ankylosing spondylitis (AS) is a chronic inflammatory disease manif ested

by back pain and progressive spinal stiffness. It belongs to the axial gro up of the spondyloarthritis family of arthritis (SpA). AS characteristically aff ects young adults with a peak age of onset between 20 and 30 years. Although cla ssically 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 i n adults are presented here. The clinical manifestations and diagnosis of ankylo sing spondylitis in adults, and a detailed discussion of the clinical manifestat ions, approach to diagnosis, pathogenesis, and treatment of SpA in children are presented separately. (See "Clinical manifestations of ankylosing spondylitis in adults" and "Diagnosis and differential diagnosis of ankylosing spondylitis in adults" and "Pathogenesis of spondyloarthritis" and "Spondyloarthropathy in chil dren".) GOALS OF MANAGEMENT The primary goal of management for patients with AS is to ma ximize long term health-related quality of life through the following: Symptomatic relief To eliminate, or reduce to the minimum level possible, sympto ms such as pain, stiffness, and fatigue. Restoration of function To return the patient to the best possible functional ca pacity. Prevention of complications of spinal disease To prevent flexion contractures es pecially of the cervical spine. Minimizing extraspinal and extraarticular manifestations To reduce the impact of AS-associated disorders such as uveitis and aortic valve insufficiency. Our approach to achieving these goals is outlined in the following discussion. O ur recommendations are generally consistent with those jointly developed by the Assessments in Ankylosing Spondylitis International Society (ASAS) and the Europ ean League against Rheumatism (EULAR) [1,2]. ASSESSMENT AND MONITORING Treatment decisions depend upon an accurate assessment of disease impact (table 1). In general, four approaches are required: Information is elicited in the medical history to assess the degree of disease a ctivity, functional disability, and health-related quality of life. Physical examination is used to detect inflammation, contractures and limitation s 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 activit y. Patient history The medical history is used to assess disease activity, function al disability and health-related status. The following parameters are recommende d: The patient global assessment on a scale of 0-10 or (1-10). The physician global assessment on a scale of 1 (mild) to 4 (severe). The BASDAI disease activity questionnaire (table 2) It is available in several l anguages at the websites of the Spondylitis Association of America (www.spondyli tis.org) and Assessment of SpondyloArthritis International Society (www.asas-gro up.org). It consists of six questions concerning overall symptoms during the wee k immediately prior to answering the questions, including: 1. How would you describe the overall level of fatigue/tiredness you have experi enced? 2. How would you describe the overall level of AS neck, back or hip pain you hav e had? 3. How would you describe the overall level of pain/swelling in joints other tha n neck, back, hips you have had? 4. How would you describe the level of discomfort you have had from an area tend er to touch or pressure? 5. How would you describe the level of morning stiffness you have had from the t

ime you wake up? 6. How long does your morning stiffness last from the time you wake up? Each question is scored on a scale of 0-10. Except for the last question, 0 indi cates none and 10 indicate very severe. For the last question, 0 is 0 hours, 5 i s one hour and 10 is two or more hours. To calculate the BASDAI score, the sum of the scores for questions one through f our is added to the mean of the sum of the scores for questions five and six; th e total is divided by five to calculate the disease activity score. A BASDAI sco re of at least 4.0 (out of a maximum of 10) indicates severe disease activity. Functional disability and health related status In clinical practice, the partic ular daily activities and quality of life parameters to be assessed depend upon the judgment of each attending physician. In clinical research on 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 (http://www.asas-group.org/). Physical examination In addition to the general physical examination, the physic al examination in AS focuses on three areas: axial joints, including the hips; p eripheral joints; and entheses. Details of the assessment used in research are a vailable (http://www.asas-group.org/ and [3-5]).The parameters below are those u sed in clinical practice. 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 erec t with heels and buttocks against a wall and to extend his or her neck, while ke eping the chin (mandible) horizontal in an attempt to touch the wall. A normal i ndividual can touch the wall with the occiput. The distance between the occiput and the wall in a patient with AS reflects the degree of cervical deformity (pic ture 1). In addition, the range of flexion, extension, lateral flexion and rotat ion are also recorded. Thoracic spine The range of motion of the costovertebral joints is measured by t he degree of chest expansion. Chest expansion is measured at the level of the fo urth intercostal space or just below the breasts in females. The patient is inst ructed to exert a maximal forced expiration followed by a maximal inspiration. N ormal expansion is usually >2.5 cm. Lower spine Range of motion of the lower spine is tested in the sagittal plane b y the Schober test, and in the coronal plane by the extent of lateral spinal fle xion. Schober test The Schober test measures the forward flexion of the lumbar spine ( picture 2). 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 wi thout bending the knees and the distance is measured again. In normal individual s, the difference between the two measurements should exceed 4 cm. Lateral spinal flexion With the patient standing erect with heel and back agains t a wall and knees and hands extended, the distance between the tip of the middl e finger and the floor is measured. The patient is then instructed to bend sidew ays 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 average d 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 g ait. It is verified by testing whether there is limitation of flexion, internal and external rotation, or pain at the extremes of these joint motions. Destructi ve disease at the hip joints in AS can lead to flexion deformities. However, a u nilateral flexion deformity is frequently masked by compensatory motion in the s pine. To eliminate this problem during physical examination, the patient is aske d to lie supine and maximally flex one hip. If there is a flexion deformity of t he 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 th igh (picture 3A-B).

Peripheral joint count This involves a 44 joint count of the number of tender an d/or swollen joints, including those of the ankles, feet and the sternoclavicula r joints (page II40 in handbook in http://www.asas-group.org/) [6]. Sausage digit (dactylitis) The number of digits that have sausage appearance sho uld be determined. Enthesitis count At least 18 entheseal sites are assessed during clinical trials (http://www.asas-group.org/). In practice, the minimum should be at the heel, a t the sites where the Achilles tendon and the plantar fascia are each attached t o the calcaneus. Assessment by imaging In research, radiographic damage of the spine is assessed using lateral views of the cervical and lumbar spine, graded vertebra by vertebr a, and scored, for example, using the Modified Stokes Ankylosing Spondylitis Spi ne Score (mSASSS) [7]. In clinical practice, it is useful to examine the anteros uperior and anteroinferior margins of the lumbar vertebrae on a lateral spine ra diograph, and to record those with syndesmophytes. In advanced disease, plain ra diographs of the spine will reveal "bamboo spine" with virtually complete fusion of the vertebral column. At that stage there is usually fusion of the sacroilia c joints (picture 4A-B). 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. Assessment by acute phase reactants 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. Extra-articular involvement The methods of monitoring extra-articular involvemen t such as uveitis are based on standards used for the organs being involved. AS is associated with a higher risk for osteoporosis and for cardiovascular disease . Recommendations for office practice The following are a suggested set of indicat ors for minimum evaluation in initial visits and for monitoring disease progress ion: Patient self assessment of pain (1-10) Bath Ankylosing Spondylitis Disease Activity index (BASDAI) 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 disea se and the therapies being used. PROGNOSIS Most AS patients with mild disease that is restricted to a small area of involvement are able to maintain almost full functional and employment capaci ty. However, a minority of patients develop severe skeletal restrictions or life -threatening extra-musculoskeletal complications. A questionnaire survey found t hat employment is affected in approximately 30 percent of the males with AS. How ever, the majority of patients can work well into their fifties [8]. Disease activity usually fluctuates in the individual patient, with symptoms usu ally persisting over decades. Approximately 1 percent of patients develops a sta ge of "burn-out" of disease activity and enters long-term remission [9]. Prognostic indicators A number of prognostic indicators were identified before t he use of biologics in patients with AS. One study, for example, evaluated 328 p atients with spondyloarthropathy; seven variables at entry correlated with incre ased disease severity [10]: 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 (sensiti vity 93 percent, specificity 78 percent). However, a severe outcome was predicta ble if the hip were involved or if three factors were present (sensitivity 50 pe

rcent), and mild disease could be virtually excluded (specificity 98 percent). P atients with these features should therefore be followed at more frequent interv als. A number of other factors have been associated with a poor outcome in patients w ith AS [11-13]. These include cigarette smoking, increasing severity of radiogra phic 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 bow el disease), male sex, a history of uveitis, and occupational activities involvi ng either dynamic flexibility (ability to quickly and repeatedly bend, twist, an d stretch) or exposure to whole body vibration (such as driving a truck or opera ting heavy equipment). It is possible that the prognosis of AS has improved with the use of TNF blocker s, especially in those treated very early in disease [14]. Spinal cord injury Patients with AS suffer an increased rate of spinal fractures . In Finland, the incidence of spinal cord injury among those with AS has been e stimated to be increased more than 10-fold, compared with the general population [15]. 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). Mortality Among patients with AS admitted to the hospital for medical care, mort ality is about 1.5 times higher than that of the general population [16]. Overal l, mortality may be modestly increased. This was illustrated in a review of eigh t studies on mortality in AS that concluded that there was an increase in standa rdized mortality rates (SMR) [17]. Patients with AS had SMR ranging from 1.32 to 2.62 [17]. Those patients who died were older, and had a higher ESR and more in flamed peripheral joints when first seen than did surviving patients. Secondary amyloidosis and cardiovascular complications were the major causes of death attr ibutable to AS. There was also an increased frequency of deaths due to accidents and suicide [17]. In contrast to some other chronic rheumatic diseases (eg, rheumatoid arthritis a nd Sjgren's syndrome) the risk of developing lymphoma does not appear to be signi ficantly increased in patients with AS [18]. NONPHARMACOLOGICAL TREATMENT Patient education, exercise, and medications are al l important in the management of ankylosing spondylitis. Patient education and support, in addition to that provided by the patient s physi cian, is frequently available from support groups such as the Spondylitis Association of America 14827 Ventura Blvd. # 222 Sherman Oaks, CA 91403 Phone: 1-800-777-8189 or 1-818-981-1616 E-mail: info@spondylitis.org or web site www.spondylitis.org/ Smoking cessation is recommended for everyone who smokes. It is a modifiable ris k factor for poor functional outcome in AS [11]. (See "Patterns of tobacco use a nd benefits of smoking cessation" and "Management of smoking cessation in adults ".) Home exercises are effective, but supervised exercise programs or formal physica l therapy can be of greater benefit [19]. Optimally, an initial evaluation and t raining by a physical therapist should be part of the therapeutic regimen. Exerc ises include postural training, range of motion stretching, recreational activit ies, and perhaps hydrotherapy. In addition, pain relief measures such as local h eat or cold can be given a trial. At a minimum, patients with AS should particip ate in an unsupervised home exercise program [20]. Inpatient rehabilitation is r arely needed [21]. An animated demonstration of exercises tailored for ankylosing spondylitis is av ailable on the following website: http://www.nass.co.uk/exercise/. Guide books, audio and video aids on compact disc and digital video disc are ava ilable from the Spondylitis Association of America. PHARMACOLOGIC THERAPY Pharmacotherapy includes one or more of the following: non steroidal antiinflammatory drugs (NSAIDs), analgesics, sulfasalazine, and anti-T

NF agents. Systemic corticosteroids have a limited role, but intraarticular inje ctions may be helpful to some patients. Nonsteroidal antiinflammatory drugs From 70 to 80 percent of AS patients report substantial relief of their symptoms with NSAIDs [22]. This is significantly mor e than the 15 percent observed in mechanical low back pain. Unless contraindicat ed, NSAIDs should be the first line of treatment for all symptomatic AS patients . In many patients, NSAIDs are the only medications required. There are two issu es related to NSAID therapy in AS: The choice of NSAID, including the possible role of selective COX-2 inhibitors I nitial anecdotal evidence suggested that indomethacin is the most effective NSAI D [23]. However, multiple studies support the view that other NSAIDs are also ef fective [24]. 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 sustai ned dose on a regular basis for at least four weeks. (See "Nonselective NSAIDs: Overview of adverse effects".) Short-term studies indicate that selective COX-2 inhibitors, such as celecoxib a nd etoricoxib, are as effective as nonselective NSAIDs [25-28]. (See "Overview o f selective COX-2 inhibitors" and "COX-2 selective inhibitors: Adverse cardiovas cular effects" and "COX-2 inhibitors and gastroduodenal toxicity major clinical trials".) Continuous versus on-demand therapy One study has suggested that continuous dail y use of NSAIDs may suppress radiographic progression. This study was a randomiz ed trial in which 215 patients were assigned to either continuous or on-demand N SAID therapy [29]. At two years, the degree of radiographic progression was sign ificantly reduced (by 73 percent) in the patients who were treated continuously with NSAIDs. However, recommending continuous NSAIDs for all AS patients based u pon the results of this single trial may be premature, and these findings requir e further confirmation [30,31]. We agree with the 2010 ASAS/EULAR recommendation that patients who have persistent, active, symptomatic disease should use conti nuous NSAIDs. Analgesics Analgesics and opioids, when used alone, 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 approved in th e United States and Europe for use in AS are infliximab, etanercept, adalimumab, and golimumab. Concomitant use of an immunomodulatory drug, such as methotrexat e is not required, as this provides no additional benefit but may increase the c ost and the risk of adverse effects [32]. Overall efficacy A 2007 meta-analysis indicated that all three of the anti-TNF a lpha agents then available (adalimumab, etanercept, and infliximab) were similar in efficacy in patients with AS [33]. These medications have not been compared directly with each other, but indirect comparisons were unable to distinguish si gnificant 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 a chieve 50 percent improvement (using a composite measure, the ASAS50). Approxima tely 80 percent of patients with AS respond to treatment with one of these agent s and approximately one half get at least 50 percent improvement in a composite index, such as that adopted by the Ankylosing Spondylitis Assessment Group that includes [34]: Patient global assessment Patient assessment of pain A functional assessment, such as ability to carry out certain activities with wh ich the patient had difficulty prior to treatment Degree of inflammation as assessed by morning stiffness The responses are typically rapid. Eighty percent of patients who experienced a >50 percent response 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 [35-37]. Patients who do not respond to or do not tolerate one

anti-TNF agent may respond to an alternate anti-TNF agent [38]. Use of anti-TNF therapy may also decrease the frequency of recurrences of uveiti s in patients with AS [39]. Despite their efficacy, the indiscriminate use of anti-TNF-alpha drugs is discou raged because of cost concerns and a lack of long-term safety data [40]. A guide line for selecting patients for whom anti-TNF therapy is indicated, dosing (amou nt and frequency), and monitoring for efficacy and adverse effects has been deve loped and updated by an international panel of physicians with expertise in the treatment of AS [41-43]. A summary of guidelines is presented separately. (See " General guidelines for cost-conscious use of anti-tumor necrosis factor alpha ag ents in ankylosing spondylitis and axial spondyloarthritis".) Use of TNF antagonists in early and advanced axial spondyloarthritis Most studie s of anti-tumor necrosis factor (TNF) therapy have recruited patients whose stat es 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 [44], and patients with advanced disease have a lso benefited from anti-TNF therapy [45]. Predictors of response The following parameters are possible predictors of a goo d response to TNF antagonists [46,47]: 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 p atients [14]. Switching to a second TNF antagonist A large open label study addressed the effe ctiveness of switching to adalimumab when patients failed etanercept or inflixim ab because of either an inadequate response or adverse effect. Such patients wer e compared with those begun on adalimumab who had never received etanercept or i nfliximab. After 12 weeks, a BASDAI50 response was observed in 63 percent of pat ients who had never received TNF antagonists, and 40.8 percent of patients who h ad been treated with prior TNF antagonists [48]. In general, switching to anothe r TNF antagonist is more useful for patients who have loss of response to the fi rst one. Stopping TNF antagonists when patients have obtained a major clinical response T he majority of patients will relapse soon after discontinuing the TNF antagonist s [14]. It is possible that the dose or interval of treatment can be modified, b ut this has not been systematically studied. Improvement in bone density Some data suggest that use of anti-TNF biologic agen ts may be associated with improved bone density. Three studies utilizing anti-TN F biologic agents in the treatment of 75 patients with various forms of spondylo arthritis were reviewed [49]; when the changes in bone density from baseline to the end of observation were compared, patients receiving anti-TNF agents had inc reases 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 The side effects of these agents when used to treat rheumat ic disease are discussed separately. Potential adverse effects such as an increa sed risk of reactivation of latent tuberculosis and the exacerbation or developm ent of demyelinating disease must be considered when using these agents. (See "O verview of biologic agents in the rheumatic diseases", section on 'TNF inhibitio n' and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".) Infliximab, when used in patients with AS, has been temporally associated with t he development of palmoplantar pustulosis [50]. (See "Neutrophilic dermatoses", section on 'Palmoplantar pustulosis'.) Three cases of retropharyngeal abscess we re 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 [50-55]. Infliximab use also resulted in improvement in the synov ial histopathology [56]. Decreases in vascularity, thickness of the lining layer , and the degree of infiltration of synovium by neutrophils, and T cells were se

en, and have been confirmed in a subsequent study in two additional cohorts [57] . The largest study of this anti-TNF agent randomly assigned 357 North American an d European patients to receive infliximab (5 mg/kg at week 0, 2, 6, 12, and 16) or placebo (The ASSERT trial) [58]. Patients with complete spinal ankylosis were excluded from this study, as were those with a recent infection, active or late nt tuberculosis, or immunosuppression due to HIV/AIDS or solid organ transplanta tion. Patients with other diseases that could be exacerbated by infliximab, incl uding demyelinating disorders and heart failure, were also excluded. Methotrexat e and other 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 [59,60], which is higher than the usual dose of 3 mg/kg for patients with rheumatoid arth ritis. The 5 mg/kg dose appears to remain effective when used for periods of at least three years [37,61,62]. Whether a lower dose would be equally effective is uncertain. When 21 patients were given the 3 mg/kg dose in one of the observati onal studies cited above [54], infliximab appeared to be effective; however, thr ee 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 con trolled with infusions every eight weeks may benefit from a reduced interval bet ween treatments (eg, six weeks) [63]. The time to maximal response may be as long as six weeks, some patients experien ce pain relief shortly after the first infusion. Our experience suggests that pa tients with longstanding disease are less likely to respond to infliximab therap y. Most initial studies with infliximab in AS were carried out with patients who ha d definite sacroiliitis by plain radiography. A recent placebo-controlled study was carried out in a group of patients in whom the majority did not have plain r adiographic sacroiliitis. These were inflammatory back pain patients with positi ve MRI changes of sacroiliitis and positive testing for HLA-B27. Infliximab was also effective in these patients [64]. In one case report, infliximab was effective in reversing symptoms of cauda equi na syndrome [65]. No other interventions have previously been of benefit, but th e utility of this approach in other patients has not yet been demonstrated. Methotrexate, although routinely used in combination with infliximab to treat rh eumatoid arthritis, has not been found to be necessary or provide additional ben eficial when infliximab is being used to treat AS [66]. The importance of coadmi nistration of MTX on efficacy has not been studied with other TNF-alpha antagoni sts in AS. Etanercept Several open studies and randomized trials have demonstrated the effi cacy of etanercept in AS [67-72]. Limited data suggest that the symptomatic bene fits of etanercept are quickly lost after cessation of therapy [73,74]. As with infliximab, etanercept use also resulted in improvement in synovial pathology in the peripheral joints [75]. The largest trial confirmed the efficacy of etanercept; it was a well designed, international trial that randomly assigned 277 patients to receive etanercept (2 5 mg sc twice weekly) or placebo [70]. After 12 weeks of treatment, the proporti on of patients achieving improvements of 20 percent, 50 percent or 70 percent we re about 60 percent, 45 percent 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 exa minations of the spine, there was a mean 54 percent decrease in T2-weighted sign al in those treated with etanercept, suggesting decreased spinal inflammation, w hile the placebo group had a slight worsening (increase of 13 percent) [76]. Sig nificant improvement was also noted in spinal and chest wall mobility. Hence, th ese are also useful follow up parameters for patients receiving anti-TNF therapi es. 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 [77]. Further support for the efficacy of etanercept in AS was provided by a multicent

er 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 [71]. 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 d osing with 50 mg appears to result in similar efficacy to 25 mg twice weekly [78 ,79]. Adalimumab Adalimumab, a humanized anti-TNF monoclonal antibody, is also far mor e efficacious than placebo [44,80,81]. This was illustrated in a study that rand omly assigned 315 patients in a 2:1 ratio to adalimumab (40 mg every other week by subcutaneous injection) or placebo injections [80]. The study population was predominantly Caucasian, male, and HLA-B27 positive with a mean duration of dise ase of 10 years. A significantly greater proportion of adalimumab-treated patien ts achieved the primary efficacy endpoint, an ASAS20 response at the end of 12 w eeks (58 versus 21 percent). Patients who did not achieve an ASAS20 after 12 wee ks 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 [36]. Of 61 patients treated weekly, ASAS20 responses were achieved af ter 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 o pen-label extension of the trial [36]. 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 [36]. 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 ye ars of follow-up in the open-label phase of the study. At two years, the frequency of patients with serious adverse events that were po ssibly drug-related was 5.5 percent. No cases of tuberculosis, heart failure, lu pus-like symptoms, or demyelinating disease were reported. Golimumab Golimumab is a human anti-TNF alpha monoclonal antibody that is admini stered by subcutaneous injections once every four weeks. Efficacy for patients w ith 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, 100 mg or place bo injections every four weeks [82]. After 14 weeks ASAS20 responses occurred in 59, 60, and 22 percent of patients in the three groups, respectively. These res ponses appear to be comparable to those of other TNF antagonists. The recommende d dose is 50 mg subcutaneously every four weeks. The precautions and possible si de effects are the same as those for the other FDA-approved TNF antagonists. Can TNF antagonists halt progression of AS? Although use of these biologic agent s has drastically improved the well being of many patients, many unanswered ques tions remain, including why some patients do not respond to these interventions. The other major question is whether they can halt the radiographic progression of the disease. So far, in comparison to cohorts followed longitudinally prior t o the introduction of TNF antagonists, there is no convincing evidence that TNF antagonists can halt the radiological progression of AS [83]. From results with animal models, inflammation and bone remodeling are probably two independent pro cesses, and only inflammation may be controlled by anti-TNF agents. (See "Pathog enesis of spondyloarthritis".) Disease modifying agents (DMARDs) The only DMARD regarded as potentially useful in AS is sulfasalazine. Sulfasalazine The use of sulfasalazine has steadily declined since the introduct ion of the TNF antagonists, which are more effective for both axial and peripher al disease [84,85]. A 2006 meta-analysis that included data from 11 randomized c linical trials concluded that sulfasalazine was significantly more effective tha n placebo in reducing spinal stiffness and lowering the ESR [86]. However, most of the clinical trials of sulfasalazine have been relatively small. Two of the l arger trials involved 89 and 264 patients with AS, respectively [87,88]. In both

of these trials sulfasalazine was more effective for the treatment of periphera l arthritis than for axial disease. Most experts in the care of patients with sp ondyloarthropathy recommend sulfasalazine only for AS patients with peripheral a rthritis. A typical dose of sulfasalazine used in clinical trials was one 500 mg tablet da ily 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 dos e was not tolerated. Approximately 60 percent of the sulfasalazine-treated patie nts reported side effects, all reversible on withdrawal of the drug. The most co mmon side effects were nausea, dizziness, headache, and rash. We typically use sulfasalazine in patients with peripheral arthritis for whom a drug other than an anti-TNF agent is desirable, and prefer it to methotrexate in this setting. We discontinue sulfasalazine if there is no improvement after a f our-month trial. 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. There is no guideline as to how patients on sulfasalazine should be monitored fo r side effects. Leukopenia and neutropenia can develop quite suddenly, with an i ncidence varying from 1 to 5 percent. We recommend that blood counts be monitore d at least every three months, and more frequently in the initial period. (See " Sulfasalazine in the treatment of rheumatoid arthritis".) Other DMARDs Some studies have suggested that methotrexate may be effective in s Methotrexate ome patients with AS [89,90]. However, a 2006 meta-analysis of the efficacy of m ethotrexate in AS found no evidence of benefit in this disease [91]. Additionall y, the combination of methotrexate and infliximab did not increase the efficacy or decrease the risk of adverse effects compared with infliximab alone [66,92,93 ]. Thus, there is currently a lack of evidence to support the use of methotrexat e in the treatment of AS. Leflunomide Limited data suggest that leflunomide is of little or no benefit for patients with AS [94,95]. Glucocorticoids The efficacy of systemic glucocorticoids in AS has not been asse ssed in clinical trials [96]. These patients already have significant loss of bo ne density, which can be exacerbated by steroid therapy. We suggest not using sy stemic glucocorticoids on a long-term basis for patients with AS. (See "Pathogen esis, clinical features, and evaluation of glucocorticoid-induced osteoporosis". ) 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 inj ections into the area of Achilles tendon are not recommended as rupture of the t endon may follow glucocorticoid infiltration at this site. Injection of long-acting glucocorticoids into the sacroiliac joints may be benef icial in patients who complain of marked pain at the sacroiliac joints that is u nresponsive to systemic medications. Benefit of injection of long-acting cortico steroid has been found in some but not all studies [97,98]. A double-blind study reported more than 70 percent relief in over 80 percent of injected sacroiliac joints [98]. Relief persisted for as long as six months or more after the inject ion and no complications were seen. Other therapies Pamidronate Pamidronate, a bisphosphonate, has been evaluated in the treatment o f AS, because of some evidence of antiinflammatory activity and its effect on bo ne turnover [99-102]. Dose-dependent benefit of pamidronate treatment was demons trated in a trial involving 84 patients with AS with a suboptimal response to NS AID therapy who were randomly assigned to one of two doses of pamidronate (60 mg /month or 10 mg/month), administered intravenously for six months [100]. There w as a significantly greater decrease in the BASDAI, a measure of disease activity , with high-dose therapy (35 versus 15 percent). Benefit developed slowly, with the maximum response at six months. Transient arthralgia was seen in both groups

. Other observational studies have reported modest clinical benefit with pamidro nate (60 mg/month), but several patients have experienced serious adverse effect s with this regimen [101-103]. Thalidomide The potential benefit of thalidomide has been examined in AS because of its immunomodulatory properties, including its effects on tumor necrosis fac tor (TNF) [104-106]. A 2002 review of observational studies reported that among more than 50 patients treated with thalidomide, 68 percent improved and 19 perce nt withdrew from treatment due to lack of efficacy or adverse effects [106]. As an example, thalidomide (300 mg/day for one month, followed by 200 mg/day therea fter) was beneficial in two patients with refractory AS, prior to the availabili ty of biologic anti-TNF therapies [104]. In the author's experience, the maximum response is relatively slow, being observed 6 to 12 months after initiation of therapy [105]. Randomized trials are needed to better define the role of thalido mide in the treatment of AS. Rituximab Rituximab, a monoclonal antibody that depletes B cells, has undergone preliminary study in 20 patients with active AS, based in part upon previous fin dings of dense B cell infiltration in subchondral bone of inflamed sacroiliac jo ints of patients with AS [107]. Significant efficacy at week 24 following initia l intravenous administration of rituximab was observed in patients who were naiv e to tumor necrosis factor (TNF) inhibitor therapy, but not in those who had alr eady failed to respond to a TNF inhibitor (ASAS20 response 50 versus 30 percent, BASDAI50 response 50 versus 0 percent). Further study, including randomized tri als, will be required to determine whether there is a role for rituximab in the treatment of AS. SURGERY Hip and spine surgery may be beneficial in selected patients with AS. Ph ysicians and anesthetists should be cautioned that such patients may have reduce d chest expansion and more rigid cervical spines. Total hip arthroplasty Total hip arthroplasty (THA, total hip replacement) is in dicated 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 patie nts with early onset of disease, axial, and entheseal involvement [108]. (See "T otal hip arthroplasty".) 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 w ith older, less active patients, excellent long term results were found in a gro up of 340 patients with AS who had undergone initial THA at a mean age of 40 yea rs [109]. 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 a nother analysis of 181 hips, the survival of the prosthetic joint was 71 percent at 27 years [110]. Currently, the ASAS/EULAR recommendations are that age not b e a factor in decisions regarding THA. Patients with AS may be at higher risk of developing heterotopic ossification fo llowing joint replacement, but this remains an unusual complication [111]. If, h owever, this complication has occurred following a prior joint arthroplasty, pro phylactic therapy has been recommended, such as a nonsteroidal antiinflammatory drug beginning on the day of surgery or radiation therapy (preoperative or posto perative). (See "Complications of total hip arthroplasty", section on 'Heterotop ic ossification'.) Spinal surgery Cervical fusion is indicated for the very small number of patient s who develop atlantoaxial subluxation with impairment in neurologic function. T his problem is managed in a fashion similar to that in rheumatoid arthritis. (Se e "Cervical subluxation in rheumatoid arthritis".) Wedge osteotomy is indicated in those patients who develop flexion deformities s evere enough to impair the ability to look in a forward direction. Spinal surgeons should be consulted in the event of acute vertebral fractures. SUMMARY AND RECOMMENDATIONS We concur with treatment guidelines formulated by an international working group of experts in the treatment of AS [1,2]. The gradin g of evidence in the summary and recommendations that follow is assigned by the authors and editors of this UpToDate topic review, and differs slightly from tha t in the ASAS/EULAR recommendations.

Treatment of patients with AS must be individualized. The level of disease activ ity, the presence of poor prognostic factors or concomitant illnesses, the degre e of functional impairment, the patient's tolerance of the risk of adverse effec ts and expectations of treatment must be considered. The level of disease activi ty can be scored by using the BASDAI questionnaire. (See 'Assessment and monitor ing' above.) We recommend use of an NSAID as initial therapy (Grade 1A). Any NSAID may be eff ective. Regular use for a period of four weeks allows the maximal effect of a gi ven NSAID to be assessed. If some, but not satisfactory improvement is noted, th e NSAID may be continued indefinitely while other interventions (see below) are initiated. (See 'Nonsteroidal antiinflammatory drugs' above.) The NSAID can be supplemented by use of an analgesic; occasionally, low potency opioids may be used. (See "NSAIDs (including aspirin): Primary prevention of gas troduodenal toxicity".) We recommend an exercise program for all patients (Grade 1B). Individual physica l therapy may be needed by some. (See 'Nonpharmacological treatment' above.) We suggest NOT using systemic glucocorticoids (Grade 2C). We suggest intraarticu lar glucocorticoids for persistent peripheral joint involvement, enthesitis at s ites other than the Achilles tendon, and for pain of sacroiliitis (Grade 2B). (S ee 'Glucocorticoids' above.) We recommend traditional DMARD therapy with sulfasalazine for patients with pred ominantly peripheral arthritis who do not respond adequately to NSAIDs, unless t here are contraindications (eg, allergy to sulfonamide antibiotics) to this drug (Grade 1A). (See 'Sulfasalazine' above.) Methotrexate is being used by some phy sicians as an alternative. (See 'Other DMARDs' above.) For patients with axial disease who do not respond to NSAIDs we recommend an ant i-TNF agent (Grade 1A). Traditional nonbiologic DMARDs (eg, sulfasalazine, metho trexate, leflunomide, or penicillamine) are ineffective for those with axial dis ease. (See 'Tumor necrosis factor alpha antagonists' above.) Prior to initiating anti-TNF therapy, active infection and latent tuberculosis s hould be excluded. (See "Diagnosis of tuberculosis in HIV-negative patients" and "Treatment of latent tuberculosis infection in HIV-negative adults".) If there is failure to one anti-TNF agent, it is possible that an alternate anti -TNF agent can be effective. There is a paucity of data to guide therapy if the treatments recommended above are ineffective or contraindicated. One can consider monthly infusion of pamidro nate (60 mg) or the use of oral thalidomide (200 mg/day). (See 'Other therapies' above.) Surgical interventions are used selectively. Total joint replacement may be nece ssary for those whose joints are already destroyed. Wedge osteotomy of the spine is reserved for those patients with severe spinal deformities, as in patients w ith neck flexion so pronounced that useful forward vision is difficult or imposs ible. 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 arthr itis. (See 'Surgery' above and "Cervical subluxation in rheumatoid arthritis".)