Ankylosing spondylitis

Updated 2011 Aug 05 08:01:00 AM: etanercept improves short-term symptoms of ankylosing spondylitis compared to sulfasalazine (Arthritis Rheum 2011 Jun) view updateShow more updates review of spondyloarthritis (Lancet 2011 Jun 18) view update ankylosing spondylitis not associated with significant increased risk of myocardial infarction (Arthritis Care Res (Hoboken) 2011 Apr) view update General Information (including ICD-9/-10 Codes) Description: rheumatic disease, seronegative spondyloarthropathy chronic, systemic inflammatory disorder of axial skeleton (sacroiliac joints and spine) Also called: AS Bechterew's disease Bechterew syndrome Marie-Strumpell disease spondyloarthritis ICD-9 codes: 720.0 ankylosing spondylitis ICD-10 codes: M45 ankylosing spondylitis optional subclassification codes to indicate site of involvement 0 multiple sites in spine 1 occipito-atlanto-axial region 2 cervical region 3 cervicothoracic region 4 thoracic region 5 thoracolumbar region 6 lumbar region 7 lumbosacral region 8 sacral and sacrococcygeal region 9 site unspecified Types: ankylosing spondylitis sometime called primary or uncomplicated ankylosing spondylitis secondary ankylosing spondylitis has been used to describe similar disease entity associated with reactive arthritis (Reiter syndrome), psoriasis (psoriatic arthritis), ulcerative colitis or Crohn's disease (enteropathic arthritis) Organs involved: inflammatory arthropathy with sacroiliitis, axial arthritis (fused vertebrae), 25%-35% peripheral oligoarticular arthritis (hips, shoulders)

virtually 100% have sacroiliitis or spondylitis, sacroiliitis symmetric, about 25% peripheral joint involvement, 25%-30% eye involvement (predominantly acute anterior uveitis), 1%-4% cardiac involvement, no skin or nail involvement sacroiliac (SI) joints affected earliest; other axial sites typically affected include discovertebral, apophyseal, costovertebral and costotransverse joints and paravertebral ligamentous structures seronegative spondyloarthropathies affect spine, peripheral joints and/or periarticular structures, and variably associated with extra-articular manifestations such as acute or chronic gastrointestinal or genitourinary inflammation (sometimes due to bacterial infection), anterior ocular inflammation, psoriasiform skin and nail lesions and uncommonly lesions of aortic root, cardiac conduction system and pulmonary apices Who is most affected: young men 3 times more common than women, onset < 30-40 years old juvenile-onset spondylitis (age < 16 years) rare but relatively more common in Native Americans, Mexican Mestizos and in many developing countries Incidence/Prevalence: #1 spondyloarthropathy uncommon, estimated 0.1%-0.2% prevalence in white North Americans, 1%-2% of 6% population with HLA-B27 10%-20% prevalence in adult first-degree relatives inheriting HLA-B27 in families of patients with ankylosing spondylitis Causes and Risk Factors Causes: probably autoimmune (possibly antigen persistence or molecular mimicry) Pathogenesis: pathologic lesions sacroiliitis pathologic hallmark and usually early manifestation early lesion consists of subchondral granulation tissue which ultimately erodes joint gradual replacement by fibrocartilage regeneration then ossification in spine initial lesion thought to be inflammatory granulation tissue at junction of annulus fibrosus of intervertebral disc and margin of vertebral bone outer annular fibers may be replaced by bone (calcification of annulus fibrosis), forming syndesmophyte inflammation and destruction of disc-bone border inflammatory arthritis of apophyseal joints with erosion progressing to bony ankylosis (bone fusion) peripheral joint arthritis synovial hyperplasia, lymphoid infiltration, pannus formation central cartilaginous erosions due to proliferation of subchondral granulation tissue common lack of features seen in rheumatoid arthritis such as synovial villi proliferation, fibrin deposits, ulceration enthesitis inflammation at sites of tendinous or ligamentous attachment to bone pathologic hallmark of spondyloarthropathies

especially common at sites localized around spine and pelvis, may undergo ossification elevated serum antibody levels, mainly IgA, to Klebsiella pneumoniae has been reported controversial finding for almost 20 years 6 amino acids of HLA-B27.1 are the same as Klebsiella pneumoniae nitrogenase Likely risk factors: HLA-B27 has strong association HLA-B27 is serologically defined allele of HLA-B locus, 11 allelic subtypes designated B*2701 through B*2711 90% Caucasian patients and 50% black patients with A.S. have HLA-B27 < 10% with HLA-B27 have A.S. but 200 times the risk nearly 100% have HLA-B27 if uveitis or aortitis twin concordance < 60% family history of inflammatory bowel disease (and/or ankylosing spondylitis) associated with increased risk of ankylosing spondylitis based on Icelandic genealogy database and population-wide data with 205 Icelanders with ankylosing spondylitis and 1,352 with inflammatory bowel disease Reference - Arthritis Rheum 2007 Aug;56(8):2633 single nucleotide polymorphisms in STAT3, TNFRSF1A, 2p15 and ERAP1 associated with ankylosing spondylitis in Han Chinese population based on a case-control study of 775 patients with ankylosing spondylitis and 1,587 controls in Han Chinese population Reference - Ann Rheum Dis 2011 Feb;70(2):289 Complications and Associated Conditions Complications: osteoporosis, spinal fracture, spondylodiscitis review of ocular manifestations of autoimmune disease can be found in Am Fam Physician 2002 Sep 15;66(6):991 Associated conditions: chronic enteritis, anterior uveitis (25%-30%, formes fruste as only symptom, 50% of idiopathic anterior uveitis), 1%-4% cardiac involvement (AV block, aortic regurgitation, mitral regurgitation), apical pulmonary fibrosis (rare), cauda equina syndrome (rare), enthesopathy, pseudoarthrosis, 5% aortitis, amyloidosis, chronic prostatitis (rare) ankylosing spondylitis associated with increased risk of neuropsychiatric disorders based on prospective cohort consisting of entire population of Sweden with follow-up between 1973 to 2004 neuropsychiatric disorders included affective, psychotic, neurotic and personality disorders, dementia and delirium standardized incidence ratios for neuropsychiatric disorders 1.69 for men and 1.95 for women comparing persons with vs. without ankylosing spondylitis Reference - Arch Gen Psychiatry 2008 May;65(5):501 History Chief concern (CC):

pain and/or stiffness in back, diffuse pain, occasionally sciatic pain or chest pain, 25-30% eye pain, increased lacrimation, photophobia, blurred vision, 25% peripheral joint involvement (usually hips and shoulders) History of present illness (HPI): gradual onset, chronic (but initially episodic) sacroiliac (SI) joints involved first, later rigidity and fixation of spine worse in morning or with inactivity study of 5 screening questions 1. morning back stiffness? 2. improvement in discomfort with exercise? 3. back pain begin before age 40? 4. did problem begin slowly? 5. pain persisted > 3 months? positive response to 4 questions was 95% sensitive and 85% specific for A.S. Reference - JAMA 1977 Jun 13;237(24):2613 in Cortlandt Forum 1996 Mar;9(3):97-9,75 back pain and/or stiffness about 75% patients with adult-onset A.S. usually insidious onset, dull in character, difficult to localize often felt deep in gluteal area or sacroiliac region pain may be increased with coughing, sneezing, sudden twisting pain may start unilateral or intermittent, but becomes bilateral and persistent within a few months lumbar area may be painful, stiff and tender backache and stiffness tend to worsen after prolonged inactivity, at night or early morning, may interfere with sleep; back stiffness tends to increase with moving, hot shower or exercise patients may have difficulty getting out of bed, rolling to avoid flexing or rotating spine other symptoms (some patients have little or no back pain) may include fleeting muscle aches, musculotendinous tender spots that worsen with cold and dampness, mild constitutional symptoms (anorexia, malaise, weight loss, mild fever) enthesitis can present with tenderness at costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, Achilles tendon insertion or site of plantar fascial attachment to calcaneus one-third involvement of hips and shoulders, especially in juvenile-onset A.S., usually bilateral Family history (FH): seronegative spondyloarthropathy often genetically linked; patients with fibromyalgia or chronic pain often have family history of alcoholism, depression, migraine or panic attacks; patients with systemic inflammatory disorders may have family history of identical or related disorder, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis or myasthenia gravis Social history (SH):

ask about functional impact including limitations in ability to work, meet family responsibilities or enjoy leisure time Review of systems (ROS): if considering rheumatic syndrome, ask about sicca symptoms, uveitis, pleurisy, chest pain, oral or genital ulcers, urethral or vaginal discharge, skin rash or photosensitivity, hair loss, diarrhea, dysphagia, Raynaud's phenomenon extraskeletal manifestations 25%-30% acute anterior uveitis at some time in course of disease almost always unilateral usually subsides within 2-3 months, recurrences common symptoms include pain, increased lacrimation, photophobia, blurred vision exam shows circumcorneal congestion, iris edematous and discolored, pupil small and may be irregular if posterior synechiae, copious exudate in anterior chamber on slit-lamp exam rarely residual visual impairment if treatment inadequate or delayed cardiovascular involvement usually in patients long-standing A.S. with peripheral joint involvement aortitis of ascending aorta and resulting fibrosis can dilate aortic ring and cause aortic valve insufficiency fibrosis of subaortic area can cause cardiac conduction abnormalities fibrosis of anterior leaflet of mitral valve can cause mitral insufficiency chest wall rigidity rarely slowly progressive apical pulmonary fibrosis, usually incidental finding, may cavitate and become secondarily infected spinal fracture is most dreaded complication cervical spine fracture can cause quadriplegia with high mortality and morbidity neck or back pain warrants x-ray even after mild trauma spontaneous atlantoaxial subluxation uncommon, may present with occipital pain or signs of spinal cord compression cauda equina syndrome uncommon amyloidosis (secondary type) rare but should be considered if proteinuria, IgA nephropathy has also been reported Physical General physical: patient may be always bent over characteristic rigid gait common late in disease with flexion contractures at hip joints and flexion at knees to maintain erect posture enthesitis may cause tenderness over ischial tuberosities, greater trochanters, costochondral or manubriosternal junctions, anterosuperior iliac spines or iliac crest, and sometimes over calcanei, tibial tubercles or pubic symphysis HEENT: 25% iritis, 25%-30% circumcorneal congestion, discolored iris with edema Lungs: limited chest expansion due to involvement of costovertebral and costotransverse joints Back:

stiff back, always begins in sacroiliac (SI) joints (symmetric), can't touch occiput to wall while standing erect, pain on SI joint compression, limited forward flexion may have tenderness of SI joints or soreness of spinal processes or paraspinal muscles some limitation of spinal motion common, best assessed by checking lateral flexion, hyperextension, axial rotation and forward flexion sacroiliac pain sometimes elicited by pressure over anterior superior iliac spines or by compressing iliac bones toward or away from each other while patient supine eventually flattening of lumbar spine, thoracic kyphosis, flattening of anterior chest, protuberant abdomen, increasingly diaphragmatic breathing Schober test, also called Wright-Schober test assessment of lumbar flexion with patient erect, mark placed at midline between "dimples of pelvis" at S2 and second mark made 10 cm superiorly patient flexes in attempt to touch toes normally lumbar curve flattens as patient flexes and distance between marks increases > 5 cm in ankylosing spondylitis, lumbar curve flattened with patient erect, minimal if any true lumbar flexion with bending forward Extremities: enthesopathy, resisted hip abduction (with SI joint pathology up) Diagnosis Making the diagnosis: limited lumbar motion, low back pain at least 3 months improved with exercise and not relieved by rest, reduced chest expansion, sacroiliitis on x-ray criteria for classification of spondyloarthropathy must have 1 of: inflammatory spinal pain - history or present symptoms of spinal pain in back, dorsal, or cervical region with at least 4 of: onset before age 45 insidious onset improved by exercise associated with morning stiffness duration at least 3 months synovitis - past or present asymmetric arthritis or arthritis predominantly in lower limbs must have 1 of: positive family history - any of the following conditions in any first-degree or second-degree relatives: ankylosing spondylitis psoriasis acute uveitis reactive arthritis inflammatory bowel disease psoriasis diagnosed by physician in past or present inflammatory bowel disease - past or present Crohn's disease or ulcerative colitis diagnosed by physician and confirmed by radiography or endoscopy

nongonococcal urethritis or cervicitis or acute diarrhea within 1 month before arthritis buttock pain alternating between right and left gluteal areas - past or present enthesopathy - past or present spontaneous pain or tenderness at site of insertion of Achilles tendon or plantar fascia sacroiliitis - bilateral grade 2-4 or unilateral grade 3-4 using radiographic grades 0 normal, 1 possible, 2 minimal, 3 moderate, 4 ankylosis criteria yields 78.4% sensitivity and 89.6% specificity, addition of radiographic evidence of sacroiliitis improves sensitivity to 87% with 86.7% specificity Reference - European Spondylarthropathy Study Group preliminary criteria in Arthritis Rheum 1991 Oct;34(10):1218 guidelines for early identification of ankylosing spondylitis from the Australian 3E initiative in rheumatology consider ankylosing spondylitis if inflammatory back pain in patients < 45 years old response to appropriate course of non-steroidal anti-inflammatory drugs (NSAIDs) elevated inflammatory markers may be present but absence does not rule out ankylosing spondylitis radiologic evaluation plain spinal and pelvic radiographs are appropriate initial imaging techniques magnetic resonance imaging is useful in detecting early changes in the condition refer patients with inflammatory back pain to a rheumatologist for further evaluation Reference - Med J Aust 2008 Feb 18;188(4):235 Rule out: sprain, strain, ankylosing hyperostosis (Forestier's disease, diffuse idiopathic skeletal hyperostosis), disc disease, osteoarthritis seronegative enthesopathy and arthropathy (SEA) syndrome (children and women tend not to have back symptoms and negative x-ray) psoriasis, Reiter's syndrome, inflammatory bowel disease Blood tests: negative rheumatoid factor (RF) negative antinuclear antibody (ANA) up to 75-90% increased ESR or CRP, correlates with disease activity frequently increased IgA, correlates with acute phase reactants 15% mild normocytic, normochromic anemia up to 50% increased alkaline phosphatase, does not correlate with disease activity some patients have increased creatine phosphokinase (CPK) with normal aldolase, does not correlate with disease activity HLA-B27 determination may help determine likelihood of disease but not generally useful diagnostically Imaging studies: x-ray changes evolve over many years SI joints - earliest, most consistent and most characteristic findings sacroiliitis bilateral, usually symmetric starts with blurring of subchondral bone plate followed by bony erosions and sclerosis, typically seen first on iliac side

progression of subchondral bone erosions may cause "pseudowidening" of joint space gradual fibrosis, calcification, interosseous bridging, ossification may ultimately lead to complete bony ankylosis and even resolution of juxta-articular bony sclerosis bony erosions and osteitis (whiskering) occur at entheses sites of bony attachment of tendons and ligaments seen at ischial tuberosities, iliac crest, calcanei, femoral trochanters and vertebral spinous processes spinal involvement reactive bone sclerosis first seen as highlighting of corners of vertebral bodies subsequent bone resorption can lead to squaring of vertebral bodies gradual ossification of superficial layers of annulus fibrosus and vertical bridges between vertebrae (syndesmophytes) ossification of anterior spinal ligament ankylosis of apophyseal joints ultimately complete fusion of vertebral column (bamboo spine) spinal osteoporosis hip joint involvement symmetric concentric joint space narrowing irregularity of subchondral bone place with subchondral sclerosis osteophyte formation at outer margins of articular surfaces ultimately bony ankylosis no periarticular or widespread osteopenia shoulder girdle involvement concentric narrowing of glenohumeral joint space, rarely osseous ankylosis erosions on superolateral aspect of humeral head erosions or osseous ankylosis of acromioclavicular joint osseous proliferation at acromial attachment of acromioclavicular ligament ("bearded acromion") no periarticular or widespread osteopenia chest x-ray may show apical pulmonary interstitial fibrosis computed tomography or magnetic resonance imaging (MRI) may be useful in patients with high clinical suspicion but normal or equivocal x-rays multiple vertebral corner inflammatory lesions on whole body MRI may have diagnostic utility for ankylosing spondylitis and recent-onset inflammatory back pain (level 2 [mid-level] evidence) based on diagnostic case-control study 60 patients 45 years old with ankylosing spondylitis or recent-onset inflammatory back pain and 35 healthy matched controls had whole body MRI scan evaluated for vertebral corner inflammatory lesions vertebral noncorner inflammatory lesions lateral inflammatory lesions facet joint or other posterior element inflammatory lesions diagnostic performance for cutoff of 2 vertebral corner inflammatory lesions on MRI

for detecting ankylosing spondylitis sensitivity 69% specificity 94% positive likelihood ratio 12 for detecting recent-onset inflammatory back pain sensitivity 32% specificity 96% positive likelihood ratio 8 Reference - Arthritis Rheum 2009 Jul 15;61(7):900 magnetic resonance imaging (MRI) detection of spondylarthritis in sacroiliac (SI) joints may identify ankylosing spondylitis or inflammatory back pain (level 2 [mid-level] evidence) based on diagnostic case-control study 128 patients 45 years old (75 patients with ankylosing spondylitis with symptom duration 10 years, 27 patients with preradiographic inflammatory back pain, and 26 patients with nonspecific back pain) and 59 healthy controls had MRI of SI joints independently evaluated by 8 readers reference standard for diagnosis of ankylosing spondylitis was modified New York classification criteria proposed definition of spondylarthritis on MRI defined as any of bone marrow edema in 2 SI joint quadrants in same slice or single SI joint quadrant in 2 consecutive slices erosion in 2 SI joint quadrants in same slice or single SI joint quadrant in 2 consecutive slices bone marrow edema and erosion in any SI joint quadrant (not necessarily same quadrant) diagnostic performance of MRI for detecting ankylosing spondylitis (vs. nonspecific back pain or healthy controls) sensitivity 90% specificity 97% diagnostic performance of MRI for detecting preradiographic inflammatory back pain (vs. nonspecific back pain or healthy controls) sensitivity 51% specificity 97% Reference - Arthritis Rheum 2010 Oct;62(10):3048 clear presence of bone marrow edema or osteitis considered essential for defining active sacroiliitis based on consensus of Assessment in Ankylosing Spondylitis/Outcome Measures in Rheumatoid Arthritis Clinical Trials MRI working group active inflammatory lesions of sacroiliac joints detected by MRI needed for confirmation of axial spondyloarthritis bone marrow edema (BMO) on short tau inversion recovery images or osteitis on T1 post-gadolinium images highly suggestive of spondyloarthritis must be clearly present and located in subchondral or periarticular bone marrow not sufficient for definition of sacroiliitis on MRI sole presence of other active inflammatory lesions (synovitis, enthesitis or capsulitis) without concomitant BMO or osteitis

sole presence of structural lesions (fat deposition, sclerosis, erosions or bony ankylosis) without concomitant BMO or osteitis Reference - Ann Rheum Dis 2009 Oct;68(10):1520 1 inflammatory lesion present in posterior elements of spine on magnetic resonance imaging (MRI) in majority of patients with ankylosing spondylitis based on cohort study from randomized trials 32 patients with ankylosing spondylitis recruited to placebo-controlled trials of anti-tumor necrosis factor therapy had MRI 1 inflammatory lesion in posterior elements of spine (majority in thoracic spine) in 87.5% Reference - Arthritis Care Res (Hoboken) 2010 Jan 15;62(1):4 scintigraphy of the sacroiliac joints of limited value in diagnosing ankylosing spondylitis in systematic review of 25 articles (Ann Rheum Dis 2008 Nov;67(11):1535) Other diagnostic testing: inflamed synovium - Group II inflammatory fluid - PMNs, no distinctive features Prognosis Prognosis: highly variable course, generally favorable, often mild or self-limited patients with hip joint involvement or completely ankylosed cervical spine more likely to be disabled excess mortality only after 20 years and only in more severe cases of disease structural damage and inflammation of spine associated with spinal mobility impairment in ankylosing spondylitis based on cohort study 214 patients with ankylosing spondylitis were assessed for inflammation on MRI, structural damage and spinal mobility inflammation appears to have greater effect in early disease, structural damage in later disease Reference - Ann Rheum Dis 2010 Aug;69(8):1465 ankylosing spondylitis not associated with significant increased risk of myocardial infarction (level 2 [mid-level] evidence) based on systematic review of observational studies systematic review of 38 studies with 34,132 patients with ankylosing spondylitis (AS) and 83,705 controls myocardial infarction in 7.4% with AS vs. 4.6% in control (risk ratio 1.88, 95% CI 0.83-4.28) Reference - Arthritis Care Res (Hoboken) 2011 Apr;63(4):557 Treatment Treatment overview: patient education important for increasing compliance and early recognition of complications exercise and physical therapy most important treatments not shown to be helpful - special diets, radiotherapy, splints, braces, corsets, methotrexate Activity: postural instruction - keep spine as straight as possible

walk erect, avoid prolonged stooped posture sleep on firm mattress with as thin a pillow as possible, do not sleep curled on 1 side spinal extension exercises 1-2 times daily breathing exercises 1-2 times daily swimming is best overall exercise physical therapy interventions may improve pain and function in ankylosing spondylitis (level 2 [mid-level] evidence) based on Cochrane review of trials with limited evidence systematic review of 11 randomized or quasi-randomized trials evaluating physical therapy interventions in 763 patients with ankylosing spondylitis individualized home exercise programs improved spinal mobility and physical function compared to no intervention in 4 low-quality trials supervised group physical therapy improved spinal mobility and patient global assessment compared to individualized home exercise programs in 3 moderate-quality trials addition of 3 weeks of inpatient spa-exercise therapy to 37 weeks of weekly outpatient group physical therapy improved pain, physical function and patient global assessment in 1 moderate-quality trial experimental exercise program improved spinal mobility and physical function compared to conventional exercise program in 1 trial no significant differences comparing outpatient balneotherapy plus exercise program vs. exercise program alone (1 trial) or balneotherapy vs. fresh water therapy (1 trial) Reference - systematic review last updated 2008 Jan 23 (Cochrane Library 2008 Issue 1:CD002822), also published in J Rheumatol 2005 Oct;31(10):1899 group physical therapy superior to individualized therapy in improving thoracolumbar mobility and enhancing overall health (Arthritis Care Res 1993 Mar;6(1):17) self- and manual-mobilization treatment for 8 weeks may improve chest expansion, posture and spine mobility in patients with ankylosing spondylitis (level 3 [lacking direct] evidence) based on small randomized trial without clinical outcome 32 male patients, aged 23-60 years with ankylosing spondylitis were randomized to active treatment or no treatment for 8 weeks and were followed for 4 months active treatment group associated with chest expansion increased at level of processus xiphoideus (p < 0.01) posture improvement C7-wall distance (p < 0.001) thoracic spine (p < 0.05) thoracic spine flexion improvement (p < 0.01) lumbar spine flexion improvement (p < 0.001) sagittal range of motion improvement (p < 0.01) Bath Ankylosing Spondylitis (BAS) Metrology Index total scoring improvement (p < 0.001) at 4 months follow-up of treatment group, cervical spine posture, lumbar flexion and range of motion BAS Metrology Index were still improved

Reference - Clin Rehabil 2009 Jul;23(7):599 exercise associated with improved health or no difference in health status measures in prospective observational study of 220 patients with ankylosing spondylitis followed median 4.5 years (Arch Intern Med 2000 Oct 23;160(19):2969) Counseling: genetic counseling family counseling psychosocial and vocational counseling, patient engaged in physically demanding work may need career counseling Medications: nonsteroidal anti-inflammatory drugs (NSAIDs) NSAID therapy needs to be individualized newer NSAIDs generally more effective than salicylate indomethacin or diclofenac up to 200 mg/day usually well tolerated goal of treatment in A.S. is to achieve sufficient control of pain and stiffness to allow an active, sustained program of exercise and physical therapy celecoxib (Celebrex) 200 mg daily FDA approved for spondylitis (Cortlandt Forum 2005 Sep;18(9):17) celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen/ketoprofen) may reduce C-reactive protein (CRP) levels in patients with ankylosing spondylitis (level 3 [lacking direct] evidence) based on retrospective cohort study without clinical outcomes Reference - Rheumatology (Oxford) 2010 Mar;49(3):536 steroid injections intra-articular corticosteroid injections into acutely inflamed joints do not have as dramatic or as sustained a response as in rheumatoid arthritis steroid injection of sacroiliac joint usually done under fluoroscopic guidance, 79% response rate in series of 24 such injections (Arthritis Rheum 1992 May;35(5):564) systemic steroids have been used in severe flares, but no controlled trials sulfasalazine sulfasalazine reduces erythrocyte sedimentation rate (ESR) and morning stiffness, but no evidence of benefit in physical function, pain, spinal mobility, enthesitis, or global assessment systematic review of 11 randomized and quasi-randomized trials sulfasalazine increased rate of withdrawals (NNH 17) and withdrawals due to adverse events (NNH 23) but severe side effects were rare (1 of 469 patients taking sulfasalazine) Reference - systematic review last updated 2005 Feb 23 (Cochrane Library 2005 Issue 2:CD004800), also published in J Rheumatol 2006 Apr;33(4):722 sulfasalazine ineffective in 2 randomized trials with inconsistent subgroup analyses sulfasalazine no more effective than placebo in 6-month randomized trial in 230 patients with inflammatory back pain and active undifferentiated spondyloarthritis or ankylosing spondylitis, although efficacy reported in subgroup of patients without peripheral arthritis (Ann Rheum Dis 2006 Sep;65(9):1147) sulfasalazine 2000 mg/day vs. placebo in 264 patients inadequately controlled by NSAIDs had similar 38% vs. 36% response at 36 weeks, but sulfasalazine was

effective for small subgroup with peripheral joint involvement (60% vs. 30%) (Arthritis Rheum 1996 Dec;39(12):2004 in J Watch 1997 Jan 15;17(2):18) methotrexate insufficient evidence to support efficacy of methotrexate in A.S.; systematic review of 2 randomized or quasi-randomized trials with 81 patients; 1 trial evaluated addition of oral methotrexate 7.5 mg/week to naproxen for 12 months, 1 trial evaluated oral methotrexate 10 mg/week vs. placebo for 24 weeks; no significant differences in symptoms, functional outcomes or inflammatory markers; systematic review last updated 2003 May 8 (Cochrane Library 2004 Issue 3:CD004524) methotrexate may be useful; 24-week open study of 11 patients, clinical improvement occurred, 3 of 5 patients who discontinued treatment had disease flares (J Rheumatol 1995 Jun;22(6):1104) leflunomide 20 mg daily not associated with significant benefit (level 2 [mid-level] evidence) in 24-week randomized placebo-controlled trial of 45 patients with active A.S. (Ann Rheum Dis 2005 Dec;64(12):1761) Tumor necrosis factor inhibitors: include adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), golimumab anti-TNF therapy may reduce ankylosing spondylitis disease activity (level 2 [mid-level] evidence) based on systematic review of trials with methodologic limitations systematic review of 9 randomized trials of anti-TNF-alpha therapy (adalimumab, etanercept or infliximab) in 1,611 adults with active ankylosing spondylitis all randomized trials were placebo-controlled and evaluated adalimumab (2 trials), etanercept (5 trials) and infliximab (2 trials) 3 trials had allocation concealment, 6 not stated 1 trial had blinding of outcome assessors, 1 did not, 7 not stated comparing TNF inhibitors vs. placebo 62.1% vs. 24.8% achieved 20% improvement in Assessment in Ankylosing Spondylitis (ASAS) at 2-12 weeks (p < 0.00001, NNT 3) in 8 trials with 1,347 patients 42.3% vs. 11.7% achieved 50% improvement in ASAS at 2-12 weeks (p < 0.00001, NNT 4) in 7 trials with 1,068 patients 23.9% vs. 6% achieved 70% improvement in ASAS at 2-12 weeks (p < 0.00001, NNT 4) in 6 trials with 999 patients results significant for each individual drug in subgroup meta-analyses no significant differences between drugs in indirect comparisons Reference - Health Technol Assess 2007 Aug;11(28):1 full-text PDF anti-TNF therapy may reduce symptoms and improve quality of life in patients with spondyloarthritis unresponsive to NSAIDs or methotrexate based on systematic review systematic review of 2 randomized trials of infliximab (5 mg/kg IV over 2 hours at 0, 2 and 6 weeks) and 4 randomized trials of etanercept (25 mg subcutaneously twice weekly) for spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, spondyloarthropathy) anti-TNF-alpha agents improved symptom control, physical function and quality of life

Reference - J Rheumatol 2003 Jun;30(6):1356 in ACP J Club 2004 May-

Jun;140(3):71 EBSCOhost Full Text tumor necrosis factor antagonists may not increase risk of serious infections in patients with ankylosing spondylitis (level 2 [mid-level] evidence) based on systematic review with inadequate power systematic review of 14 randomized trials comparing tumor necrosis factor antagonists to placebo or NSAIDs in 3,345 patients with ankylosing spondylitis serious infections defined as life-threatening, requiring IV antibiotics, or hospitalization tumor necrosis factor antagonists associated with very small (but not significant) increase in risk of serious infections compared to placebo in analysis of 9 trials with 1,496 patients, but authors state 5,500 patients would be required to detect significant difference Reference - Ann Rheum Dis 2010 Oct;69(10):1756 full-text adalimumab adalimumab may reduce disease activity in active ankylosing spondylitis (level 2 [mid-level] evidence) based on randomized trial with allocation concealment not stated 315 patients > 18 years old with active ankylosing spondylitis randomized to adalimumab 40 mg vs. placebo subcutaneously every 2 weeks for 12 weeks open-label adalimumab provided for patients without improvement after 12 weeks 307 patients (97%) followed up at 12 weeks comparing adalimumab vs. placebo 58% vs. 21% had at least 20% reduction in disease activity (p < 0.001, NNT 3) 40% vs. 13% had at least 40% reduction in disease activity (p < 0.001, NNT 4) 75% vs. 60% had adverse events (p < 0.05, NNH 6) 10.1% vs. 2.8% injection site reactions (p < 0.05, NNH 13) Reference - ATLAS trial (Arthritis Rheum 2006 Jul;54(7):2136 full-text) adalimumab associated with improved quality of life in this trial (Arthritis Rheum 2007 Aug 15;57(6):1050) adalimumab associated with reduced pain, fatigue, and stiffness in this trial (J Rheumatol 2008 Jul;35(7):1346) improvements in disease activity and quality of life reported to be maintained at 3 years in open-label follow-up of 82% of ATLAS trial participants (Arthritis Res Ther 2009;11(4):R124 full-text) adalimumab may be effective for treatment of patients with axial spondylarthritis without radiographically defined sacroiliitis (level 2 [mid-level] evidence) based on small randomized trial 46 patients with active axial spondylarthritis without radiographically defined sacroiliitis randomized to adalimumab 40 mg subcutaneously every 2 weeks vs. placebo for 12 weeks at 12 weeks all patients were enrolled in open-label extension and followed to week 52 40% response in improvement criteria in 54.5% of adalimumab group compared with 12.5% of placebo group at 12 week (p = 0.004, NNT 3) a similar response in patients who switched to adalimumab response maintained in all patients until week 52

Reference - Arthritis Rheum 2008 Jul;58(7):1981 infliximab infliximab reduces disease activity in active ankylosing spondylitis 70 patients with active ankylosing spondylitis randomized to infliximab 5 mg/kg vs. placebo IV at weeks 0, 2, and 6 with follow-up for 12 weeks; 1 infliximab patient withdrawn and not included in analysis 53% infliximab group vs. 9% placebo group had at least 50% regression of disease activity (p < 0.0001, NNT 2.3, 95% CI 1.6-4.3) function and quality of life also improved significantly with infliximab but not with placebo 3 patients (9%) had to stop infliximab due to systemic tuberculosis, allergic pulmonary granulomatosis, or mild leucopenia (NNH 11)

Reference - Lancet 2002 Apr 6;359(9313):1187 EBSCOhost Full Text infliximab may reduce symptoms and signs in ankylosing spondylitis based on randomized trial 279 patients with ankylosing spondylitis randomized to infliximab 5 mg/kg vs. placebo comparing infliximab vs. placebo at 24 weeks 20% improvement in ASAS criteria (ASAS20 response) in 61.2% vs. 19.2% (p < 0.001, NNT 3) adverse events (mostly mild or moderate) in 82.2% vs. 72% (NNH 9) Reference - ASSERT trial (Arthritis Rheum 2005 Feb;52(2):582 full-text) infliximab appeared to maintain efficacy and safety after two years Reference - Arthritis Rheum 2008 Sep 15;59(9):1270 infliximab may reduce anemia and improve physical function and fatigue based on post-hoc analysis of above ASSERT trial at week 24, infliximab associated with improved (p < 0.001 for all) mean hemoglobin levels mean Bath Ankylosing Spondylitis Functional Index mean fatigue Visual Analog Scale score normal hemoglobin levels by week 24 in patients with anemia (hemoglobin level

patients treated with infliximab had greater reductions in spinal inflammation measured by magnetic resonance imaging (MRI) compared to patients treated with placebo at 12 weeks (p < 0.001) Reference - J Rheumatol 2010 Aug 1;37(8):1728 infliximab may be associated with reduced disease activity for patients with sacroiliitis (level 2 [mid-level] evidence) based on small randomized trial 40 adults (mean age 28-29 years) positive for HLA-B27 with back pain and MRI-identified sacroiliitis were randomized to infliximab infusion 5 mg/kg vs. placebo at 0, 2, 6 and 12 weeks comparing infliximab vs. placebo at 16 weeks 40% improvement in 61.1% vs. 17.6% (p = 0.009) partial remission in 55.6% vs. 12.5% (p = 0.009) infliximab group associated significantly with reduced disease activity scores (p = 0.002) improved functional index scores (p = 0.004) improved quality of life scores (p = 0.007) increased lesion resolution (p < 0.001) Reference - Arthritis Rheum 2009 Apr;60(4):946 infliximab associated with significant increase in bone mineral density over 2 years in ankylosing spondylitis (level 3 [lacking direct] evidence) based on randomized crossover trial without clinical outcomes 279 patients with ankylosing spondylitis randomized to infliximab 5 mg/kg vs. placebo every 6 weeks for 96 weeks Reference - Ann Rheum Dis 2009 Feb;68(2):175 infliximab use may be required lifelong to prevent relapse (level 2 [mid-level] evidence); 42 patients with ankylosing spondylitis treated with infliximab for 3 years discontinued infliximab; at 1 year, 41 patients (98%) required repeat treatment with infliximab due to relapse of disease activity, mean time to relapse 17.5 weeks after discontinuation (Arthritis Research & Therapy 2005 Feb 21;7:R439) etanercept etanercept improves short-term symptoms of ankylosing spondylitis compared to sulfasalazine (level 1 [likely reliable] evidence) based on randomized trial 566 adults with ankylosing spondylitis were randomized to etanercept 50 mg once weekly vs. sulfasalazine titrated to maximum 3 g/day for 16 weeks 20% improvement in Assessment of SpondyloArthritis international Society (ASAS) in 75.9% of etanercept group vs. 52.9% of sulfasalazine group (p < 0.0001, NNT 5) more patients receiving etanercept achieved 40% ASAS improvement and 20% ASAS improvement in 5 of 6 domains at all time points, including as early as week 2 vs. sulfasalazine (p < 0.0001) no significant difference in adverse events between groups Reference - Arthritis Rheum 2011 Jun;63(6):1543 etanercept reduces disease activity in active ankylosing spondylitis based on randomized trial 84 adults with ankylosing spondylitis randomized to etanercept 25 mg vs. placebo twice weekly for 12 weeks

comparing etanercept vs. placebo at 12 weeks ASAS20 response in 60% vs. 23.1% (p < 0.001, NNT 3) ASAS50 response in 48.9% vs. 10.3% (p < 0.01, NNT 3) ASAS70 response in 24.4% vs. 10.3% (p < 0.05, NNT 7) Reference - Ann Rheum Dis 2004 Dec;63(12):1594 PDF etanercept reduces disease activity in active ankylosing spondylitis 40 patients with active inflammatory ankylosing spondylitis (with inflammatory back pain [stiffness and pain worsened with rest and improved with exercise] and morning stiffness at least 45 minutes) randomized to etanercept 25 mg vs. placebo subcutaneously twice weekly for 4 months treatment response defined as 20% or greater improvement in at least 3 of 5 measures of disease activity (duration of morning stiffness, degree of nocturnal spinal pain, Bath Ankylosing Spondylitis Functional Index, patient global assessment of disease activity, score for joint swelling) and no worsening in any of these measures 80% etanercept group vs. 30% placebo group had treatment response (p = 0.004, NNT 2) etanercept patients were more likely than placebo patients to be receiving corticosteroids, disease-modifying antirheumatic drugs, and multiple medications treatment response sustained throughout 10 months during 6-month open-label extension study following the 4-month randomized trial

Reference - N Engl J Med 2002 May 2;346(18):1349 EBSCOhost Full Text,

editorial can be found in N Engl J Med 2002 May 2;346(18):1399 EBSCOhost

Full Text, commentary can be found in ACP J Club 2003 Jan-Feb;138(1):19 EBSCOhost Full Text, commentary can be found in N Engl J Med 2003 Jan

23;348(4):359 EBSCOhost Full Text etanercept may improve heel pain and function in patients with spondyloarthritis and heel enthesitis (level 2 [mid-level] evidence) based on small randomized trial 24 patients with spondyloarthritis and refractory heel enthesitis were randomized to etanercept vs. placebo for 12 weeks comparing etanercept vs. placebo at 12 weeks follow-up mean reduction in patient's global assessment of disease activity 37.6 vs. 11.6 (p = 0.007) mean reduction in heel pain 36.7 vs. 13.1 (p = 0.022) mean reduction in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale 23.2 vs. 7.8 (p = 0.024) no significant differences in magnetic resonance imaging (MRI) findings Reference - Ann Rheum Dis 2010 Aug;69(8):1430 etanercept may not decrease risk of job loss despite improvements in function (level 2 [mid-level] evidence) based on small randomized trial 40 patients with ankylosing spondylitis and working but work unstable randomized to etanercept 25 mg twice weekly vs. placebo for 12 weeks etanercept associated with significant improvements in assessments of disease activity, quality of life, functional ability, and gait parameters

Reference - Ann Rheum Dis 2010 Nov;69(11):1926 golimumab reduces signs and symptoms in ankylosing spondylitis (level 1 [likely reliable] evidence) based on randomized trial 356 patients (mean age 38 years) with active ankylosing spondylitis randomized to golimumab 50 mg vs. 100 mg vs. placebo subcutaneously every 4 weeks for 24 weeks at 16 weeks, patients with < 20% improvement from baseline in total back pain and morning stiffness measures were treated with "early escape" under double-blind conditions placebo group switched to golimumab 50 mg subcutaneously every 4 weeks golimumab 50 mg group switched to golimumab 100 mg subcutaneously every 4 weeks golimumab 100 mg group continued golimumab 100 mg subcutaneously every 4 weeks primary endpoint was ASAS20 response (defined as 20% improvement in Assessment in Ankylosing Spondylitis (ASAS) scale) at 14 weeks comparing golimumab 50 mg vs. 100 mg vs. placebo ASAS20 response rate at 14 weeks 59.4% vs. 60% vs. 21.8% (p < 0.001, NNT 3) ASAS20 response rates favored golimumab groups at 4, 8, 12, 16, 20 and 24 weeks ASAS40 response rate at 24 weeks 43.5% vs. 54.3% vs. 15.4% (p < 0.001, NNT 3-4) 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index at 24 weeks in 50.8% vs. 47.8% vs. 14.7% (p < 0.001, NNT 3) adverse events comparing golimumab (combination of both groups originally assigned golimumab) vs. placebo (including patients given golimumab during early escape) drug discontinuation due to adverse event in 2.9% vs. 1.3% any infection in 48.6% vs. 36.4% any serious infection 0.7% vs. 1.3% adverse events more common with golimumab included nasopharyngitis, upper respiratory tract infection, fatigue, headache, diarrhea, and injection site erythema Reference - Arthritis Rheum 2008 Nov;58(11):3402 golimumab reduces sleep disturbance in patients with ankylosing spondylitis (level 1 [likely reliable] evidence) based on prespecified analysis of above trial median change in sleep score (0-20 point scale with higher scores indicating greater sleep disturbance) comparing golimumab vs. placebo at 14 weeks -3 vs. 0 (p < 0.001) at 24 weeks -3 vs. -1 (p < 0.001) differences were significant compared to placebo with both doses of golimumab Reference - Arthritis Care Res (Hoboken) 2010 Sep;62(9):1266 golimumab (Simponi) FDA approved for treatment of active ankylosing spondylitis in adults (FDA Press Release 2009 Apr 24)

FDA reminds healthcare providers of risk of serious fungal infections associated with TNF-alpha blockers including golimumab, and requests reporting of such adverse events (FDA MedWatch 2009 May 27) adverse effects tumor necrosis factor antagonists associated with reactivation risk for tuberculosis (level 2 [mid-level] evidence); infliximab (Remicade) previously known to have substantial risk in patients with latent tuberculosis; etanercept (Enbrel) associated with reactivated tuberculosis in 25 reports to the FDA in first 40 months of Enbrel

marketing (Clin Infect Dis 2004 Aug 1;39(3):295 EBSCOhost Full Text in J Watch Online 2004 Sep 3) infliximab (Remicade) labeling updated to include warning of severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis (FDA MedWatch 2004 Dec 22) anti-TNF therapy (infliximab or etanercept) may rarely induce systemic lupus erythematosus; 866 rheumatology and internal medicine practitioners in France contacted by e-mail requesting reports of TNF-induced systemic lupus erythematosus, 22 cases reported (15 with infliximab, 7 with etanercept); because infliximab had greater use than etanercept, overall incidence similar (0.19% with infliximab, 0.18% with etanercept) (Arthritis Research & Therapy 2005 Mar 1;7(3):R545) Surgery: total hip arthroplasty prevents partial or total disability from severe hip disease follow-up of 103 patients with ankylosing spondylitis who had 181 total hip arthroplasties, mean follow-up 10.3 years; 96% hips had low pain scores, 29% hips had near-normal function scores, probability of implant survival 71% at 27 years (J Arthroplasty 2002 Jun;17(4):427 in JAMA 2002 Oct 23/30;288(16):1962) vertebral wedge osteotomy can correct severe kyphosis, but high risk of paraplegia Consultation and referral: acute anterior uveitis should be managed jointly by rheumatologist and ophthalmologist topical steroid drops first-line therapy, systemic steroids sometimes needed goal to resolve inflammation before synechiae formation and subsequent glaucoma steroid-sparing agents for refractory ocular disease include methotrexate, azathioprine, cyclosporin A Other management: avoid smoking to help maintain chest expansion special wide-view mirrors helpful for patients with difficulty driving due to impaired neck mobility in cases of cervical spine injury requiring immobilization, hard collar should not be used or at least kyphotic neck should not be immobilized in neutral position, based on case report of quadriplegia caused by immobilization (BMJ 1999 Jul 17;319(7203):171) probiotics not associated with improvement in symptoms or quality of life in patients with spondyloarthritis (level 2 [mid-level] evidence) based on randomized trial with inadequate statistical power

63 patients with active spondyloarthritis randomized to oral probiotic (Bifidobacterium lactic, Lactobacillus acidophilus, Streptococcus salivarius) vs. placebo for 12 weeks small improvements on symptom and quality of life scales in both groups (difference not significant between groups) Reference - J Rheumatol 2010 Oct;37(10):2118 Prevention and Screening not applicable References including Reviews and Guidelines General references used: Primer on the Rheumatic Diseases, 11th edition, 1997, pp. 89,92,180-195,456 MEDLINE search: to search MEDLINE for (Ankylosing spondylitis) with targeted search (Clinical Queries), click therapy, diagnosis or prognosis Reviews: review can be found in Lancet 2007 Apr 21;369(9570):1379, commentary can be found in Lancet 2007 Jul 7;370(9581):27 review can be found in BMJ 2006 Sep 16;333(7568):581 review of spondyloarthritis can be found in Lancet 2011 Jun 18;377(9783):2127 review of spondyloarthropathies can be found in Am Fam Physician 2004 Jun 15;69(12):2853 treatment update on spondyloarthropathy can be found in Postgrad Med 2004 Nov;116(5):31 review of use of tumor necrosis factor (TNF) antagonists in ankylosing spondylitis can be found in Bulletin on the Rheumatic Diseases 2003 Jan 22;51(12):1 review of treatment effects of NSAIDs/TNF blockers in ankylosing spondylitis can be found in Rheumatology (Oxford) 2010 Jul;49(7):1317 case presentation on clinical management of injured patients with ankylosing spondylitis can be found in BMJ 2009 Jul 17;339:b2568 Guidelines: Ankylosing Spondylitis International Society/European League against Rheumatism (ASAS/EULAR) guideline on management of ankylosing spondylitis can be found in Ann Rheum Dis 2011 Jun;70(6):896 full-text Assessment of SpondyloArthritis International Society (ASAS) guide for assessing spondyloarthritis can be found in Ann Rheum Dis 2009 Jun;68 Suppl 2:ii1 3E Initiative in Rheumatology recommendations for management of ankylosing spondylitis based on systematic literature search can be found in Rheumatology (Oxford) 2008 Mar;47(3):355 EULAR recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis can be found in Ann Rheum Dis 2010 Feb;69(2):325 international consensus statement on relevant aspects of the International Classification of Functioning in patients with ankylosing spondylitis can be found in Rheumatology (Oxford) 2009 Aug;48(8):997 NICE guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis can be found at NICE 2008 May:TA143 or at National Guideline Clearinghouse 2008 Sep 15:12615

Assessment of SpondyloArthritis International Society and World Health Organization (ASAS/WHO) consensus statement on how to classify impact of ankylosing spondylitis on function and health can be found in Ann Rheum Dis 2010 Jan;69(1):102 Austrian expert consensus on use of tumour necrosis factor alpha-blockers in daily

routine Clin Rheumatol 2010 Feb;29(2):167 EBSCOhost Full Text Haute Autorit de Sant conseils pour spondylarthrite grave se trouvent sur le site Haute Autorit de Sant 2008 Dec [French] Haute Autorit de Sant conseils pour Diagnostic, prise en charge thrapeutique et suivi des spondylarthrites se trouvent sur le site Haute Autorit de Sant 2008 Dec [French]