Weinblatt ME, Keystone EC, et al. Adalimumab, a fully human anti-tumor necrosis factor alph a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomi tant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48: 35 \200\22345. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumor necrosis factor a lpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomi tant methotrexate: a randomized phase III trial. ATTRACT Study Group. Lancet 1999; 354: 193 2 \200\2239. See also: Organ involvement and rheumatological disease (p. 408); Glucocorticoid induced os teoporosis (p. 408), Medications/drugs used in rheumatic disease (p. 529) O \200\231Dell JR, Leff R, et al. Treatment of rheumatoid arthritis with methotrexate and h ydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medication s: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rhe um 2002; 46: 1164 \200\22370. Smolen JS, van der Heijde DM, et al. Predictors of joint damage in patients with early rheu matoid arthritis treated with high-dose methotrexate with or without concomitant in \202 i ximab: results from the ASPIRE trial. GUIDELINES 208 Guidelines for the management of rheumatoid arthritis (the \201 rst 2 years) 1 A diagnosis of RA should be made as early as possible, on the basis of persistent joint i n \202 ammation affecting at least three joint areas, involvement of the MCP or MTP joints, or early morning stiffness of at least 30 min duratio n. 2 In order to identify and treat patients with RA at an early stage, it is necessary for pa tients with suspected early synovitis to have rapid access to a multidisciplinary team that includes specialists in rheumatology, and includes members from both primary and secondary care in order to provide a seamless service for patients. 3 Access to individual elements of the multidisciplinary service should be available accord ing to patient need. 4 Patients with RA should be provided with a plan of care from diagnosis, which outlines th e principles of management including a commitment to training patients to self-manage some aspects of their disease. 5 Specialist rheumatology nurses can provide the ideal support for patients in accessing el ements of the multidisciplinary team and in providing important lifestyle advice. 6 RA is a signi \201 cant independent risk factor for ischaemic heart disease, with the ri sk related to the severity and duration of in \202 ammation. Control of in \202 ammation should also be accompanied by addressing ea ch patient \200\231s other risk factors for ischaemic heart disease, using the established primary care services where appropriate. 7 All patients should have their disease and its impact assessed and documented at onset, p rior to starting DMARD therapy. Once established on DMARD therapy, all patients should have a formal assessment of treatment response, or lack of it, in order to justify continuing t herapy or changing it. Remission should be de \201 ned and documented when achieved, in or der to plan reduction or maintenance therapy. 8 Patients with RA should be established on disease-modifying therapy as soon as possible a fter a diagnosis of RA is established. Disease modifying therapy should be part of an aggre ssive package of care, incorporating escalating doses, intra-articular steroid injections, parenteral methotrexate and combination therapy, rather than sequential monotherapy, progre ssing to biologic (anti-TNFA) therapy, when required. 9 Systemic glucocorticoid therapy may have an important early role in establishing control of synovitis or bridging disease control between different DMARD therapies but long-term use is not justi \201 ed. 10 Patients with RA require assessment of both pain and optimum effective therapy to ensure early symptom control (grade of recommendation A). Long-term use of NSAIDs should be at the lowest effective dose. 11 Current concern over the potential cardiovascular toxicity of coxibs and NSAIDs suggests that such drugs should be avoided in high risk individuals, and used with caution in others who cannot be managed with analgesia, ste roid injections, and one or more DMARDs. 12 Patients with RA require early assessment of sleep patterns (grade of recommendation A). Early management of sleep disturbance should include tricyclic agents, behavioral therapy and consider also the use of exercise ( grade of recommendation B). Consider the impact of fatigue on quality of life in early RA. 13 The evidence for the effectiveness of complementary therapy is con \202 icting and no \201 rm recommendations can be made. 14 Timing and format (group/individual/written) of education to meet individual needs must be considered in early disease (grade of recommendation A). Patients should be offered a cognitive behavioral approach to patient ed ucation, delivered at the appropriate time in order to promote long-term adherence to manag ement strategies (grade of recommendation C). Patients should be helped to contact support organizations such as National RA Society, Arthritis Care (AC) and the Arthritis Research C ampaign (arc). 15 Patients should be encouraged to pace activities and recognize the potential lower, as w ell as upper limits of physical activity, facilitating a realistic readjustment of the patient \200\231s own expectations, guided by members of the multidisciplinary team. Patients should be helped to participate in exercise programs. 16 Aerobic exercise should be encouraged to help combat the adverse effects of rheumatoid d isease on muscle strength, endurance and aerobic capacity, without, in the short-term, exacerbating disease activity or joint destru ction. 17 Hydrotherapy should be accessible to maximize positive effects on pain, function and sel f-ef \201 cacy. 18 Transcutaneous electrical nerve stimulation use in RA patient may be effective in pain r elief, but trials lack standardization. 19 Heat and cold applications may provide short-term symptomatic relief of symptoms of pain and stiffness. There is no evidence of long-lasting bene \201 t. Paraf \201 n wax baths combined with exercise are bene \201 ci al for hands in arthritic conditions. 20 Joint protection, energy conservation and problem-solving skills training should be taug ht early on in the disease course. 21 Hand function should be maintained and improved with a combination of hand exercises and appropriate devices to improve ef \201 ciency of action. OT can be helpful for those experiencing problems at work when t hese are due to the symptoms of arthritis. Altering work methods, posture, pacing and assis tive devices can improve functional ability. 22 When hands and wrists are painful and/or swollen, splints (hand/wrist resting splints an d functional wrist splints) should be offered, but the role of splinting at other times remains uncertain. 23 The goals of foot care for patients with RA are to relieve pain, maintain function and i mprove quality of life using safe, cost-effective treatments, such as palliative foot care, prescribed foot orthoses, and specialist footwear. An annual foot review and assessment is recommended for patients at risk of developing serious complications in order to detect pr oblems early. Foot orthoses are an important and effective intervention in RA. 24 Health professionals should provide opportunities to discuss sexuality and relationship issues where RA affects these. Problems may include pain, dysfunction and changes in relationships, for example dependence and loss of role. Information and help on sexuality and relationship issues should be given backed up w ith written lea \202 ets and contact details of organizations that can offer support. Luqmani R, Hennell S, et al., on behalf of the British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group. Britis h Society for Rheumatology and British Health Professionals in Rheumatology Guideline for t he Management of Rheumatoid Arthritis (the \201 rst 2 years). Rheumatology (Oxf) 2006; 45 : 1167 \200\2239. 209 Chapter 7 The spondylarthropathies The spondylarthropathies: disease spectrum (including undifferentiated spondylarthropathy) 210 Ankylosing spondylitis 214 Psoriatic arthritis 220 Reactive arthritis 226 Enteropathic spondylarthropathy 230 Juvenile spondylarthropathy/enthesitis-related arthritis 232 SAPHO ( Le Syndrome Acn , Pustulose, Hyperostose, Ost ite) 236 THE SPONDYLARTHROPATHIES: DISEASE SPECTRUM 210 The spondylarthropathies: disease spectrum (including undifferentiated spondylarthropathy) The spondylathropathy concept Spondylarthropathy (SpA) is the term given to a group of cond itions characterized by a number of features common to all; particularly in \202 ammation in spinal, sacroiliac, and peripheral musculoskeletal structures, chie \202 y entheses. Th e principle SpA conditions are: \200 Ankylosing spondylitis (AS). \200 Reactive arthrit is (ReA). \200 Psoriatic arthritis (PsA). \200 Enteropathic SpA (ESpA) also termed vari ably: Enteropathic arthritis, in \202 ammatory bowel disease-related arthritis or Crohn \200\231s/UC-related arthritis. Juvenile SpA (see p. 232). Undifferentiated SpA (USpA). The simpler European SpA Study Group (ESSG) criteria are shown below. The two data sets hav e been validated in many different countries now. The two systems have similar sensitivity (85-95%), similar speci \201 city (90-95%) and -ve predictive value (99% both). The Amor c riteria may have a slightly higher positive predictive value (73% vs. 60%). The European Spondylarthropathy Study Group (ESSG) Classi \201 cation Criteria for Spondyl arthropathy In \202 ammatory spinal pain or Synovitis (asymmetrical or predominantly in the lower limb s) and one or more of: Positive family history Psoriasis In \202 ammatory bowel disease Al ternate buttock pain Enthesopathy \200 The concept of SpAs as a linked group of conditions was originally proposed by Wrigh t and Moll (1974) and developed over ensuing years (reviewed in Calin 1998). The three key pathophysiological features common to all SpAs are: \200 \200 Axial skeletal in \202 ammation. Pathological changes at entheses \200\223 the site of in sertion of ligaments or tendons into bone. An association with HLA B27. Frequency of associ ation depends on ethnic group and disease type (e.g. from about 50% in ESpA to over 95% in AS). sacroiliitis* *Adding sacroiliitis to the core dataset improves sensitivity, but does no t change speci \201 city. Epidemiology Information about speci \201 c conditions is included in the relevant chapter . However, if the SpAs are considered a single condition the prevalence may be about 2% in Cauca- sians (Braun et al., 1998). The principle features of the SpAs \200 \200 Sacroiliitis. In \202 ammatory neck and back pain: \200 \200 \200 Enthesopathy Dacty litis Uveal in \202 ammation (e.g. acute anterior uveitis) Aortitis/aortic valve disease S kin lesions (psoriasis, balanitis, keratoderma) Clinical overlap within the individual and family members Familial aggregation Urethritis (sterile) HLA B27 association pain with stiffness associated with immobility; waking due to symptoms in the early hours; symptoms easing with movement. Pathphysiology Genetic There is clearly genetic predisposition for SpAs, partly mediated by presence of HLA B27. \200 \200 \200 \200 \200 \200 The association of HLA B27 with different SpAs varies with the association with AS the stro ngest. The role of HLA B27 is discussed in the next chapter. Environmental \200 \200 \200 Bacterial triggering of SpA clearly occurs in ReA. The organisms and immunopathological mec hanisms are discussed in the chapter on AS. Clear links to bacterial triggers in AS, ESpA, JSpA, and USpA have not been substantiated though a substantial body of work investigating the role of Klebsiella in triggering AS exists. Arguably the least \200\230comfortable \201 t \200\231 within the SpA group is PsA. A nu mber of different forms of PsA exist, the link with HLA B27 probably being the weakest of t he SpA condi- tions, except perhaps in psoriatic spondylitis. Controver- sies are discussed on p. 223. Immunopathogenesis See under \200\230Ankylosing spondylitis \200\231. Tissue pathophysiology Lesions in SpA are present at entheses, in synovium and bone. The la tter are varied (e.g. bone oedema as shown on MR in AS, bone erosion at joints and perioste al apposition and whiskering \200\223 a hallmark sign in PsA). Classi \201 cation criteria To accommodate the wide spectrum and degree of over- lap of fe atures in SpA conditions, two over-arching classi \201 - cation systems have been develope d: \200 The Amor criteria (Amor et al., 1990) scores out of 12 features covering 4 domains (symptom s, radiographic and genetic features, and response to treatment). CHAPTER 7 The spondylarthropathies 211 The enthesis \200 \200 A sensitive approach to enquiring about previous (puta- tively triggering) genital infectio n is necessary particu- larly in women, where Chlamydia trachomatis infection is often asym ptomatic. ReA can follow infection with Campylobacter, Shigella and Salmonella, all of whic h invariably cause diarrhea. An attachment of a ligament or tendon to bone. Enthesitis occurs in all SpAs and it disting uishes SpAs from other arthritides, such as rheumatoid arthritis, which is a synovial-based condition. Entheses thus are primarily extra-articular although MR data highlight in \202 ammation at entheses in and around synovial joints in SpAs. Where tendons and ligaments in sert into metaphyseal bone, entheses are generally rich in \201 brocartilage. Fibrocartil age-rich tissue is likely to be an adaption to compressive load (Benjamin & Ralphs 1998). F ibrocartilage tissue in joints, at entheses, within tendons and periosteum is the focus for recent proposals that this tissue is key in determining the anatomical distribu- tion of d isease in the SpAs, although how it relates to autoimmune processes is unknown. Table 7.1 Features of in \202 ammatory back pain (IBP) in young adults (<50 years old) tha t should raise the suspicion of a SpA Symptom Features Chronic pain >3 months Morning stiffness >30 min Improvement with movement Symptoms easier or abolished with movement not eased or worsened by rest Prognosis and natural history \200 Disturbed sleep Awakening during the second part of the night SpAs can produce episodic symptoms over a considera- ble length of time. It is likely that there may be long symptom-free periods. Patients diagnosed with SpA may disclose a long his tory of features suggestive of a chronic SpA condition. Studies documenting this are sparse . Early detection of SpA and wider adoption of the ESSG SpA classi \201 cation into clinic al practice may broaden understanding and acceptance of SpAs, and result increasingly to a diagnosis of USpA being made. Longitudinal studies will show whether USpA is likely to evol ve into an alternate SpA condition. Progressive disease in SpAs is recognized, but variable (e.g. substantial proportion in AS; minority in ReA). Buttock pain Alternating (?sacroiliitis) A new classi \201 cation of IBP has been recently proposed on the basis of these features (Rudwaleit et al., 2006). Key features on examination \200 Spinal mobility may be reduced in all directions. Reduced Schober \200\231s test or modi \201 ed Schober \200\231s test. Sacroiliitis stress tests may be positive, although they ar e not speci \201 c for sacroiliitis. There may be enthesial tenderness especially origin o f plantar fascia, insertion of Achilles \200\231 tendons, inferior patellar poles, anterior superior iliac spines, and humeral epicondyles. Joint synovitis is not always present in U SpA (joints may be painful owing to enthesitis alone). If present, synovitis is typically a symmetrical, oligoarticular, and lower limb predominant. Synovitis can be monoarticular thu s SpA is a differential diagnosis of crystal arthritis. A careful search for psoriasis is a ppropriate. Check posterior hairline, over scalp, in umbilicus, natal cleft. Enthesitis in USpA can be mistaken for \201 bromyalgia tender points by the unwary. Clinical features Clinical spectrum The diagnosis of SpA or USpA, applied using broad crite ria in the clinic, perhaps re \202 ecting the ESSG or Amor criteria, has a number of uses illustrated by the following: \200 To putatively label PsA-sine-Ps: where psoriasis is absent, radiographic and other imaging signs may be sub- tle or absent and where misdiagnosis (e.g. osteoarthritis or Fibromyalgia notably) is best avoided. To label \200\230limited \200\231 SpA: a number clinical scenar ios \200\223 some reported in the context of being \200\230SpA families \200\231 \200 \223 highlight probable limited forms of SpA, such as unilateral sacro- iliitis, isolated i n \202 ammatory spinal symptoms or dactylitis, (suspicious) recalcitrant or bilateral late ral humeral epicondylitis or plantar fasciitis (see Plate 28). Recognizing early SpA: undia gnosed in \202 ammatory monoarthritis and oligoarthritis in patients with HLA B27 may repr esent the \201 rst manifestation of a SpA. Investigations For details see individual sections. In the context of inflammatory spine sy mptoms, the presence of HLA B27 increases the chance of ultimately diagnosing a SpA. Laboratory \200 ESR and CRP can be raised particularly in severe AS, acute exacerbations (notably ReA and P sA), but are often in the normal range. Where in \202 ammatory disease is severe and prolo nged, features of anemia of chronic disease may be evident. Persistently elevated serum IgA is a common, but non-speci \201 c \201 nding. Key features in history \200 Eliciting the history in early SpA often requires detailed and close questioning (previous relevant symptoms may have been mild, forgotten, or due to other conditions). The features of in \202 ammatory back pain are consistent. A high chance of SpA exists where in \202 a mmatory back pain is chronic (>3 months) in a young or middle-aged adult with certain featu res (see Table 7.1). Imaging \200 Radiographs may be normal, although if there is a long history of suspiciously relevant (pr eviously undiagnosed) symptoms, radiographs may be revealing. Ultrasound of entheses can im prove an assessment of enthesitis (Lehtinen et al., 1994). THE SPONDYLARTHROPATHIES: DISEASE SPECTRUM 212 MR \200 An important part of the management of USpA is to keep patients under review for detecting evolution of the disease (e.g. to AS, PsA or IBD-related SpA particu- larly or involving ot her SpA features). Using conventional scanning protocols, even using fat- suppression T2-weighted sequences, a ny signal change in enthesial tissue in SpA may be dif \201 cult to detect. Bone oedema un derlying entheses is often seen how- ever in AS and in SpAs, where clinical features are ma rked. The cause of the bone oedema is unknown (Figure 7.1). Enthesitis and sub-enthesial os teitis have been identi \201 ed at joints affected by synovitis in patients with SpA. Patt erns of abnormal bone oedema may be viewed as non-speci \201 c, but say, for the spine, if multiple, there should be suspicion of underlying SpA. Bone scintigraphy \200 Whole body 99mTc-MDP scans can be useful in highlighting the distribution of lesions. Simul tanous tracer localiza- tion to Achilles \200\231 tendon insertion, origin of plantar fasci a, patella ligament insertion, and sacroiliac joint(s), for example, is suggestive of SpA. The upper limb lesions associated with SpAs are less well reported in the nuclear medicine literature. Isotope bone scans are likely to be insensitive in identifying spinal enthesiti s or mild SpA-linked osteitis. Aseptic discitis is a recognized lesion seen with bone scint igraphy, but studies linking this (rather non-speci \201 c pattern) to a diagnosis of SpA are lacking. Figure 7.1 USpA. Fat-suppressed T2-weighted MR of SIJs showing sacroiliitis of the right SI J (high signal) and low signal of juxta-SIJ bone (left SIJ). The right SIJ is acutely in \202 amed; the left was probably in \202 amed in the past with current low juxta-SIJ bone signal suggestive of bone sclerosis. Differential diagnosis SpAs can present in a wide variety of ways. \200 In \202 ammatory back pain type symptoms in adults can be due to an in \202 ammatory phas e of disc degeneration or frank discitis. In the elderly axial skeletal CPPDD disease shoul d be considered. Dactylitis can typically occur in sarcoid, as well as SpA. Occasionally, S pA dactylitis can be mistaken for gout dactylitis, but the latter generally involves more e ccentric digital swelling. Enthesitis almost certainly can occur in chronic sarcoid, as wel l as in all SpAs. If sacroiliitis is con \201 rmed on imaging there are few other conditio ns to consider and caution in diagnosing \200\230degen- erative \200\231 sacroiliiac arthr itis is advised when PsA is a clinical possibility [PsA associated sacroiliac joint (SIJ) d isease can be unilateral and be characterized by subtle SIJ nar- rowing, sclerosis, and mar ginal periosteal apposition]. Figure 7.2 Enthesitis and arthritis in the feet in a patient with USpA shown on 99mTc-MDP s cintigraphy. Bilateral plantar fascia origin enthesitis and midfoot disease. Patient develo ped more characteristic features of PsA ultimately. Current controversies There is an overlap of features in the SpAs. This means that patients with one distinct condition may be at increased risk of another. More commonly, features o f different con- ditions can be present in the same person without there necessarily being a full set of clinical features to satisfy (formal or informal) criteria for one SpA or ano ther. The degree to which this occurs is not known precisely chie \202 y owing to the dif \201 culties of case ascertainment, recall, and a lack of appropriate prospective studies. \200 Treatment Most patients with SpA bene \201 t from a regular NSAID and spinal physiotherapy input. \200 Disease-related fatigue and functional impact needs to be recognized and addressed accordin gly. IBD-related SpA should be treated with NSAIDs cautiously. Sulphasalazine is a reasonab le \201 rst choice therapy for persistent peripheral synovitis/enthesitis. There is littl e evidence for a therapeutic effect of any immunosuppressant on axial SpA disease. There no convincing evidence that antibiotics change the course of any SpA in the long-term if it i s triggered or aggravated by identi \201 able disease (e.g. Campylobacter, Chlamydia, etc) . Intravenous bisphosphonates can help axial symptoms, although serial injections may be ne cessary. There is evidence that anti-TNFA therapy can improve USpA symptoms, although long- term studies are lacking. The risk of various features of HLA B27-related disease occurring in patients over time has not been precisely determined. However, it may be useful to explain to patients that, if ( for example) they are HLA B27 and have a SpA lesion, they are at risk of their condition ev olving in a number of ways. This concept of relapsing and remit- ting SpA-related features over a lifetime is often poorly understood, but unless appreciated there can be diag- nosti c dif \201 culties. The concept of SpA potentially varying/relapsing can cause confusion. This notably occurs if enthesitis is not recognized as part of the SpA. \200\230Tennis elb ow \200\231, plantar CHAPTER 7 The spondylarthropathies 213 fasciitis, and rotator cuff tendonitis might be diagnosed as distinct problems, rather than SpA-related enthesitis of humeral epicondyle, plantar fascia origin, and deltoid origin, r espectively. \200\230In \202 ammatory \200\231 lesions may be present, but not suf \201 - ciently severe (or noticeable) for patients to be referred to specialist (or present to t heir primary care doctor). At various times, symptoms may lead to recognition, but then reg ress or be treated. Patients (particularly the HLA B27+ ones) and their doctors should be a lerted to the potential for SpA lesions to \200\230 \202 are-up \200\231 through life. ICD-10 codes M46.0 M76.9 M46.1 Spinal enthesopathy Enthesopathy of lower limb, unspeci \201 ed Sacroiliitis not elsewhere classi \201 ed References Amor B, Dougados M, Mijiyawa M. Crit res de classi \201 cation des spondylarthropathies. Rev Rheumat 1990; 57: 85 \200\2239. Benjamin M, McGonagle D. The anatomical basis for disease locali- sation in seronegative sp ondyloarthropathy at entheses and related sites. J Anat 2001; 199: 503 \200\22326. Benjamin M, Ralphs JR. Fibrocartilage in tendons and ligaments \200\223 an adaptation to compressive load. J Anat 1998; 193: 481 \200\22394. Musculoskeletal (e.g. enthesitis or dactylitis) Blocka KLN, Sibley JT. Undiagnosed chronic monoarthritis. Arthritis Rheum 1987; 30: 1357 \200\22361. Inflammatory bowel symptoms Braun J, Bollow M, Remlinger G, et al. Prevalence of SpAs in HLA B27 positive and negative blood donors. Arthritis Rheum 1998; 41: 58 \200\22367. Psoriasis Acute uveitis Calin A. Terminology, introduction, diagnostic criteria and overview. In: The Spondylarthri tides. Eds Calin A and Taurog JD. OUP, Oxford 1998; pp3-6. Acute uveitis Khan MA, van der Linden SM. A wider spectrum of spondylar- X1 thropathies. Sem Arthritis Rheum 1990; 20: 107 \200\22313. Lehtinen A, Taavitsainen M, Leirisalo-Repo M. Sonographic analysis of enthesopathy in the l ower extremeties of patients with SpA. Clin Exp Rheumatol 1994; 12: 143 \200\2238. Time (years) Figure 7.3 An example of features of SpA over time. Schema to show patients how different S pA lesions can relapse and remit, be severe or so mild \200\223 even absent (say below the dotted line X1) - that they are shrugged off or not taken to the doctor. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. In \202 ammatory back pain in ankylos ing spondylitis. Arthritis Rheum 2006; 54: 569 \200\22378. Schattenkirchner M, Kruger K. Na tural course and prognosis of HLA-B27 positive oligoarthritis. Clin Rheumatol 1987; 6(Suppl 2): 83 \200\2236. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing s pondylitis: a proposal for modi \201 cation of the New York criteria. Arthritis Rheum 1984 ; 27: 361 \200\2238. Resources Assessment tools See under Ankylosing spondylitis. Internet sites Webpage on Spondylarthritis American College of Rheu- matology (www.rheumato logy.org/public/ factsheets/) ANKYLOSING SPONDYLITIS 214 Ankylosing spondylitis De \201 nition The clinical hallmark of AS is in \202 ammatory spinal pain and stiffness. Pathological changes typically occur at entheses. There are three main classi \201 cation criteria for AS. The most recent is shown below. Genetic \200 HLA B27 is heterogenic. There are >20 allotypes. Most allotypes preferentially predispose t o AS, some may not (e.g. B*2706 and B*2709). Concordance in MZ B27+ twins is 63%, but 24% i n DZ twins, indicating a role for genes other than HLA B27. Potentially combinations of cer tain HLA B27 alleles with polymorphisms in genes encoding for Killer cell Ig-like receptors (KIRs) or Leucocyte Ig-like receptors (LILRs) may predispose to AS (see below). Modi \201 ed New York Criteria for diagnosis of AS See van der Linden 1984. Clinical \200 Low back pain and stiffness >3 months, which improves with exercise, but is not relieved by rest. Limitation of movement of the lumbar spine in both the sagittal and frontal planes. Limitation of chest expansion relative to normal values corrected for age and sex. Environmental A link to Klebsiella has been postulated. Evidence for Klebsiella alone trigg ering AS in all ethnic groups and geographical locations is not persuasive. Immunopathology \200 Radiological \200 \200 The HLA B27 heavy chain has a free unpaired cysteine residue; which may lead to abnormal pe ptide binding or B27 folding, and heavy chain dimerization (in vitro). B27 heavy chains can be expressed at cell surfaces in patients with AS. HLA B27 heavy chain multimers may be re cognized, in the absence of B2-microglobulin, by some lymphocytes. There is some evidence f or increased numbers of CD57 natural killer cells in the blood of AS patients. HLA B27 may be recognized in vitro by certain NK cells or other leucocytes through an interaction with speci \201 c KIRs or LILRs. The balance of activating and inhibitory B27-recognizing KIRs may be important in generating AS and other HLA B27-related SpAs. In early AS, sacroiliitis may be characterized by CD+ T-cells and CD68+ macrophages in the joint and adjacent bone m arrow. Anatomical site-speci \201 c immunopathological data from AS patients is lacking fr om SI joints and spinal entheses particularly. Bilateral sacroiliitis \211 grade 2 or Unilateral sacroiliitis grade 3 or 4. AS is diagnosed if a radiological criterion is present with at least one clinical criterion Epidemiology \200 \200 \200 Prevalence in Caucasians about 1%. Strong link to HLA B27 (about 95% Caucasians). HLA B27 p revalence varies in ethnic groups, although does not always correlate with AS prevalence [e .g. in Native Americans where prevalence of HLA B27 is 18 \200\223 50%, AS is frequent, whe reas in the Fula in Gambia, HLA B27 is highly prevalent (6 \200\22368%), but AS is unusual] . Gender ratio in Caucasians M:F is about 2.5:1. Typically develops in late teenage or earl y adult years. \200 Pathphysiology Various theories have been proposed to explain the asso- ciation of HLA B27 and AS (see below). Uniquely, the HLA B27 molecule itself may be immunogenic and trigger sp eci \201 c lymphocyte reactions. Tissue-speci \201 c pathophysiology \200 Tissue changes associated with disease progression have been illustrated almost exclusively by imaging. MR has been particularly illuminating in this respect. In the SIJ, in \202 am mation progresses through \201 brosis to ankylosis. Sub-chondral bone in \202 ammation i s probably an early associated feature. In the spine in \202 ammation precedes calci \201 cation and bone formation at entheses. Reactive bone sclerosis at sub-enthesial bone ensue s and bony bridges between vertebrae develop (syndesmophytes) (See Plate 34). If subenthesi al bone in \202 ammation/oedema/pathology is severe, vertebral osteopaenia/osteoporosis oc curs. In \202 ammation at entheses both in the spine and peripher- ies is characterized by enthesial in \202 ammation, sub-enthesial bone oedema/in \202 ammation and ultimately en thesophyte formation. Because of the consistent occurrence of in \202 ammation at sites in tendon rich in \201 brocartilage (i.e. entheses), it has been postulated that \201 bro cartilage may be a key target tissue for the immune response in AS. Why AS might be associated with HLA B27 \200 HLA B27 is in genetic linkage with a disease- associated gene. HLA B27 binds and presents \200\230arthritogenic \200\231 peptides. HLA B27 helps select T-cells in the thymus, which can cause disease. The HLA B27 free cysteine at position 67 can be modi \201 ed leading to \200\230an altered self \200\231. There is cross-reactivity of antibodies directed at som e bacterial proteins and HLA B27. HLA B27 is a receptor for a bacterial ligand. An interact ion between HLA B27 and a bacterial superantigen causes non-speci \201 c T-cell activation . HLA B27-derived peptides are presented by HLA class 2 molecules to CD4+ T-cells. \200 \200 CHAPTER 7 The spondylarthropathies 215 Natural history \200 Previous enthesitis (e.g. previous plantar fasciitis) can precede the onset of obvious AS b y many years. Given HLA B27+ is dominantly inherited there may be familial clustering of HL A B27-related diseases. A history of uveitis, psoriasis, inflammatory bowel disease, urethr itis may all be relevant. AS classically progresses from sacroiliitis with in \202 amma- tory symptoms ascending the spine leading to spinal ankylosis, kyphosis/stoop and spinal restriction. Predicting class ical or less extensive disease is dif \201 cult in early AS. Osteoporosis, as shown by lum bar spine bone mineral density (BMD) measures might predict progres- sive disease. No known therapy halts or slows the natural history, although it is hoped anti-TNFA therapy may pro ve to have a disease-modifying role. AS can have a considerable socio-economic impact in so me, although not all patients. Key features on examination \200 Global restriction of lumbar spine movements in early AS and stiffening of the whole spine as AS progresses. Ultimately completely stiff spine with kyphosis. Reduced chest expansion compared to population reference for age/sex (at 4th intercostal space level). Peripheral j oint synovitis/arthritis is unusual with primary AS (apart from hip and shoulder joints). E nthesitis is variable and more prominent in lower limbs. (see Plate 4) Associated psoriasis may not be obvious. Any evidence of eye signs should prompt a ophthalmology referral to ru le out uveitis. Cardiovascular and respiratory examination is important with in established AS or those with symptoms. Associated conditions and co-morbidities \200 \200 AS is associated with iritis (40%). Cardiac conduction defects, aortic valve (AoV) incom- p etence and cardiomegaly occur. Anatomic evidence of AoV involvement can be seen in up to 20 % AS patients, but few have valvular dysfunction. About 50% patients with isolated AoV inco mpetence are HLA B27 +ve. Frank in \202 ammatory bowel disease or low-grade (often subclin ical) disease is commonly associated. Although rare, upper lobe lung \201 brosis can occu r and affected tissue be invaded by aspergillus. Deaths from all pulmonary causes are \201 ve times higher in AS compared with normal. This may relate partly to poor thoracic ex pansion and ventilatory dif \201 culty in the presence of lung infection and cardiac patho logy. Psoriasis and psoriaform skin lesions occur, arguably more commonly, in men compared with women. \200 Investigations Laboratory HLA B27 in >90% Caucasians; modest iESR or ESR normal (increases in ESR corresponds to severity of disease (e.g. i+ in AS patients with peripheral erosive a rthritis); normochromic normocytic anemia; IgAi. Radiographs In early AS, radiographs of SI Js and spine may be normal. As AS advances sacroiliitis may be become obvious and is usuall y bilateral. The sequence of sacroiliac changes over time typically consists of: \200 \200 Clinical features Key clinical features Delays in diagnosing AS are recognized. Taking a ca reful history and identifying that chronic in \202 ammatory-type back symptoms in someone <40 years may not re \202 ect a simple mechanical back disorder or a chronic pain syn- dro me, is probably the most important step in prompting appropriate imaging to be done to make a diagnosis. Initially, blurring of sub-chondral bone plate. Erosions (like postage stamp serrations) an d sclerosis of adjacent bone (typically iliac side \201 rst). Pseudo-widening of the SIJ. Gradual interosseous bridging and joint ossi \201 cation. Sclerosis persists or becomes m ore prominent. Bony ankylosis after a number of years. (see Plate 22) \200 \200 \200 Symptoms and signs \200 \200 \200 Key radiographic features in the axial skeleton Chronic in \202 ammatory spinal pain in a young adult. Fatigue. Low back pains radiating t o buttocks and posterior thighs. History of enthesitis (e.g. plantar fasciitis). Positive f amily history of SpA. Spinal movements are symmetrically restricted. Tenderness over enthes es (particularly pelvis/lower limb). Features on axial skeleton radiographs in AS patients \200 Early spinal features: vertebral squaring; small marginal syndesmophytes; erosion/sclerosis at verte- bral body corners [ \200\230shiny corner \200\231 sign/Romanus lesion (severe)]. Late spinal features: ankylosis of vertebral seg- ments (vertebral bodies or posterior seg ments; ossi- \201 cation of supraspinous and interspinous ligaments. Occurring at any tim e: discovertebral junction ero- sions or destruction; erosion/sclerosis of odontoid or cost overtebral joints; posterior spinal subligamen- tous erosion. Pelvis changes: sacroiliac pa thology (see text); iliac enthesophytes; ischial pole erosions/enthesophytes; symphysis pub is narrowing/sclerosis/erosion and ankylosis (late). \200 \200 \200 Key features in the history \200 In \202 ammatory spinal pains are invariable \200\223 pains are often associated with sti ffness, evolve insidiously, are promi- nent with immobility, are present on waking, can dis turb sleep, and ease with movement. Onset after the age of 45 years is very uncommon. Fatig ue, weight loss, and low-grade fever may occur and appear variable. Fatigue is often scored as the most troublesome symptoms by patients. \200 ANKYLOSING SPONDYLITIS 216 Typical radiographic features in the peripheral skeleton in established AS include: \200 DISH can be discriminated from AS (Table 7.2), but doing so using MR is not emphasized in t he literature. Osteitis Condensans Ilii can mimic sacroiliitis on pelvic radiographs. It us ually occurs in nulliparous women and is asymptomatic. Sclerosis occurs on the iliac side o f the lower SIJ, but the joint is normal. At the hip: in early disease \200\223 a distinctive enthesophyte on the lateral aspect of the femoral head. Eventually, a collar of these enthesophytes can form around the femoral h ead; diffuse concentric joint space narrowing; bony ankylosis (late). At the shoulder: conc entric joint space loss; superi- olateral humeral head erosions (if severe causing a \200 \230hatchet \200\231 appearance to the humeral head); erosive acromioclavicular joint (ACJ) and SCJ changes; CA liga- ment attachment bony proliferation/periosteal changes. Periphera l joints: periarticular osteoporosis less prominent than in RA; periarticular bone prolifer ation (fuzzy osteoperiostitis), e.g. at distal humeral epicondyles, patella margins, distal lateral femoral condyles; at attach- ments of carpal ligaments. At entheses: erosions, \202 uffy bone sclerosis and spurs. Changes often seen at plantar fascia origin, insertion of peroneal tendons in midfoot, Achilles \200\231 tendon or at lesser or greater trochanter s at proximal femur. Magnetic resonance imaging \200 Features of spondylodiscitis on T1- and T2-weighted MR are seen in AS though easy descrimin ation of AS/SpA- related spondylodiscitis compared with degeneration (Modic lesion) disciti s lesions has not been reported. The appearance of \200\230vertebral corner \200\231, \200\230oedema \200\231-type changes on both T1- and T2-weighted sequences is typical in AS . The cause of high signal in vertebral corners on T1-weighted lesions is unknown, but coul d be fatty change at sites of previous subenthesial osteitis. Spinal ligament enthesitis is probably poorly visualized on MR unless lesions are severe or numerous. Gd-enhancement app ears to add little overall in aiding a diagnosis of SpA or monitoring changes in in \202 a mmatory lesions after treatment. A number of robust MR scoring tools have been devised to m easure and monitor disease in AS. Consensus opinion suggests the 6-discovertebral unit (6-D VU) method devised under the auspices of SPARCC may be of most use. Figure 7.5 T2-weighted sagittal TSp in AS. High signal (in bone ?;osteitis) can be seen in 2 vertebal bodies in the TSp. Table 7.2 Discriminating AS from DISH DISH AS