| Ann Rheum Dis. 2006 April;65(4): 442–452.Published online 2005 August 26.doi: 10.1136/ard.2005.041137 | PMCID: PMC1798102 |
Copyright© 2006 BMJ Publishing Group Ltd & European LeagueAgainst Rheumatism
ASAS/EULARrecommendations for the management of ankylosingspondylitis
J Zochling, D van der Heijde, R Burgos‐Vargas, E Collantes, JC Davis, Jr, B Dijkmans, M Dougados, P Géher, R D Inman, M A Khan,T K Kvien, M Leirisalo‐Repo, I Olivieri, K Pavelka, J Sieper, GStucki, R D Sturrock, S van der Linden, D Wendling, H Böhm, B J vanRoyen, and J BraunJ Zochling, Rheumazentrum‐Ruhrgebiet, StJosefs‐Krankenhaus, Herne, Germany, and Institute of Bone and JointResearch, Royal North Shore Hospital, Sydney, AustraliaD van der Heijde, S van derLinden, Department of Internal Medicine, Division ofRheumatology, University Hospital Maastrict and Caphri ResearchInstitute, The NetherlandsR Burgos‐Vargas, Department of Rheumatology,Hospital General de Mexico, MexicoE Collantes, Servicio de Reumatologia,Hospital Reina Sofia, Cordoba, SpainJ C Davis, Jr, Division of Rheumatology,University of California San Francisco, San Francisco, USAB Dijkmans, Department of Rheumatology, VUUniversity Medical Centre, Amsterdam, The NetherlandsM Dougados, Service de Rheumatologie B,Hospital Cochin, Paris, FranceP Géher, Department of Rheumatology andPhysiotherapy, Semmelweis University, Budapest, HungaryR D Inman, Toronto Western Hospital andUniversity of Toronto, Toronto, Ontario, CanadaM A Khan, Case Western Reserve University,University, MetroHealth Medical Center, Division of Rheumatology,Cleveland, Ohio, USAT K Kvien, Department of Rheumatology,Diakonhjemmet Hospital, Oslo, NorwayM Leirisalo‐Repo, Department of Medicine,Division of Rheumatology, Helsinki University Central Hospital,Helsinki, FinlandI Olivieri, Rheumatology Department ofLucania, S Carlo Hospital, Potenza and Madonna delle GrazieHospital, Matera, ItalyK Pavelka, Institute of Rheumatology, Prague,Czech RepublicJ Sieper, Department of Gastroenterology andRheumatology, Charitè, Campus Benjamin Franklin, Berlin,GermanyG Stucki, Department of Physical Medicine andRehabilitation, Ludwig‐Maximilians‐University, Munich,GermanyR D Sturrock, Centre for Rheumatic Diseases,University Department of Medicine, Glasgow Royal Infirmary,Glasgow, UKD Wendling, Service de Rhumatologie, CHU JeanMinjoz, Besancon, FranceH Böhm, Department for Orthopaedics, SpinalSurgery and Paraplegiology, Zentralklinik Bad Berka, Bad Berka,GermanyB J van Royen, Department of OrthopaedicSurgery, VU University Medical Centre, Amsterdam, TheNetherlandsJ Braun, Bochum University,Rheumazentrum‐Ruhrgebiet, St Josefs‐Krankenhaus, Herne,GermanyCorrespondence to: Professor J Braun
Rheumazentrum‐Ruhrgebiet, St Josefs‐Krankenhaus, Landgrafenstr 15,44652 Herne, Germany; J.Braun@rheumazentrum‐ruhrgebiet.deCopyright © 2006 BMJ Publishing Group Ltd &European League Against RheumatismAccepted August 22, 2005. This article has been citedby other articles in PMC.AbstractObjectiveTo develop evidence based recommendations for the managementof ankylosing spondylitis (AS) as a combined effort of the‘ASsessment in AS' international working group and the EuropeanLeague Against Rheumatism.MethodsEach of the 22 participants was asked to contribute up to 15propositions describing key clinical aspects of AS management. ADelphi process was used to select 10 final propositions. Asystematic literature search was then performed to obtainscientific evidence for each proposition. Outcome data forefficacy, adverse effects, and cost effectiveness were abstracted.The effect size, relative risk, number needed to treat, andincremental cost effectiveness ratio were calculated. On the basisof the search results, 10 major recommendations for the managementof AS were constructed. The strength of recommendation was assessedbased on the strength of the literature evidence, risk‐benefittrade‐off, and clinical expertise.ResultsThe final recommendations considered theuse of non‐steroidal anti‐inflammatory drugs (NSAIDs) (conventionalNSAIDs, coxibs, and co‐prescription of gastroprotective agents),disease modifying antirheumatic drugs, treatments with biologicalagents, simple analgesics, local and systemic steroids,non‐pharmacological treatment (including education, exercise, andphysiotherapy), and surgical interventions. Three generalrecommendations were also included. Research evidence (categoriesI–IV) supported 11 interventions in the treatment of AS. Strengthof recommendation varied, depending on the category of evidence andexpert opinion.ConclusionTen key recommendations for thetreatment of AS were developed and assessed using a combination ofresearch based evidence and expert consensus. Regular updating willbe carried out to keep abreast of new developments in themanagement of AS.Keywords: ankylosing spondylitis,management, recommendations, evidence based medicine,spondyloarthropathies, ASAS, EULARAnkylosing spondylitis (AS) is a chronic, inflammatoryrheumatic disease characterised by inflammatory back pain due tosacroiliitis and spondylitis, the formation of syndesmophytesleading to ankylosis, and frequently associated with peripheralarthritis, enthesitis, and acute anterior uveitis. Symptomscommonly begin in late adolescence and earlyadulthood.1,2 With an estimated prevalence of 0.9%in northern European white populations3 AS is a significant health burden tothe community.AS has long been a therapeutic challenge for the clinician.Exercise and non‐steroidal anti‐inflammatory drugs (NSAIDs) havebeen the mainstay of symptom control for decades, but there hasuntil recently been a dearth of disease modifying treatments. Theadvent of biological treatment is currently revolutionising themanagement of AS, but too little is known yet about the long termbenefits and risks of such treatment. Clearly, these treatmentsnecessitate socioeconomic cost calculations. Moreover, there is aneed for rational, evidence based recommendations to guide thephysician in the management of AS. The ASsessment in AS (ASAS)international working group has made important contributions to theevaluation and standardisation of assessments in AS in the pastdecade.4,5This project is a collaborative effort of ASAS and EULAR withthe ultimate objective to contribute to the improvement of outcomesin patients with AS by constructing evidence based managementrecommendations. To obtain and maintain a high level of intrinsicquality and comparability of this approach, the EULAR standardoperating procedures6 were followed.MethodsParticipantsA multidisciplinary guideline development committee was formedfrom within the ASAS working group, with participants selected onthe basis of publication history in AS, personal knowledge, andapproval by EULAR. Twenty two experts in the field of AS (20rheumatologists, one also a patient with AS, and two orthopaedicsurgeons) representing 14 countries took part in the study. Eachparticipant was asked to contribute independently up to 15 keypropositions relevant to the management of AS, to create acomprehensive list of potential topics of interest. A Delphitechnique was then used to reduce these to a predefined final 10propositions over three rounds. Questions were acceptedautomatically if selected by 80% or more of the participants in anyround, whereas questions receiving less than 20% of the votes wereremoved.Systematic literature searchA general search of Medline, Embase, CINHAL, PEDro, and theCochrane Library was conducted summarising the current available AStreatments from the literature, and the results reported to thecommittee before the Delphi exercise. After the 10 propositions hadbeen generated, an intervention‐specific literature search wasundertaken to identify evidence for each specifiedintervention.7 The “online first” sections ofrheumatology journals as well as the abstracts of rheumatologyscientific meetings from the years 2003 and 2004 were hand searchedfor additional relevant studies. Only studies with clinicaloutcomes for AS were included. Animal studies, narrative reviewarticles, commentaries, and guidelines were excluded.Categorising evidenceEvidence was categorised according to study design using atraditional hierarchy8 (table 11).).Questions on efficacy were answered using the “best available”evidence. The highest available category of evidence for eachintervention was reviewed in depth, and the next highest categoryconsidered when few high level studies were retrieved. Whereasefficacy was assessed specifically for AS, side effects wereevaluated specifically for the intervention, and so studies inother musculoskeletal diseases were also reviewed. | Table 1 Evidence hierarchy andtraditional strength of recommendation |
Estimation of effectiveness and cost effectivenessEffect size (ES) and 95% confidence interval (95% CI) for eachintervention were calculated for two predefined continuousoutcomes: pain relief and improvement in function.9ES is the standardised mean difference (mean change divided bystandard deviation of the change), and therefore has no units andis comparable across interventions in similar populations.Clinically, an ES of 0.2 is considered small, 0.5 is moderate, and>0.8 is large.10Statistical pooling was undertaken as appropriate.11 The percentage of patientsresponding to treatment (an ASAS20 response, pain relief of morethan 50%, or functional improvement of more than 20%) wascalculated where possible, and the number needed to treat (thenumber of patients who need to be treated to prevent one additionalpoor outcome) was estimated.12 Relative risk was calculated foradverse effects.For economic evaluations, the incremental cost effectivenessratio was calculated. Data were extracted by one investigator (JZ).A customised form was used for the data extraction.Strength of recommendationThe strength of each recommendation was graded A–D based onthe category of efficacy evidence (table 11)8 by two members of the committee(JZ, JB). A numerical rating scale (NRS) was used to quantify“expert opinion” for each intervention identified. Each member ofthe committee was asked to rate their strength of recommendationfor each intervention on a 0–10 NRS, according to both the researchevidence presented (efficacy, safety, and cost effectiveness) andtheir own clinical expertise (logistics, patient perceivedacceptance, and tolerability). The mean (SEM) for the strength ofthe recommendation was calculated for each intervention.When the final 10 recommendations had been agreed, a flowchart was constructed by the expert group to summarise the mostimportant aspects of the management of AS, based on clinicalexpertise and research evidence.ResultsDetails of the literature search results and the specificstudies discussed during the elucidation of each recommendationhave been published elsewhere.7 Table 22gives the final 10 recommendations. | Table 2 Experts' propositionsdeveloped through three Delphi rounds—order according to topic(general, non‐pharmacological, pharmacological, invasive, andsurgical) |
The first three recommendations deal with general concepts inthe management of AS, and the remaining seven describe specifictreatments in use for AS. AS.TablesTables3‐5summarise the evidence for efficacy, toxicity, and costeffectiveness for each intervention. Table 66gives the strength of each recommendation as assigned by the expertgroup. | Table 3 Evidence ofefficacy—pooled effect size (ES) and number needed to treat(NNT) |
| Table 4 Evidence of sideeffects—pooled relative risk (RR) and 95% confidence interval (CI)from randomised controlled trials (RCTs) |
| Table 5 Evidence of costeffectiveness for the proposed interventions |
| Table 6 Strength ofrecommendations |
Propositions1. Treatment of AS should be tailored accordingto:General clinical status (age, sex, comorbidity,concomitant drugs)Wishes and expectations of the patient.This statement represents ideal practice and includes clinicalmarkers that are often used to guide clinical decisions. However,although it has considerable face validity, there is littleexperimental evidence to support it. Trials to evaluate treatmentefficacy frequently include a highly selected population. Fewstudies are therefore designed to differentiate therapeutic effectsaccording to patient characteristics. General information on thesefactors can better be obtained from observational studies. Forexample, in observational cohorts, hip involvement is the mostimportant and consistent factor predisposing to severedisease.13 However, there is nointernational consensus on disease severity of patients with AS.Other clinical prognostic indicators include age, sex, number ofperipheral joints affected, smoking, raised erythrocytesedimentation rate, poor response to NSAIDs,13,14,15,16 and radiological changes atbaseline.17,18In a recent review, in which the results of two randomisedtrials of biological treatment in AS were analysed according topatient factors,19 the response to anti‐tumour necrosisfactor (TNF) treatment was better in younger patients with shorterdisease duration and less functional disability. However, becauseboth studies were carried out in patients with high diseaseactivity at baseline, it is not possible to generalise theseconclusions to a wider population of patients with AS.2. Disease monitoring of patients with AS shouldinclude: patient history (for example, questionnaires), clinicalparameters, laboratory tests, and imaging, all according to theclinical presentation as well as the ASAS core set. The frequencyof monitoring should be decided on an individual basis depending onsymptoms, severity, and drug treatmentClinical presentation includes all aspects of diseaseexpression in AS, including axial disease, peripheral disease,enthesitis, and extra‐articular manifestations (such as acuteuveitis, conjunctivitis, carditis).The ASAS working group has developed a core set for use inclinical record keeping.20,21 This core set includes domains onaxial, peripheral, and enthesopathological manifestations, and foreach domain, one or more specific instruments are recommended(table 77).Imaging is an evolving science in the evaluation of AS. Theexpert group discussed at length what might be the optimalfrequency for radiological evaluation of AS, and it was concludedthat based on the recent modified Stokes AS Spinal Scoredata,22 and clinical experience,radiographic monitoring may not be needed more often than onceevery 2 years. However, exceptions are possible becausesyndesmophytes may have developed already within 6 months in somepatients—this is considered to be the smallest interval between twox ray examinations. Films of the lateral cervical andlumbar spine are recommended for assessing change over time.Assessments of the thoracic spine may also be useful in individualpatients, especially where fractures are suspected. Similarly, anadditional anteroposterior (AP) lumbar spine film may give furtherinformation for assessing disease status in some patients. Oncediagnostic changes have been detected in the sacroiliac joints,sacroiliac x ray examinations add little information, butperiodic radiographic assessment of the hips may be of value.Recommendations on this item have not been finalised as yet.Magnetic resonance imaging (MRI) of the sacroiliac joints andthe spine is increasingly used to assess disease activity in AS.Although it has not been incorporated in the ASAS core set to date,it seems likely on the basis of recent data that MRI will have arole both in clinical trials and in daily care of the patients,because it is advantageous to have some objective evidence ofspinal inflammation.23,24,253. Optimal management of ASrequires a combination of non‐pharmacological and pharmacologicaltreatmentsOver 15% of the studies retrieved from the broadliterature search reported the effects of non‐pharmacologicaltreatments in AS. Again, no specific head to head studies have beenperformed to compare the effect of pharmacological andnon‐pharmacological treatments. The group consensus was thatnon‐pharmacological and pharmacological treatments arecomplementary and both are of value in the initial and continuingtreatment of patients with AS. Whether this combined approachapplies equally to early and advanced disease or to very active andinactive disease states has not yet been resolved. Figure 11shows the recommended management strategies for AS based onclinical expertise and research evidence. The disease progressionwith time moves vertically from top to bottom. This figureemphasises the importance of non‐pharmacological treatmentsthroughout the course of the disease, early introduction of NSAIDtreatment and options for refractory disease, and alternatives forconcomitant peripheral disease.
| Figure 1 Flow chart summary of the recommendedmanagement of AS, based on clinical expertise and researchevidence. The disease progression with time moves vertically fromtop to bottom. |
4. Non‐pharmacological treatment of AS shouldinclude patient education and regular exercise. Individual andgroup physical therapy should be considered. Patient associationsand self help groups may be usefulThe most recent systematic review ofphysiotherapy for AS reviewed six randomised controlled trials(RCTs),26showing that home exercise improved function in the short termcompared with no intervention. Supervised exercise programmesfailed to show improvements in pain or function compared with homeexercise, but patient global assessment was significantly better inpatients who underwent group therapy. Specific physical modalitieshave not been well studied. Level Ib evidence supports spa therapyfor physical functioning in patients with AS over 3 months but notlonger, and was shown to be cost effective.27,28Patient education has been shown to haveshort term benefit for function in AS29in one controlled trial. There are no studies examining the effectof education on pain. Education and behavioural therapy have,however, been shown to be beneficial for other outcomes such asmotivation and anxiety,30 and are cost effective over12 months.31 Patient associations and self helpgroups have not been studied for their effect on pain or functionaloutcomes.5. NSAIDs are recommended as first line drugtreatment for patients with AS with pain and stiffness. In thosewith increased gastrointestinal (GI) risk, non‐selective NSAIDsplus a gastroprotective agent, or a selective COX‐2 inhibitor couldbe usedThere is convincing evidence(level Ib) that NSAIDs improve spinal pain, peripheral joint pain,and function over a short time period (6 weeks). Coxibs are equallyeffective, showing large improvements in spinal pain and functionin patients with AS, but peripheral joint pain has not beenspecifically examined. Comparative studies of different NSAIDs havenot shown one preparation to be clearly better than theothers.A recent RCT comparingthe efficacy of continuous celecoxib treatment for AS withintermittent “on demand” use suggests that continuous treatmentretards radiographic disease progression at2 years.32 This is the first study to show apossible diseasemodifying effect of continuous treatment, and warrants furtherinvestigation.The GI toxicity of NSAIDs and coxibs hasbeen elegantly presented in the recent EULAR recommendations forthe management of hip osteoarthritis.33 In summary, NSAIDs cause anincreased risk of GI bleeding, which is dose dependent, and can bereduced with the use of gastroprotective agents. Table 44shows the relative risks. Coxibs have a lower risk of serious GIevents34 than NSAIDs. The GI toxicity ofNSAIDs in AS may be accounted for by the recognised risks for NSAIDgastropathy (age, concomitant corticosteroids, etc), suggestingthat there is no specific impact of the disease on GI toxicity fromNSAIDs.The evidence for cardiovascular toxicityrelated to anti‐inflammatory drugs is rapidly evolving. What wasinitially seen as a cardiovascular toxicity signal withrofecoxib35 has now also been described inlarge trials of other coxib preparations in varioussettings.36,37,38 Emerging evidence suggests thatnon‐coxib NSAIDs may possibly share some of this effect(unpublished data). In general, the choice of NSAID or coxib shouldbe based on the GI risk profile of the patient, and should takeinto account concomitant risk factors for cardiovasculardisease.6. Analgesics, such as paracetamoland opioids, might be considered for pain control in patients inwhom NSAIDs are insufficient, contraindicated, and/or poorlytoleratedParacetamol and other simple analgesicshave not been prospectively studied in AS. GI toxicity withparacetamol has been shown to be not significantly higher thanplacebo in level 1a studies in other musculoskeletaldiseases.39,407. Corticosteroid injections directed to thelocal site of musculoskeletal inflammation may be considered. Theuse of systemic corticosteroids for axial disease is not supportedby evidenceLocal inflammation is a keyfeature of AS, and can occur at many different musculoskeletalsites, including the axial joints (most commonly the sacroiliacjoints, but can also occur at the costovertebral andmanubriosternal joints), peripheral joints (usually an asymmetricoligoarthritis, with predominance of the lower limbs), andenthesitis (plantar fasciitis, Achilles enthesitis, patellar tendoninsertional enthesitis, involvement near the tibial tuberosity).Intra‐ or periarticular corticosteroid injections have been shownto be effective for the pain of sacroiliitis in small RCTs (levelIb evidence).41,42 There are no clinical studiesevaluating the efficacy of intra‐articular corticosteroid onperipheral arthritis in AS, or on the use of local corticosteroidinjections for the enthesitis of AS, although the expert groupfeels that these can be helpful in selected cases. Potentialtoxicity including tendon rupture must be considered.8. There is no evidence for the efficacy ofdisease modifying antirheumatic drugs (DMARDs), includingsulfasalazine and methotrexate, for the treatment of axial disease.Sulfasalazine may be considered in patients with peripheralarthritisThe available level Ia evidencefor the efficacy of sulfasalazine in AS is inconclusive. The mostrecent meta‐analysis43identified a possible differential response to treatment for spinalsymptoms and for peripheral joint disease. When data from theindividual trials was pooled, there was no significantly greatereffect seen on back pain (ES −2.38, 95% CI −5.78 to 1.03) orphysical function (ES 0.20, 95% CI −0.77 to 1.18) withsulfasalazine than with placebo. Long term trials of sulfasalazinein spondyloarthritis in general support an effect on peripheraljoints but not spinal inflammation—especially not in patients withlonger disease duration. There is a need for a study of theefficacy of sulfasalazine and other DMARDs for axial disease inpatients with short disease duration.In the only extended trial ofAS retrieved,44 patients treated with sulfasalazineover 3 years had significantly fewer episodes of peripheral jointsymptoms than the placebo group (p<0.05). Oneobservational study failed to show any effect of sulfasalazine onperipheral enthesitis (level IV evidence).45 The expert group felt thatsulfasalazine was more relevant for peripheral joint symptoms (mean(SEM) strength of recommendation 6.53 (0.48)) than for axialdisease (2.80 (0.60)). One RCT was retrieved showing thatsulfasalazine decreases the occurrence of recurrent acute uveitisin patients with AS.46Toxicity with sulfasalazine iscommon but usually mild: GI symptoms, mucocutaneous manifestations,hepatic enzyme abnormalities, and haematological abnormalities havebeen described (table 44).There has been no meta‐analysisof methotrexate for AS, with the only systematic review retrievedunable to combine results.47Therefore the best evidence from the literature is level Ib, withthree RCTs identified.48,49,50 Pooling results where possible didnot show a significant effect of methotrexate on spinal pain orfunction. The only study to report separate outcomes for peripheraljoint disease49 did not identify significant benefitwith treatment.The most commonly reported sideeffects occurring with methotrexate treatment include nausea andhepatic abnormalities (table 44).).Folate is effective in preventing GI symptoms and mucocutaneousadverse events.51There is little evidence tosupport the use of other DMARDs commonly used in other inflammatoryarthritides in AS (table 33).).There is level III evidence for a beneficial effect of intravenouspamidronate on both axial pain and function,52 but the study was not powered toassess an effect on peripheral joint disease. Further RCTs areneeded to answer this question. Side effects include transientpost‐infusional arthralgias and myalgias52,53,54 and an acute phase response withlymphopenia and raised C reactive protein.55Open trials suggest a beneficial effect for thalidomide on spinaldisease,56,57but toxicity is substantial, and when combined with the wellrecognised association of thalidomide with severe birth defects andpotentially irreversible peripheral neuropathies, the expertopinion of the group was that the toxicity profile of thalidomideoutweighed any potential therapeutic benefit.9. Anti‐TNF treatment should be given to patientswith persistently high disease activity despite conventionaltreatments according to the ASAS recommendations. There is noevidence to support the obligatory use of DMARDs before, orconcomitant with, anti‐TNF treatment in patients with axialdiseaseRCTs (level Ib evidence) support the use of the TNF inhibitorsetanercept58,59,60,61 and infliximab62,63 for spinal pain, function, andperipheral joint disease. Effect sizes are large (table 33),),and the number needed to treat to achieve an ASAS20 response islow. Adalimumab, the most recent TNF antagonist to become availablefor treatment in rheumatic diseases, has also been shown to beeffective in a level III study.64The onset of clinical effect with TNF blockers israpid,59 and therapeutic effect persistsfor up to 3 years with continuing treatment.65,66,67,68 Stopping treatment results in ahigh proportion of patients with clinical relapse.69 Although adding methotrexate toinfliximab treatment in rheumatoid arthritis improves clinicaloutcome70 and reduces sideeffects,71 there has been no evidence tosupport any additional benefit with concomitant methotrexate use inAS.72 The ASAS group has published acomprehensive, evidence based consensus statement for theinitiation of anti‐TNF treatment in AS73,74 (table 88))to identify appropriate therapeutic candidates. | Table 8 ASAS consensus foranti‐TNF treatment |
Toxicity with anti‐TNF treatment includes injection sitereactions with subcutaneous injections (etanercept and adalimumab)and uncommon infusion reactions with intravenous infliximab. Opentrials have shown treatment to be associated with increased risk ofinfection75,76—in particular,tuberculosis.77,78 Screening for Mycobacteriumtuberculosis is now a standard prerequisite for anti‐TNFtreatment. Demyelinating disease,79 lupus‐like syndromes,80,81,82 and worsening of pre‐existingcongestive heart failure83,84,85have also been reported in case series, although precise incidencesare not known.Although significantly more expensive than traditional AStreatments, the large improvements in pain and function with TNFblocker treatment may well outweigh the high costs in a formalcost‐benefit analysis,86,87projecting over 30 years that such treatments are even more costeffective when function and therefore productivity are preserved.Further economic evaluation is required to confirm thisprojection.There is insufficient evidence available at present to make adefinite statement on the role of interleukin 1 antagonists inAS.10. Total hip arthroplasty should be considered inpatients with refractory pain or disability and radiographicevidence of structural damage, independent of age. Spinalsurgery—for example, corrective osteotomy and stabilisationprocedures, may be of value in selected patientsThe best evidence for total hip arthroplasty (THA) is levelIV, with prospective cohort studies in patients with AS showinggood pain relief and functional improvement withsurgery.88 Although age and sex predictrevision rate in THA,89 revision rates in AS are not undulyhigh. Rates of heterotopic bone formation and re‐ankylosis afterTHA are not increased in patients with AS.90,91,92,93 Collective clinical experienceis that heterotopic ossification is no more common in the ASpopulation, dependent on surgical technique, and this is likely tobe affected by NSAID use in AS, and the routine practice ofpreoperative NSAID prophylaxis. The administration of NSAIDs on theevening before surgery (conventional practice) does not have aneffect on perioperative bleeding or complication rate. The expertgroup agreed that NSAID treatment does not need to be discontinuedfor THA surgery. The difference in long term durability orcomplications between cemented and non‐cemented hip prostheses isnot large, but THA in younger patients generally uses non‐cementedprostheses, as later revisions are technically easier (related toloss of bone structure). There are no comparative studies on thisitem in patients with AS.Spinal surgery is performed for a number of indications in AS,including disabling kyphosis, loss of horizontal vision withoutcompensation, painful spinal pseudarthrosis or Andersson lesion,pain and/or segmental instability of spinal fractures, and lesscommonly, neurological complications such as spinal stenosis,myelopathy, and rarely, cauda equina syndrome. Closing wedge lumbarosteotomy for fixed kyphotic deformity causing major disability cangive excellent functional results by restoring balance andhorizontal vision.94 Instrumentation failure has been aproblem with polysegmental wedge osteotomies,95 but permanent neurologicalcomplications are rare. Fusion procedures should be considered inpatients with segmental instability as a result of spinalpseudarthrosis or Andersson lesion, and in cases of instability orintractable pain due to spinal fracture. Corrective surgery of thecervical spine should be reserved for those patients with AS withspecific indications, and considered for patientsindividually.DiscussionThis is the first time that international recommendations forthe management of AS have been developed, and it is also the firstofficial collaboration of ASAS and EULAR. Recently, ASAS hassuccessfully collaborated with the FDA and the North Americanpatient organisation “Spondylitis Association of America” toproduce recommendations for clinical trials.96The major driving forces for this current project were(a) the rapid developments seen in available treatmentsfor AS over recent years; (b) the dedicated aim of ASAS toprovide valuable assessment tools for AS; and (c) thestandardised approach by EULAR to producing recommendations forcommon rheumatic diseases. Given the almost dramatic history ofsuccessful approvals of anti‐TNF agents in the past 3 years—whichis still continuing—it is becoming increasingly important to assessrelative benefits of the different treatments and to distinguishwhich are the most efficacious in particular patient settings. Forthis reason the ASAS and EULAR took on the challenge of developingevidence based recommendations for the management of AS.The methods used to develop the recommendations were based onthe standardised operating procedures published byEULAR,6 created to assist the promotionof high quality and comparability between studies of the managementof musculoskeletal diseases. Recommendations for the management ofknee osteoarthritis (OA)97 and for hip OA33 have already been developed usingthese methods. Evidence hierarchy was used as the primary means ofdescribing how strong or convincing the available evidence mightbe. This method considers the problem that poorly conducted orreported trials may be included, falsely increasing the level ofevidence. In those cases where a particular study was felt to be ofpoor quality, this was disclosed to the expert group and includedin the discussion of the literature.The literature supported 10 of the treatments identified forAS with level III evidence or higher, and supported negativeevidence for four modalities. Six modalities had limited level IVevidence. It is important to emphasise that this assessment focusedon an effect on pain or function, not on other outcomes which mightbe important and relevant to particular treatments, but were notused as primary outcomes in this exercise.The group decided at the outset of this project to concentrateon the effect of treatment on pain and function, two cardinalclinical features of AS which are commonly impaired and impartsignificant disability and distress to patients. The recentlydescribed ASAS20 composite measure of treatment response,comprising pain, function, spinal stiffness, and patient globalassessment,98,99 was also included as a primaryoutcome measure where available. This is a relatively new outcomemeasure, with only the anti‐TNF studies and the more recent NSAIDtrials reporting this. The expert committee emphasises that this inno way suggests that pain and function are the only importantoutcomes in AS; often the most important measure of therapeuticeffect is very treatment‐specific—for example, patientsatisfaction, compliance, confidence, and coping. Thus, a broaderapproach is usually required in individual patient care.The use of an evidence hierarchy to reflect the strength ofsupport for a treatment is intrinsically flawed when consideringsuch interventions as surgery. There can only be level III evidenceto support the use of THA in AS owing to the technical, as well asethical, impossibilities of performing a randomised, double blindcontrolled trial for a surgical procedure. In this case expertopinion is a valuable addition to the available literature.Similarly, in instances where no studies have been conducted toanswer a specific question, the absence of clinical trials meansthat expert opinion (level IV evidence) is the best availableevidence.A new method for measuring the strength of a recommendationwas recently proposed in the EULAR recommendations for hipOA,100combining available research evidence with expert opinion to give asingle index, measured by a 100 mm visual analogue scale (VAS) oran ordinal scale. The measure reflects a combination of literatureevidence, clinical experience, and patient perceived acceptance andtolerability, as rated by the experts. We have used this approachto quantify the overall support the experts gave each of thetreatment modalities, with an NRS in place of the VAS for the finalstrength of recommendation for each modality. Zhang et aldid not show good correlation between expert opinion and theresearch evidence.100This was not surprising, as in many situations with low levelevidence there is still strong expert opinion owing to clinicalexperience. Therefore the two approaches should complement eachother, but may not necessarily agree.The GRADE group has developed a multidimensional system toassess the grade of evidence,101,102,103 which is slightly moreextensive than the concept of level of evidence used for the ASrecommendations. It incorporates the study design, methodologicalquality, consistency of results between studies, applicability ofevidence to the population under consideration, and missing data,in order to assess the overall quality of the result, and theconfidence that the result of the research evidence is correct.Although a very comprehensive method of assessing treatmentmodalities, the GRADE system is complicated and difficult toimplement in extensive therapeutic reviews such as that carried outhere. The additional problems examined by GRADE were incorporatedinto the expert group discussions on each recommendation pointwhere applicable.Taken together, the expert group agreed on 10 majorrecommendations for the management of AS on the basis of the bestavailable evidence. This is considered an important starting pointto provide guidance for monitoring and treatment of patients withAS. It is important to realise that these are recommendations notguidelines; the lengthy discussions of the expert group for each ofthe 10 final points indicate that the final proposals were asynthesis of quite marked variations in opinion. Therecommendations reflect expert opinion based on the currentresearch evidence. They will be updated regularly, to keep abreastof new developments in the treatment of AS.AcknowledgementsWe acknowledge the conceptual and financial assistance ofEULAR in the development of these recommendations.AbbreviationsAS - ankylosing spondylitisASAS - ASsessment in ASCI - confidence intervalDMARDs - disease modifying antirheumatic drugsES - effect sizeMRI - magnetic resonance imagingNRS - numerical rating scaleNSAIDs - non‐steroidal anti‐inflammatory drugsOA - osteoarthritisRCT - randomised controlled trialTHA - total hip arthroplastyTNF - tumour necrosis factorVAS - visual analogue scaleReferences1. Khan M A. Update onspondyloarthropathies. 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