Annals of the Rheumatic Diseases 1996; 55: 552-557

NOW AND THEN

Recommendations for the registration of drugsused in the treatment of osteoarthritis

Group for the Respect of Ethics and Excellence in Science (GREES)*: osteoarthritis section

Osteoarthritis is a disorder which canpotentially affect all joints. It is characterisedby degeneration and regeneration of articularcartilage and bone. The pathological changescan be focal or more generalised and thesechanges correlate poorly with clinical symp-toms and signs. However, there is some evi-dence that asymptomatic osteoarthritis, diag-nosed radiologically, is a precursor ofsymptomatic disease. Osteoarthritis, particu-larly of the large joints of the lower limbs-forexample, knees and hips-is now widelyrecognised as a major cause of chronicdisability in the elderly population.

Recent technical advances have allowedsymptomatic and structural changes associatedwith osteoarthritis to be measured with greaterprecision than previously. These advances,together with increased knowledge of the bio-chemical mechanisms involved in the osteo-arthritic disease process, have encouragedclinical evaluation of several agents which mayhave a beneficial effect on the disease process.

Currently, there are inconsistencies in theclassification of drugs for the treatment ofosteoarthritis and the indications for their use.These inconsistencies are reflected in differentapproaches of national licensing authorities tothe registration of drugs for the treatment ofosteoarthritis. Accordingly, there seems to bean urgent need to standardise the registrationrequirements of such drugs. This prompted theformation of a European Working Group toconsider the issue. The group comprisedclinical and basic scientists working in the fieldof osteoarthritis in academia and the pharma-ceutical industry and representatives ofnational drug licensing authorities. This reportclassifies drugs for the treatment of osteo-arthritis as symptom modifying, structuremodifying, or both and gives recommendationsfor the preclinical and clinical studies con-sidered to be necessary prerequisites at thistime for the registration of such drugs. Therecommendations are based on currentlyavailable knowledge and technology. They willneed updating as further scientific progress ismade in this field.

Correspondence to:Dr Maxime Dougados,Rheumatology Institute,Cochin Hospital,27, rue du Fbg St Jacques,75014 Paris, France.

Accepted for publication28 March 1996

*See appendix

Objectives and nomenclatureOsteoarthritis is a chronic disease. Drugs de-veloped for its treatment are likely to be givencontinuously over many months or years withthe intention of controlling the evolution of thedisease in terms of symptoms and structuralchanges.

Committees of the International LeagueAgainst Rheumatism and the World HealthOrganisation have recently considered guide-lines for testing new drugs in osteoarthritis.The nomenclature proposed recognises threeclasses of drugs acting on osteoarthritis: fastacting drugs that induce symptomatic relief,slow acting drugs that induce symptomaticrelief, and disease modifying drugs.Two distinctions have been made in this

classification:

* The first is between symptomatic treatmentand structure modifying treatment. Thecorrelation between severity of joint pain ordisability and the pathological changes in anosteoarthritic joint is often poor betweenpatients at any point in time.

* The second is the distinction between drugswith fast and slow effects on symptoms.Arguments for classifying drugs that inducesymptomatic relief into these two subgroupsare not compelling. Although drugs that actslowly may have different mechanisms ofaction from those that act rapidly, there is arange of duration of action ofdrugs which acton symptoms. The design of trials shouldadequately take into account the timing andduration of the action of the drug onsymptoms and these factors may influencethe use of any concomitant treatment whichis permitted in a trial.

Based on these considerations, we propose aclassification of drugs for the treatment ofosteoarthritis that consists of two categories:(1) Symptom modifying drugsThese act on symptoms with no detectableeffect on the structural changes of the disease.Registration of such drugs would requiredemonstration of a favourable effect on symp-toms with no detectable adverse effect on thestructural changes of the disease.(2) Structure modifying drugsThese interfere with the progression of thepathological changes in osteoarthritis. Theycan be further subclassified by their effect onsymptoms:(a) Structure modifying, symptom relievingdrugs-Registration of such drugs wouldrequire demonstration of beneficial effects onboth symptoms and structural indices of thedisease.(b) Structure modifying drugs with no independenteffect of symptoms-There is good indirectevidence that, by favourably modifying thenatural history of osteoarthritis in terms ofstructural changes, long term clinical benefit

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will occur in a large proportion of patients.Drugs may become available which willfavourably influence joint structures withoutappreciable short term clinical benefit. Regis-tration of such drugs should be given seriousconsideration.

Preclinical studiesA standard package of preclinical toxicity testsis required in the evaluation of any drugs andtherefore also for those used in the treatmentof osteoarthritis.

In vitro and in vivo studies could be con-ducted at the discretion of the company. Thedecision whether to conduct such studies coulddepend on the properties of the drug andwhether potentially useful information couldbe obtained.

IN VITRO EVALUATIONIn vitro studies on cultures of chondrocytesand other connective tissue cells and organscan provide important information on themode of action of drugs with structuremodifying effects, but they are not necessaryfor drug registration purposes. Details of thespecies of origin and the cell or organ culturewhich are optimal for such studies will dependon the pharmacological profile of the agent tobe studied.

Effects of drugs on human articular chon-drocyte cultures, in which the long term preser-vation of the chondrocyte specific phenotypeand the reconstitution of articular cartilagearchitecture (or at least the typical extracellularmatrix molecules) from dispersed cells aremaintained, might clarify aspects of the modeof action and the pharmacological profile of thedrug. These studies might be performed atseveral realistic pharmacological doses of thedrug. Absence of detrimental effects of drugsdeveloped for long term use might be evaluatedon articular chondrocyte metabolism. Thechondrocyte cultures should be obtained fromnormal and osteoarthritic human articularcartilage.

IN VIVO EVALUATION

RationaleThere are no satisfactory animal models forhuman osteoarthritis; however, there are atleast three main reasons for using them-namely, to explore the activity of the drug inmodels of osteoarthritis; to explore possiblemodes of action of a drug, in addition to anythat may have been evaluated in in vitrostudies; and to explore potential joint toxicity.

Study designRelevant studies would assess the ability of thetest drug to prevent osteoarthritis, to retard theprogression of established osteoarthritis, and toinduce repair of an osteoarthritic joint. Anysensitive and reproducible method of assessingmorphological changes can be used, providedit has been validated with histopathological

techniques. Effects of the drug on both syn-ovial and cartilage tissues need to be assessed.

Ideally, the drug should be tested in twodifferent mammalian species, and, preferably,in models of both spontaneous and mechan-ically induced osteoarthritis.

DosageIdeally, an efficacy dose-response curve shouldbe established. A dose substantially higher thanthat which is minimally efficacious should beevaluated to assess possible toxicity tocartilage.

Duration ofstudyAs the osteoarthritic process evolves slowly,short term experiments are likely to beinconclusive. It is necessary for the duration ofin vivo experiments to take into account thenatural history of the development of osteo-arthritis in the model under study; the lifespanof the animal species being studied; and thetherapeutic target being investigated.

Clinical evaluationSELECTION OF PATIENTS

The different types of osteoarthritisOsteoarthritis is a heterogeneous disorder. Thenatural history and clinical outcomes of thedisease vary according to the main jointsaffected. Therefore, for clinical trial purposes,osteoarthritis of the different joints should beregarded as separate disorders. Selection ofpatients for trials should be based on theprevalence and clinical importance of osteo-arthritis of different joints, and on theavailability of validated outcome measures.

Osteoarthritis of the spine is common andimportant, and often coexists with disease ofthe limb joints. Patients with spinal osteo-arthritis may be included in trials, but as thereare currently no agreed objective measures ofprogression or outcome for spinal osteo-arthritis, the spine should not be used as atarget site in clinical trials. Disease of the handis to some extent related to a generalisedsusceptibility to osteoarthritis. Current meth-odological considerations indicate that clinicaltrials designed to evaluate the effects of drugsin osteoarthritis of the hand are better focusedon assessing progression of the disease inproximal and distal interphalangeal jointsrather than in trapezometacarpal joints, inwhich osteoarthritis may be more related tomechanical factors. Although osteoarthritis ofthe hand is a potential target for assessingevolution of disease in trials, it is less importantclinically than hip or knee disease. Osteo-arthritis of the hip is a common, disablingdisease with two main patterns of joint damage.Superior and lateral migration of the femoralhead are the commonest forms and are associ-ated with the highest risk of progression. Lessfrequent are medial and concentric femoralhead migration, which have a moreheterogeneous natural history. Osteoarthritis ofthe knee is also both very common and a major

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cause of disability. It presents with three over-lapping patterns of joint damage: medial(common) or lateral (uncommon) tibiofemoralinvolvement and patellofemoral disease(common). Currently, outcome measures forboth symptoms and structure are better vali-dated for medial tibiofemoral disease than forlateral or patellofemoral disease. Accordingly, itis recommended that medial tibiofemoralosteoarthritis of the knee or superolateral osteo-arthritis of the hip are the most appropriatedisease subsets for pivotal phase II or III trials,and that interphalangeal joint osteoarthritis ofthe hand is an appropriate target for studies ofthe effects of a drug on evolution of disease.

Inclusion criteria and the diagnosis ofosteoarthritisTo improve the homogeneity of the patientgroups studied, inclusion criteria should limitthe target joint to a single site. The presen-tation and natural history of the condition maybe different in younger and older age groups.Therefore, the age range of patients to beentered needs to be preselected and specified.A narrower age range will increase grouphomogeneity, possibly at the expense of thegeneralisability of the data obtained.To be enrolled in a study, patients should

have both symptomatic and structural changesof osteoarthritis in the target joint. Currently,this will mean pain related to use withradiological evidence of joint space narrowingor presence of osteophytes for knee osteo-arthritis, use related pain with joint spacenarrowing for osteoarthritis of the hip, and thediagnostic criteria of the American College ofRheumatology for hand osteoarthritis.

Aetiology of osteoarthritisPatients with osteoarthritis that is obviouslysecondary to another form of joint diseaseshould be excluded. However, the definition ofprimary osteoarthritis proposed by theAmerican College of Rheumatology seems toorestrictive. It is recommended that patientsshould only be excluded on the basis ofsecondary osteoarthritis if they have a historyor present evidence of any of the followingdiseases in the potential target joint:* Septic arthritis* Inflammatory joint disease* Gout* Recurrent episodes of pseudogout* Paget's disease* Aticular fracture* Ochronosis* Acromegaly* Haemochromatosis* Wilson's disease* Primary osteochondromatosisOther aetiologic factors, such as trauma anddysplasias, may have to be considered, but theabsence of clear criteria for quantifying pastjoint trauma or defining the presence orabsence of dysplasia, currently preclude anyspecific recommendations.

BASELINE DATATo establish the symptomatic and structuralseverity of the condition, and the presence orabsence of any factors or concomitant treat-ment that might affect outcome measures orthe natural history of osteoarthritis, datashould be collected at or as near to the pointof entry to the trial as possible.

Symptomatic severityPain and disability at entry need to berecorded. However, the minimum severity ofsymptoms related to disease in the target jointat entry will depend on the primary outcomemeasure being assessed, the potential mode ofaction of the drug, and the joint sites involved.For example, a higher baseline level of painmay be appropriate for entry into a trial of asymptom modifying drug than a trial of astructure modifying drug.

Structural severityThe severity of radiological changes in thetarget joint at entry should be established. Theentry film must be carefully characterised sothat:

* A patient group responding to an investi-gational drug can be fully described, so thatany subsequent extrapolation of data thatmay permit a more generalised use of theagent is facilitated

* An extensively damaged target joint is recog-nised, as it is unlikely that the effects of adrug on such a joint could be shown.

In studies during which radiological changesare evaluated, the baseline film should beobtained as near to the time of entry to thestudy as possible, and always within threemonths of entry.

In some trials, changes in joints other thanthe target joint may be used as secondaryoutcome measures and, if this is done, it wouldbe necessary to record the severity of radio-logical changes in these joints at entry.

Factors affecting disease progressionFactors that might affect the rate of evolutionof osteoarthritis include age, sex, obesity, majorjoint injury, and certain types of use for the kneejoint; and age, developmental abnormalities,presence of a generalised diathesis, andoccupations such as farming, for the hip joint.Any effect of a drug on rate of progression mustbe examined in the context of these factors,which should be recorded at entry.

Concomitant treatmentMany patients with osteoarthritis who arerecruited to trials are likely to have exacer-bations of symptoms ("flares") which requiretreatment during the study, irrespective of thetype of study design used. Such concomitanttreatment may interfere with outcomemeasures, and should ideally be excluded.However, in long term studies it is neither

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ethical nor practical to exclude all concomitanttreatments. For all trials, concomitant treat-ments (drugs or interventions) that are likely toaffect joint structure should be excluded, andrescue treatment should be standardised,carefully recorded, and monitored.

OUTCOME MEASURES: CIUNICALIrrespective of the particular joint beingstudied, several clinical outcomes can beassessed; in particular, pain, functional dis-ability, mobility, quality of life, flares, con-sumption of concomitant medication, globalrating, and time to surgery. Pain and functionaldisability attributable to the target joint arerecommended as primary clinical end points intrials of a drug for osteoarthritis. The methodsof statistical analysis and the timetable forcollection of data should be determined beforestarting a trial.

PainPain should be measured by self assessmentwith validated methods, such as visual analogof Likert scales. Use related and rest painshould be assessed separately. The period ofassessment should be defined-for example,now, today, this week. Pain should bemeasured often and at least every three monthsduring the first year of long term trials.

Functional disabilityA disease specific and joint specific instrumentsuch as the Western Ontario MacMasterUniversity osteoarthritis index (WOMAC)or the Lequesne index is recommended toassess disability arising from osteoarthritis ofthe hip or knee. These instruments havebeen validated for osteoarthritis of thesejoints and seem to be sensitive to relevantchanges in the clinical status of patientswith osteoarthritis. The validation of out-come measures specific for other joints isongoing. Functional disability should beassessed at least every three months duringlong term trials.

FlaresFlares may be related to episodes of jointinflammation. Such episodes may reflectperiods of rapid destruction of joints. Collec-tion of data on flares may, therefore, beimportant. However, no validated measuresspecific for flares in osteoarthritis exist.

Physical signs including range of motionThe current methods for evaluating jointmobility (for example, of motion, inter-condylar distance, heel to buttock distance) arenot sensitive or reproducible. Their place inlong term follow up remains to be established.Physical examination (for example, joint swell-ing, crepitus) is not sensitive or reproducible asan outcome measure. Performance testingmethods, such as timed walking capacity or

muscle strength, have not been fully validatedin osteoarthritis.

Quality of lifeQuality of life scales are receiving increasedattention from physicians involved in clinicaltrials and from drug regulation authorities. Thesickness impact profile (SIP), Nottingham healthprofile (NHP), and the short form-36 (SF-36)have excellent properties when used to assess ageneral population. They have only beenpartially tested in osteoarthritic populations. Iffurther validated in these populations it would bedesirable to use one or more of these scales asan outcome measure in trials of the efficacy ofdrugs in the treatment of osteoarthritis.

Global ratingThe patient's and the physician's global ratingare required by some drug regulationauthorities.

Consumption of medicationsConsumption of non-trial medications may beregarded as a semiobjective outcome measure.However, the influence of such factors as theirside effects and long term variations in their usemay introduce uncertainty into the interpret-ation of data on consumption of medications.

Time to surgeryThe need for major surgery, such as jointreplacement, can be considered as an import-ant outcome measure. However, there is noagreement on criteria for joint replacementsurgery. At the present time, replacement ratesfor hips and knees vary greatly in differentcountries and regions. Furthermore, theserates vary over time. Thus it is not possible torecommend time to surgery as a usefuloutcome measure.

OUTCOME MEASURES: STRUCTURAL

The effects of a new drug on joint structure arecentral to the assessment of outcome. Thedefinition of structural changes should includechanges in both cartilage and bone. The radio-graphic measurement of joint space width orosteophyte size remains the best establishedmethod of assessing the progression of osteo-arthritis and published studies support its use toprovide a primary endpoint in trials of structuremodifying drugs in osteoarthritis. However,stringent standardisation of positioning ofpatients, image acquisition, and measurementsmust be applied. Training of investigators toachieve the desired degree of standardisationshould be encouraged. In addition, films shouldbe read centrally. The clinical relevance of theproposed treatment induced effects on jointstructure should be evaluated.Other technologies for the evaluation of

the severity of osteoarthritis, such aschondroscopy, magnetic resonance imaging,scintigraphy, and ultrasonography, should also

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be considered as they may provide potentiallyrelevant outcome measures. However, none ofthese methods has yet been fully validated inosteoarthritis.

Materials collected during trials-forexample, radiographs and videorecordings ofarthroscopies-should be kept available for afurther reading, because the techniques forassessing structural changes that were up todate at the start of a trial may be improved orchanged during the course of a trial.

OUTCOME MEASURES: BIOCHEMICAL

If a biochemical variable is shown to reflect thedisease process of osteoarthritis, it is likely tobe classified as a surrogate marker of diseaseand would not be acceptable as a primary endpoint unless this could be justified by data onits clinical relevance. Samples of different bodyfluids (serum, urine, and possibly joint fluid)may be obtained during clinical trials and keptfrozen until required for specific assays ofbiochemical variables of interest. As with newimaging technologies, the relevance ofmeasurements of a biochemical variable has tobe established and this may be achieved bymeasurements made on specimens obtainedduring a clinical trial.Measurements of some biochemical vari-

ables may be shown to be useful in character-ising patients that are at increased risk ofdeveloping rapidly progressive disease or infollowing up the evolution of the disease. How-ever, at the present time measurements ofbiochemical variables are not a requirement fordrug registration.

STUDY DESIGN

Phase I studiesPhase I studies should determine the pharmaco-kinetics, including bioavailability, and thegeneral safety of the compound and shouldprovide an indication of doses of potentialclinical relevance.

Phase II studiesPhase II studies should provide data over arange of doses. The doses selected for thesestudies should enable the minimum effectivedose and the dose-response profile to bedetermined. Evaluation of at least three dosesis recommended. Pivotal studies should have aplacebo controlled, randomised, double blind,and parallel group design.Some agents may have both symptom and

structure modifying effects, but the optimaldose for modification of symptoms may bedifferent from that which alters structure.Modification of symptoms-The duration ofphase II studies for symptom modifying effectswill depend on the expected outcome and themode of action of the drug. Normally, even inthe case of a slow acting symptom modifyingdrug, its effects would be expected to beapparent within six months.Modification of structures-The duration ofphase II studies for a drug with structure

modifying effects will also depend on its modeof action, but is likely to be longer than thatrequired to assess modification of symptoms.Studies over a range of doses and of sufficientduration to show meaningful changes instructure are required. The magnitude of thesechanges should be predetermined.

Phase III studiesThe objectives of the definitive pivotal studiesare to confirm both the efficacy and the safetyof the drug. At least two independent pivotalstudies for showing efficacy are recommended.There should be only one target joint in a singletrial-either the hip or the knee. Intention totreat analysis should be the primary method ofevaluation. The a risk should be no greaterthan 20%. The design and the duration ofthese studies may differ according to theproperties of the drug.For symptom modification, studies should have

a randomised, double blind, parallel groupdesign. At least one of them should be placebocontrolled and have a duration of at least sixmonths (to assess the maintenance of the thera-peutic effect). The nature of the comparator inthe control group of the second study may vary,depending on the characteristics of thecompound under investigation. Data on adverseevents should be collected for at least one year.Moreover, to establish that a symptommodifying drug does not have deleterious effectson the joint, structural changes should bemonitored for at least one year.For structure modification studies should have

a randomised, double blind, placebo con-trolled, parallel group design. The durationshould be predetermined and should be at leastone year. One of the two pivotal studies maybe combined with a phase II trial. Structuralchanges are required as primary end points. Themagnitude of a clinically relevant effect of adrug on a structural variable should bepredetermined, based on the best evidencecurrently available.

AppendixGroup for the Respect of Ethics and Excellence in Science.Dougados M, Institut Rhumatologie, H6pital Cochin, 27 ruedu Fbg Saint-Jacques, 75014 Paris, France.Devogelaer J P, Service Rhumatologie, Clinique UniversitaireSaint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.Annefeldt M, Rotta Research Laboratorium, Via Valosa DiSopra 7, 20052 Monza, Italy.Avouac B, Service Rhumatologie, H6pital Henri Mondor,94010 Creteil, France.Bouvenot G, Service Medecine, H6pital Sainte-Marguerite,Avenue Vitton, 13009 Marseille, France.Cooper C, 344 Hill Lane, Upper Shirley, SouthamptonSO 2PH, UK.Dieppe P, Department Medicine, Bristol Royal Infirmary,Bristol BS2 8HW, UK.Ethgen D, Procter and Gambel, Lovett House, Lovett Road,Staines TW18 3AZ, UK.Garattini S, Istituto Mario Negri, Via Eritrea 62, 20157 Milano,Italy.Jones E A, Department Gastro and Liver Diseases, AcademicMedical Center, Meibergdreef 9, 1105 Amsterdam-Zuidoost,The Netherlands.Kaufman J M, UZG, Endocrinologie, De Pintelaan 185, 9000Gent, Belgium.Leeming M, Pfizer, Sandwich CCT13 9NJ, UK.Lemmel E M, Staatliches, Rheumakrankkeenhaus, Postfach640, 75484 Baden Baden, Germany.Lohmander S, Department of Orthopedics, UniversityHospital, 22185 Lund, Sweden.Menkes C J, Service de Rhumatologie A, H6pital Cochin,75014, Paris, France.

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Nuki G, Rheumatic Diseases Unit, Western General Hospital,Crewe Road South, Edinburgh EH4 EXU, UK.Paolozzi L, Laboratoires Cassenne, 1, Terrasse Bellini, 92800Puteaux, France.Pujol J P, Laboratoire Biochimie Tissu Conjonctif, Chu C6tede Nacre, 14033 Caen, France.Rovati L, Department of Clinical Pharmacology, RottaResearch Laboratorium, Via Valosa di Sopra 7, 20052 Monza,Italy.Semi U, Istituto Ortopedico Toscano, USL-1OB, VialeMichangelo 41, Firenze, Italy.Spector T, Department of Rheumatology, St Thomas'Hospital, Lambeth Place Road, London SE1 7EH, UK.Tsouderos Y, Institut Recherches Internationales Servier-Iris, 6Place des Pleiades, 92415 Courbevoie, France.Veys E M, Service Rhumatologie, Universitair Ziekenhuis, dePintelaan 185, 900 Gent, Belgium.Weseloh G, Orthopadische Universitat-Klinik, Abeitlung furOrthopadische Rheumatologie, Rathsbergerstraat 67, 91054Erlangen, Germany.Reginster J Y, Service Metabolisme Osseux, Policlinique LBrull, 45 quai Godefroid Kurth, 4020 Liege, Belgium.

1 Bombardier C, Melfi C A, Paul J, et al. Comparisons of ageneric and a disease-specific measure of pain andphysical function after knee replacement surgery. MedCare 1995; 33: AS131-44.

2 Davis M A, Ettinger W H, Neuhaus M, Mallon K P. Kneeosteoarthritis and physical functioning: evidence from the

NHANES I epidemiologic follow up study. Rheumatol1991; 18: 591-8.

3 Dieppe P, Altman R D, Buckwater J A, et al. Standard-ization of methods used to assess the progression ofosteoarthritis of the hip or knee joints. In: Kuettner K E,Goldberg V M, eds. Osteoarthritic disorders. Symposium ofthe American Academy of Orthopaedic Surgeons, Montery,CA, 1994. Rosemont, IL: American Academy ofOrthopedic Surgeons, 1995; 481-500.

4 Dougados M. Clinical assessment of osteoarthritis inclinical trials. Curr Opin Rheumatol 1995; 7: 87-91.

5 Hochberg M C, Lawrence R C, Everett D F, Comoni-Huntley J. Epidemiologic associations of pain in osteo-arthritis of the knee: data from the national health andnutrition examination survey and the national health andnutrition examination-I epidemiologic follow up survey.Semin Arthritis Rheum 1989; 18 (supply): 4-9.

6 Hunt S M, McKenna S P, Williams J. Reliability of apopulation survey tool for measuring perceived healthproblems: a study of patients with osteoarthrosis;Epidemiol Community Health 1991; 35: 297-300.

7 Lequesne M, Brandt T K, Bellamy N, Moskowitz R,Menkes C J, Pelletier J P. Guidelines for testing slowacting drugs in osteoarthritis.JRheumatol 1994; 21 (suppl41): 65-71.

8 Summers M N, Haley W E, Reveille J D, Alarcon G S.Radiographic assessment and psychologic variables aspredictors of pain and functional impairment inosteoarthritis of the knee and hip. Arthntis Rheum 1988;31: 204-9.

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