eular evidence based recommendations for the diagnosis … · abstract objectives: to develop...

EULAR EVIDENCE BASED RECOMMENDATIONS FOR THE DIAGNOSIS OF KNEE OSTEOARTHRITIS

W Zhang, M Doherty, G Peat, S M A Bierma-Zeinstra, N K Arden, B Bresnihan, G Herrero-Beaumont, S Kirschner, B F Leeb, L S Lohmander, B Mazières, K Pavelka, L Punzi, A K So, T Tuncer, I Watt, J W Bijlsma Correspondence to: Dr Weiya Zhang Academic Rheumatology University of Nottingham Clinical Sciences Building City Hospital Nottingham NG5 1PB UK [email protected]

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ARD Online First, published on September 17, 2009 as 10.1136/ard.2009.113100

Copyright Article author (or their employer) 2009. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.

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ABSTRACT

Objectives: To develop evidence based recommendations for the diagnosis of knee osteoarthritis (OA).

Methods: The multidisciplinary guideline development group, representing 12 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the sensitivity, specificity and likelihood ratio were calculated for individual diagnostic indicators and a diagnostic ladder was developed using Bayes’ method. Secondary analyses were undertaken to directly test the recommendations using multiple predictive models in two populations from the UK and the Netherlands. Strength of recommendation was assessed by the EULAR visual analogue scale.

Results: Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests, and differential diagnosis. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged 45 years and older, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all 6 symptoms and signs were present. The performance of the recommendations in the study populations varied according to the definition of knee OA, background risk and number of tests applied.

Conclusion: 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus. Although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.

Key words: EULAR recommendations, knee osteoarthritis, diagnosis


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INTRODUCTION

Osteoarthritis (OA) is the third most common diagnosis made by general practitioners in older patients1, and OA is the most common arthropathy to affect the knee2;3. About 25% of adults aged over 55 years experience significant knee pain; half of these have radiographic changes of OA and a quarter have significant disability.4 Risk factors for knee OA include ageing5, female gender6 , being overweight7, prior knee injury8 and a positive family history9. However, knee OA is not a discrete entity, showing variability with respect to compartmental involvement, accompanying inflammation and calcium crystal deposition, concurrence of OA at other joint sites10, and outcome. Classification criteria developed by the American College of Rheumatology (ACR) in 1986 are often used to standardise case definitions for research purposes11. Currently there is no guideline primarily for the purpose of clinical diagnosis of knee OA. Radiography is often used as a “gold” standard, but it is not the only marker for OA. Definition of knee OA may change according to different levels of care and clinical requirements. Therefore the EULAR OA Task Force undertook the following project to develop evidence-based recommendations for diagnosis of knee OA using a systematic review of research evidence and expert consensus12. Performance of the recommendations was tested in two European populations. The target audience for these recommendations is any health professional who is involved with the diagnosis of knee OA. METHODS A multidisciplinary guideline development group, comprising 17 OA experts from 12 European countries, was commissioned by the EULAR Standing Committee for Clinical Affairs (ESCCA). Following a single face-to-face meeting, each participant independently submitted up to 10 propositions related to key aspects in diagnosis of knee OA. Consensus was reached using the Delphi technique13. As with previous EULAR projects to develop recommendations for diagnosis14;15, a systematic search of the literature published between January 1950 and January 2008 was undertaken; the search for knee OA was combined with searches for diagnostic test and study design (Appendices 1-7, available from www.ard.org). Further search for specific diagnostic test/feature was undertaken after consensus to ratify the evidence. Outcome measures As there is no agreed single reference standard for the diagnosis of knee OA, a pragmatic decision was made to include studies that included either clinical, radiographic, magnetic resonance imaging (MRI) or arthroscopic reference standards. The ability of individual tests to discriminate between patients with and without knee OA was then summarised by sensitivity, specificity, and likelihood ratios (LR) (LR = sensitivity / (1-specificity))16;17. LRs above 10 or below 0.1 are considered strong evidence to respectively rule in or rule out a diagnosis in most circumstances17. The probability of having knee OA given a positive test result was estimated using Bayes’ theorem17. Test reliability was


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summarised using kappa statistics (dichotomous data) and intra-class correlation coefficients (continuous data). Relative risk (RR) and odds ratio (OR) were calculated for risk factors and co-morbidities associated with knee OA18. For economic evaluations, the incremental cost-effective ratio (ICER) was presented19. Best available evidence was used according to the EULAR evidence hierarchy for diagnosis (Ia = meta-analysis of cohort studies; Ib = meta-analysis of case control or cross sectional studies; IIa = cohort studies; IIb = case control or cross sectional studies; III = non-comparative descriptive studies; IV = expert opinion)14. Statistical pooling was undertaken as appropriate within the same study design if there was no systematic review and random effects model was used when the results were heterogenous20. Strength of recommendation (SOR) was graded using the EULAR 0-100 mm visual analogue scale (VAS)21. The performance of the recommended tests was examined in two populations22;23, where multiple logistic regression was used to estimate the likelihood of knee OA given a composite of the diagnostic tests24. All measures were reported with 95% confidence interval (CI) unless otherwise specified. Future research agenda After the propositions for diagnosis had been searched, reviewed and discussed, each participant submitted independently 10 propositions for future research. Consensus was again obtained using the Delphi technique. RESULTS Systematic literature search The literature search yielded 1738 hits. After deleting duplications, 1604 studies remained, of which 313 met the inclusion criteria (Figure 1). Clinical features (36%) and radiographs were the most often used reference standards (35%). The majority of studies were cross-sectional (55%), followed by case control (29%), cohort (13%) and systematic review (3%). No randomised controlled trials or economic evaluations were identified from the search. EULAR recommendations Of 166 propositions suggested initially, 10 were agreed after 4 anonymous Delphi rounds. Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests, and differential diagnosis (Table 1). Evidence regarding validity (sensitivity, specificity etc) and reliability of each diagnostic test/feature were summarised in Table 2. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged 45 years and older, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all 6 symptoms and signs were present. Strength of recommendation was generated based on research evidence and clinical expertise with 95% confidence interval (Table 1). Details of each recommendation and supporting evidence are available online in EULAR


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recommendations for the diagnosis of knee osteoarthritis and supporting evidence on www.ard.org.


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Table 1. Propositions and strength of recommendation (SOR) – order according to topic (definition, subsets, symptoms, physical findings, images, laboratory tests, risk factors and differential diagnosis) No.

Proposition LoE SOR (95%CI)

1 Knee OA is characterised clinically by usage-related pain and/or functional limitation. It is a common complex joint disorder showing focal cartilage loss, new bone formation and involvement of all joint tissues. Structural tissue changes are mirrored in classical radiographic features.

IIb 88 (83-92)

2 Risk factors that are strongly associated with the incidence of knee OA can help identify patients in whom knee OA is the most likely diagnosis. These include increasing age over 50 years, female gender, higher body mass index, previous knee injury or malalignment, joint laxity, occupational or recreational usage, family history and the presence of Heberden’s nodes.

Ia-IIb 89 (83-95)

3 Subsets with different risk factors and outcomes can be defined according to: varying compartmental involvement (patellofemoral, medial tibiofemoral, lateral tibiofemoral); bone response (atrophic, hypertrophic); the global pattern of OA (generalised, localised); by crystal presence (pyrophosphate, basic calcium phosphates); and by the degree of inflammation. However, the ability to discriminate subsets and the relevance for routine practice are unclear.

Ib-IIb 75 (63-87)

4 Typical symptoms of knee OA are usage-related pain, often worse towards the end of the day, relieved by rest; the feeling of “giving way”; only mild morning or inactivity stiffness; and impaired function. More persistent rest and night pain may occur in advanced OA. OA symptoms are often episodic or variable in severity and slow to change.

Ib-IIb 76 (64-87)

5 In adults aged >40 years with usage-related knee pain, only short-lived morning stiffness, functional limitation and one or more typical examination findings (crepitus, restricted movement, bony enlargement) a confident diagnosis of knee OA can be made without a radiographic examination. This applies even if radiographs appear normal.

Ib 80 (67-92)

6 All patients with knee pain should be examined. Findings indicative of knee OA include: crepitus; painful and/or restricted movement; bony enlargement; and absent or modest effusion. Additional features that may be present include: deformity (fixed flexion and/or varus - less commonly valgus); instability; periarticular or joint-line tenderness; and pain on patellofemoral compression.

Ia-III 90 (85-95)

7 Red flags (eg severe local inflammation, erythema, progressive pain unrelated to usage) suggest sepsis, crystals or serious bone pathology. Involvement of other joints may suggest a wide range of alternative diagnoses. Other important considerations are referred pain, ligamentous and meniscal lesions and localised bursitis.

IV 87 (80-94)

8 Plain radiography (both knees, weight-bearing, semi-flexed PA (MTP) view, plus a lateral and skyline view) is the current “gold” standard for morphological assessment of knee OA. Classical features are focal joint space narrowing, osteophyte, subchondral bone sclerosis and subchondral “cysts”. Further imaging modalities (MRI, sonography, scintigraphy) are seldom indicated for diagnosis of OA

Ib-IIb 83 (71-95)

9 Laboratory tests on blood, urine or synovial fluid are not required for the diagnosis of knee OA, but may be used to confirm or exclude coexistent inflammatory disease (e.g. pyrophosphate crystal deposition, gout, rheumatoid arthritis) in patients with suggestive symptoms or signs.

IIb 86 (78-94)

10 If a palpable effusion is present synovial fluid should be aspirated and analysed to exclude inflammatory disease and to identify urate and calcium pyrophosphate crystals. OA synovial fluid is typically non-inflammatory with <2000 leukocytes/mm3; if specifically sought, basic calcium phosphate crystals are often present.

IIb 73 (56-89)

LoE=level of evidence (Ia=meta-analysis of cohort studies, Ib=meta-analysis of case control or cross sectional studies, IIa=cohort study, IIb=case control or cross-sectional studies, III=non-comparative descriptive studies, IV=expert opinion); SOR=strength of recommendation on visual analogue scale (0-100 mm, 0=not recommended at all, 100=fully recommended); CI: confidence interval.


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Table 2. Validity and reliability of diagnostic tests in the diagnosis of knee osteoarthritis – pooled results Test No. studies

(designs) No subjects

Mean age (range)

F% Reference standards

Sensitivity (95%CI)

Specificity (95%CI)

LR (95%CI)

ICC/kappa (95%CI) Intra Inter

Refs

Age≥50 1 (cs) 2865 - 54% Radiographic 0.90 0.23 1.20 - - 25 Female 2 (1 cc, 1 cs)) 3102 - 55% Clinical or

radiographic 0.76 (0.69, 0.83)

0.31 (0.22, 0.40)

1.10 (0.94, 1.29)

- - 11;25

Knee pain

Persistent*

Usage-related

7 (1 cc, 6 cs) 3 (3cs) 4 (1cc, 3cs)

5401 1505 3896

62 (40-92) (40-79) 72 (50-92)

62% 100% 54%

Clinical, radiographic or MRI Clinical, radiographic Clinical, radiographic

0.58 (0.40, 0.77) 0.53 (0.47, 0.58) 0.95 (0.91, 0.99)

0.62 (0.45, 0.79) 0.71 (0.62, 0.79) 0.19 (0.11, 0.26)

1.57 (1.26, 1.96) 1.67 (1.44, 1.94) 1.16 (1.15, 1.29)

0.84 (0.69, 1.00)

0.72 (0.67, 0.76)

11;25-30

Functional limitation

5 (3 cc, 2 cs) 1945 64 (50-90) 54% Clinical or radiographic

0.56 (0.27, 0.86)

0.63 (0.40, 0.87)

1.50 (1.23, 1.84)

- - 11;26;31-33

Morning stiffness


0.88 (0.82, 0.93)

0.52 (0.43, 0.62)

1.84 (1.49, 2.27)

0.90 (0.74, 1.00)

0.62 (0.51, 1.73)

11;25;27

Crepitus 4 (2 cc, 2 cs) 942 65 (50-92) 72% Clinical or radiographic

0.89 (0.85, 0.93)

0.60 (0.54, 0.67)

2.23 (1.90, 2.63)

0.78 (0.60, 0.96)

0.23 (0.01, 0.45)

11;27;32;34

Bony enlargement


0.55 (0.46, 0.64)

0.95 (0.91, 0.99)

11.81 (4.94, 28.22)

0.91 - 11;25;34

Restricted movement

6 (3 cc, 2 cs, 1 sr)

3661 62 (50-90) 54% Clinical or radiographic

0.17 0.96 4.4 0.73 – 0.79 0.48 – 1.00 25;32;34-37

Palpable effusion


0.43 (0.34, 0.52)

0.41 (0.32, 0.50)

0.73 (0.56, 0.95)

- - 11;25

Instability 2 (1 cc, 1 cs) 243 58 (44-82) 72% Clinical or radiographic

0.26 (0.07, 0.46)

0.79 (0.69, 0.89)

1.25 (0.89, 1.77)

- - 11;34

JSN 8 (4 cc, 4 cs) 2615 55 (25-80) 78% Clinical, MRI, or arthroscopic

0.44 (0.27, 0.62)

0.79 (0.66, 0.92)

2.19 (1.58, 3.03)

0.66 (0.51, 0.81)

0.44 (0.33, 0.54)

11;38-44

OST 8 (5 cc, 6 cs) 3250 57 (25-80) 74% Clinical, MRI or arthroscopic

0.51 (0.32, 0.69)

0.83 (0.76, 0.89)

3.29 (2.41, 4.48)

0.71 (0.61, 0.82)

0.62 (0.56, 0.67)

11;38-47

KL 4 (2 cc, 2 cs) 1853 55 (25-85) 87% Clinical 0.43 (0.01, 0.85)

0.85 (0.75, 0.96)

2.62 (2.10, 3.26)

0.78 (0.65, 0.90)

0.67 (0.53, 0.80)

11;39;43;48

Sclerosis 5 (3 cc, 2 cs) 788 55 (25-77) 60% Clinical or arthroscopic

0.33 (0.03, 0.63)

0.89 (0.0.76, 1.02)

2.56 (1.92, 3.42)

0.00 - 0.86 (range)

-0.04 - 0.67 (range)

11;39-41;44

Cysts 2 (cc) 387 53 (35-77) 63% Clinical or arthroscopic

0.24 (-0.04, 0.51)

0.93 (0.82, 1.05)

2.98 (1.76, 5.03)

- - 11;40

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SF CPPD 3 (1 cc, 2 cs) 3894 67 (34-98) 51% Clinical or radiographic

0.56 (0.48, 0.64)

0.70 (0.64, 0.76)

1.87 (1.46, 2.40)

- - 49-51

RF (+) 1 (cc) 237 55 73% Clinical 0.05 (0.003, 0.11)

0.51 (0.40, 0.63)

0.11 (0.04, 0.30)

- - 11

CI=confidence interval; LR=likelihood ratio; ICC=intraclass correlation coefficient; JSN=joint space narrowing; OST osteophyte;

KL=Kellgren and Lawrence; cc=case control; cs=cross sectional; sr=systematic review * most day for at least a month

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Performance of recommendations The two populations selected have investigated plain radiographs and clinical features, permitting performance testing for some of the recommendations. 1. In the UK We used cross-sectional data from the Knee Clinical Assessment Study (CAS(K)) conducted in North Staffordshire UK. After excluding 16 people with a pre-existing diagnosis of inflammatory arthritis, 745 adults with knee pain aged 50 years and over (mean age: 65 years, SD 8.6, range 50-93; 56% female; mean BMI: 29.6 kg/m2, 41% obese) were available for analysis22.

Of 745, 570 (76%) and 292 (39%) subjects had radiographic OA according to two definitions based on standing postero-anterior, supine lateral and supine skyline views: osteophytosis (broadly equivalent to KL≥1) and JSN (broadly equivalent to KL≥3). Compartmental distribution of knee OA differed according to the definition. With the first definition, the PF was the most commonly affected compartment (38%); with the second, the medial TF was the most commonly affected (38%). The proportions with chondrocalcinosis in the same knee were 8% and 12% respectively.

Age, gender, BMI, morning stiffness (<30 minutes), crepitus, reduced flexion, bony enlargement, fixed flexion deformity, palpable effusion, and intercondylar/intermalleolar gap (a surrogate for varus/valgus malalignment) were entered in the logistic regression models and backward LR was used to select significant variables. Morning stiffness and intercondylar gap were excluded from the model because they were non-significant.

The probability of radiographic knee OA increased with an increasing number of positive tests (Figure 3). The likelihood of having radiographic knee OA (KL≥1) was 88% for a person aged over 60 years, who is overweight and has crepitus, restricted movement and bony enlargement. The likelihood was smaller when the diagnostic criterion was higher (e.g., KL≥3) (Figure 3). 2. In the Nethelands The Rotterdam study is a population-based, longitudinal cohort study for incidence and risk factors for chronic disabling conditions52. Of 10,275 residents in one district of Rotterdam (Ommoord), 7983 agreed to participate (mean age: 70.6 SD: 9.8, range 55 to 106; 61.1% female, mean BMI: 26.3, SD 3.7), 3456 with baseline knee AP x-rays formed the study population for this analysis. Of 3456 subjects, 1624 (47%) and 129 (3.7%) were classified as having knee OA according to the cut-offs: KL≥1 and KL≥3. Diagnostic variables examined included age, gender, BMI, knee pain in the last 5 years, morning stiffness, functional impairment, family history of OA, radiographic varus malalignment, hand OA (KL≥2), hip OA (KL≥2) and serum C-reactive protein (CRP) <5. Of these, gender, morning stiffness, family history, hip OA and CRP were not significant so were excluded from the logistic regression models. Only 4 clinical features (age, BMI, knee pain and functional limitation) were available to test the performance of the clinical diagnosis. The probability of having any radiographic knee OA (KL≥1) increased gradually with an increasing number of positive tests. It reached 52% when all these clinical features were positive, i.e.,


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aged over 60 years of age, being overweight and having knee pain and impaired function. Future research agenda One hundred and thirteen initial propositions were submitted by the Task Force members. After 3 anonymous Delphi rounds, 9 of these obtained over 50% votes and went forward as the proposed future research agenda: 1. Development of internationally agreed criteria sets for diagnosis of knee OA

for clinical practice, clinical trials and epidemiological studies 2. Development of a scoring system for accurate diagnosis of knee OA based on

the sensitivity and specificity of risk factors and symptoms and signs 3. Delineation of the attributable risk factor profile, both for development and

progression, for each suggested subset of knee OA. 4. Development of diagnostic criteria for early symptomatic knee OA (e.g. by

prospective investigation of people with knee pain who fulfil criteria of knee OA several years later)

5. Investigation of whether individual pain patterns (usage-related, episodic, night pain) have different utility as diagnostic markers of knee OA

6. Determination of clinical, diagnostic and prognostic relevance of MRI changes in knee OA

7. Determination of the utility of ultrasonography in the diagnosis and prognosis of knee OA

8. Assessment of the possible role of biomarkers (including genetic markers) in the early diagnosis, phenotypic characterisation, and prediction of outcome of knee OA

9. Assessment of the accuracy of red flags in identifying serious pathology in patients presenting with knee symptoms

DISCUSSION Knee OA can variably involve cartilage, bone, synovium and surrounding tissues of the three biomechanically discrete compartments, and may associate with OA at other joints due to shared genetic and constitutional risk exposures. Thus the clinical phenotype is very variable, requiring consideration of several characteristics for accurate diagnosis. Although the ACR criteria are a useful tool for classification of knee OA11 they were developed using hospital-referred patients and a control group that comprised patients with other arthritis (over 50% had rheumatoid arthritis)11, thus making them most useful for differentiation of knee OA from inflammatory arthritis rather than for diagnosis of knee OA per se in a routine clinical setting. The focus of the current recommendations, however, was on the risk factors, symptoms, signs and tests that might contribute to a clinical diagnosis. Although there is no “gold standard” for diagnosis of knee OA, an important conclusion was that in adults aged 45 years or older, an adequate history and examination alone may lead to a confident clinical diagnosis of knee OA. This may contrast with the situation in some care settings in which practitioners devote insufficient time to patient enquiry and physical examination and instead place undue emphasis on tests, especially radiographs.


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The recommendations were developed systematically and combine both expert opinion (Delphi exercise) and research evidence (systematic review and meta-analysis)12;14. Evidence was derived both from community and hospital based studies to improve generalisability. The recommendations have been examined initially in datasets derived from two general populations in Europe.

According to the recommendations and the supporting evidence the diagnosis of knee OA can be made based on: the background risk (the population prevalence of knee OA); the patient’s risk factors for OA (e.g. age, gender, BMI, occupation); their symptoms (persistent knee pain, brief morning stiffness and functional limitation); and an adequate physical examination (crepitus, restricted movement and bony enlargement). Plain radiographs are the main test to consider, but are an adjunct, rather than a central feature, for the purposes of diagnosis (Figure 4). The more positive results a patient presents the more likely the diagnosis of OA. Knowledge of the background risk (that is, the local source population prevalence of knee OA) is crucial for estimating the likelihood of knee OA. The higher the risk in the source population, the more possible it is to diagnose knee OA based on clinical features.

There are limitations to these recommendations. Firstly, the evidence to support these recommendations were derived largely from literature based on different studies. The LRs (Table 2) are unadjusted and the subsequent probabilities (Figure 2) are for reference only. The application of these recommendations should be based on the individual patient characteristics and the knee OA risk in the source population. Secondly, the LRs pooled from the literature may be affected by many factors such as the number of studies involved, the populations selected (hospital or community), the gold standard used, and the cut-off values selected. For example, the LR for bony enlargement (11.81, 95%CI 4.94, 28.22) was mainly based on a hospital-based case control study where the gold standard was clinical diagnosis of knee OA and the controls predominantly were RA patients11. The validity and reliability of this LR is questionable, compared to those LRs derived from multiple studies including both hospital and community data, such as for persistent knee pain28-30 and crepitus 27;32;34. Therefore caution must be exercised when interpreting results obtained using this feature. Thirdly, there is no universally applicable reference standard for knee OA, so the recommendations were mainly based on radiographic evidence when clinical features were examined, or on clinical, MRI or arthroscopic evidence when radiographic features were examined. Whether this is an appropriate approach is open to debate. Finally, all propositions relate to people over age 40 which is the target age for common OA. Whether recommendations would differ for less typical patients under this age was not addressed. In conclusion, 10 key recommendations for the diagnosis of knee OA have been produced based both on expert consensus and a systematic literature review. A confident diagnosis may be made according to three symptoms (knee pain, short-lived morning stiffness and functional limitation) and determination of three signs on examination (crepitus, restricted movement and bony enlargement) without a requirement for imaging. This may be especially useful


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for primary care. Nevertheless, plain radiography and occasionally other investigations may be considered for the diagnosis of atypical cases when additional pathology is suspected. These recommendations were examined in two test populations and the level of evidence and summary strength of recommendations were provided to guide their use.


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AUTHORS’ AFFILIATIONS N K Arden, MRC Environmental Epidemiology Resource Centre, Southampton General Hospital, Southampton/Musculoskeletal Biochemical Research Unit, University of Oxford, United Kingdom S M A Bierma-Zeinstra, Department of General Practice, Erasmus MC University Medical Center, Rotterdam, The Netherlands J W Bijlsma, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands B Bresnihan, Department of Rheumatology, St Vincent’s University Hospital, Dublin, Ireland M Doherty, Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom G Herrero-Beaumont, Servicio de Reumatologia, Fundación Jiménez Diaz, Madrid, Spain S Kirschner, Universitätsklinik für Orthopädie, Dresden, Germany B F Leeb, 2nd Department of Medicine, Centre for Rheumatology Lower Austria, Stockerau, Austria L S Lohmander, Department of Orthopaedics, Clinical Sciences Lund, Lund University, Lund, Sweden B Mazières, Department of Rheumatology, Larrey University Hospital, Toulouse, France K Pavelka, Institute of Rheumatology, Na Slupi 4, Prague, Czech Republic G Peat, Arthritis Research Campaign National Primary Care Research Centre, Keele University, Keele, UK L Punzi, Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Italy A K So, Service de RMR, Centre Hospitalier Unviersitaire Vaudois, Lausanne, Switzerland T Tuncer, Department of PMR, Rheumatology Division, Akdeniz University, Antalya, Turkey. I Watt, Department of Radiology. Leiden University Medical Centre, Leiden, the Netherlands W Zhang, Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom Acknowledgement: The authors would like to thank the European League Against Rheumatism for financial support, Helen Richardson for co-ordination and Joanna Ramowski for assistance with the literature search and paper collection. Funding: Financial support was received from the European League Against Rheumatism.


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Figure legend: Figure 1. Study selection Figure 2. Likelihood ratio and probability of knee OA (reference standard: radiographic KL≥2) Figure 3. Clinical features and cumulative probability of radiographic knee OA – evidence from the UK population Figure 4. Major components in the diagnosis of knee osteoarthritis


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15. Zhang W, Doherty M, Leeb BF, Alekseeva L, Arden NK, Bijlsma JW et al. EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT. Ann Rheum Dis 2009;68:8-17.

16. Altman DG,.Bland JM. Statistics Notes: Diagnostic tests 1: sensitivity and specificity. BMJ 1994;308:1552.

17. Deeks JJ,.Altman DG. Diagnostic tests 4: likelihood ratios. BMJ 2004;329:168-9.

18. Kleinbaum DG, Kuppler LL, Morgenstern H. Epidemiologic Research - Principles and Quantitative Methods. John Willey & Sons, INC., 1982.

19. Briggs A,.Gray A. Economics notes: Using cost effectiveness information. BMJ 2000;320:246.

20. Whitehead A,.Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials. Statistics in Medicine. 1991;10:1665-77.

21. Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther KP et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669-81.

22. Peat G, Thomas E, Handy J, Wood L, Dziedzic K, Myers H et al. The Knee Clinical Assessment Study--CAS(K). A prospective study of knee pain and knee osteoarthritis in the general population. BMC Musculoskeletal Disorders 2004;5:4.

23. Hofman A, Breteler MM, Van Duijn CM, Krestin GP, Pols HA, Stricker BH et al. The Rotterdam Study: objectives and design update. European Journal of Epidemiology 2007;22:819-29.

24. Chan SF, Deeks JJ, Macaskill P, Irwig L. Three methods to construct predictive models using logistic regression and likelihood ratios to facilitate adjustment for pretest probability give similar results. Journal of Clinical Epidemiology 2008;61:52-63.

25. Claessens AA, Schouten JS, Van Den Ouweland FA, Valkenburg HA. Do clinical findings associate with radiographic osteoarthritis of the knee? Ann Rheum Dis 1990;49:771-4.

26. Duncan R, Peat G, Thomas E, Hay E, McCall I, Croft P. Symptoms and radiographic osteoarthritis: not as discordant as they are made out to be? Ann Rheum Dis 2007;66:86-91.

27. Jones A, Hopkinson N, Pattrick M, Berman P, Doherty M. Evaluation of a method for clinically assessing osteoarthritis of the knee. Ann Rheum Dis 1992;51:243-5.

28. Lachance L, Sowers M, Jamadar D, Jannausch M, Hochberg M, Crutchfield M. The experience of pain and emergent osteoarthritis of the knee. Osteoarthritis and Cartilage 2001;9:527-32.

29. O'Reilly SC, Muir KR, Doherty M. Screening for pain in knee osteoarthritis: Which question? Ann Rheum Dis 1996;55:931-3.

30. Sengupta M, Zhang YQ, Niu JB, Guermazi A, Grigorian M, Gale D et al. High signal in knee osteophytes is not associated with knee pain. Osteoarthritis and Cartilage 2006;14:413-7.

31. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Determinants of disability in osteoarthritis of the knee. Ann Rheum Dis 1993;52:258-62.


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32. Peat G, Thomas E, Duncan R, Wood L, Wilkie R, Hill J et al. Estimating the probability of radiographic osteoarthritis in the older patient with knee pain. Arthritis Care and Research 2007;57:794-802.

33. Williams DA, Farrell MJ, Cunningham J, Gracely RH, Ambrose K, Cupps T et al. Knee pain and radiographic osteoarthritis interact in the prediction of levels of self-reported disability. Arthritis Care and Research 2004;51:558-61.

34. Cibere J, Bellamy N, Thorne A, Esdaile JM, McGorm KJ, Chalmers A et al. Reliability of the knee examination in osteoarthritis: effect of standardization. Arthritis & Rheumatism 2004;50:458-68.

35. Brage ME, Draganich LF, Pottenger LA, Curran JJ. Knee laxity in symptomatic osteoarthritis. Clinical Orthopaedics and Related Research 1994;304:184-9.

36. Nagao N, Tachibana T, Mizuno K. The rotational angle in osteoarthritic knees. International Orthopaedics 1998;22:282-7.

37. Terwee CB, Mokkink LB, Steultjens MP, Dekker J. Performance-based methods for measuring the physical function of patients with osteoarthritis of the hip or knee: a systematic review of measurement properties. Rheumatology (Oxford) 2006;45:890-902.

38. Ding C, Garnero P, Cicuttini F, Scott F, Cooley H, Jones G. Knee cartilage defects: Association with early radiographic osteoarthritis, decreased cartilage volume, increased joint surface area and type II collagen breakdown. Osteoarthritis and Cartilage 2005;13:198-205.

39. Gunther KP,.Yi S. Reliability of radiographic assessment in hip and knee osteoarthritis. Osteoarthritis and Cartilage 1999;7:239-46.

40. Kijowski R, Blankenbaker DG, Stanton PT, Fine JP, De Smet AA. Radiographic findings of osteoarthritis versus arthroscopic findings of articular cartilage degeneration in the tibiofemoral joint. Radiology 2006;239:818-24.

41. Kijowski R, Blankenbaker D, Stanton P, Fine J, Smet A. Correlation between radiographic findings of osteoarthritis and arthroscopic findings of articular cartilage degeneration within the patellofemoral joint. Skeletal Radiology 2006;35:895-902.

42. Lanyon P, O'Reilly S, Jones A, Doherty M. Radiographic assessment of symptomatic knee osteoarthritis in the community: definitions and normal joint space. Ann Rheum Dis 1998;57:595-601.

43. Spector TD, Hart DJ, Byrne J, Harris PA, Dacre JE, Doyle DV. Definition of osteoarthritis of the knee for epidemiological studies. Ann Rheum Dis 1993;52:790-4.

44. Szebenyi B, Hollander AP, Dieppe P, Quilty B, Buddy J, Clarke S et al. Associations between pain, function, and radiographic features in osteoarthritis of the knee. Arthritis and Rheumatism 2006;54:230-5.

45. Boegard T, Rudling O, Petersson IF, Jonsson K. Correlation between radiographically diagnosed osteophytes and magnetic resonance detected cartilage defects in the tibiofemoral joint. Ann Rheum Dis 1998;57:401-7.

46. Felson DT, McAlindon TE, Anderson JJ, Naimark A, Weissman BW, Aliabadi P et al. Defining radiographic osteoarthritis for the whole knee. Osteoarthritis Cartilage 1997;5:241-50.


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47. Wu H, Webber C, Fuentes CO, Bensen R, Beattie K, Adachi JD et al. Prevalence of knee abnormalities in patients with osteoarthritis and anterior cruciate ligament injury identified with peripheral magnetic resonance imaging: A pilot study. Canadian Association of Radiologists Journal 2007;58:167-75.

48. McAlindon TE, Snow S, Cooper C, Dieppe PA. Radiographic patterns of osteoarthritis of the knee joint in the community: The importance of the patellofemoral joint. Ann Rheum Dis 1992;51:844-9.

49. Hamilton E, Pattrick M, Hornby J, Derrick G, Doherty M. Synovial fluid calcium pyrophosphate dihydrate crystals and alizarin red positivity: analysis of 3000 samples. Br J Rheumatol 1990;29:101-4.

50. Ledingham J, Regan M, Jones A, Doherty M. Radiographic patterns and associations of osteoarthritis of the knee in patients referred to hospital. Ann Rheum Dis 1993;52:520-6.

51. Nalbant S, Martinez JAM, Kitumnuaypong T, Clayburne G, Sieck M, Schumacher J. Synovial fluid features and their relations to osteoarthritis severity: New findings from sequential studies. Osteoarthritis and Cartilage 2003;11:50-4.

52. Brouwer GM, Van Tol AW, Bergink AP, Belo JN, Bernsen RMD, Reijman M et al. Association between valgus and varus alignment and the development and progression of radiographic osteoarthritis of the knee. Arthritis and Rheumatism 2007;56:1204-11.


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ONLINE SUPPLEMENTAL FILE: EULAR recommendations for the diagnosis of knee osteoarthritis and

supporting evidence

1. Knee OA is characterised clinically by usage-related pain and/or functional limitation. It is a common complex joint disorder showing focal cartilage loss, new bone formation and involvement of all joint tissues. Structural tissue changes are mirrored in classical radiographic features.

Level of evidence: IIb, Strength of recommendation: 88 (95%CI 83-92) There is good evidence that multiple risk factors, including heredity, constitutional, biomechanical and environmental, predispose to knee OA, justifying the term “common complex disorder”1. Although focal loss of hyaline cartilage and osteophyte are the pathological hallmarks of established OA, involvement of all other joint tissues (meniscal fibrocartilage, synovium, capsule, ligaments and muscle) has been documented in MRI studies and in studies of human knee OA pathology 2-5. The definition of knee OA varies according to the study purpose. Radiographs are relatively insensitive in showing pathological change and although radiographic change, most commonly a global Kellgren and Lawrence (KL) score ≥2, is often used to define knee OA in epidemiological studies this has limited value in clinical practice, especially in a primary care setting, where pain and disability are the main causes for consultation6. For the purpose of the EULAR recommendations, the definition of knee OA should at least reflect the three clinical domains associated with OA - pain, disability and structure change - to ensure adequate diagnosis and management of the disease in different health care settings. The level of evidence to support this proposition is IIb. 2. Risk factors that are strongly associated with the incidence of knee OA

can help identify patients in whom knee OA is the most likely diagnosis. These include increasing age over 50 years, female gender, higher body mass index, previous knee injury or malalignment, joint laxity, occupational or recreational usage, family history and the presence of Heberden’s nodes.

Level of evidence: Ia – IIb, Strength of recommendation: 89 (95%CI 83-95) Ageing is a major risk factor for knee OA7-13. Knee OA is uncommon in people younger than 40 years of age, and the incidence increases gradually until 80 years of age with greater risk in women than men7. A systematic review of gender difference has confirmed a higher incidence (RR=1.82, 95%CI 1.06, 3.12) and prevalence (RR=1.59, 95%CI 1.33, 1.89) of knee OA in women 14. High Body Mass Index (BMI) is also associated with knee OA with a relative risk ranging from 2 to 8 depending on the study design, the cut-off value of high BMI and the knee compartment involved9;15-18 (Table 3). The effect of elevated BMI may become more significant in people with knee malalignment19. Varus


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(RR=2.06, 95%CI 1.28, 3.23) and valgus malalignment (1.54, 95%CI 0.94, 2.44) are risk factors for the development of knee OA20. They are also strongly associated with the progression of the disease (Table 3) 20-23. Other risk factors include knee laxity24;25, family history26, knee injury27, mechanically demanding occupational activity28 or high level of physical activity (running 20 miles/week) 29(Table 3). In summary, a number of risk factors for knee OA have been identified, the most established being increasing age over 40, female gender and being overweight. They should be considered in the diagnosis of knee OA, at least as part of the background information. The evidence to support this proposition ranges from Ia to IIb (Table 3). 3. Subsets with different risk factors and outcomes can be defined

according to: varying compartmental involvement (patellofemoral, medial tibiofemoral, lateral tibiofemoral); bone response (atrophic, hypertrophic); the global pattern of OA (generalised, localised); by crystal presence (pyrophosphate, basic calcium phosphates); and by the degree of inflammation. However, the ability to discriminate subsets and the relevance for routine practice are unclear.

Level of evidence: Ib – IIb, Strength of recommendation: 75 (95%CI 63-87) OA may affect different compartments of the knees. The distribution varies according to the population selected, reflecting differences in disease severity, risk factors and associations30-33. Compartmental distribution tends to be symmetrical in patients with bilateral disease, although tibio-femoral (TF) but not patello-femoral (PF) changes tend to be more severe on the right 34. In one hospital based study a hypertrophic pattern of bone response was seen in 207 (44%) knees, an atrophic pattern in 89 (19%) and a mixed pattern in 174 (37%)31. More severe and multi-compartmental radiographic change may be associated with calcium pyrophosphate crystal deposition (CPPD), nodal change, interphalangeal (IP) OA and body mass index (BMI)31;35. Two community-based case control studies (n=608 and 325 respectively)15;17 showed that BMI (highest vs lowest tertiles) was more associated with combined TF and PF OA (pooled OR=7.07, 95%CI 4.01, 12.46), than with isolated TF (OR=2.18, 95%CI 1.41, 3.36) or isolated PF OA (OR=2.79, 95%CI1.61, 4.85). More severe and rapid progression of knee OA is reported in those with clinical signs of inflammation36-

39. Knee OA is associated with other joint OA, including distal IP (OR=1.8,

95%CI 1.1, 3.1), proximal IP (2.4, 95%CI 1.3, 4.4), carpometacarpal (CMC) (2.4, 95%CI 1.5, 4.4) and hip (2.1, 95%CI 1.2, 3.4) OA40. These data support the concept of “�eneralized OA” in which some individuals are at increased risk of multiple joint involvement by OA. Classification criteria for �eneralized versus localized OA have been proposed41 although it appears that no single cut-off for the number of joints affected is applicable to all age ranges 40. There is clear justification to include assessment of other target joints for OA for the purpose of prognosis and thus management of knee OA.


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In brief, there are data to support division of “subsets” of knee OA according to the variables listed (evidence level IIb). Different compartmental involvement may associate with different risk exposures and outcomes (evidence level Ib). Full assessment of different compartments as well as other joints (e.g., nodal change) should prove helpful for both diagnosis and prognosis. However, the ability to discriminate subsets, and whether this would alter management in routine practice, has not been formally tested. 4. Typical symptoms of knee OA are usage-related pain, often worse

towards the end of the day, relieved by rest; the feeling of “giving way”; only mild morning or inactivity stiffness; and impaired function. More persistent rest and night pain may occur in advanced OA. OA symptoms are often episodic or variable in severity and slow to change.

Level of evidence: Ib - IIb, Strength of recommendation: 76 (95%CI 64-87) Pain is the major cause of consultation for patients with knee OA6. Knee OA pain often shows worsening towards the afternoon and evening42. People with severe structural change may experience pain at night and this may be more common among hospital-referred patients. Seven studies (n=5401) have examined the value of knee pain in the diagnosis of knee OA 43-49. Of these studies, 5 used radiographs, one clinical diagnosis and one MRI as the gold standard for diagnosis. Pooled data show a sensitivity of 0.58 (95%CI 0.40, 0.77), a specificity of 0.62 (95%CI 0.45, 0.79) and an LR of 1.57 (95%CI 1.26, 1.96). Usage-related pain was investigated in 4 studies (n=3896)43-46. This was very sensitive (sensitivity=0.95, 95%CI 0.91, 0.99) but not specific (specificity=0.19, 0.19, 95%CI 0.11, 0.26), resulting in a small LR (LR=1.16, 95%CI 1.15, 1.29). Persistent knee pain (e.g., pain on most days for at least a month) was examined in 3 studies (n=1505)47-49. It was not as sensitive (sensitivity=0.53, 95%CI 0.47, 0.58) but was more specific (specificity=0.71, 95%CI 0.62, 0.79) than usage-related pain. The pooled LR was 1.64 (95%CI 1.45, 1.86) (Table 2). Similar LRs were obtained for self-reported functional impairment (LR=1.50, 95%CI 1.23, 1.84)43;45;50-52, and short-lasting (<30 minute) morning and inactivity stiffness (LR=1.84, 95%CI 1.49, 2.27)43;44;46 (Table 2).

The probability of having knee OA, given each of these clinical symptoms is less than 20%, based on the estimate of the UK population risk of knee OA of 12.5% in people aged over 45 years old53. However, the probability increases to 34% if all three symptoms are present (Figure 2). In summary, persistent knee pain, only brief morning or inactivity stiffness and self-reported functional impairment appear to be typical symptoms of knee OA (level of evidence Ib). However, they have limited value for the diagnosis of knee OA per se, even if all three are present (IIb). Pain is often worse towards the end of the day and may extend into the night, but these features have not been examined as diagnostic markers.


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5. In adults aged >40 years with usage-related knee pain, only short-lived morning stiffness, functional limitation and one or more typical examination findings (crepitus, restricted movement, bony enlargement) a confident diagnosis of knee OA can be made without a radiographic examination. This applies even if radiographs appear normal.

Level of evidence: Ib, Strength of recommendation: 80 (95%CI 67-92) Clinical examination findings play a critical role in the diagnosis of knee OA. Eight studies (n=3947) have examined the value of clinical findings of crepitus, restricted movement and bony enlargement in the diagnosis of knee OA.43;44;46;51;54-57 The majority of these studies used radiographic evidence of knee OA as the gold standard 44;46;51;54-56. Although crepitus appears very sensitive, restricted movement and bony enlargement are extremely specific for knee OA (Table 2). The LRs are 2.23 (95%CI 1.90, 2.63) for crepitus43;46;51;55, 4.4 (95%CI not available) for restricted movement44;51;54-57, and 11.81 (95%CI 4.94, 28.22) for bony enlargement43;44;55 (Table 2). Consequently, the probabilities of a patient having knee OA according to these LRs are 24%, 39% and 63% respectively (Figure 2). The probability increases with a composite of multiple tests (Figure 2), reaching 99% when combining these three physical findings with the previous three key symptoms (i.e. persistent knee pain, morning stiffness and functional impairment). This suggests that a clinical diagnosis of knee OA can be made in most people without radiographic examination.

Knee OA shows a strong age relationship, being uncommon before the age of 40 but increasing steadily with age from then onwards. 7;9;13 However, because of its high prevalence after age 40, there is no clear cut-off in middle or old age that can be used to assist diagnosis44. In summary, research evidence provides strong support for the clinical diagnosis of knee OA based on the 3 key symptoms (persistent knee pain, morning stiffness and functional impairment) and the 3 typical clinical signs (crepitus, restricted movement and bony enlargement) (evidence level Ib). This composite gives rise to a probability of over 90% in a population with a background risk of knee OA of 12.5%53, and is especially useful in primary care. However, the presence of just one sign is not highly predictive. 6. All patients with knee pain should be examined. Findings indicative of

knee OA include: crepitus; painful and/or restricted movement; bony enlargement; and absent or modest effusion. Additional features that may be present include: deformity (fixed flexion and/or varus - less commonly valgus); instability; periarticular or joint-line tenderness; and pain on patellofemoral compression.

Level of evidence: Ia – III, Strength of recommendation: 90 (95%CI 85-95) People with knee pain often are not adequately examined. In one study only 60% of people who consulted their GP for persistent knee pain (pain for most days for at least a month or longer in the past year) underwent any examination of their knees58. This may reflect time constraints, insufficient training in


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musculoskeletal assessment, or lack of confidence in the usefulness of clinical signs in diagnosis. As discussed in the previous section, the combined presence of 3 typical signs (crepitus, restricted movement and bony enlargement) greatly increases the chance of the diagnosis. In contrast, palpable effusion is less often present in knee OA than in knees with inflammatory arthritis (LR=0.73, 95%CI 0.56, 0.95).43;44 Knee instability is inconstant and present to a similar extent in people with knee OA and controls (LR=1.25, 95%CI 0.89, 1.77)43;55 (Table 2). Varus and valgus malalignment both associate with knee OA. The risk of having knee OA is more than 2 times greater in someone with malalignment than in someone without (OR=2.29, 95%CI 1.70, 3.09)20-23;55. Varus deformity carries greater risk (OR=3.02, 1.66, 5.49) than valgus (OR=2.20, 95%CI 1.43, 2.78) (Table 3). Research evidence is sparse for other physical findings such as tenderness and pain on PF compression. In brief, adequate physical assessment is required in patients with knee pain to confirm the diagnosis of knee OA (evidence level III). The presence of restricted movement, bony enlargement, and either varus or valgus malalignment add support to the diagnosis (evidence level Ia). Clinically evident effusion is uncommon in knee OA. This indicates inflammation and requires differentiation from inflammation caused by other arthritis (evidence level Ib). 7. Red flags (e.g. severe local inflammation, erythema, progressive pain

unrelated to usage) suggest sepsis, crystals and serious bone pathology. Involvement of other joints may suggest a wide range of alternative diagnoses. Other important considerations are referred pain, ligamentous and meniscal lesions and localised bursitis.

Level of evidence: IV, Strength of recommendation: 87 (95%CI 80-94) Clearly the presence of features that are unexplained by knee OA but which are characteristic of other diseases should lead to consideration, and investigation, of other pathologies. This is particularly important in the presence of “red flags” such as “bony pain” and acute synovitis with overlying erythema. To diagnose any regional abnormality it is important to consider the whole patient, to include a screen of the whole musculoskeletal system (and often other systems), and to combine a detailed history with a sufficient physical examination to determine the likely cause of pain and functional impairment. Although these statements are self-evident and underpin the rationale for clinical assessment, there are no research data that specifically examine the justification of a detailed patient assessment to differentiate knee OA from the many other possible causes of pain experienced in or around the knee (evidence level IV). A recent attempt by EULAR and the European Federation of National Associations of Orthopaedics and Traumatology (EFFORT) to develop evidence-based and consensus recommendations for diagnosis and management of patients with acute or recent onset knee swelling failed to identify relevant, sound research evidence and all recommendations were supported primarily by expert opinion (i.e. level IV evidence)59.


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8. Plain radiography (both knees, weight-bearing, semi-flexed PA (MTP) view, plus a lateral and skyline view) is the current “gold” standard for morphological assessment of knee OA. Classical features are focal joint space narrowing, osteophyte, subchondral bone sclerosis and subchondral “cysts”. Further imaging modalities (MRI, sonography, scintigraphy) are seldom indicated for diagnosis of OA.

Level of evidence: Ib – IIb, Strength of recommendation: 83 (95%CI 71-95) Structural changes on plain radiographs have been used by 35% of studies as the gold standard for the assessment of a diagnostic test. Two cross sectional studies, one based in hospital (n=377) and the other in the community (n=777), found the sensitivity of a weight-bearing PA (MTP) view plus a lateral or skyline view (0.90, 95%CI 0.84, 0.96) to be higher than that of the PA view alone (0.58, 95%CI 0.55, 0.50)30;60. When both the skyline and lateral views were used with the PA view, 98.7% cases of radiographic OA were identified30. Specificity could not be determined as the studies had no normal controls. Another study comparing 150, 300, 400 flexion and fully extended PA views found the 150 flexion view to be the most sensitive for demonstrating JSN 61.

The validity of radiographic change has been examined in a number of studies in which the clinical diagnosis32;43;62, MRI (cartilage defect score ≥2 of the 0-4 scale63) or arthroscopy (cartilage degeneration, yes/no64) was used as the gold standard. Classical radiographic features such as joint space narrowing (JSN) and osteophyte are moderately sensitive (0.44, 95%CI 0.27, 0.62 and 0.51, 95%CI 0.32, 0.69) and very specific (0.79, 95%CI 0.66, 0.92 and 0.83, 95%CI 0.76, 0.89). LRs were 2.19 (1.58, 3.03) for JSN32;43;62;63;65-68 and 3.29 (2.41, 4.48) for osteophyte32;43;62;63;65-71. Similar LRs were obtained for the KL score (LR=2.62, 2.10, 3.26)33;43;65;68, subchondral bone sclerosis (LR=2.56, 1.92, 3.42)43;62;65-68 and subchondral cysts (LR=2.98, 95%CI 1.76, 5.03)43;66(Table 2). The resultant probabilities of each of these radiographic features ranges from 24-32%, so none alone can lead to the diagnosis of knee OA. However, a composite of JSN, osteophyte, sclerosis and cysts increases the probability from 24% up to 89%. The value of MRI and ultrasound (US) in the diagnosis of knee OA have yet to be confirmed. A community based case-control study demonstrated that the cartilage defects determined by MRI were sensitive (0.93, 95%CI 0.84, 1.02), but not specific (0.33, 95%CI 0.16, 0.50) for knee OA defined by KL ≥172. However, abnormal MRI signals may associate with pain, as shown for bone marrow lesions (BML) or “edema” (OR=1.63, 95%CI=1.30, 2.04) 73-77 and particularly for effusion (OR=9.9, 95%CI 1.13, 149)75. This is supported by two cross-sectional studies where US was used to determine effusion. People with US defined effusion are 3 and a half times more likely to have pain than those without effusion (OR=3.55, 95%CI 1.75.7.20)38;39. Bone scintigraphy is a useful predictor of future structure change/progression but is an invasive investigation with no advantages to offer over other imaging modalities with respect to the diagnosis of knee OA 78;79.


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In conclusion, a weight bearing semi-flexed plain radiograph is a well validated imaging technique to determine structural change of knee OA. It has moderate sensitivity and reasonable specificity to detect cartilage loss and osteophyte (evidence level Ib). Multiple radiographic features greatly increase the likelihood of the diagnosis. MRI is more sensitive but less specific (evidence level IIb), but may be more useful in demonstrating features that associate with pain (evidence level Ib). Ultrasound is a simple and accessible technique to demonstrate effusion and synovial thickening (evidence level Ib). 9. Laboratory tests on blood, urine or synovial fluid are not required for

the diagnosis of knee OA, but may be used to confirm or exclude coexistent inflammatory disease (e.g. pyrophosphate crystal deposition, gout, rheumatoid arthritis) in patients with suggestive symptoms or signs.

Level of evidence: IIb, Strength of recommendation: 86 (95%CI 78-94) Rheumatoid factor may be present in patients with knee OA though less commonly and at lower titre than in those with rheumatoid arthritis43, and serum C-reactive protein may be mildly elevated in patients with symptomatic knee OA80. Additional biomarkers are under investigation in OA but no marker currently has sufficient specificity and sensitivity for clinical use in diagnosis of knee OA. Knee OA may co-exist with deposition of CPPD and basic calcium phosphate crystals. Analysis of synovial fluid aspirated from OA knees often demonstrate CPPD crystals (35%, 95%CI 19% - 50%)31;81;82, especially in severe cases31;82, and basic calcium phosphates, often in combination with CPPD82. In addition, synovial joints affected by OA predispose to monosodium urate crystal deposition83. Knees affected by OA are three time more likely to have gout than those unaffected by OA (OR=3.07, 95%CI 1.05, 8.96)83. Synovial fluid examination is the gold standard to confirm coexistence of gout and knee OA84 and is also the way in which to determine presence of CPPD. In brief, although laboratory investigations do not assist, and are not essential for, the diagnosis of knee OA, they may become useful for differential diagnosis and to identify coexistent diseases, especially crystal deposition (evidence level IIb). 10. If a palpable effusion is present synovial fluid should be aspirated and

analysed to exclude inflammatory disease and to identify urate and calcium pyrophosphate crystals. OA synovial fluid is typically non-inflammatory with <2000 leukocytes/mm3; if specifically sought, basic calcium phosphate crystals are often present.

Level of evidence: IIb, Strength of recommendations: 73 (95%CI 56-89) Clinically evident effusion is not a typical clinical marker of knee OA although it may present in some severe or symptomatic cases37-39;51;75;85. It is important to aspirate affected knees to determine whether there is coexistent crystal deposition or other disease. OA synovial fluid is typically non-inflammatory with


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<2000 leukocytes/mm3. Larger volumes may associate with “apatite associated destructive arthropathy” although alizarin red staining (at acidic pH) of synovial fluid aspirated from OA knees commonly shows less plentiful basic calcium phosphate aggregates 82. The level of evidence to support this proposition is predominantly IIb.

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2. Conaghan PG, Tennant A, Peterfy CG, Woodworth T, Stevens R, Guermazi A et al. Examining a whole-organ magnetic resonance imaging scoring system for osteoarthritis of the knee using Rasch analysis. Osteoarthritis & Cartilage 2006;14:Suppl-21.

3. Hernandez-Molina G, Guermazi A, Niu J, Gale D, Goggins J, Amin S et al. Central bone marrow lesions in symptomatic knee osteoarthritis and their relationship to anterior cruciate ligament tears and cartilage loss. Arthritis & Rheumatism 2008;58:130-6.

4. Hill CL, Gale DR, Chaisson CE, Skinner K, Kazis L, Gale ME et al. Periarticular Lesions Detected on Magnetic Resonance Imaging: Prevalence in Knees With and Without Symptoms. Arthritis and Rheumatism 2003;48:2836-44.

5. Hill CL, Seo GS, Gale D, Totterman S, Gale ME, Felson DT. Cruciate ligament integrity in osteoarthritis of the knee. Arthritis & Rheumatism 2005;52:794-9.

6. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60:91-7.

7. Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis & Rheumatism 1995;38:1134-41.

8. Andrianakos AA, Kontelis LK, Karamitsos DG, Aslanidis SI, Georgountzos AI, Kaziolas GO et al. Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The ESORDIG study. Journal of Rheumatology 2006;33:2507-13.

9. Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: The Chingford study. Arthritis and Rheumatism 1999;42:17-24.

10. Kacar C, Gilgil E, Urhan S, Arikan V, Dundar U, Oksuz MC et al. The prevalence of symptomatic knee and distal interphalangeal joint osteoarthritis in the urban population of Antalya, Turkey. Rheumatology International 2005;25:201-4.

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Figure 1. Study selection

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Inclusion criteria:1. Knee OA2. Diagnosis issues3. Clinical studies

Exclusion criteria:1. Other arthritis or other joint OA2. Progression3. Therapy4. Non-clinical researches (eg, DNA?)5. Case reports, editorial or reviews

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doi: 10.1136/ard.2009.113100 published online September 17, 2009Ann Rheum Dis

W Zhang, M Doherty, G Peat, et al. the diagnosis of knee osteoarthritisEULAR evidence based recommendations for

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