Department of Epidemiology and Preventive Medicine, Monash University Medical School, Melbourne, Victoria and 1 Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia.
Correspondence: F. M. Cicuttini, Department of Epidemiology and Preventive Medicine, Monash University, Central and Eastern Clinical School, Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. E-mail: flavia.cicuttini{at}med.monash.edu.au
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Abstract |
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Methods. One hundred and seventeen subjects with symptomatic knee OA underwent magnetic resonance imaging of their dominant knee at baseline and 2 yr later. Cartilage defects were identified as prevalent (defect score 2) in each knee compartment. Occurrence of joint replacement by 4 yr was documented.
Results. Cartilage defects were present in 81% of medial, 64% of lateral tibiofemoral compartments and 55% of patellar cartilages. Annual patellar cartilage loss was highest in those with defects compared with no defects (5.5% vs 3.2%, P = 0.01). Tibial cartilage loss was not associated with defects in the medial (4.6% vs 5.8%, P = 0.42) or lateral (4.7% vs 6.5%, P = 0.21) tibial cartilages. Higher total cartilage defect scores (815) were associated with a 6.0-fold increased risk of joint replacement over 4 yr compared with those with lower scores (27) (95% confidence interval 1.6, 22.3), independently of potential confounders.
Conclusions. Articular cartilage defects are associated with disease severity in knee OA and predict patellar cartilage loss and knee replacement.
KEY WORDS: Articular cartilage, Cartilage defect, Joint replacement, Osteoarthritis, Progression
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Introduction |
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In healthy people, cartilage defects increase in both prevalence and severity with increasing age and body mass index (BMI) [8, 9]. The role of cartilage defects in the pathogenesis of knee OA is not yet understood. Cartilage defects have been described in asymptomatic knees and have been attributed to trauma, both in isolation, where no other abnormality is present, and in conjunction with anterior cruciate ligament and meniscal injuries [10]. They have also been associated with osteophytes and metaphyseal area at the knee, suggesting a link with OA [11]. Thus it is possible that cartilage defects are an early manifestation of OA and may progress to knee OA, but there is no study of the natural history of these defects in healthy subjects or in established human OA. Large longitudinal studies have been precluded by the need for invasive assessment with arthroscopy.
Although it is well established that social, cultural and economic factors contribute to the decision to undergo joint replacement surgery, the disease-related factors that predispose to joint replacement surgery have been difficult to establish [1215]. Clinical and radiographic predictors of joint replacement perform similarly when the indication for listing for hip replacement surgery has been studied [15]. We have recently shown that people with mild to moderate OA who lose cartilage most rapidly over 2 yr have approximately a 7-fold increase in risk of joint replacement surgery of that joint, compared with those who lose cartilage least rapidly [16].
We performed cross-sectional and longitudinal magnetic resonance imaging (MRI) studies in subjects with mild to moderate symptomatic knee OA, to characterize the factors affecting the prevalence and severity of cartilage defects, and to examine whether the presence of cartilage defects affects the rate of change in knee cartilage volume over 2 yr or the risk of joint replacement over 4 yr.
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Patients and methods |
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One hundred and thirty-two subjects entered the study; they underwent an MRI scan and radiographs at baseline and a follow-up MRI scan at 2 yr [16]. Inclusion criteria were age over 40 and symptomatic [at least one pain dimension of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [18] score above 20% and osteophytes present] knee OA (ACR clinical and radiographic criteria [19]). Subjects were excluded if they had any other form of arthritis, a contraindication to MRI (e.g. pacemaker, cerebral aneurysm clip, cochlear implant, presence of shrapnel in strategic locations, metal in the eye, and claustrophobia), inability to walk 50 feet without the use of an assistive device, hemiparesis of either lower limb, or planned total knee replacement.
Weight-bearing anteroposterior and skyline knee radiographs were performed at baseline to determine the presence of osteophytes for study inclusion. Where both knees were symptomatic and showed changes of radiographic OA, the knee with the least severe radiographic disease was used, to reduce loss to follow-up due to joint replacement.
Weight was measured to the nearest 0.1 kg (with shoes, socks and bulky clothing removed) using a single pair of scales. Height was measured to the nearest 0.1 cm (with shoes and socks removed) using a stadiometer. BMI (kg/m2) was calculated. The baseline and 2-yr follow-up questionnaires were used to obtain information regarding demographic data, symptoms (WOMAC [18]) and general health status [Short Form 36 (SF-36) [20]]. At 4 yr all subjects were contacted to identify whether they had undergone knee replacement surgery on the knee studied at baseline and year 2. This was confirmed by contacting the treating physician in all cases, as previously described [16].
Radiographic severity of disease
Radiographs were assessed by two trained observers. The radiological features of tibiofemoral and skyline OA were graded in each compartment, on a four-point scale (03) for individual features of osteophytes and joint space narrowing [21]. In the case of disagreement between observers, the films were reviewed with a third independent observer. Intraobserver reproducibility was 0.93 for osteophytes and 0.93 for joint space narrowing. Interobserver reproducibility was 0.86 for osteophytes and 0.85 for joint space narrowing ( statistic) [22].
MRI
An MRI scan of the study knee was performed. Knees were imaged in the sagittal plane on a 1.5-T whole-body magnetic resonance unit (GE) with use of a commercial transmitreceive extremity coil. The following image sequence was used: a T1-weighted fat saturation 3D gradient recall acquisition in the steady state; flip angle 55°; repetition time 58 ms; echo time 12 ms; field of view 16 cm; 60 partitions; 512 x 512 matrix; acquisition time 11 min 56 s; one acquisition. Sagittal images were obtained at a partition thickness of 1.5 mm and an in-plane resolution of 0.31 x 0.31 (512 x 512 pixels). The image data were transferred to the workstation.
Cartilage defect assessment
The cartilage defects were graded on MR images with a modification of the previous classification system [8, 9, 11, 2325] at medial tibial, medial femoral, lateral tibial, lateral femoral and patellar sites: grade 0, normal cartilage; grade 1, focal blistering and intracartilaginous low-signal intensity area with an intact surface; grade 2, irregularities on the surface or base and loss of thickness of less than 50%; grade 3, deep ulceration with loss of thickness of more than 50%; grade 4, full-thickness chondral wear with exposure of subchondral bone. We found that the cartilage surface in some images was still regular but cartilage adjacent to subchondral bone became irregular, so we included these changes in the classification system, as described above. A cartilage defect had also to be present on at least two consecutive slices. The cartilage was considered to be normal if the band of intermediate signal intensity had a uniform thickness. The scores of cartilage defects at medial tibiofemoral (04), lateral tibiofemoral (04) and patellar (04) compartments were used for analysis in this study. A prevalent cartilage defect was defined as a cartilage defect score of 2 at any site of that compartment. A single observer graded cartilage defects in all knees, blind to the result of cartilage volume assessment. Intraobserver reliability in the whole sample [expressed as the intraclass correlation coefficient (ICC)] was 0.90 for the medial tibiofemoral compartment, 0.89 for the lateral tibiofemoral compartment, 0.94 for the patellar compartment and 0.94 for the whole compartments. Interobserver reliability was assessed in 50 MR images and yielded an ICC of 0.90 for the medial tibiofemoral compartment, 0.85 for the lateral tibiofemoral compartment and 0.93 for the patellar compartment.
Cartilage volume measurement
Two trained observers (different from the observer who scored cartilage lesions) read each MR image independently, as previously described [22]. Each subject's baseline and follow-up MRI scans were scored unpaired and blinded to subject identification and timing of MRI [17]. The observers measured cartilage volume on each scan. If these results were within ±20%, an average of the two observers' results was used. If they were outside this range, the measurements were repeated until the independent measures were within ±20%. Repeat measurements were made blind to the results of the comparison of the previous results. The coefficients of variation for the measurement of medial and lateral cartilage volume measures were 3.4 and 2.0%, respectively [22].
Knee bone size measurement
Knee tibial plateau bone area was determined using image processing on an independent workstation using the software program Osiris (Hospitaux Universitaires de Geneve, website: http://www.sim.hcug.ch/osiris/01OsirisPresentationEN.htm), from reformatted axial images [22]. The coefficient of variation for medial and lateral tibial plateau area was 2.3 and 2.4% respectively. Patellar bone volume was determined as previously described, with a coefficient of variation of 2.2% [26].
Statistics
Descriptive statistics for characteristics of the subjects were tabulated. Cartilage defect scores for the medial and lateral tibial, femoral and patellar cartilage, cartilage volumes and change scores for cartilage volume were assessed for normality. Regression methods were used to describe the relationship between the severity of cartilage lesions in the respective compartment and possible significant explanatory variables. Multivariate regression models were constructed to account for a possible effect of age, gender, BMI, initial cartilage volume, bone size (either medial or lateral tibial bone area, patellar bone volume), radiographic severity of OA and the cartilage defect score for the relevant compartment of the knee joint. To assess the relationship between the presence and absence of cartilage defects with cartilage volume, change in cartilage volume, symptoms of knee OA and change in symptoms of knee OA, multivariate regression models were constructed for the different outcomes, adjusting for likely significant confounding factors. We performed a median split of the total score of medial and lateral tibiofemoral cartilage defects and used binary regression to identify whether the tibiofemoral cartilage defect score was predictive of joint replacement over the next 4 yr. Adjustment was made for potential confounders [age, gender, BMI, rate of cartilage loss over the first 2 yr, symptoms and severity of radiographic disease (KellgrenLawrence grade)]. All analyses were performed using the SPSS statistical package (version 10.0.5, SPSS, Cary, NC, USA) with a P value less than 0.05 considered statistically significant.
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Results |
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In contrast, the presence of cartilage defects in the patellar cartilage predicted loss of patellar cartilage volume. Subjects with defects lost 5.5% (95% CI 4.4%, 6.6%) patellar cartilage volume annually compared with 3.2% (95% CI 2.0%, 4.5%) in those without (P = 0.01). These results were unchanged after adjustment for age, gender, BMI, initial cartilage volume, bone size and radiographic characteristics of OA, and KellgrenLawrence grade in the regression equation.
Tibiofemoral lesions did not affect change in patellar cartilage and vice versa.
Severity of cartilage defect scores and clinical endpoints, including risk of joint replacement
Eighteen study participants underwent total knee joint replacement. Of the 56 subjects with higher total cartilage defect scores (815), 13 underwent total knee replacement, and were six times more likely to require a total knee joint replacement than those with lower defect scores (27) over the subsequent 4 yr (odds ratio 6.0, 95% CI 1.6, 22.3). This result was stable when examined for confounding by age, gender, BMI, symptoms (WOMAC), annual percentage cartilage loss and radiographic severity. No effect of site-specific defects was identified.
There were no consistent or significant relationships identified between the site (tibial or femoral defects, medial or lateral compartment), presence or severity of chondral defects and total WOMAC score or subscale score (pain, stiffness or function) in univariate or multivariate analysis, accounting for age, gender, body mass index, grade of radiographic feature of osteoarthritis and cartilage volume (results not shown). Similarly, the presence or grade of chondral defects did not predict change in symptoms (results not shown). A reduction in total WOMAC score over the course of the study was weakly associated with the presence of lesions in the lateral tibiofemoral compartment (P = 0.03).
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Discussion |
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Although cartilage defects, detected by arthroscopy or MRI, are a recognized manifestation of knee OA, factors influencing their number and severity, apart from radiographic knee OA, have not been examined [5, 27, 28]. In this study, cartilage defects were associated with cartilage volume but not age, gender or BMI. This relationship was independent of the relationship between cartilage defects and the radiographic characteristics of knee OA. Thus, it may be that the cartilage defect score may be useful as a potential additional marker of disease severity, being independently associated with radiographic change and cartilage volume and also independently predictive of clinically significant outcomes, such as joint replacement surgery. In predominantly healthy populations, age and BMI are strongly associated with the presence and severity of cartilage defects [8, 9]. It may be that once OA is established this relationship is less important in the progression of defects.
The presence of more severe patellar cartilage defects predicted both absolute and percentage patellar cartilage loss over 2 yr: these results were not reflected in the tibiofemoral joint. It may be that factors affecting progression of patellofemoral and tibiofemoral OA differ in a similar fashion as for risk factors for the incidence of patellofemoral OA and tibiofemoral OA [29, 30]. It may also be that the prevalence of significant defects was so high in the tibiofemoral compartment that we did not have the power to show the effect of lower grade defects in that compartment. This is supported by our finding that the severity of tibiofemoral cartilage defects at baseline was an independent risk factor for knee replacement surgery over 4 yr. Indeed, our ability to detect a difference may have been limited by the overall scoring system we used for the presence of cartilage defects in an individual cartilage rather than a regional approach.
This study examined only subjects with symptomatic knee OA, so whether our results are generalizable to asymptomatic subjects has yet to be determined. All subjects had established symptomatic knee OA and a high proportion had significant cartilage defects in the tibiofemoral compartments. It may be that cartilage defects may be predictors of cartilage loss in early, asymptomatic disease, as suggested by our findings at the patellofemoral joint. Our subjects were recruited from the community on the basis of symptoms only, so it is unlikely that this biases them towards having disease that is more likely to progress than among subjects with OA recruited by other methods. Since all our subjects were symptomatic, we may have had limited power to identify a relationship between tibiofemoral defects, structural change and range of pain.
This study suggests that the presence and severity of tibiofemoral cartilage lesions may be useful as an independent marker of disease severity, even in the presence of established OA, and may aid in predicting which people with symptomatic knee OA are more likely to develop disease which requires joint replacement. It may be that where disease is less severe these cartilage defects may be more useful in predicting cartilage loss, as seen in the patellofemoral compartment. Thus these lesions may have a role as predictors of cartilage loss in early or predisease states, where disease may be more regional. This warrants further investigation.
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Acknowledgments |
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The authors have declared no conflicts of interest.
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References |
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