In our study we sought to assess the feasibility of a quantitative score for monitoring changes in cartilage lesion and BMEP size at the knee joint in subjects with and without early OA using 3.0 T MRI. Findings were compared with the semi-quantitative WORMS, which was developed as a multi-feature, whole organ evaluation method of the knee in OA. Results were correlated with clinical and radiographic findings. A subset of the A9001140 study subjects was retrospectively analyzed. The study comprised an observation period of 2 years with a total of three surveys including 12- and 24-month follow-up examinations.
As expected, OA patients had higher clinical parameters of OA and higher WORMS global scores of the whole knee. They presented with significantly higher semi-quantitative cartilage WORMS scores and quantitative determined cartilage lesion sizes in all compartments of the knee at BL. During follow-up, a significant increase in the cartilage lesion WORMS score and size in OA patients compared with the controls occurred at the lateral patella. These results could be explained by increasing cartilage degeneration during OA progression, including preceding thinning and erosion. It is in agreement with previous findings, with the patellofemoral compartment being the most affected [41
], and also in concordance with the radiographic findings, showing a significant reduction in JSW in our patients. However, applying the quantitative score an increase in cartilage lesion size was additionally observed at the trochlea, at the medial compartment, and in the whole knee, indicating a higher sensitivity to subtle cartilage changes of this approach than the WORMS. This is supported by the findings of Le Graverand et al. [20
], who analyzed 145 subjects from the A9001140 study and revealed a significant decrease in cartilage thickness in the central medial femorotibial compartment in OA patients with a KL grade of 3.
Using the semi-quantitative WORMS, 3.8% of the cartilage lesions in OA patients and 2.5% in controls increased. However, by using the quantitative score the rate of change was also more sensitively monitored than with the WORMS score: an increase in cartilage lesion size was shown in 23.8% of the lesions in OA patients and in 6.6% of the controls; a decrease was observed in 14.2% of the OA patients and in 3.6% of the controls.
Bone marrow edema pattern had significantly higher WORMS scores and sizes in OA patients when evaluated for the whole knee. The frequency of this pathology at BL was 23.3% in OA patients and 8.6% in controls. This is in agreement with the literature and reflects the high prevalence of this abnormality in OA, but also to a lesser extent in healthy subjects [9
]. The change at the follow-up examinations yielded mixed results: an increase over all time points was observed in OA patients at the lateral femur with both scores. The quantitative score revealed in addition in OA patients a significant increase at the trochlea and at the lateral patella as well as a temporary reduction at the lateral tibia; controls had a small increase in BMEP size at the lateral tibia and a small decrease at FU1 at the lateral patella.
Applying the WORMS, BMEP decreased in 3.4% and increased in 4.9% of the lesions in our OA patients, whereas a decrease was found in 13.8% and an increase in 12.8% when the lesions were assessed with the quantitative score. For controls, these numbers were 9.2% and 1.8% applying the WORMS in comparison to 9.8% and 2.6% for the quantitative score. Therefore—similar to cartilage lesions—the quantitative score is more sensitive to changes in the BMEP sizes than the WORMS score. However, the fluctuation of BMEP parallels that of other studies, where in OA patients after 2 years a significant change in up to 66–80% of the lesions is reported [13
]. It illustrates the dynamic process of this imaging parameter in the course of the disease. Therefore, care should be taken when BMEP is utilized as a surrogate endpoint.
We demonstrated low correlations between changes in the WOMAC total score and its subscores with changes in cartilage and BMEP morphology indices in the OA patients in several subregions of the knee, whereby mostly the lateral compartments were affected. Changes in SF-36 PCS and VAS scores correlated in a considerably lower amount of compartments with changes in cartilage or BMEP morphology. We conclude that the use of a disease-specific health score like WOMAC is more sensitive in the evaluation of changes in the early disease processes in contrast to the utilization of only general outcomes scores like SF-36 or VAS. However, since changes in volume approximation of cartilage and BMEP lesions were almost equally correlated with changes in the clinical parameters, like changes in the respective WORMS scores we think that both methods have a comparable sensitivity to draw conclusions from morphology as to the clinical status of the disease. The overall lack of strong correlations of clinical OA scores with morphological findings may be related to the fact that the knee becomes more accustomed to cartilage damage. Link et al. [10
] found most symptoms in patients with lower grade cartilage lesions and concluded that clinical symptoms are more substantial at the onset of OA. Furthermore, controversy still exists about the cause of knee pain in OA patients. Felson et al. [43
] found a moderately strong association between the change in BMEP with the development of frequent knee pain, whereas this association was not found by Link et al. [10
]. Kornaat et al. [48
] found that the presence of large central osteophytes are associated with pain. Hunter et al. [49
] reported that alterations in patella volume are associated with pain and other subscores of the WOMAC. Since hyaline cartilage does not contain pain fibers it is hypothesized that other factors like inflammation within the joint or enlargement of effusions might also play an important role [43
Our study was conducted with HF-MRI at 3.0 Tesla. Visualization of the morphological and pathological features of cartilage has been shown to be improved at 3.0 T compared with the clinically widely-used 1.5-T systems in cadaver studies [23
] and in specimens [23
]. One recent larger scale clinical study [25
] utilizing MRI at 3.0 T and validation of the findings with arthroscopy has shown further promise with higher specificity, higher accuracy, and higher diagnostic confidence for detecting cartilage lesions, but not for higher sensitivity. However, Wong et al. [50
] found even increased sensitivity in a similar setting with a smaller sample size. We therefore assume that detection of lesions and estimation of their size in our study was improved in comparison to using lower field strengths.
Several limitations can be identified in our study. First is the small sample size of subjects in the OA patient and control groups. Second, there was no true gold standard in the study; none of the study subjects underwent arthroscopy, which could not be ethically justified in healthy subjects. Also, no histopathological examination has been performed. However, the subjects were thoroughly monitored. Careful simultaneous assessment of accepted clinical and radiographic progress indicators of OA was also performed. Third, obesity is a known risk factor for OA. Although differences in BMI were outlined in the inclusion criteria, BMI was adjusted for the analysis of each group given the presence of confounding. Fourth, reducing WORMS partitioning to seven compartments could have potentially affected the number of grade 4 or grade 6 lesions. Grade 6 lesions, however, were not expected in this cohort with early disease and grade 4 lesions are very rare, as usually full thickness lesions are present before >75% partial thickness lesions in one subcompartment occur. Finally, our study was limited to women, so it is questionable whether the results could be extrapolated to men.
In summary, with our retrospective analysis of longitudinal data at 3.0 T by application of a quantitative scoring system, we were able to detect changes in cartilage and BMEP morphology between OA patients and controls within a follow-up period of 24 months. More compartments of the knee in OA patients are affected by changes in comparison to the semi-quantitative WORMS score. The amount of lesions that experience changes is also higher with the quantitative scoring system. Since a progression of the disease in our OA patients is indicated by significant narrowing of the JSW, we conclude that the quantitative score is more sensitive to changes in cartilage and BMEP morphology in the course of the disease than the semi-quantitative technique. Since it has a good reproducibility and can be applied relatively quickly, we believe that the quantitative score is feasible for study evaluation and has potential usage in clinical settings. However, verification in a larger number of patients is needed to ascertain whether the method could be used as an alternative to time-consuming approaches like qMRI. Only weak associations were found when the rate of change of the lesions correlated with health-related quality of life, as assessed by the WOMAC and SF-36 scores. But these findings were not unexpected and had been demonstrated by previous studies [9
], indicating that structural imaging findings do not correlate well with the clinical progression of OA.