Very few studies have examined the quantitative changes in cartilage volume over time in a symptomatic knee OA population. Through the use of MRI in a longitudinal study of 107 subjects with symptomatic OA of the knee, we demonstrate a significant global cartilage volume loss at as early as 12 months. The changes in values are in line with those from a pilot study [13
], and are also in accordance with the rate of progression published by another group that looked specifically at tibial cartilage volumes in a younger population of patients with knee OA [24
]. The mean changes in cartilage volume seen at 12 and 24 months are relevant as they exceed the precision of our qMRI assessment (RMS CV%) as presented in our previous study [13
The present study further reinforces the heterogeneity of the OA patient population that previous clinical trials have described [28
] According to our patient cohort, fast progressors as assessed by qMRI may be associated with baseline clinical variables: older age, having an elevated BMI, severe meniscal extrusion and tear, and bone edema. Some of these predictors, which have already been identified in major epidemiological studies [13
], make clinical sense. These variables may assist in identifying patients with disease that is likely to show marked progress over time and for whom the consideration of therapeutic interventions is crucial for preventing further joint damage. It is, however, unknown whether such a population is adequately representative of the entire patient population for monitoring the efficiency of new therapeutics in the form of DMOADs. As the disease could be cyclical, patients may experience rapid progression at some point in the course of their disease that may not reflect long-term progression.
Questions remain regarding patients with slow disease progression. It is unlikely that this process reflects merely the normal aging process, as these patients experienced pain and loss of function and met the American College of Rheumatology criteria for knee OA. We hypothesize that the slow progressors might constitute a subgroup of patients in a quiescent phase of the disease.
Many consider the measurement of the change in the minimal JSW of standardized knee radiographs to be the best available methodology for evaluating the anatomical progression of OA [3
]. The present data, however, show that in only 13% of the cases, the changes in JSW at 24 months, as measured in full accordance with the Buckland-Wright protocol, demonstrated cartilage loss greater than the JSW measurement error (>0.6 mm). These radiological findings contrast with the qMRI data over the same period, where 77% of patients showed a significant loss of cartilage volume, that is, greater than the precision error of 2% (data not shown). Thus, these results suggest no strong relationship between these methods. The lack of correlation between these two parameters may be related to a larger relative variability in the JSW measurements. For example, for all patients, a mean loss of 597 mm3
of global cartilage volume with a standard deviation of 459 mm3
was detected at 24 months, a change that was smaller than the mean. In comparison, for the same cohort, a JSW loss of 0.16 mm with a standard deviation of 0.49 mm, roughly three times greater than the mean change, was detected at 24 months. Therefore, the 'effect size', defined as the mean change divided by its standard deviation, of qMRI assessments appears superior to that of JSW assessments.
In this study, we found some association between the extent of cartilage volume loss and changes in pain at 24 months (p
= 0.03) when using a multivariate analysis approach, which was, however, not demonstrated by direct correlation. The patients' analgesic and NSAID washout period prior to the clinical evaluation likely reinforces the explanation of this phenomenon. Our findings are in accordance with Hunter and colleagues [35
], who found that pain was associated with patellar but not with tibio-femoral cartilage loss, and somewhat with Wluka and colleagues [36
], who demonstrated a weak association between the worsening of OA symptoms (knee pain and stiffness) and increased tibial cartilage loss. The relative paucity of association between symptoms and cartilage loss found in our study is perhaps unsurprising, as pain does not originate from the cartilage itself; rather, it likely originates from the surrounding bones, menisci, capsule, and ligaments. This weak association with OA symptoms may also be related to the limited number of articular features assessed by our MRI scoring system. Yet, since our cohort was relatively small, the statistical significance of our findings demonstrated only by a multivariate approach could be due to insufficient statistical power. Taken together, these data suggest that knee OA structural progression may be distinct from symptomatic changes.
We found an important relationship between cartilage volume loss and the surrounding knee tissue damage as assessed by MRI. For instance, the presence of meniscal damage, especially meniscal extrusion, was strongly associated with cartilage volume loss. In fact, 101 of our patients had at least some meniscal damage, either medial or lateral. We tried to analyze patients without meniscal damage to look at other predictors but, unfortunately, the subcohort of six patients was not large enough to yield other conclusions. The progression rate of patients without meniscal damage was -3.0% for global cartilage and -2.7% for the medial compartment. Five of these patients were classified as slow progressors and one as intermediate (data not shown).
This high level of meniscal damage (78%) may appear unusual. Our patients were selected based on inclusion/exclusion criteria for which the presence of radiological knee OA on the medial compartment plus the presence of JSW between 2 and 4 mm was necessary. It is probable that these patients may represent a more advanced disease state and that a meniscal lesion, a structure that greatly influences the JSW assessment, could almost be a prerequisite to obtain a JSW of 2 to 4 mm on standing X-rays. To further reinforce this hypothesis, our previous study on 32 subjects [13
] showed a similar proportion of patients with knee meniscal damage (75%). Interestingly, inclusion in this cohort required the same JSW criteria with respect to the medial compartment. Our findings are in agreement with previous studies that reported that a significant percentage of patients with symptomatic knee OA had meniscal damage when assessed by MRI [37
Cicuttini and colleagues [30
] suggested that an accelerated loss of cartilage over time was evident in patients who underwent partial meniscectomy. These results suggest that the key role of the meniscal apparatus is protecting cartilage, especially in elderly subjects with obesity or joint instability. Biswal and colleagues [40
] also recently studied risk factors associated with progressive cartilage loss in the knee using MRI in 43 patients. Patients were evaluated at baseline and after an average 1.8 year follow-up. This study demonstrated that meniscal and anterior cruciate ligament tears were associated with more rapid cartilage loss.
Our study also demonstrated the association between cartilage volume loss and the presence of bone edema. Felson and colleagues (([41
] have already demonstrated the influence of structural changes in assessing knee OA. This group also demonstrated that bone edema as assessed by MRI was strongly associated with pain in knee OA, which was not clearly found in our study (data not shown). A possible explanation for this discrepancy may be the fact that the patient cohort recruited for our large clinical trial was less symptomatic than patients who had potentially more severe knee pain.
The lack of correlation between the U-CTX-II levels and the cartilage volume loss found in the present study contradicts other studies [4
] The large variability in this marker, including its diurnal variation, in our cohort may explain the lack of association; nonetheless, it is still not certain whether such a marker may be more useful in larger patient cohorts followed for a longer period.
This study, like any other, has its limitations. Our cohort is representative of the average patient population with typical knee OA that is seen at a rheumatology clinic. This study is of notable confirmatory value in terms of the results obtained from a smaller number of patients [13
]. However, as no therapeutic intervention to decelerate or halt disease progression has been assessed with qMRI, the extent to which such effective intervention could translate to the patients' clinical features remains unclear. As we are unaware whether all OA patients experience fast disease progression at the same time (for example, another group may have progression in year 3 while the previous progressors remain dormant), it is unclear which subpopulation could benefit the most from DMOADs. Hypothetically, favoring the treatment of patients with fast disease progression, as they likely have the poorest prognoses and the greatest need for surgical intervention, seems logical.
One may also question the potential partiality of the non-blinding of the cartilage when meniscal or bone assessment was done. However, as the radiologist evaluation was performed completely separately from the assessment of cartilage volume, it is unlikely that the grading of meniscal damage was biased by the concomitant visualization of the cartilage. We also acknowledge that the FISP sequence may not be the optimal MR sequence for identifying all the meniscal and bone lesions. It has sufficient contrast, however, to identify significant lesions, especially edema, as demonstrated in this previous work, and this acquisition has the unique advantage of being able to assess simultaneously the cartilage, menisci and bone.