Association between findings on delayed gadolinium-enhanced magnetic resonance imaging of cartilage and future knee osteoarthritis

Abstract

Objective

To examine the predictive value of the delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index with regard to future radiographic osteoarthritis (OA).

Methods

In 1998, 17 knees in 11 men and 4 women with knee pain, normal results of weight-bearing radiography, and arthroscopic cartilage changes ranging from superficial fibrillation to fissuring and softening were examined using dGEMRIC. Six years later, 16 of the 17 knees were reassessed for radiographic OA changes.

Results

At followup, 9 of the 16 knees showed radiographic OA changes. Two of them had undergone a knee joint replacement due to OA. In the knees with radiographic OA, the dGEMRIC index at baseline was lower than that in the knees without radiographic OA (P = 0.03).

Conclusion

The results of the present study support the dGEMRIC index as a clinically relevant measure of cartilage integrity and suggest that a low index may be predictive of the development of knee OA.

Knee osteoarthritis (OA) is a slowly developing, degenerative cartilage disease that commonly affects the elderly. Loss of cartilage, which is the main feature in OA, is considered to be the result of an imbalance between biosynthesis and degradation of cartilage constituents, in which degradative processes outpace compensatory repair (1). Despite efforts to survey risk factors for disease progression, OA pathogenesis is not fully understood, and the disease remains heterogeneous. This may be particularly true in the earlier stages of the disease (2). At present, radiographic changes in combination with joint pain define OA. Recently, it was shown that cartilage loss may occur for several years before minor OA changes can be detected on radiographs (3). Accordingly, prognostic markers for preradiographic disease progression are needed.

Magnetic resonance imaging (MRI) has improved our ability to detect cartilaginous lesions at an earlier stage compared with radiography. However, despite cartilage-specific MRI sequences that have improved the resolution of cartilage, MRI is still used to diagnose only macroscopic defects. In addition, certain studies indicate that once macroscopic changes have occurred, the damaged tissue is beyond repair (4). In this respect, molecular damage to type II collagen molecules that constitute the fiber network of the cartilage matrix is considered a crucial point of no return (5). Generally, the loss of glycosaminoglycans (GAGs), which are embedded in the collagen network and are mainly responsible for load distribution and compressive stiffness, is considered an earlier event in the OA process (1). Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a well-documented and validated imaging technique to study cartilage GAG content in vivo. In dGEMRIC, the negatively charged contrast medium (Gd-DTPA²⁻) distributes inversely to the negatively charged GAG in the cartilage (6). Because Gd-DTPA²⁻ shortens the MRI parameter T1, the GAG content of articular cartilage can be estimated from T1 analysis within a specified cartilage volume, the dGEMRIC index (7).

We previously showed that the dGEMRIC index is lower in patients with early cartilage lesions than that in asymptomatic volunteers, despite the lack of joint space narrowing (JSN) on weight-bearing radiographs (8). The objective of this study was to examine the predictive value of the dGEMRIC index with respect to signs of radiographic knee OA in these patients, 6 years after the initial dGEMRIC examination.

PATIENTS AND METHODS

Baseline evaluation by dGEMRIC.

Seventeen knees in 11 men and 4 women (ages 35–70 years [mean 50 years]) with knee pain, normal results of weight-bearing radiography, and arthroscopic cartilage changes ranging from superficial fibrillation to fissuring and softening were examined in 1998 using dGEMRIC. A standard 1.5T MRI system (Magnetom Vision; Siemens Medical Systems, Erlangen, Germany) with a dedicated knee coil was used for the investigations at baseline. Approximately 1.5 hours after an intravenous injection of Gd-DTPA²⁻ (Magnevist; Schering, Berlin, Germany), quantitative T1 relaxation time measurements were obtained in 2 sagittal slices (5 mm thick) that were positioned over the medial and lateral femoral condyles, respectively (repetition time 2,000 msec; time to echo 15 msec; turbofactor 11; field of view 120 × 120 mm²; matrix 256 × 256 pixels; inversion recovery time 100 msec, 200 msec, 400 msec, 800 msec, and 1,600 msec). In these slices, a full-thickness region of interest in the cartilage was drawn in the central parts of the medial and lateral femoral weight-bearing cartilage between the center of the tibial plateau and the rear insertion of the meniscus. The mean T1 value for the medial and lateral femoral cartilage was calculated for each knee (dGEMRIC index) (8). In one patient, the T1 value was obtained only on the medial femoral cartilage.

Arthroscopy.

The surgery reports obtained at baseline were retrospectively reviewed by a skilled arthroscopist (FN) according to the rating system recommended by the International Cartilage Repair Society (ICRS; www.cartilage.org) (Table 1) (9). The depth of the lesion was classified as superficial softening assessed based on indentation or superficial fissures and cracks (ICRS grade 1), lesions extending to less than half of the cartilage thickness (ICRS grade 2), lesions extending to half or more of the cartilage thickness but not into the subchondral bone (ICRS grade 3), or osteochondral lesion (ICRS grade 4).

Table 1. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index and arthroscopy results at baseline, and results of radiography at the 6-year followup*

Patient/sex	Baseline					Followup radiography, tibiofemoral OA
	dGEMRIC index, T1, msec	Arthroscopy
		Lateral femur	Lateral tibia	Medial femur	Medial tibia
* Results of arthroscopy were based on the International Cartilage Repair Society grading system, where 1 = superficial softening assessed based on indentation or superficial fissures and cracks, 2 = lesions extending to less than half of the cartilage thickness, 3 = lesions extending to half or more of the cartilage thickness but not into the subchondral bone, and 4 = osteochondral lesion. OA = osteoarthritis.
1/M	194	2	1	0	0	Yes
2/M	263	3	3	0	0	Yes
3/M	270	0	0	1	1	Yes
4/F	286	0	0	1	3	No
5/M	289	0	0	3	0	Yes
6/M	327	0	0	2	1	Yes
7/M	329	0	0	3	1	Yes
8/M	335	0	0	2	0	No
9/F	356	0	0	1	3	Yes
10/F	375	0	0	1	0	Yes
11/M	375	0	0	1	1	No
12/F	386	0	0	3	0	No
13/M	402	0	3	1	3	Yes
14/M	405	0	0	3	3	No
15/F	424	0	0	1	0	No
16/M	471	0	0	3	0	No

Radiography.

Six years after the initial dGEMRIC investigation, we reassessed 16 of the 17 knees with respect to radiographic OA changes. Weight-bearing anteroposterior radiographs were obtained under fluoroscopic control. Each patient was standing with equal weight on both legs, with the knees in a semiflexed position and with both patellae touching the table of the fluoroscopy unit. The medial aspect of the foot of the examined leg was parallel to the central x-ray beam, and the beam was adjusted to be tangential to the anterior and posterior aspects of the medial tibial condyle. OA scoring was performed by one of the authors (PN), using the criteria described by Englund et al (10). Marginal osteophyte grades from the femur and tibia of the same compartment were added (sum osteophyte compartment score). The criteria defining radiographic OA were as follows: JSN grade ≥2, sum osteophyte compartment score ≥2, or grade 1 JSN in combination with grade 1 sum osteophytes in the same compartment. This cutoff approximates grade 2 knee OA based on the Kellgren/Lawrence scale (11).

Statistical analysis.

The Mann-Whitney rank sum test, linear regression analysis, and maximum likelihood estimation using logistic regression were used for statistical evaluation.

RESULTS

The dGEMRIC index in the 16 knees ranged from 194 msec to 471 msec at baseline. Six years later, 9 of the 16 knees showed radiographic OA changes. In these knees, the mean baseline dGEMRIC index was lower than that in the knees without radiographic OA (mean ± SD 312 ± 64 msec and 383 ± 60 msec, respectively; P = 0.03) (Figure 1).

Figure 1. Baseline delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index, for knees with and those without radiographic osteoarthritis (OA) at the 6-year followup. Bars show the mean.

The radiographic changes were as follows: 1 knee had JSN grade ≥2, 3 knees had a sum osteophyte compartment score ≥2, and 5 knees had grade 1 JSN in combination with grade 1 sum osteophytes in the same compartment. Two of the knees had undergone joint replacement due to OA (dGEMRIC indices 194 msec and 329 msec, respectively). Table 1 shows the results of dGEMRIC and arthroscopy at baseline as well as radiographic findings at followup. There was no detectable correlation between the arthroscopic findings and results of dGEMRIC at baseline, nor was there an association between arthroscopic findings and the development of radiographic changes at followup (Table 1).

Figure 2 shows the relationship between the dGEMRIC index and the probability of development of radiographic OA 6 years later (odds ratio 0.98, P = 0.07).

Figure 2. Baseline dGEMRIC index versus probability of radiographic OA at the 6-year followup. See Figure 1 for definitions.

DISCUSSION

Previously, we showed that the patients included in the present study, all of whom had knee pain, normal results of weight-bearing radiography, and arthroscopic minor cartilage changes, had variable R1 (1/T1) values (msec) (8). The results of this followup study of these patients suggest that a low dGEMRIC index is associated with an increased risk of radiographic OA developing within 6 years. Recently, Williams et al (12) confirmed a wide range of dGEMRIC indices in the radiographically spared compartment in patients with unilateral tibiofemoral OA. Those investigators suggest that dGEMRIC may differentiate the biomechanical status of cartilage when state-of-the-art radiography approaches do not indicate disease. With regard to the hip, Cunningham et al (13) showed, in a longitudinal study examining the dGEMRIC index in patients with acetabular dysplasia, that a low dGEMRIC index before correction with a periacetabular osteotomy was the strongest predictor for failure (total hip replacement) at the time of clinical and radiographic followup 3 years later (13). This indicates that the outcome of the osteotomy may depend on the quality of hip cartilage, as assessed by dGEMRIC.

The dGEMRIC index is an estimate of cartilage GAG content that in turn reflects cartilage quality and biomechanical properties (14). Hypothetically, cartilage matrix with insufficient GAG content relative to the iterated load applied transmits more stress to the collagen network. Subsequently, this may result in increased mechanical shearing, causing progressive damage to the collagen network and later fibrillations and overt OA changes (5).

With respect to cartilage quality, the significance of exercise has been studied. A cross-sectional examination of healthy individuals showed that regular physical activity was related to a high GAG content in cartilage, as assessed by dGEMRIC (15). In a longitudinal dGEMRIC study by Roos and Dahlberg in patients at high risk of OA who had undergone meniscectomy, the dGEMRIC index increased after a 4-month intervention with moderate exercise (16). These studies indicate that in asymptomatic individuals and patients without radiographic OA, the knee cartilage is susceptible to training, in which exercise stimulates GAG synthesis in order to improve the mechanical stiffness of the cartilage. In contrast, in joints with more static compartmental joint loading, the dGEMRIC index may decrease. In patients with established OA, Williams et al showed a lower dGEMRIC index laterally in valgus-aligned knees, whereas varus-aligned knees showed a lower dGEMRIC index medially (12). This further supports the concept that dGEMRIC has the potential to evaluate the effects of altered joint biomechanics on cartilage biochemical status.

As shown in the present study and in numerous previous studies, the correlation between structural changes, as assessed by arthroscopy or radiography, and symptoms is weak. Likewise, we did not observe any relationship between arthroscopic changes and the development of OA.

In summary, the results of the present study suggest that a low dGEMRIC index may be predictive of the development of knee OA. These results, together with the findings of recent studies, further support the dGEMRIC index as a clinically relevant measure of cartilage integrity. With dGEMRIC, we have the potential to examine how molecular changes are related to exogenous factors in order to increase our understanding of joint health and the pathogenesis of OA.

AUTHOR CONTRIBUTIONS

Dr. Dahlberg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Owman, Tiderius, Dahlberg.

Acquisition of data. Owman, Tiderius, Neuman, Nyquist.

Analysis and interpretation of data. Owman, Tiderius, Neuman, Nyquist, Dahlberg.

Manuscript preparation. Owman, Tiderius, Dahlberg.

Statistical analysis. Owman, Tiderius.