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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Objective

To evaluate the association of magnetic resonance imaging (MRI)–based knee cartilage T2 measurements and focal knee lesions with knee pain in knees without radiographic osteoarthritis (OA) among subjects with OA risk factors.

Methods

We studied the right knees of 126 subjects from the Osteoarthritis Initiative database. We randomly selected 42 subjects ages 45–55 years with OA risk factors, right knee pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score ≥5), no left knee pain (WOMAC pain score 0), and no radiographic OA (Kellgren/Lawrence [K/L] score ≤1) in the right knee. We also selected 2 comparison groups: 42 subjects without knee pain in either knee and 42 with bilateral knee pain. Both groups were frequency matched to subjects with right knee pain only by sex, age, body mass index, and K/L score. All of the subjects underwent 3T MRI of the right knee. Focal knee lesions were assessed and cartilage T2 measurements were performed.

Results

Prevalences of meniscal, bone marrow, and ligamentous lesions and joint effusion were not significantly different between the groups (P > 0.05), while cartilage lesions were more frequent in subjects with right knee pain only compared to subjects without knee pain (P < 0.05). T2 values averaged over all of the compartments were similar in subjects with right knee pain only (mean ± SD 34.4 ± 1.8 msec) and in subjects with bilateral knee pain (mean ± SD 34.7 ± 4.7 msec), but were significantly higher compared to subjects without knee pain (mean ± SD 32.4 ± 1.8 msec; P < 0.05).

Conclusion

These results suggest that elevated cartilage T2 values are associated with findings of pain in the early phase of OA, whereas among morphologic knee abnormalities only knee cartilage lesions are significantly associated with knee pain status.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Osteoarthritis (OA) affects nearly 27 million people in the US (1). The most commonly affected joint is the knee, and the predominant clinical symptom in most OA patients is pain (2). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a reliable and frequently used tool to evaluate clinical symptoms of knee OA, including the presence and grade of pain during different activities (3, 4). OA is characterized by the progressive loss of hyaline articular cartilage, which can be evaluated by using magnetic resonance imaging (MRI) (5, 6). Previous studies reported an inverse relationship between MRI-based cartilage volume measurements and knee pain assessed using the WOMAC pain score (7, 8). Furthermore, knee pain appears to be associated with prevalent bone marrow edema pattern, synovitis, joint effusion, meniscal tears, and denuded subchondral bone (9–14). While most of these studies were performed in subjects with radiographic evidence of OA, little is known about these associations in subjects in the early phase of OA who have knee pain but no radiographic evidence of OA. Such individuals are of particular interest, since they may benefit most from treatment or behavioral interventions.

The early phase of OA is characterized by biochemical changes of the cartilage, including proteoglycan loss, increased water content, and deterioration of the collagen network (15). These changes can be noninvasively detected by quantitative MRI measurements such as T2 relaxation time mapping (16, 17). Therefore, it could be interesting to analyze the association of knee pain not only with focal knee lesions such as cartilage and meniscal abnormalities, but also with knee cartilage T2 measurements in subjects in the early phase of knee OA.

The National Institutes of Health launched the Osteoarthritis Initiative (OAI), a longitudinal, observational, multicenter study with 4,796 participants, to better understand the natural evolution of OA (online at http://www.oai.ucsf.edu/). The OAI database contains radiographs and MRIs as well as clinical data, including the WOMAC pain score (18). The OAI progression cohort consists of subjects with radiographic tibiofemoral knee OA (defined as a definite tibiofemoral osteophyte) and frequent knee symptoms (“pain, aching, or stiffness in or around the knee” on most days for at least 1 month in the past 12 months) at baseline. Subjects in the OAI incidence cohort did not fulfill these criteria at baseline, but had OA risk factors such as overweight or obesity, history of knee injury, history of knee surgery, and knee symptoms (“pain, aching, or stiffness in or around the knee” in the past 12 months for at least 1 month but not on most days).

The purpose of this study was to analyze whether MRI-based knee cartilage T2 measurements as well as the prevalence of focal knee lesions in subjects from the OAI incidence cohort (no radiographic or clinical evidence of OA) are associated with knee pain as quantified with the WOMAC pain score.

Significance & Innovations

  • Among morphologic knee abnormalities, only knee cartilage lesions are significantly associated with knee pain status in subjects without radiographic osteoarthritis (OA), but with OA risk factors.

  • Elevated cartilage T2 values are associated with findings of pain in the early phase of OA.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Subjects.

Data used in the preparation of this article were obtained from the OAI database, which is available for public access at http://www.oai.ucsf.edu/. Specific OAI data sets used were baseline clinical data set 0.2.2 and baseline imaging data sets 0.E.1 and 0.C.2.

We selected 126 subjects from the OAI incidence cohort for this study. Subjects from the OAI incidence cohort did not have symptomatic knee OA, defined as frequent symptoms and radiographic OA in the same knee, in either knee at baseline, but had at least one of the following OA risk factors at baseline: knee symptoms (“pain, aching, or stiffness in or around the knee” in the past 12 months for at least 1 month but not on most days), overweight or obesity, history of knee injury, history of knee surgery, family history of total knee replacement, or Heberden's nodes.

Forty-two subjects (21 men, 21 women) ages 45–55 years with right knee pain (WOMAC pain score ≥5), no left knee pain (WOMAC pain score 0), and Kellgren/Lawrence (K/L) score ≤1 (i.e., no osteophytes or minimal osteophytes and a joint space narrowing score of 0) in the right knee were randomly selected from the OAI incidence cohort. The sample was designed to have an equal number of men and women and an equal number of K/L grade 0 and K/L grade 1 knees. The age range of 45–55 years was used to focus on younger subjects who may benefit most from treatment or behavioral interventions. A WOMAC pain score threshold of 5 was used based on a previous study that used WOMAC pain scores to study eligibility for individuals to be included in an OA knee trial (19). There were no specific inclusion criteria based on body mass index (BMI).

In addition, sex-, age-, BMI-, and K/L frequency–matched control groups were identified: 42 subjects without knee pain (WOMAC pain score of 0 in either knee) and 42 subjects with bilateral knee pain (WOMAC pain score of ≥5 in both knees) from the OAI incidence cohort were also included in this study.

All of the subjects included in this study provided informed consent. The study protocol, amendments, and informed consent documentation were reviewed and approved by the local institutional review boards.

WOMAC questionnaire.

The WOMAC is a well-established tool to evaluate clinical symptoms of OA in the knee, including pain, stiffness, and physical function, over the last 7 days (3, 4). All of the subjects completed the WOMAC questionnaire for the right and left knees on the day knee radiographs and MRIs were acquired. They were asked 5 activity questions and had to provide a pain score for each activity (0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme pain). Using this grading system, summed scores ranged from 0 to 20 for each knee. The recruited subjects with WOMAC pain scores of ≥5 had at least 1 activity where they had moderate amounts of pain. Based on the WOMAC pain scores of both knees, subjects were stratified into 3 groups with no knee pain, right knee pain, and bilateral knee pain.

Imaging.

Bilateral standing posteroanterior fixed-flexion knee radiographs were acquired. Knees were positioned in a Plexiglas frame (SynaFlexer, CCBR-Synarc) with 20–30° of flexion and 10° of internal rotation of the feet. Right knee radiographs were graded by 2 radiologists (LN with 4 years of experience and WV with 7 years of experience) in consensus using the K/L scoring system (20).

All of the subjects underwent 3T MRI (Trio, Siemens) of the right knee. The following 5 sequences were used in this study as described in the OAI MRI protocol (18): 1) a sagittal 3-dimensional (3-D) double-echo steady-state (DESS) sequence with water excitation and coronal and axial reformations (echo time [TE] 4.7 msec, repetition time [TR] 16.3 msec, field of view [FOV] 14 cm, slice thickness 0.7 mm, in-plane spatial resolution 0.365 × 0.456 mm2, flip angle 25°, bandwidth 185 Hz/pixel); 2) a sagittal 2-dimensional (2-D) intermediate-weighted turbo spin-echo (TSE) sequence with fat suppression (TE 30 msec, TR 3,200 msec, FOV 16 cm, slice thickness 3 mm, in-plane spatial resolution 0.357 × 0.511 mm2, flip angle 180°, bandwidth 248 Hz/pixel); 3) a coronal 2-D intermediate-weighted TSE sequence (TE 29 msec, TR 3,850 msec, FOV 14 cm, slice thickness 3 mm, in-plane spatial resolution 0.365 × 0.456 mm2, flip angle 180°, bandwidth 352 Hz/pixel); 4) a coronal 3-D T1-weighted fast low-angle shot sequence with water excitation (TE 7.57 msec, TR 20 msec, FOV 16 cm, slice thickness 1.5 mm, in-plane spatial resolution 0.313 × 0.313 mm2, flip angle 12°, bandwidth 130 Hz/pixel); and 5) a sagittal 2-D multislice multiecho spin-echo sequence for T2 mapping (TR 2,700 msec; 7 TEs: 10 msec, 20 msec, 30 msec, 40 msec, 50 msec, 60 msec, and 70 msec; FOV 12 cm; slice thickness 3 mm with a 0.5-mm gap; in-plane spatial resolution 0.313 × 0.446 mm2; bandwidth 250 Hz/pixel).

Whole-Organ Magnetic Resonance Imaging Score (WORMS) grading.

MRIs of the right knee were transferred to picture archiving communication system workstations (Agfa) and assessed for the presence and grade of meniscal, cartilage, and ligamentous lesions as well as bone marrow edema pattern (BMEP) and joint effusion using a modified WORMS, as previously described (21–23). Three radiologists (LN with 4 years, WV with 7 years, and TML with 22 years of experience) analyzed 16 MRI studies in consensus to calibrate thresholds for grading abnormalities. The remaining 110 MRI studies were read by 2 radiologists (LN and WV) independently. In case of disagreement, consensus reading was performed with the third, most experienced, radiologist (TML). The radiologists were blinded to the WOMAC pain scores of the subjects.

Meniscal lesions were graded separately in 6 regions (medial/lateral and anterior/body/posterior) using the following 4-point scale: 0 = normal, 1 = intrasubstance abnormal signal, 2 = nondisplaced tear, 3 = displaced or complex tear, and 4 = complete destruction/maceration. Compared to the original WORMS system, grade 1 was added to better reflect the presence of early degenerative meniscal disease.

The anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament, lateral collateral ligament, patellar tendon, and popliteal tendon were evaluated using a 4-point scale (0 = no lesion, 1 = signal changes around the ligament, 2 = partial tear, and 3 = complete tear).

Joint effusion was graded using a 4-point scale (0 = normal, 1 = <33% of maximum potential distention, 2 = 33–66% of maximum potential distention, and 3 = >66% of maximum potential distention).

Cartilage lesions and BMEP were not assessed by using the original 15 regions, but 6 condensed regions (patella, trochlea, medial/lateral femur, and medial/lateral tibia).

BMEP were defined as poorly marginated areas of increased T2 signal intensity and graded using a 4-point scale: 0 = none, 1 = diameter of <5 mm, 2 = diameter of 5–20 mm, and 3 = diameter of >20 mm.

Cartilage lesions were graded using an 8-point scale: 0 = normal thickness and signal intensity; 1 = normal thickness or swelling with abnormal signal on fluid-sensitive sequences; 2 = partial-thickness focal defect <1 cm in greatest width; 2.5 = full-thickness focal defect <1 cm in greatest width; 3 = multiple areas of partial-thickness (grade 2) defects intermixed with areas of normal thickness, or a grade 2 defect wider than 1 cm but <75% of the region; 4 = diffuse (>75% of the region) partial-thickness loss; 5 = multiple areas of full-thickness loss (grade 2.5) or a grade 2.5 lesion wider than 1 cm but <75% of the region; and 6 = diffuse (>75% of the region) full-thickness loss. Condensing the anatomic regions from 15 to 6 would have potentially affected the frequency of grade 4 and 6 lesions. However, grade 4 lesions are very rare and usually if there is >75% partial-thickness cartilage loss, full-thickness lesions are present and grade 6 lesions are not expected in this cohort with K/L scores of ≤1.

Similar to previous studies (21–23), a WORMS maximum score (WORMS Max) was assigned to each knee by the greatest WORMS score in any compartment. WORMS Max >0 in any joint structure was taken as an indication of a lesion. A meniscal WORMS Max >1 indicated a nondisplaced tear or worse, while a cartilage WORMS Max >1 identified subjects with at least one partial thickness defect. Cartilage WORMS Max >1 was also used to exclude lesions characterized only by signal abnormalities, i.e., grade 1 lesions.

T2 measurements.

The multislice multiecho spin-echo sequences were transferred to a SUN workstation (Sun Microsystems). Studies have suggested that excluding the first echo from a multiecho Carr-Purcell-Meiboom-Gill sequence minimizes error from stimulated echoes in calculated T2 values for cartilage (24, 25). Raya et al showed that fit to a noise-corrected exponential improves the accuracy and precision of cartilage T2 measurements (26). Therefore, T2 maps were calculated with custom-built software on a pixel-by-pixel basis skipping the first echo and using a noise-corrected exponential fitting, as previously described (27). Five distinct compartments (patella, medial/lateral femur, and medial/lateral tibia) were segmented using in-house software based on Interactive Data Language (Research Systems) directly in the T2 maps. In order to exclude both fluid and chemical shift artifacts from the region of interest, a technique was used that allowed adjustment of the region of interest simultaneously in the T2 map and first echo of the multiecho sequence by opening separate image panels at the same time with a synchronized cursor, slice number, and zoom. This segmentation procedure has been applied in previous studies (21, 23, 27). T2 maps were segmented by one operator (AA) and supervised by a radiologist (TB). Mean T2 values for each compartment were calculated after completed segmentation. Segmentation of the trochlea compartment was not performed due to flow artifacts from the popliteal artery.

Statistical analysis.

The statistical analyses were performed with SPSS software using a 2-sided 0.05 level of significance. Pearson's chi-square test and t-test were used to compare frequencies of OA risk factors and WOMAC pain score between subjects with no knee pain and right knee pain and between subjects with right knee pain and bilateral knee pain. Multivariate linear and logistic regression models were used to compare T2 measurements as well as the prevalence of focal knee lesions between subjects with no knee pain and right knee pain and between subjects with right knee pain and bilateral knee pain, adjusting for sex, age, K/L score, BMI, and other OA risk factors. In addition, odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated for the association between subject groups and the prevalence of cartilage lesions.

Reproducibility.

To assess intra- and interreader reproducibility of the WORMS grading, 13 subjects were randomly selected and WORMS grading was performed 2 times by 2 readers (LN and WV) independently. Intraclass correlation coefficients were calculated to compare the exact WORMS score for meniscal and cartilage lesions and BMEP in each compartment (28). Reproducibility for ligamentous lesions and joint effusion was not performed due to their low prevalence in the study population.

The intrareader reproducibility of the 2 radiologists for meniscal WORMS grading was 0.93 and 0.94 (interreader reproducibility 0.94), for cartilage WORMS grading was 0.92 and 0.93 (interreader reproducibility 0.92), and for BMEP WORMS grading was 0.98 and 0.99 (interreader reproducibility 0.98).

The intrareader reproducibility for T2 measurements was determined in 13 randomly selected subjects in each cartilage compartment. T2 maps of each subject were segmented 3 times by a single operator (AA). Reproducibility errors for each compartment were calculated in absolute numbers as the root mean square average of the errors for each knee and on percentage basis as the root mean square average of the single coefficients of variation per knee, according to Gluer et al (29).

Intrareader reproducibility for T2 measurements of the compartments ranged from 0.82% to 3.43% (mean 1.76%) and from 0.30 msec to 0.98 msec (mean 0.56 msec), respectively. The highest reproducibility errors were observed in the patella, and the lowest reproducibility errors were observed in the medial femur.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Subject characteristics.

Mean ± SD age, BMI, and WOMAC pain scores as well as frequencies of sex, K/L score, and OA risk factors are listed in Table 1. The WOMAC pain score of the right knee was significantly different between subjects with right and bilateral knee pain (mean ± SD 7.0 ± 2.0 versus 8.4 ± 2.4; P = 0.008). Differences in WOMAC pain scores of the right and left knees in subjects with bilateral knee pain were not significant (P = 0.120) (Table 1). The OA risk factor “knee symptoms in the past 12 months” was prevalent in 85.7% of the subjects without knee pain, although these subjects had a WOMAC pain score of 0 in either knee. That is explained by the definition of the WOMAC pain score focusing on the previous 7 days. All of the subjects with right and bilateral knee pain had knee symptoms in the past 12 months (Table 1).

Table 1. Characteristics of subjects without knee pain, with right knee pain, and with bilateral knee pain*
 Subjects without knee pain (n = 42)Subjects with right knee pain (n = 42)Subjects with bilateral knee pain (n = 42)
  • *

    Values are the number (percentage) unless otherwise indicated. K/L = Kellgren/Lawrence; BMI = body mass index; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

  • Statistically significant differences (P < 0.05) between subjects without knee pain and subjects with right knee pain.

  • Statistically significant differences (P < 0.05) between subjects with right knee pain and subjects with bilateral knee pain.

  • §

    Statistically significant differences (P < 0.05) between subjects without knee pain and subjects with right knee pain and between subjects with right knee pain and subjects with bilateral knee pain.

Men21 (50.0)21 (50.0)21 (50.0)
K/L score 021 (50.0)21 (50.0)21 (50.0)
K/L score 121 (50.0)21 (50.0)21 (50.0)
Knee symptoms in the past 12 months36 (85.7)42 (100.0)42 (100.0)
History of knee injury24 (57.1)24 (57.1)20 (47.6)
History of knee surgery7 (16.7)12 (28.6)10 (23.8)
Family history of knee replacement surgery6 (14.3)12 (28.6)3 (7.1)
Heberden's nodes9 (21.4)6 (14.3)7 (16.7)
Age, mean ± SD years50.4 ± 2.750.0 ± 3.050.6 ± 2.9
BMI, mean ± SD kg/m228.3 ± 3.628.3 ± 4.627.6 ± 4.4
Right knee WOMAC pain score, mean ± SD0.0 ± 0.07.0 ± 2.0§8.4 ± 2.4
Left knee WOMAC pain score, mean ± SD0.0 ± 0.00.0 ± 0.07.7 ± 2.6

Focal knee lesions.

A significantly higher prevalence of meniscal lesions (WORMS >0) in the medial posterior horn was observed in all 3 subject groups, compared to the 5 other compartments (P < 0.05) (Table 2). Seven subjects without knee pain (16.7%), 9 subjects with right knee pain (21.4%), and 3 subjects with bilateral knee pain (7.1%) had a meniscal tear in the medial posterior horn (WORMS >1). Differences between the groups were not statistically significant (P > 0.05). The prevalence of meniscal lesions (WORMS Max >0) was not significantly different between subject groups (P > 0.05) (Table 3). Similarly, subject groups showed no significant difference in the prevalence of meniscal tears (WORMS Max >1), as shown in Table 3 (P > 0.05).

Table 2. Prevalence of meniscal, cartilage, and ligamentous lesions (WORMS >0) in the right knee of subjects without knee pain, with right knee pain, and with bilateral knee pain*
 Subjects without knee pain (n = 42)Subjects with right knee pain (n = 42)Subjects with bilateral knee pain (n = 42)
  • *

    Values are the number (percentage). WORMS = Whole-Organ Magnetic Resonance Imaging Score; ACL = anterior cruciate ligament; PCL = posterior cruciate ligament; MCL = medial collateral ligament; LCL = lateral collateral ligament.

Meniscus   
 Medial anterior WORMS >01 (2.4)0 (0.0)1 (2.4)
 Medial body WORMS >09 (21.4)8 (19.0)4 (9.5)
 Medial posterior WORMS >024 (57.1)25 (59.5)12 (28.6)
 Lateral anterior WORMS >02 (4.8)4 (9.5)1 (2.4)
 Lateral body WORMS >05 (11.9)5 (11.9)5 (11.9)
 Lateral posterior WORMS >08 (19.0)7 (16.7)5 (11.9)
Cartilage   
 Patella WORMS >023 (54.8)26 (61.9)29 (69.0)
 Trochlea WORMS >017 (40.5)20 (47.6)19 (45.2)
 Medial femur WORMS >07 (16.7)20 (47.6)7 (16.7)
 Lateral femur WORMS >05 (11.9)5 (11.9)5 (11.9)
 Medial tibia WORMS >03 (7.1)3 (7.1)3 (7.1)
 Lateral tibia WORMS >019 (45.2)18 (42.9)17 (40.5)
Ligaments   
 ACL WORMS >02 (4.8)3 (7.1)2 (4.8)
 PCL WORMS >00 (0.0)1 (2.4)0 (0.0)
 MCL WORMS >00 (0.0)0 (0.0)0 (0.0)
 LCL WORMS >00 (0.0)0 (0.0)0 (0.0)
 Patella tendon WORMS >00 (0.0)2 (4.8)1 (2.4)
 Popliteal tendon WORMS >00 (0.0)2 (4.8)0 (0.0)
Table 3. Prevalence of focal knee lesions of subjects without knee pain, with right knee pain, and with bilateral knee pain*
 Subjects without knee pain (n = 42)Subjects with right knee pain (n = 42)Subjects with bilateral knee pain (n = 42)Knee pain vs. right knee pain, PRight knee pain vs. bilateral knee pain, P
  • *

    Values are the number (percentage). WORMS Max >0 in any joint structure indicates a lesion. WORMS Max >1 specifies prevalence of meniscal tear (of grade 2 or higher cartilage lesion). WORMS Max = Whole-Organ Magnetic Resonance Imaging Score maximum score.

  • Adjusted for sex, age, Kellgren/Lawrence score, body mass index, and other osteoarthritis risk factors.

  • Statistically significant (P < 0.05).

Meniscus     
 WORMS Max >028 (66.7)28 (66.7)20 (47.6)0.7710.101
 WORMS Max >114 (33.3)15 (35.7)9 (21.4)0.9100.272
Cartilage     
 WORMS Max >032 (76.2)36 (85.7)37 (88.1)0.1930.513
 WORMS Max >120 (47.6)28 (66.7)26 (61.9)0.0160.379
Ligaments     
 WORMS Max >02 (4.8)6 (14.3)3 (7.1)0.0800.526
Bone marrow edema pattern     
 WORMS Max >017 (40.5)16 (38.1)14 (33.3)0.9590.388
Joint effusion     
 WORMS Max >00 (0.0)3 (7.1)4 (9.5)0.9970.502

Cartilage lesions (WORMS >0) were most frequent in the patella and trochlea compartment in all 3 subject groups (Table 2). A higher prevalence of cartilage lesions (WORMS Max >0) was observed in subjects with right (85.7%) and bilateral knee pain (88.1%) compared to subjects without knee pain (76.2%) (Table 3). However, differences were not statistically significant between subjects with no knee pain and right knee pain and between subjects with right knee pain and bilateral knee pain (P > 0.05) (Table 3). The prevalence of grade 2 or higher cartilage lesions (WORMS Max >1) was significantly higher in subjects with right knee pain compared to subjects without knee pain (P = 0.016) (Table 3). An OR of 3.52 (95% CI 1.26–9.80) was calculated for the association between subjects with right knee pain/subjects without knee pain and the prevalence of WORMS Max >1 cartilage lesions. There were no differences between the subjects with right and bilateral knee pain (P > 0.05) (Table 3).

Ligamentous lesions were prevalent in 4.8%, 14.3%, and 7.1% of the subjects with no, right, and bilateral knee pain, respectively (P > 0.05) (Tables 2 and 3). The prevalence of BMEP and joint effusion was not significantly different between the subject groups, as shown in Table 3 (P > 0.05).

T2 measurement results.

There were no significant differences of cartilage T2 measurements between the subjects with right compared to those with bilateral knee pain in any compartment (P > 0.05) (Table 4). However, subjects with right knee pain showed significantly elevated T2 values in the medial femur, medial tibia, and lateral tibia compartments compared to the subjects without knee pain (P < 0.05) (Table 4 and Figure 1). Averaged over all 5 compartments, T2 values were similar in subjects with right knee pain (mean ± SD 34.4 ± 1.8 msec) and with bilateral knee pain (mean ± SD 34.7 ± 4.7 msec), but significantly higher compared to subjects without knee pain (mean ± SD 32.4 ± 1.8 msec; P < 0.05) (Table 4).

Table 4. Mean ± SD T2 values of the 5 segmented compartments and averaged over the 5 compartments in subjects without knee pain, with right knee pain, and with bilateral knee pain
 Subjects without knee pain (n = 42)Subjects with right knee pain (n = 42)Subjects with bilateral knee pain (n = 42)Knee pain vs. right knee pain, P*Right knee pain vs. bilateral knee pain, P*
  • *

    Adjusted for sex, age, Kellgren/Lawrence score, body mass index, and other osteoarthritis risk factors.

  • Statistically significant (P < 0.05).

Patella T2, msec31.4 ± 2.330.7 ± 1.931.3 ± 4.90.1380.495
Medial femur T2, msec35.9 ± 2.538.3 ± 2.538.2 ± 5.0< 0.0010.880
Medial tibia T2, msec31.3 ± 2.534.4 ± 2.634.5 ± 5.6< 0.0010.919
Lateral femur T2, msec33.2 ± 2.434.2 ± 2.234.8 ± 4.60.0800.589
Lateral tibia T2, msec30.4 ± 2.834.2 ± 2.834.5 ± 5.0< 0.0010.927
T2 averaged over all 5 compartments, msec32.4 ± 1.834.4 ± 1.834.7 ± 4.7< 0.0010.770
thumbnail image

Figure 1. T2 color maps of the medial femur and medial tibia compartments of the right knee overlaid with the first-echo images of the multislice multiecho sequence for A, a representative subject without knee pain and B, a representative subject with right knee pain. Blue indicates low and red indicates high cartilage T2 values. The subject with right knee pain showed elevated T2 values compared to the subject without knee pain (41.6 msec in the medial femur and 35.7 msec in the medial tibia versus 35.3 msec in the medial femur and 33.9 msec in the medial tibia, respectively).

Download figure to PowerPoint

Independent of group, subjects with a meniscal tear in the medial posterior horn (WORMS >1) showed no significantly elevated cartilage T2 values in any compartment compared to subjects with medial posterior horn WORMS scores of 0 or 1 (P > 0.05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

This study demonstrated that cartilage T2 values in subjects without radiographic OA but with OA risk factors were significantly elevated in those with knee pain compared to those without knee pain. The prevalence of cartilage lesions was related to knee pain. However, other focal knee lesions such as meniscal abnormalities and BMEP were not associated with knee pain in this study population.

The pathogenesis of OA-related knee pain is clinically relevant and therefore an important research topic. Subchondral bone and synovium may be responsible for nociceptive stimuli in OA and not the cartilage itself, since it does not contain nerve fibers and therefore cannot directly generate pain (30). These facts suggest that cartilage lesions are not a major determinant of knee pain. However, the results of the present study demonstrated a relationship between cartilage lesions and knee pain. Increased prevalence of cartilage lesions in subjects with knee pain was observed compared to subjects without knee pain. These results are consistent with previous studies that reported an association of cartilage loss with knee pain (7, 8). One likely possibility for the association of cartilage lesions with pain is that the biomechanical load is altered by the cartilage lesions, placing greater deforming stress upon the underlying subchondral bone (2, 30).

BMEP and joint effusion could be responsible for knee pain. However, we observed a low prevalence of joint effusion, thus limiting the statistical analysis. We found that the prevalence of BMEP in subjects with and without knee pain in this study was not significantly different. In contrast to these findings, previous studies reported associations of knee pain with BMEP and joint effusion (9, 11, 13). While these studies included subjects with symptomatic and radiographic OA, we focused on subjects who had knee pain but no radiographic OA. The varied subject selection between the studies may explain why no associations of pain with BMEP and joint effusion were found in our study.

A degenerative meniscal tear suggests early-stage knee OA, and a recent study reported elevated articular cartilage T2 values in subjects with prevalent meniscal tears of the medial posterior horn (31, 32). Interestingly, we observed no association between the prevalence of meniscal tears of the medial posterior horn and cartilage T2 values. Furthermore, meniscal and ligamentous lesions were not associated with pain in this study population, which is consistent with previous studies (9, 14). Therefore, cartilage seems to be the most appropriate joint structure reflecting a morphologic correlate of knee pain prevalence in subjects in the early phase of OA.

In addition to higher prevalence of cartilage lesions, significantly elevated cartilage T2 values were found in subjects with knee pain compared to subjects without knee pain. Since increased T2 relaxation times are based on biochemical changes of the cartilage such as proteoglycan loss and increased water content, these results suggest that deterioration of cartilage quality is associated with findings of pain in the early phase of OA. While previous studies reported a significant correlation between WOMAC pain sore and cartilage T2 measurements in subjects with radiographic OA (33, 34), our study demonstrated that cartilage T2 measurements may also be a sensitive assessment tool for early cartilage degeneration and related knee pain as found in subjects with no radiographic OA but with OA risk factors. This finding is in particular important, since these subjects may benefit most from treatment or behavioral interventions. These results underline once more the potential of cartilage T2 measurements to detect early cartilage degeneration in subjects with OA risk factors (21, 23, 35).

This study had several limitations. First, subjects were included in this study based on their self-reported subjective pain perception. We used the WOMAC pain score, which is a reliable tool to evaluate OA-related knee pain (3, 4). However, the WOMAC questionnaire focuses on the last 7 days and is not a long-term evaluation tool, which may be a limitation of this study. Since the WOMAC questionnaire is well established and has been used in previous studies with similar purposes (7–10, 12, 13), we based our inclusion criteria regarding knee pain on this questionnaire. Second, malalignment is a known OA risk factor (36, 37). We did not adjust for malalignment in the statistical analysis because the baseline data collected by the OAI only included goniometer alignment readings, which have been found to be inaccurate (38). Third, increased cartilage volume (cartilage softening) is observed in the diseased compartments in the early phase of knee OA (39). We did not investigate whether higher T2 values are associated with increased cartilage volume (cartilage softening), since cartilage segmentation was directly performed in the T2 maps, which are not suited for cartilage volume measurements because of a slice thickness of 3 mm and a 0.5-mm gap. An additional segmentation of the cartilage compartments in the DESS images is necessary to investigate possible associations of cartilage T2 and cartilage volume. This is very time consuming and was beyond the scope of this study. Future studies have to shed light on this issue. Lastly, reproducibility of cartilage T2 measurements and WORMS grading is critical and may also be a limitation. However, we found acceptable reproducibility errors in this study, and the OAI established quality assurance methods to achieve high quality of cartilage T2 measurements (40).

In conclusion, the prevalence of cartilage lesions as well as cartilage T2 measurements was related to knee pain in subjects without radiographic OA but with OA risk factors using the WOMAC questionnaire. This study suggests that cartilage T2 measurements may be a quantitatively measurable biomarker for knee pain in the early phase of OA, but larger-scale studies are required to better assess the full significance of these findings.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Baum 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 conception and design. Baum, Joseph, Nevitt, McCulloch, Link.

Acquisition of data. Baum, Joseph, Arulanandan, Nardo, Virayavanich, Carballido-Gamio, Nevitt, Lynch, McCulloch, Link.

Analysis and interpretation of data. Baum, Joseph, Arulanandan, Nardo, Virayavanich, Carballido-Gamio, Nevitt, Lynch, McCulloch, Link.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

This study was independently performed from the Osteoarthritis Initiative (OAI) private funding partners Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer, Inc. These companies were not involved in study design, data collection, data analysis, and writing of the manuscript. This manuscript has received the approval of the OAI Publications Committee based on a review of its scientific content and data interpretation. The publication of this manuscript was not contingent on the approval of the OAI private funding partners.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
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