Arthritis & Rheumatism

~ Arthritis & Rheumatism Official Journal of the American College of Rheumatology RELATIONSHIP BETWEEN ARTHROSCOPIC EVIDENCE OF CARTILAGE DAMAGE AND RADIOGRAPHIC EVIDENCE OF JOINT SPACE NARROWING IN EARLY OSTEOARTHRITIS OF THE KNEE ROSE S. FIFE, KENNETH D. BRANDT, ETHAN M. BRAUNSTEIN, BARRY P. KATZ, K. DONALD SHELBOURNE, LORRIE A. KALASINSKI, and SARAH RYAN We examined the relationship between articular cartilage degeneration, as visualized arthroscopically, and joint space narrowing (JSN) in standing anteropos. terior knee radiographs of 161 patients with chronic knee pain. The majority of these patients had radiographic findings of mild osteoarthritis. Twenty-five (33%) of the 76 patients in the series whose radiographs showed tibiofemoral JSN had grossly normal articular cartilage in both tibiofemoral compartments at arthroscopy (false-positive). The specificity of medial JSN for From the Indiana University School of Medicine, the Specialized Center of Research in Osteoarthritis, and the Multipurpose Arthritis Center, and the Sports Medicine Clinic, Methodist Hospital of Indianapolis, Indianapolis, Indiana. Supported in part by NIH grants AR-20582, AR-39250, and AR-7448, and by awards from the Arthritis Foundation and the Grace M. Showalter Trust. Dr. Fife is the recipient of an Arthritis Foundation Biomedical Research Grant. Rose S. Fife, MD: Associate Professor of Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine: Kenneth D. Brandt, MD: Professor of Medicine and Head, Rheumatology Division, Indiana University School of Medicine, Director, Indiana University Specialized Center of Research in Osteoarthritis, and Director, Indiana University Multipurpose Arthritis Center: Ethan M. Braunstein, MD: Professor of Radiology, lndiana University School of Medicine: Barry P. Katz, PhD: Associate Professor of Medicine, Indiana University School of Medicine; K. Donald Shelbourne, MD: Staff Orthopaedic Surgeon, Sports Medicine Clinic, Methodist Hospital of Indianapolis: Lorrie A. Kalasinski, MPH: Applied Statistician, Indiana University Specialized Center of Research in Osteoarthritis: Sarah Ryan, RN, MSN: Rheumatology Division, Indiana University School of Medicine. Address reprint requests to Rose S. Fife, MD, Rheumatology Division, Indiana University School of Medicine, 541 Clinical Drive, Indianapolis, IN 46202. Submitted for publication May 29, 1990: accepted in revised form October 12, 1990. the presence of medial compartment articular cartilage degeneration was 0.61, i.e., only 61% of patients with normal (grade 0) medial compartment cartilage had a normal medial joint space. Of 22 patients with >50% medial JSN, 9 (41%) had normal articular cartilage in the medial compartment at arthroscopy. Of 6 patients with >SO% lateral JSN, 3 (50%) had normal lateral compartment articular cartilage at arthroscopy. Among 36 patients with >25% JSN who had neither medial nor lateral compartment articular cartilage degeneration, JSN was associated with articular cartilage degeneration in the patellofemoral compartment in 8 (22%), with meniscus degeneration in 18 (50%), and with both in 8 (22%). Thus, in these patients with chronic knee pain, radiographic evidence of JSN in the tibiofemoral compartment did not permit confident prediction of the status of the articular cartilage. Pain is the clinical feature that leads most patients with osteoarthritis (OA) to seek medical attention. Although the pathologic hallmark of OA is loss of articular cartilage, since the cartilage has no nerve supply, the pain in OA arises only after secondary involvement of other structures, e.g., subchondral bone, synovium, or muscle (1). Thus, by the time the patient with OA presents to the physician, articular cartilage breakdown is often far advanced. No practical, reproducible, noninvasive method exists at present for the detection of early articular cartilage loss in OA. Imaging techniques, such as magnetic resonance imaging (2) and ultrasonography (3), have not proved to be sensitive or to produce Arthritis and Rheumatism, Vol. 34, No. 4 (April 1991) 377

378 FIFE ET AL sufficiently reproducible results for detection of preclinical OA. Similarly, efforts to develop a serologic marker of OA for this purpose have not yet been successful (4-6). Therefore, radiography, although insensitive in detecting early OA and in monitoring disease progression, remains a mainstay in diagnosis and management of OA (7,8). It has been shown that an anteroposterior knee radiograph taken while the subject is standing more accurately reflects joint space narrowing (JSN) than does a knee radiograph obtained with the subject supine (9-1 1). Notably, the radiographic grading scale most widely employed today, the KellgredLawrence scale (8,12), was developed prior to the demonstration that a standing knee radiograph is more sensitive for assessment of JSN than a radiograph taken when the patient is supine. Furthermore, the KellgredLawrence radiographic criteria permit the diagnosis of definite OA in the presence of osteophytosis alone, without JSN. However, loss of articular cartilage, not osteophytosis, is the predominant pathologic feature of OA. Indeed, in the absence of JSN or bony changes, osteophytosis may be due to aging, and not to OA (13-15). We undertook the present study to examine the specificity of JSN, as demonstrated in the standing knee radiograph, for articular cartilage changes of OA. The results in this series of patients, which consisted predominantly of patients with radiographic evidence of relatively early or mild OA, indicate that false-positive radiographic evidence of articular cartilage loss, i.e., JSN in the absence of articular cartilage damage, was common. PATIENTS AND METHODS Patient selection. The study subjects consisted of 161 consecutive patients undergoing arthroscopy at a sports medicine practice, for evaluation of chronic knee pain. A small number of these patients were included in a previous study of a serologic marker for OA (4). Patients with known inflammatory arthritis, e.g., rheumatoid arthritis or gout, were excluded from analysis, and patients were included in the study only if a standing anteroposterior knee radiograph had been obtained shortly before arthroscopy. All radiographs were performed in the same facility by the same staff of 2 technicians, using consistent standardized techniques (cassette posterior to the knee; beam aimed at the midpoint of the patella; distance from tube to film 40 ). Standing radiographs were obtained with the patient standing on both feet, with hidher knees in as full extension as possible for the individual. Lateral knee radiographs were obtained with the patient in a supine position. grading of OA. At the time of arthroscopy, the severity of the defects visible on each of 6 articular surfaces (medial and lateral femoral condyles, medial and lateral tibial plateaus, patellar surface, and trochlear groove) was graded as follows (16): grade 0 = no defect; grade 1 = superficial erosion(s); grade 2 = partial-thickness erosion(s) <2.5 cm2; grade 3 = partial-thickness erosion(s) >2.5 cm2; and grade 4 = full-thickness erosion(s). The status of the menisci also was evaluated. Radiographic analyses. Lateral and standing anteroposterior radiographs of the knees were evaluated and graded by an experienced skeletal radiologist (EMB). A judgment concerning the degree of JSN as seen in the anteroposterior radiograph was made by comparing medial and lateral compartments of the same knee, and the right and left knee of each patient. If both compartments or both knees were abnormal, a knee radiograph from a normal subject of the same sex was used for comparison. The effects of beam position and of knee flexion on the width of the joint spaces were examined using knee radiographs of a normal volunteer. The medial and lateral joint spaces were measured using a perpendicular line drawn between the most distal aspect of the cortex of the condyle and the cortex of the adjacent tibial plateau. The radiographic severity of OA was graded according to the scale of Kellgren and Lawrence (8,12), where grade 0 = normal; grade I = doubtful narrowing of joint space and possible osteophytic lipping; grade I1 = definite osteophytes and possible narrowing of joint space; grade 111 = moderate multiple osteophytes, definite narrowing of joint space, some sclerosis, and possible deformity of bone contour; and grade IV = large osteophytes, marked narrowing of joint space, severe sclerosis, and definite deformity of bone contour. Statistical analysis. Sensitivity, specificity, and predictive value of the standing knee radiograph for the detection of OA were calculated, using the arthroscopic findings as the gold standard. Medial, lateral, and patellofemoral compartments were examined separately. Data for medial and lateral compartment JSN were further stratified based on the presence or absence of meniscal abnormalities. Sensitivity was calculated as the proportion of patients with cartilage changes of OA (based on arthroscopy) who were classified as having JSN by radiography. Specificity was calculated as the proportion of patients with no arthroscopic evidence of articular cartilage damage who were classified as having no JSN by radiography. The positive predictive value is the probability that those who were classified as having JSN by the radiographic criteria actually had OA by arthroscopy. The negative predictive value is the probability that those classified as normal (i.e., no JSN) by the radiographic criteria had normal articular cartilage at arthroscopy. RESULTS One hundred thirty-four of the 161 patients studied were male, reflecting the fact that the subjects were derived from a sports medicine practice. The

RELATIONSHIP OF JSN TO SEVERITY OF KNEE OA 379 mean k SD age of the entire group was 36.4? 12.9 years, with a range of 12-69 years. In 13 patients, meniscectomy had previously been performed in the involved knee (8 medial, 4 lateral, 1 both menisci). Radiographs of 83 of the 161 patients (52%) were scored as grade 0 or I according to the Kellgrenl Lawrence criteria for OA severity, while 55 (34%) were scored as grade 11; only 14% of the patients had radiographically severe OA (grade III or IV). Tibiofemoral JSN. Radiographs of 76 patients showed >25% JSN in either or both tibiofemoral compartments. Twenty-five (33%) of these patients had grossly normal articular cartilage in both tibiofemoral compartments at arthroscopy (radiographic false-positive findings). Medial compartment. Of the 113 patients with no medial compartment articular cartilage degeneration at arthroscopy (grade 0), 44 (39%) had >25% medial JSN by radiography ( false-positive ) (Table 1). Nine of these patients (8%) had >50% JSN. Conversely, of the 38 patients with grade 24 medial compartment AC changes at arthroscopy, 11 (29%) did not have medial JSN by radiography and were considered to be radiographically false-negative. Based on the above results, the sensitivity of medial JSN for the diagnosis of grade 2-4 medial compartment articular cartilage changes at arthroscopy was 0.71. For the diagnosis of medial compartment articular cartilage degeneration of any degree (i.e., grade 1-4), the sensitivity of medial JSN was 0.67. The specificity of medial JSN for the presence of medial compartment articular cartilage degeneration was 0.61, i.e., 61% of the patients with normal (grade 0) medial compartment cartilage did not have medial JSN radiographically. The positive predictive value of medial JSN for Table 1. Relationship of medial joint space narrowing to medial Compartment cartilage degeneration at arthroscopy Severity of radiographic grade of cartilage degeneration* None t 25-50% >50% 69 3% 9t 5 4t 1t 25 0 0 88 12 7 18 3 5 * See Patients and Methods for explanation of grading scales. t Joint space narrowing <25%. t False-positive joint space narrowing. 0 False-negative joint space narrowing. Table 2. Relationship of lateral joint space narrowing to lateral compartment cartilage degeneration at arthroscopy grade of cartilage degeneration* 0 1 2 3 4 Seventy of radiographic None? 25-50% >SO% 115 10t 3t 9 0 0 26 1 0 136 2 I 0 3 2 * See Patients and Methods for explanation of grading scales. t Joint space narrowing <25%. t False-positive joint space narrowing. 5 False-negative joint space narrowing. the presence of grade 2-4 medial compartment articular cartilage degeneration on arthroscopy was 0.36, i.e., 36% of the patients with >25% medial JSN had significant medial compartment articular cartilage changes at arthroscopy. When any medial compartment articular cartilage changes (grade 1-4) were present at arthroscopy, the positive predictive value of medial JSN was 0.42. Eighty-five patients were judged not to have medial JSN by radiography; of these, 69 (81%) had normal medial compartment articular cartilage at arthroscopy, while another 5 exhibited only grade 1 changes. Hence, the negative predictive value, i.e., the likelihood that a patient with no medial JSN would have essentially normal medial compartment articular cartilage (i.e., grade 0 or l), was 0.87. Lateral compartment. Thirteen of the 128 patients (10%) with normal lateral compartment articular cartilage at arthroscopy (grade 0) had >25% lateral JSN; 3 of these patients had >50% JSN. Conversely, 15 of the 24 patients (63%) with advanced arthroscopic changes in the lateral compartment, i.e., grades 24, did not have lateral JSN (Table 2). Thus, the sensitivity of lateral JSN for grade 1-4 OA was 0.27, and for grade 2-4 OA it was only 0.38-much poorer than that for medial JSN; its specificity was 0.90-much higher than that for medial JSN. The positive predictive value of lateral JSN for grades 2-4 OA was 0.41 and the negative predictive value was 0.89, similar to the findings for medial JSN. Patellofemoral compartment. In 17 patients, arthroscopic evidence of articular cartilage degeneration was confined to the patella or the trochlear groove. Of these, 7 exhibited >25% medial compartment JSN, while 5 had >25% JSN in both compartments.

380 FIFE ET AL Table 3. Medial compartment arthroscopic findings and radiographic joint space narrowing in patients with a tear or degeneration of the medial meniscus Severity of medial compartment grade of OA in medial compartment* Nonet 25-50% >50% 0 32 17 3 1 2 2 1 2 1 0 0 3 6 8 3 4 0 2 2 * See Patients and Methods for explanation of grading scales. OA = osteoarthritis. i Joint space narrowing <25%. Relation of meniscal abnormalities to JSN. To assess the contribution of meniscal abnormalities to JSN, the association between the arthroscopic grade of OA, the radiographic findings, and the appearance of the menisci at arthroscopy was examined. Of the 13 patients who had previously undergone meniscectomy, 7 exhibited radiographic JSN in the ipsilateral tibiofemoral compartment. In 4, this was accompanied by articular cartilage degeneration, but in the other 3, JSN was seen in the presence of arthroscopically normal articular cartilage. Excluding the patients who had undergone meniscectomy, 113 patients had normal medial compartment articular cartilage (grade 0) at arthroscopy. Gross medial meniscal abnormalities were present at arthroscopy in 52 of these patients (46%). Twenty (38%) had >25% medial JSN (Table 3). This subgroup accounted for 26% of all patients in the series with >25% medial JSN. Of the 128 patients who had normal lateral compartment articular cartilage at arthroscopy (grade 0), gross lateral meniscal abnormalities were observed arthroscopically in 24 (19%). Four (17%) exhibited >25% lateral JSN (Table 4). These individuals represented 18% of all patients with >25% lateral JSN in this series. JSN with normal tibiofemoral articular cartilage. Thirty-six (47%) of the 76 patients in the series who had >25% JSN had normal tibiofemoral compartment cartilage at arthroscopy. JSN was associated with articular cartilage degeneration in the patellofemoral compartment in 8 of these patients, with meniscal degeneration in 18, and with both in 8. Effects of knee flexion and beam position. Radiographs of a normal knee revealed a progressive loss in the width of the medial compartment joint space with flexion. Thus, with 0" of flexion, the joint space measured 6.0 mm; with lo" of flexion, it was 4.5 mm, a decrease of 25%. The lateral compartment joint space, which was 7.0 mm when the knee was in the neutral position, was only 5.0 mm when the knee was flexed to lo", a decrease of 29%. Similarly, when the x-ray beam was directed 1 cm below the midpoint of the patella, the width of the medial joint space of the normal knee was 17% less than when the beam was centered at the midpoint of the patella. When the beam was aimed 0.5 cm above the midpoint of the patella, the width of the medial joint space was -8% less than when it was centered. DISCUSSION The majority of the patients in the present study had early OA based on radiographic criteria, and, since they were derived from a sports medicine clinic, the patient population was somewhat younger than most reported series of OA patients. The importance of the present study is that it permitted comparison of radiographic JSN with the anatomic changes in articular cartilage seen at arthroscopy, Our results indicate that the correlation between articular cartilage loss and tibiofemoral JSN is poor. In all but 2 of the 36 patients with >25% JSN who had no evidence of tibiofemoral articular cartilage degeneration, JSN was associated with degeneration of the patellofemoral compartment, of a meniscus, or both. The KellgredLawrence criteria, which are widely used for grading the severity of knee OA, were derived from analyses of knee radiographs obtained with the patients in a supine position, and with these criteria, the diagnosis of definite OA can be made when osteophytes are the only radiographic abnormal- Table 4. Lateral compartment arthroscopic findings and radiographic joint space narrowing in patients with a tear or degeneration of the lateral meniscus Severity of lateral compartment grade of OA in lateral compartment* Nonet 25-50% >50% 20 3 1 0 0 0 2 1 0 4 1 1 0 0 2 * See Patients and Methods for explanation of grading scales. OA = osteoarthritis. t Joint space narrowing <25%.

RELATIONSHIP OF JSN TO SEVERITY OF KNEE OA 38 1 ity (8,12). In the absence of JSN or bony features of OA (subchondral sclerosis, geodes), however, osteophytes alone may not represent OA; at least in the hip and knee, osteophytes may have a greater association with aging than with OA (9,13-15). Detailed studies of radiographic techniques for the evaluation of OA suggest that standing knee radiographs more accurately indicate the status of articular cartilage in OA than do images obtained when the patient is supine (10). Such studies, however, have not included radiographic-pathologic correlations. The absence of any previous investigation of whether radiographic JSN accurately reflects anatomic loss of articular cartilage in OA was the rationale for the present study. There is currently great interest in developing methods for evaluating whether pharmacologic agents retard the progression of articular cartilage breakdown in OA (17,18). Considerable effort has been directed toward the development of ultrasonographic (3), scintigraphic (19), magnetic resonance imaging (2), and serologic markers of cartilage damage in OA (4-6). None of these techniques, however, has yet proved to be suitable for monitoring the course of OA. Thus, radiographic evaluation, though insensitive to the pathologic changes of OA, remains the gold standard for assessing progression of the disease. The results of the present study confirm the insensitivity of the standing knee radiograph for identifying articular cartilage changes in OA. The sensitivity of medial JSN for identifying grade 2-4 articular cartilage medial compartment changes was 0.71, and the sensitivity of lateral JSN for identifying grade 2-4 lateral compartment articular cartilage changes was only 0.38. In studies to evaluate a disease-modifying agent, patients with radiographically mild OA, rather than those with more severe changes, constitute the most suitable group for investigation. Therefore, it is important to know whether JSN accurately measures articular cartilage integrity in such patients. For this reason in particular, attention in the present study was directed chiefly toward patients with radiographically mild OA. While JSN may correlate better with articular cartilage loss in patients with more advanced OA, our data show that in patients with radiographically mild OA, JSN often does not accurately reflect the integrity of articular cartilage. Thus, in symptomatic patients with radiographic evidence of relatively mild OA, the efficacy of a therapeutic intervention intended to modify articular cartilage breakdown cannot be assessed with confidence by analyzing serial changes in the width of the tibiofemoral joint space as seen on standing knee radiographs. Finally, our findings emphasize the technical problems inherent in obtaining suitable knee radiographs for assessment of JSN. Minor degrees of knee flexion or small deviations in beam positioning produce a significant degree of JSN. ACKNOWLEDGMENTS The authors are grateful to Tinker Gray and to all of Dr. Shelbourne s staff for their assistance in gathering the data for this study, and to Freda Hill and Roberta Fehrman for secretarial assistance. REFERENCES 1. Brandt KD: Pain, synovitis, and articular cartilage changes in osteoarthritis. Semin Arthritis Rheum 18 (suppl2):77-80, 1989 2. Adams ME, Li DKB: Magnetic resonance imaging of joint lesions, Articular Cartilage Biochemistry. Edited by KE Kuettner, R Schleyerbach, VC Hascall. New York, Raven Press, 1986 3. Aisen AM, McCune WJ, MacGuire A, Carson PL, Silver TM, Jafri SZ, Martel W: Sonographic evaluation of the knee. Radiology 153:781-784, 1984 4. Fife RS, Brandt KD, Braunstein EM, Myers SL, Katz BP, Ehlich J, Shelbourne KD, Kalasinski LA: The presence of cartilage matrix glycoprotein in serum is not a sensitive indicator of early osteoarthritis of the knee. J Lab Clin Med (in press) 5. Brandt KD, Thonar EJ-MA: Lack of association between serum keratan sulfate concentrations and cartilage changes of osteoarthritis after transection of the anterior cruciate ligament in the dog. Arthritis Rheum 32:647-651, 1989 6. Brandt KD: A pessimistic view of serologic markers for diagnosis and management of osteoarthritis: biochemical, immunologic and clinicopathologic barriers. J Rheumatol 16 [Suppl 18]:39-42, 1989 7. Cobb S, Merchant WR, Rubin T: The relation of symptoms to osteoarthritis. J Chronic Dis 5:197-204, 1957 8. Kellgren JH, Lawrence JS: Radiologic assessment of osteoarthritis. Ann Rheum Dis 16:494-502, 1957 9. Ahlback S: Osteoarthritis of the knee: a radiographic investigation. Acta Radio1 [Suppl] (Stockh) 277:7-72, 1968 10. Leach RE, Gregg T, Siber FJ: Weight-bearing radiography in osteoarthritis of the knee. Radiology 97:265-268, 1970 11. Altman RD, Fries JF, Bloch DA, Carstens J, Cooke TD, Genant H, Gofton P, Groth H, McShane DJ, Murphy WA, Sharp JT, Spitz P, Williams CA, Wolfe F: Radio-

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