Subject: Lack of association between chondrocalcinosis and increased risk of cartilage loss in knees with osteoarthritis: Results of two prospective longitudinal magnetic resonance imaging studies
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Research Article
*Correspondence to T. Neogi, Clinical Epidemiology Research and Training Unit, 715 Albany Street, A203, Boston, MA 02118 Drs. Nevitt, Carbone, Chen, Harris, and Kwoh represent the Health ABC study. Funded by:
Received: 17 October 2005; Accepted: 3 March 2006
10.1002/art.21903 About DOI
Calcium pyrophosphate dihydrate (CPPD) crystals are commonly deposited in aging and osteoarthritic articular cartilages. CPPD crystals are frequently observed in the synovial fluid in end-stage osteoarthritis (OA) ([1]). These crystals move from cartilage to synovium and have the potential to promote expression of certain matrix metalloproteinases (MMPs) and inflammatory cytokines, including CXCL8 ([2]). Moreover, direct infusion of CPPD crystals into mechanically stressed rabbit knee joints has been shown to exacerbate degenerative arthritis ([3]). Because of their association with inflammatory changes in cartilage and synovium in OA, CPPD crystals have been assumed to increase the risk of disease progression through multiple mechanisms, either by initiating or worsening cartilage damage ([4]). Large macroscopic CPPD crystal deposits in hyaline and/or meniscal fibrocartilage are frequently detected radiographically as stereotypical linear calcification. The term chondrocalcinosis refers to the radiographic appearance of such calcification. Both OA and chondrocalcinosis increase in prevalence with age and are commonly seen together. A number of cross-sectional studies have found an association between the presence and severity of OA and chondrocalcinosis ([1][5-13]). However, chondrocalcinosis was not associated with worsening of OA, as defined by the progression of radiographic joint space narrowing (JSN), in some prospective, longitudinal radiographic studies ([14-19]). This apparent lack of an association between chondrocalcinosis and loss of cartilage may have been related to the techniques used to detect radiographic changes. The importance of appropriate positioning of the knee to allow for reproducible and sensitive assessment of change in joint space longitudinally has been given much attention recently ([20]). An extended weight-bearing anteroposterior view of the knee may have lacked the sensitivity required to detect subtle JSN. With magnetic resonance imaging (MRI) technology, cartilage changes can be directly assessed without having to infer loss of cartilage thickness from measured radiographic joint space loss. To date, there has not been an MRI-based study that has examined the relationship between chondrocalcinosis and cartilage loss. The purpose of this study was to evaluate, in 2 prospective cohorts, the relationship between chondrocalcinosis and the progression of knee OA using longitudinal MRI assessments of cartilage loss as a more sensitive measure than radiographs. In the Boston OA Knee Study (BOKS), we found a protective association between chondrocalcinosis and cartilage loss, although the number of subjects studied with chondrocalcinosis was small, raising concerns about the robustness of our findings. Therefore, we sought to confirm this association in a second cohort. SUBJECTS AND METHODS
Study participants. Participants from BOKS, a prospective natural history study of symptomatic knee OA, and from the Health, Aging, and Body Composition (Health ABC) Study, a prospective cohort, were included in this study. In BOKS, participants were recruited using a variety of sources, which have been previously described in detail ([21]). Briefly, participants were recruited from 2 prospective studies of quality of life among veterans, 1 in men and 1 in women; from clinics at Boston Medical Center in Boston, Massachusetts; and from advertisements placed in local newspapers. Participants were enrolled in the study if they met the American College of Rheumatology OA criteria for symptomatic knee ([22]), if other forms of arthritis were excluded, and if the individual could walk with or without a cane (n = 324). The Institutional Review Boards of Boston University Medical Center and the Veterans Administration Boston Health Care System approved the protocol, and participants provided informed consent. In Health ABC, well-functioning African American and white adults, ages 70-79 years at baseline, were recruited at 2 field centers, Pittsburgh, Pennsylvania (n = 1,527), and Memphis, Tennessee (n = 1,548). Recruitment was undertaken from a random sample of white Medicare beneficiaries and all age-eligible African American community residents in designated zip codes surrounding the field centers. To be eligible for the study, participants had to report no difficulty in walking one-quarter of a mile, climbing 10 steps, or in performing activities of daily living. Participants were eligible to obtain bilateral knee radiographs and knee MRIs at the second annual clinic visit if they reported symptoms of OA in at least 1 knee. A knee was defined as having symptoms of OA if the participants reported pain, aching, or stiffness on most days for at least 1 month during the past 12 months, or if they reported moderate or worse knee pain during the last 30 days in association with 1 activities assessed by the Western Ontario and McMaster Universities Osteoarthritis Index pain scale ([23]). For the purposes of this study, we included only Health ABC participants with radiographic evidence of knee OA in the tibiofemoral joint, as defined by a grade of 2 on the Kellgren and Lawrence (K/L) scale ([24][25]). The study's protocol was approved by the Institutional Review Boards of the University of Pittsburgh and the University of Tennessee, Memphis, and participants provided informed consent. Radiographic assessments. In BOKS, fluoroscopically positioned, semiflexed, weight-bearing posteroanterior (PA) radiographs of the most symptomatic knee were obtained from participants at baseline, as well as a baseline weight-bearing skyline view of the same knee ([20][26]). In Health ABC, bilateral, fixed-flexion weight-bearing PA knee radiographs were obtained at baseline ([27]). Each knee was graded for OA on the K/L scale using the Osteoarthritis Research Society International atlas, and was graded for the presence of chondrocalcinosis ([25][28]). Chondrocalcinosis was defined as being present if there was definite linear cartilage calcification on the PA view in a compartment-specific manner. Intrarater reliability kappa values were 0.81 (95% confidence interval [95% CI] 0.76-0.85) and 0.87 (95% CI 0.83-0.91) for K/L scores, and 0.74 and 0.66 for chondrocalcinosis in BOKS and Health ABC, respectively. Kappa values for chondrocalcinosis were lower than the K/L scores due to the low prevalence of chondrocalcinosis. MRI assessments. In BOKS, MRI studies were performed at baseline and at 15 and 30 months using a Signa 1.5T MRI system (General Electric Signa, Milwaukee, WI) with a phased-array knee coil. A positioning device was used to ensure uniformity among patients. Coronal, sagittal, and axial images were obtained. The imaging protocol included sagittal spin-echo proton density and T2-weighted images (repetition time [TR] 2,200 msec, time to echo [TE] 20/80 msec) with a slice thickness of 3 mm, a 1-mm interslice gap, 1 excitation, field of view (FOV) 11-12 cm, and a matrix of 256 × 192 pixels, and coronal and axial spin-echo fat-saturated proton density and T2-weighted images (TR 2,200 msec, TE 20/80 msec) with a slice thickness of 3 mm, a 1-mm interslice gap, 1 excitation, and the same FOV and matrix. In Health ABC, MRI studies were also obtained using a Signa 1.5T MRI system with a standard unilateral, commercial circumferential knee coil at baseline and 3 years (median 37 months, range 23-47 months). Coronal, sagittal, and axial images were obtained. Coronal views were T2-weighted fast spin-echo (FSE) (TR 3,500 msec, TE 20/60 msec) with a slice thickness of 4 mm, a 0.5-mm interslice gap, 2 excitation, FOV 14 cm, and a matrix of 256 × 256 pixels. Sagittal views were T2-weighted FSE, including the entire synovial cavity with frequency-selective fat suppression (TR 4,127 msec, TE 20/60 msec), a 0.5-mm interslice gap, 2 excitation, and the same FOV and matrix. Axial views were T2-weighted FSE (TR 2,500 msec, TE 20/60 msec) with a 1-mm interslice gap, 1 excitation, FOV 12 cm, and a matrix of 256 × 256 pixels). Cartilage morphology was evaluated on paired sagittal and coronal longitudinal 2-dimensional MRIs using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) ([29]). Cartilage scores were read in 5 cartilage subregions, or regions of interest (ROI), of each of the medial and lateral tibiofemoral joints. In this scoring system, 0 = normal thickness and signal, 1 = normal thickness but increased signal on T2-weighted images, 2 = partial- or full-thickness focal defect <1 cm in greatest width, 3 = multiple areas of partial-thickness 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 or a full-thickness loss wider than 1 cm but <75% of the region, and 6 = diffuse ( 75% of the region) full-thickness loss ([29]). In BOKS, the cartilage readings were read unblinded to sequence, whereas in Health ABC, the readings were read blinded to sequence. Interrater intraclass correlations for the MRI WORMS cartilage score were 0.85 in BOKS and 0.99 in Health ABC ([29]). Using WORMS, grade 1 does not represent a morphologic abnormality, but rather, a change in signal in cartilage of otherwise normal morphology. Grades 2 and 3 represent similar types of abnormality of the cartilage, focal defects without overall thinning. Therefore, as in previous work ([30]), to create a consistent and logical scale for the evaluation of cartilage morphologic change and a fair comparison with radiographic changes in JSN, we collapsed the WORMS cartilage score to a 0-4 scale, in which the original WORMS scores of 0 and 1 were collapsed to 0, the original scores of 2 and 3 were collapsed to 1, and the original scores of 4, 5, and 6 were considered 2, 3, and 4, respectively, in the new scale. Cartilage loss in an ROI was therefore defined as an increase in cartilage score of 1 (0-4 scale). Meniscal scores were also evaluated in each compartment, with a separate score (0-4 scale) assigned to the anterior horn, body, and posterior horn of each meniscus. A meniscus was defined as damaged if the summed meniscal score in a compartment was >6. Other measurements. In both BOKS and Health ABC, subjects were weighed, with shoes off, on a balance-beam scale, and height was assessed. Body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m2). Statistical analysis. Analyses in both BOKS and Health ABC were conducted in a similar manner. We examined the relationship of the baseline radiographic presence of compartment-specific (medial and lateral) chondrocalcinosis to the risk of cartilage loss on MRI as the primary outcome. Participants with baseline and followup knee MRIs and baseline knee chondrocalcinosis radiographic readings were included in the analyses. We assessed the risk for change in the number of ROIs within each compartment with cartilage loss over time using Poisson regression. Because the MRI features among the 5 plates per knee compartment are likely correlated, we used generalized estimating equations (GEE) to account for correlations ([31][32]). In BOKS, the followup MRIs were obtained at 2 time points, 15 months and 30 months. In this analysis, we used MRI readings from the subject's last visit to calculate the change in the number of ROIs within a compartment with cartilage loss. The proportion of MRIs obtained at 15 months and 30 months was similar between subjects with and those without baseline chondrocalcinosis. Because of the possibility of a ceiling effect, the number of ROIs in each compartment that could potentially experience a change in cartilage score at baseline was used as an offset variable in the regression models. Analyses were adjusted for age, sex, BMI, and presence of damaged menisci (dichotomous variable). In the analysis of the risk of cartilage loss, we also adjusted for compartment-specific baseline cartilage score. Because adjustment for such a baseline measure is controversial, we also performed these analyses without adjusting for baseline cartilage score ([33][34]). The results were similar with and without the adjustment, and the adjusted results are presented here. To address the possibility that chondrocalcinosis was a proxy for the presence of intact menisci, we performed separate stratified analyses in which compartments were defined as having intact versus damaged menisci. All analyses were performed using SAS 8.0 (SAS Institute, Cary, NC). Two-sided P values less than 0.05 were considered statistically significant. RESULTS
In BOKS, there were 265 participants (265 knees), with a mean ± SD age of 67 ± 9 years, of whom 42% were women. Twenty-three knees (9%) had chondrocalcinosis at baseline. In Health ABC, 230 participants (373 knees), with a mean ± SD age of 74 ± 3 years, met the radiographic OA inclusion criteria. Of these, 69% were women. In this group, 69 knees (18.5%) had chondrocalcinosis at baseline. Participant characteristics are shown in Table 1.
As shown in Table 2, in BOKS there was a lower risk of cartilage loss in knees with baseline chondrocalcinosis compared with knees without chondrocalcinosis (adjusted risk ratio [RR] 0.4, 95% CI 0.2-0.7) (P = 0.002). In Health ABC, a smaller protective association was noted, but this did not reach statistical significance (adjusted RR 0.9, 95% CI 0.6-1.5) (P = 0.7).
In BOKS (Table 2), among knee compartments with damaged menisci as well as those with intact menisci, there was a lower risk of cartilage loss in those with baseline chondrocalcinosis compared with those without baseline chondrocalcinosis (adjusted RR 0.3 and 0.5, respectively) (P < 0.0001 and P = 0.02, respectively). In Health ABC, we did not find significant associations between chondrocalcinosis and cartilage loss, either in compartments with damaged menisci or in those with intact menisci. DISCUSSION
In these analyses of 2 prospective cohorts using longitudinal MRI data, we did not demonstrate a harmful effect of the presence of chondrocalcinosis on cartilage loss; in fact, chondrocalcinosis was significantly associated with less OA progression in 1 cohort. Given the association of CPPD crystals with inflammation, we expected that chondrocalcinosis would identify knees at high risk of progression. Our results did not support this expectation, however, which is consistent with some previous longitudinal radiographic studies ([14-19]). It may be that CPPD is a marker for metabolically active chondrocytes. Certain inflammatory mediators up-regulated in OA cartilage promote the transformation of chondrocytes into their hypertrophic form and promote calcification ([35]). Hypertrophic chondrocytes are intimately linked with cartilage calcific deposits in situ in OA and sporadic chondrocalcinosis ([36][37]). The presence of hypertrophic chondrocytes is not only associated with a propensity to generate inorganic pyrophosphate and to calcify the extracellular matrix, but it is also related to dysregulated matrix synthesis, characterized by decreased type II collagen and aggrecan expression, increased MMP-13, and type X collagen expression ([38]). Hence, it has been proposed that chondrocalcinosis may be a marker for hypertrophic chondrocyte differentiation in articular cartilage and a state of preserved chondrocyte viability, with a dysregulated, but nevertheless functional, chondrocyte matrix reparative response to injury ([17][39]). This study lends support to the hypothesis that CPPD may be a marker for a hypertrophic response indicative of a robust, albeit dysfunctional, reparative process by metabolically active chondrocytes. The reason for this may be, for example, inorganic pyrophosphate, which is a marker of a hypertrophic response to injury and is also the extracellular substrate for CPPD production and deposition. Chondrocytes found in cartilage with CPPD present are known to produce greater extracellular inorganic pyrophosphate compared with normal cartilage or even OA cartilage with no CPPD ([40]). Such extracellular inorganic pyrophosphate can either be produced de novo or can be the result of intracellular inorganic pyrophosphate being transported out of the cell ([41]). Additionally, CPPD crystals tend to occur in areas of altered pericellular matrix and, possibly, matrix vesicles ([41]). Although 1 study found high inorganic pyrophosphate levels in the knee joint to be negatively correlated with worsening OA status (K/L grade), and extremes of inorganic pyrophosphate levels to be associated with increased radiographic JSN, another found the levels of inorganic pyrophosphate in OA to be no different than those in normal knees ([42][43]). Clearly, the pathophysiology of the relation between these 2 diseases requires further elucidation. We were unable to assess the relationship between incident chondrocalcinosis on cartilage loss compared with no chondrocalcinosis because there were no cases of incident chondrocalcinosis in BOKS, and only 11 participants (14 knees) in Health ABC developed chondrocalcinosis during the followup period. The 2 cohorts were composed of different populations with different risks for OA progression, and this may partially explain the difference in results between the 2 cohorts. In BOKS, all knees studied had symptomatic OA, while this was not the case in Health ABC, a cohort in which the participants were not selected for symptomatic OA. BOKS participants had BMIs that were, on average, higher, and they were drawn primarily from a Veterans Administration population that differed in many ways compared with the healthy, well-functioning elderly in Health ABC; thus, one may expect to see more progression of OA in the BOKS population, despite their younger age. Despite that expectation, we were able to demonstrate a significantly protective effect of the presence of chondrocalcinosis, even in knees with damaged menisci. Second, the 2 cohorts have different racial compositions. We performed analyses to determine whether race could account for the differences in results between the 2 cohorts. BOKS participants were predominantly white (88% white, 9% African American, 3% other), while in the Health ABC sample, 113 were white (49%; 181 knees) and 117 were African American (51%; 192 knees). In Health ABC, whites had an RR of 1.2 (P = 0.6), while African Americans had an RR of 0.8 (P = 0.5) for risk of cartilage loss in those compartments with chondrocalcinosis compared with those without. Thus, there does not appear to be a clear association with race to explain the differences noted. The 2 cohorts also had different sex compositions, with women comprising 42% of the study sample in BOKS and 69% of Health ABC. In BOKS, males had an RR of 0.4 (P = 0.01) and females had an RR of 0.5 (P = 0.06) for risk of cartilage loss in compartments with chondrocalcinosis compared with those without chondrocalcinosis. In Health ABC, the RR values were 0.7 (P = 0.6) for males and 0.8 (P = 0.6) for females. Thus, sex also does not appear to explain the differences noted in the results between the 2 cohorts. As an additional analysis, we combined the 2 cohorts, recognizing that the cohorts are not directly comparable due to their composition and the timing of evaluations. Nonetheless, when the cohorts were combined, we again found a protective association for the presence of baseline chondrocalcinosis on risk of cartilage loss (RR 0.7, 95% CI = 0.5-0.99) (P = 0.05). Because of the small number of knees with chondrocalcinosis, missing cartilage loss in such a knee could have an effect on our estimate of risk for progression of cartilage loss. We therefore performed sensitivity analyses to address this concern. In BOKS, if we were to assume that the compartments with damaged menisci that had no cartilage loss actually did exhibit cartilage loss in 2 cartilage subregions, the point estimate (RR) would be 0.6. Similarly, in those with intact menisci, increasing the number of subregions with cartilage loss would change the point estimate to 0.7. In both situations, the association remained protective, although the 95% CI included the null due to the small numbers. We believe that for such misclassification to occur, it would be necessary for 2, 3, or more subregions (out of 5) in a knee compartment to be misread for cartilage loss, which would be unlikely. A limitation of our study lies in the imprecise method applied to identify chondrocalcinosis. Identification of calcium crystals is difficult both radiographically and by direct tissue or synovial fluid analysis. However, radiography continues to be a convenient, noninvasive means of identifying knees in which calcium crystals have accumulated in sufficient quantity to be detectable, even though specific crystal types may not be absolute or adequately identified. Currently, radiographic detection of chondrocalcinosis relies on plain radiographs, because MRI techniques cannot clearly reveal the existence of the crystal deposition. However, the possible low sensitivity in detecting chondrocalcinosis implies an expectation of an underestimate in our study results. Additionally, the relatively short followup of 2.5-3 years in these 2 cohorts may have been insufficient to see more definitive changes in cartilage. It is possible that with longer followup times, the difference with respect to cartilage loss in knees with chondrocalcinosis compared with those without may have been more definitive in both cohorts. In summary, no harmful effects of the presence of chondrocalcinosis on OA progression in 2 prospective cohorts using MRI data to assess cartilage loss over time were found.
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