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. Author manuscript; available in PMC: 2016 May 1.
Published in final edited form as: Arthritis Rheumatol. 2015 May;67(8):2085–2096. doi: 10.1002/art.39176

What comes first?

Multi-tissue involvement leading to radiographic osteoarthritis: MRI-based trajectory analysis over 4 years in the Osteoarthritis Initiative

Frank W Roemer 1,2, C Kent Kwoh 3,4, Michael J Hannon 4, David J Hunter 5, Felix Eckstein 6, Tomoko Fujii 4, Robert M Boudreau 4, Ali Guermazi 1
PMCID: PMC4519416  NIHMSID: NIHMS690581  PMID: 25940308

Abstract

Background

To assess whether presence of structural osteoarthritis features over up to 4 years prior incident radiographic (ROA) increases risk for ROA in a nested, case-control design.

Methods

355 knees from the Osteoarthritis Initiative cohort that developed ROA before the 48-month visit were studied. They were matched one-to-one by gender, age and radiographic status with a control knee. MR images were read for bone marrow lesions (BMLs), cartilage, meniscus (including tears and extrusion), Hoffa- and effusion-synovitis. Conditional logistic regression was applied to assess risk of ROA in regard to presence of BMLs (≥2), cartilage lesions (≥1.1), meniscal damage (any) and extrusion (≥3 mm), Hoffa- and effusion-synovitis (any). Time points were defined as P0 = incident ROA visit; P-1 = visit prior reported incidence; P-2 = two visits prior etc.

Results

The presence of Hoffa-synovitis (OR 1.76, 95% CI [1.18,2.64]), effusion-synovitis (OR 1.81, 95% CI [1.18,2.78]), and medial meniscal damage (OR 1.83 95% CI [1.17,2.89]) at P-2 predicted ROA incidence. At P-1, all features but meniscal extrusion predicted ROA, with highest odds for medial BMLs (OR 6.50 95% CI [2.27,18.62]) and effusion-synovitis (OR 2.50 95% CI [1.76,3.54]). The findings at P-3 and P-4 did not reach statistical significance.

Conclusion

Presence of specific structural features of MRI-detected joint damage two years prior incident ROA increases the risk of incident ROA. However, one year prior ROA, the presence of almost any abnormal morphologic feature increases risk of ROA in the subsequent year.

Introduction

Osteoarthritis (OA) is a complex, heterogeneous condition that is the most common cause of disability in the aging population (1). The hallmarks of the pathophysiology of OA are the breakdown of cartilage and associated changes in adjacent soft tissue and subchondral bone that lead to debilitating joint symptoms such as pain and disability accompanied by structural deformity (1). As a consequence of OA, rates of knee replacement have more than doubled in the United States in the period from 1999 to 2008 (2).

Imaging markers have been used as indirect surrogate measures of disease status and activity with variable plausibility and success (3, 4). While radiography is only able to depict osseous tissue alterations and only in advanced stages of the disease, magnetic resonance imaging (MRI) provides insights concerning all involved joint tissues that are clinically relevant at a much earlier disease stage (5–7).

Knowledge about the early stages of knee OA is sparse. The accepted definition of OA is based on the presence of a definite osteophyte on the posterior-anterior (p.a.) radiograph (defined as grade 2 according to the Kellgren and Lawrence (K-L) classification) (3). However, large population-based studies applying MRI have suggested that structural joint pathology is widely present in persons without radiographic evidence of disease (5, 6). The relevance of these morphologic abnormalities is not known, and some of these may be precursors of disease. A recent analysis based on a subset of the Osteoarthritis Initiative (OAI), a large ongoing observational study of knee OA, assessed subjects without radiographic OA at two defined time points, i.e. at 12 and 48 months, using cartilage loss and incident knee symptoms as the outcome parameters and found that structural joint damage was associated with incident persistent symptoms and that more concomitant lesion types were associated with a greater risk of symptom outcomes and incident tibio-femoral cartilage damage (8). From this, the authors concluded that the observed findings are not incidental in persons at increased risk for OA and may represent early disease and illness. Studies examining multiple time points prior to disease onset are not available to date.

Given that MRI features often coexist in knees with established disease and increase the risk of progression (9), it would be important to understand the chronology of events to be able to tackle individual lesions early to avoid progression to more advanced stages. Although hyaline articular cartilage loss is one of the structural disease hallmarks, the evidence that joint deterioration begins with cartilage pathology is sparse (1). Several authors have suggested that incidental meniscal pathology might be one of the main triggers of disease onset (10); however, the role of the meniscus in disease onset is under debate (11, 12). Synovial activation, which is reflected on MRI as joint effusion and synovial thickening appears to increase risk of cartilage loss and might play a crucial yet not fully understood role in early disease (13–15). Furthermore, the subchondral bone seems to be an important driver of disease progression, and animal models have suggested that bone marrow changes might be the earliest structural manifestation of disease onset (16). Finally, prevalent cartilage damage and focal defects increase risk for further progression markedly; indeed, such lesions might still be one of the most important triggers for progression on a subregional level and later also on a joint basis leading to manifest radiographic OA (9, 17). Eventually, a more or less concomitant appearance of these lesions may be possible (8).

The purpose of the current study was to test the hypotheses whether 1.) presence of MRI-based measures of structural joint tissue damage, including cartilage, subchondral bone, menisci and synovium, differ between knees developing incident ROA and matched control knees that did not develop ROA during the 48 months prior to developing disease; 2.) whether incidence and fluctuation of abnormal structural features prior to developing disease differs between cases and controls; and, finally, 3.) whether cumulative presence of abnormal structural features increases risk for incident ROA.

Methods

The Osteoarthritis Initiative (OAI)

The Osteoarthritis Initiative (OAI) is an ongoing longitudinal cohort study designed to identify biomarkers of the onset and/or progression of knee OA. Both knees of 4,796 participants were studied using 3 Tesla (T) MRI and fixed-flexion radiography at baseline, 12, 24, 36, and 48 months of follow-up (18). OAI participants were 45 to 79-years-old at baseline, with symptomatic knee OA in at least one knee or were at increased risk of developing symptomatic knee OA with the presence of two or more of the following risk factors: being overweight, history of knee injury or surgery, family history of knee replacement, or Heberden’s nodes. General exclusion criteria were presence of rheumatoid or other inflammatory arthritis, bilateral end-stage knee OA, inability to walk without aids, and MRI contraindications. Patients were recruited at four clinical sites in the United States. The Institutional Review Boards at each of the sites approved the study, and all participants gave informed consent.

Radiography

OAI knee radiographs were acquired using the posterior-anterior fixed-flexion weight-bearing protocol (19, 20) using a plexiglass positioning frame (SynaFlexer™, Synarc Inc., San Francisco, CA) (21). The K-L grade was determined by central readings of baseline serial fixed-flexion knee radiographs (22). In brief, two senior musculoskeletal experts, who are not co-authors, assessed each film centrally, blinded to each other’s reading and all other data. For each subject, all radiographs were read paired. The weighted kappa for inter-reader agreement was 0.79 for K-L grade. Pre-specified discrepancies were adjudicated in a consensus session with a third reader (22).

Case and Control Knee Selection

Cases were defined as study participants who had at least one knee that developed incident radiographic OA during the four years of follow-up. Incident radiographic OA was defined as the first occurrence of radiographic findings compatible with OA (K-L grade of ≥2 on the p.a. view) during the course of study. This time point was called P0 with P-1 being defined as the time point 1 year before radiographic OA was detected, P-2 defined as 2 years prior, P-3 meaning 3 years prior and P-4 defining the time point 4 years prior incidence was read. All participants with available images at the time point when incidence was read or the time point prior fulfilling the case definition were included. An identical number of control knees were selected from knees that did not develop incident radiographic OA during the study period. The controls were matched to case knees according to gender, age (within five years), and contralateral knee OA status (i.e. K-L grade = 0, 1, or 2+ in the other knee). Each case was matched to those who were at risk at the time of case occurrence and those with available images at relevant time points, whether this was at 12, 24, 36 or 48 months of follow-up. Both cases and control knees were either K-L 0 or 1 at baseline. A detailed overview of subject inclusion is presented as a flow chart in Figure 1.

Figure 1.

Figure 1

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Flow chart of subject inclusion.

MRI Acquisition

MRI of both knees was performed on 3 T systems (Siemens Trio, Erlangen, Germany) at the four OAI clinical sites. MRIs were acquired with a dedicated quadrature transmit/receive knee coil using a coronal intermediate-weighted (IW) two-dimensional (2D) turbo spin-echo, a sagittal three-dimensional (3D) dual echo at steady state (DESS) sequence, and a sagittal IW fat-suppressed turbo spin-echo sequence. Additional parameters of the full OAI pulse sequence protocol and the sequence parameters have been published in detail (18).

MRI Assessment

Two musculoskeletal radiologists with 11 (F.W.R.) and 14 (A.G.) years experience of semiquantitative assessment of knee OA, blinded to clinical data and case-control status, read the MRIs according to a validated scoring system (23). Baseline and follow-up MRIs were read with the chronological order known to the readers. Each reader scored half of the cases that were blinded to case or control status. The following joint structures were assessed: cartilage morphology, subchondral bone marrow lesions (BMLs), meniscal status, meniscal extrusion, Hoffa-synovitis and effusion-synovitis (Figure 2).

Figure 2.

Figure 2

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Examples of the different MRI risk factors in knees without radiographic osteoarthritis. A. Effusion synovitis. Axial dual echo at steady state image shows intraarticular hyperintensity (asterisk) and slight distension of the joint capsule reflecting effusion-synovitis. B. Bone marrow lesion. Sagittal intermediate-weighted fat suppressed image shows a large bone marrow lesion in the central subregion of the medial femur (white arrows). Note additional concomitant MRI features including effusion-synovitis (asterisk) and superficial focal cartilage damage (black arrow). C. Cartilage damage. Coronal intermediate-weighted image shows a focal full-thickness cartilage defect in the lateral tibial plateau (arrow). D. Meniscal damage. Sagittal intermediate-weighted fat suppressed image depicts a degenerative horizontal-oblique meniscal tear of the posterior horn of the medial meniscus (large arrow). Note that in addition there is a small subchondral bone marrow lesion in the central medial femur (small arrow) but no adjacent cartilage damage.

Cartilage was scored in 14 articular subregions (5 subregions in the medial and lateral tibio-femoral compartments and 4 subregions in the patello-femoral compartment), incorporating area size per subregion (from 0 to 3) and percentage of subregion that was affected by full thickness cartilage loss (from 0 to 3).

BMLs were assessed from 0 to 3 in the same 14 subregions taking into account percentage of a subregion that was affected by BML (i.e. lesion size). As the used scoring system only uses one parameter of lesion size, which incorporates both cystic and ill-defined parts of BMLs in a given subregion, analysis of subchondral cysts was included in the definition of BMLs. Meniscal status was scored in the anterior horn, body segment, and posterior horn of the medial and lateral menisci from 0 to 8 taking into account intrameniscal signal changes, different types of meniscal tears and meniscal maceration, i.e. substance loss. Meniscal extrusion was scored in the coronal planes from 0 to 3 with grade 2 defining extrusion ≥3 mm. Signal alterations in the intercondylar region of Hoffa’s fat pad were scored from 0 to 3 as a surrogate for synovial thickening termed Hoffa-synovitis. Joint effusion (also called effusion-synovitis as it is not possible to discern joint fluid from synovial thickening on MRI) was graded from 0 to 3 in terms of the estimated maximal distention of the synovial cavity.

One radiologist (FWR) re-scored 20 randomly chosen MRIs in random order for the same features after a 4-week interval to determine intra-reader reliability. Inter-observer reliability between the two readers was assessed using the same 20 cases. Summarizing the intra- and inter-observer reliability results, all of the measures showed substantial (0.61–0.8) or reached almost perfect agreement (0.81–1.0) (24). Appendix 1 gives a detailed overview of the reliability results.

Statistical Analysis

Analyses were performed on a compartmental and knee level using several analytic approaches:

  1. ) Conditional logistic regression was used to assess the risk of incident ROA related to presence of structural parameters at each individual time point for a maximum of four time points (i.e. years) prior to the case defining visit when incident ROA was established. Based on the available literature in regard to relevance of each feature for potential structural progression and on personal experience of the authors, presence of structural features was defined as any effusion- or Hoffa-synovitis (≥ 1), moderate and large bone marrow lesions (BMLs) (≥ 2), moderate and severe cartilage damage (≥ 1.1), meniscal tear or maceration (≥ 2), and presence of medial and lateral meniscal extrusion in the coronal plane (≥ 2). (8, 13, 25–31)

  2. ) In addition risk of incident radiographic OA was assessed for presence of these same features at the baseline visit, at the case defining visit (P0) and for presence of these features at any of the assessed time points from P-4 to P0 and from P-4 to P-1, the visit before the case defining visit.

  3. ) Further, we stratified knees into knees that did not exhibit a given feature at any of the time points (i.e., absent), knees where the feature was incident (i.e., was not present at baseline but was present at least at one of the follow-up time points and all subsequent relevant time points with available images until P0), knees where the feature was variable (i.e., that showed a feature at least at one of the time points but not all of them), and knees where the feature was prevalent (i.e., exhibited a feature at all time points). We assessed risk of incident radiographic OA for each of these subgroups using the group that did not exhibit a feature at any of the time points as the reference.

  4. ) Finally, the risk of incident radiographic OA was determined including number of features present at a given time point differentiating six structural features (Hoffa-synovitis, effusion-synovitis, BMLs, cartilage damage, meniscal damage, and meniscal extrusion) with the same cut-offs as described above using presence of no feature or only one feature as the reference.

Because we tested up to five different codings for each feature, we used a Bonferroni adjustment of 5 to the normal two-tailed significance level of 0.05. Weighted kappa statistics were applied to determine inter- and intra-observer reliability. All statistical calculations were performed using Stata/IC 11.2 for Windows (StataCorp, College Station, TX) and SAS 9.3 (SAS Institute Inc, Cary, NC).

Results

Altogether 355 case knees and 355 match control knees were included. Participants were on average 60.2 years old (SD ± 8.6), predominantly female (66.5%) and overweight (mean BMI 28.3 kg/m2, SD ± 4.4). No differences were observed for age and gender, but cases had a slightly higher BMI compared to controls (28.9 kg/m2 vs. 27.7 kg/m2, p=0.001). 84% of subjects were white with no significant differences in regard to ethnicity in the case and control group. The baseline K-L grades for the matched pairs were 63 (17.8%) grade 0 in both knees, 76 (21.4%) grade 0 in one knee and grade 1 in the contralateral knee, 83 (23.4%) grade 1 in both knees, 59 (16.6%) grade 0 in one knee and grade ≥ 2 in the other, and 74 (20.9%) grade 1 in one knee and grade ≥ 2 in the contralateral knee. The case-defining visit of radiographic OA incidence was 12 months for 119 (33.5%), 24 months for 83 (23.4%), 36 months for 103 (29.0%), and 48 months for 50 (14.1%) knees.

The trajectory of the presence of structural damage at specific time points from one to fours years prior to incident radiographic OA showed that at two years prior the case-defining visit (P-2) presence of Hoffa-synovitis (Hazard ratio (HR) 1.76, 95% confidence interval (CI) [1.18,2.64]), effusion-synovitis (HR 1.81, 95% CI [1.18,2.78]), and medial meniscal damage (HR 1.83, 95% CI [1.17,2.89]) increased risk of incident radiographic OA. One year prior to the case-defining visit, multiple structural features predicted incident radiographic OA one year later, with the strongest risk factors being medial (HR 6.50 95% CI [2.27,18.62]) and any tibio-femoral BMLs (HR 3.70, 95% CI [1.84,7.44]), and effusion synovitis (HR 2.50, 95% CI [1.76,3.54]). With regard to earlier time points, there was a trend toward the presence of Hoffa-synovitis at P-4 increasing the risk of incident radiographic OA, but this finding did not reach statistical significance. The detailed results of the trajectory over time are presented in Table 1.

Table 1.

Risk for incident radiographic OA in regard to presence of MRI structural features over 4 years prior to the diagnosis of ROA

Time point P-4 P-3 P-2 P-1
MRI Biomarker N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)
Any Hoffa-Synovitis 26 (52.0) 16 (32. 0) 1.91 (0.91,4.00) 75 (51.4) 70 (48.0) 1.16 (0.71,1.90) 122 (56.0) 93 (42.7) *1.76 (1.18,2.64) 195 (59.3) 127 (38.5) *2.42 (1.71,3.42)
Any Effusion-Synovitis 26 (52.0) 21 (42.0) 1.71 (0.68,4.35) 68 (46.6) 62 (42.5) 1.21 (0.73,2.02) 114 (52.3) 88 (40.4) *1.81 (1.18,2.78) 194 (58.8) 128 (38.8) *2.50 (1.76,3.54)
BML
Medial BML ≥2 3 (6.0) 1 (2.0) 3.00 (0.31,28.8) 5 (3.4) 1 (0.7) 5.00 (0.58,42.8) 13 (6.0) 4 (1.8) 3.25 (1.06,9.97) 26 (7.9) 4 (1.2) *6.50 (2.27,18.62)
Lateral BML ≥2 1 (2.0) 0 (0.0) n/a 5 (3.4) 3 (2.1) 1.67 (0.40,6.97) 8 (3.7) 5 (2.3) 1.60 (0.52,4.89) 16 (4.9) 7 (2.1) 2.29 (0.94,5.56)
PFJ BML ≥2 18 (36.0) 12 (24.0) 1.67 (0.73,3.81) 45 (30.8) 40 (27.4) 1.19 (0.70,2.01) 70 (32.1) 60 (27.5) 1.24 (0.82,1.90) 104 (31.5) 83 (25.2) 1.36 (0.96,1.94)
Whole Knee (Excluding PFJ) ≥2 3 (6.0) 1 (2.0) 3.00 (0.31,28.8) 9 (6.2) 4 (2.7) 2.25 (0.69,7.31) 19 (8.7) 9 (4.1) 2.25 (0.98,5.18) 38 (11.5) 11 (3.3) *3.70 (1.84,7.44)
Whole Knee, BML ≥2 20 (40.0) 13 (26.0) 1.88 (0.80,4.42) 50 (34.3) 43 (29.5) 1.26 (0.75,2.11) 84 (38.5) 66 (30.3) 1.46 (0.96,2.22) 130 (39.4) 91 (27.6) *1.66 (1.19,2.33)
Cartilage
Medial, ≥1.1 10 (20.0) 21 (42.0) 0.31 (0.11,0.85) 33 (22.6) 37 (25.3) 0.85 (0.50,1.46) 65 (29.8) 62 (28.4) 1.08 (0.69,1.68) 129 (39.1) 94 (28.5) *1.71 (1.20,2.46)
Lateral, ≥1.1 11 (22.0) 10 (20.0) 1.13 (0.43,2.92) 37 (25.3) 38 (26.0) 0.96 (0.55,1.68) 56 (25.7) 55 (25.2) 1.03 (0.64,1.64) 107 (32.4) 93 (28.2) 1.24 (0.86,1.77)
PFJ, ≥1.1 33 (66.0) 33 (66.0) 1.00 (0.40,2.51) 96 (65.8) 98 (67.1) 0.94 (0.57,1.54) 154 (70.6) 139 (63.8) 1.40 (0.91,2.13) 245 (74.2) 222 (67.3) 1.44 (1.01,2.06)
Whole Knee (Excluding PFJ) ≥1.1 18 (36.0) 29 (58.0) 0.27 (0.09,0.80) 56 (38.4) 67 (45.9) 0.69 (0.42,1.14) 99 (45.4) 101 (46.3) 0.96 (0.62,1.49) 188 (57.0) 160 (48.5) 1.49 (1.05,2.12)
Whole Knee (≥1.1) 39 (78.0) 42 (84.0) 0.57 (0.16,2.08) 117 (80.1) 120 (82.2) 0.84 (0.43,1.64) 182 (83.5) 175 (80.3) 1.27 (0.73,2.20) 291 (88.2) 267 (80.9) 1.86 (1.16,2.99)
Meniscus
Medial: Any tear or maceration (≥2) 14 (28.0) 16 (32.0) 0.80 (0.32,2.03) 40 (27.4) 36 (24.7) 1.17 (0.67,2.03) 76 (34.9) 51 (23.4) *1.83 (1.17,2.89) 132 (40.0) 81 (24.6) *2.19 (1.50,3.18)
Lateral: Any tear or maceration (≥2) 11 (22.0) 6 (12.0) 2.00 (0.66,6.06) 21 (14.4) 14 (9.6) 1.64 (0.76,3.52) 34 (15.6) 24 (11.0) 1.56 (0.85,2.84) 53 (16.1) 40 (12.1) 1.50 (0.91,2.46)
Medial extrusion (≥2) 2 (4.0) 4 (8.0) 0.33 (0.04,3.21) 5 (3.4) 8 (5.5) 0.57 (0.17,1.95) 15 (6.9) 11 (5.1) 1.40 (0.62,3.15) 31(9.4) 22(6.7) 1.47 (0.82,2.64)
Lateral extrusion (≥2) 1 (2.0) 0 (0.0) n/a 1 (0.68) 1(0.68) 1.00 (0.06,15.99) 3 (1.38) 1 (0.5) 3.00 (0.31,28.84) 3(0.9) 2(0.6) 1.50 (0.25,8.98)
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*

statistically significant at p <0.01

We also examined the impact of the presence of structural damage across multiple time points. Focusing on the baseline visit, medial and whole knee BMLs, Hoffa- and effusion-synovitis increased risk of OA, while at the time point of incident radiographic OA (P0) all structural features were significant except patello-femoral BMLs (HR 1.41, 95% CI [0.98, 2.03]) and lateral meniscal extrusion (HR 5.50 95% CI [1.22,24.81]). Assessing all time points combined (a feature being positive at any of the analyzed time points from P-4 to P0, presence of any of the features but patello-femoral BMLs and lateral extrusion increased risk of incident ROA. Incorporating only the time points from P-4 to P-1 many features remained significant except lateral and patello-femoral BMLs and cartilage damage, lateral meniscal damage and any meniscal extrusion. Table 2 presents these results in detail.

Table 2.

Risk for incident radiographic OA with regard to presence of MRI-detected joint damage at baseline, at the time point of diagnosis and for all time points combined

Time point Baseline
710 knees		 P0
670 knees		 Ever (P-4 to P0)
710 knees		 Ever (P-4 to P-1)
710 knees
MRI Biomarker N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)
p-value		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)
p-value		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)
p-value		 N Cases (%) N Controls (%) Risk for incident
ROA
Hazard Ratio (95% confidence intervals)
p-value
Any Hoffa-synovitis 191 (54.0) 137 (38.6) *1.90 (1.37,2.63) 208 (62.3) 131 (39. 2) *2.71 (1.90,3.87) 230 (64.8) 147 (41.4) *2.77 (1.95,3.92) 212 (59.7) 143 (40.3) *2.26 (1.63,3.12)
Any effusion-synovitis 174 (49.0) 138 (38.9) *1.62 (1.18,2.23) 216 (64.5) 137 (40.9) *2.98 (2.08,4.26) 268 (75.5) 189 (53.2) *3.39 (2.29,5.02) 222 (62.5) 163 (45.9) *2.23 (1.58,3.15)
BML
Medial BML ≥2 21 (5.9) 5 (1.4) *4.20 (1.58,11.14) 58 (17.3) 11 (3.3) *6.22 (3.10,12.51) 74 (20.9) 15 (4.2) *5.92 (3.24,10.81) 32 (9.0) 9 (2.5) *3.88 (1.78,8.43)
Lateral BML ≥2 11 (3.1) 7 (2.0) 1.57 (0.61,4.05) 28 (8.4) 7 (2.1) *4.00 (1.73,9.27) 38 (10.70) 12 (3.4) *3.17 (1.64,6.11) 22 (6.2) 10 (2.8) 2.20 (1.04,4.65)
PFJ BML ≥2 112 (31.6) 86 (24.2) 1.44 (1.02, 2.03) 105 (31.4) 84 (25.2) 1.41 (0.98;2.03) 148 (41.7) 117 (33.0) 1.49 (1.07,2.08) 135 (38.0) 110 (31.0) 1.40 (1.00,1.95)
Whole Knee (Excluding PFJ) ≥2 28 (7.9) 12 (3.3) 2.46 (1.22,4.95) 80 (23.9) 18 (5.4) *5.13 (2.96,8.91) 101 (28.5) 27 (7.6) *4.36 (2.76,6.91) 48 (13.5) 19 (5.4) *2.71 (1.55,4.72)
Whole Knee, BML ≥2 130 (36.6) 95 (26.8) *1.60 (1.14,2.26) 155 (46.3) 94 (28.1) *2.36 (1.63,3.41) 208 (58.6) 133 (37.5) *2.50 (1.77,3.53) 166 (46.8) 121 (34.1) *1.74 (1.25,2.41)
Cartilage
Medial, ≥1.1 114 (32.1) 97 (27.32) 1.28 (0.91,1.81) 184 (54.9) 112 (33.4) *2.53 (1.80,3.57) 194 (54.7) 114 (32.1) *2.70 (1.93,3.79) 137 (38.6) 105 (29.6) *1.56 (1.11,2.19)
Lateral, ≥1.1 110 (31.0) 95 (26.8) 1.25 (0.88,1.77) 138 (41.2) 92 (27.5) *1.96 (1.36,2.82) 146 (41.1) 100 (28.2) *1.84 (1.30,2.59) 119 (33.5) 98 (27.6) 1.34 (0.95,1.91)
PFJ, ≥1.1 251 (70.7) 233 (65.6) 1.29 (0.92,1.81) 264 (78.8) 226 (67.5) *1.86 (1.29,2.69) 278 (78.3) 244 (68.7) *1.71 (1.20,2.44) 263 (74.1) 240 (67.6) 1.40 (1.00,1.97)
Whole Knee (Excluding PFJ) ≥1.1 181 (51.0) 164 (46.2) 1.24 (0.90, 1.72) 256 (76.4) 170 (50.8) *3.61 (2.42,5.38) 270 (76.1) 179 (50.4) *3.53 (2.41,5.18) 204 (57.5) 173 (48.7) 1.51 (1.08,2.11)
Whole Knee (≥1.1) 299 (84.2) 283 (79.7) 1.42 (0.92,2.19) 316 (94.3) 275 (82.1) *4.15 (2.24,7.71) 335 (94.4) 293 (82.5) *4.00 (2.20, 7.29) 315 (88.7) 288 (81.1) *1.93 (1.21,3.07)
Meniscus
Medial: Any tear or maceration (≥ 2) 115 (32.4) 85 (23.9) 1.60 (1.11,2.31) 170 (50.8) 85 (25.4) *3.07 (2.13,4.43) 178 (50.1) 91 (25.6) *2.93 (2.07,4.16) 139 (39.2) 89 (25.1) *2.02 (1.42,2.88)
Lateral: Any tear or maceration (≥2) 49 (13.8) 41 (11.6) 1.26 (0.78,2.03) 71 (21.2) 40 (11.9) *2.29 (1.41,3.72) 72 (20.3) 43 (12.1) *2.12 (1.32,3.39) 59 (16.6) 42 (11.8) 1.61 (1.00,2.59)
Medial extrusion (≥2) 18 (5.1) 23(6.5) 0.76 (0.40,1.46) 90(26.9) 27 (8.1) *4.32 (2.62,7.12) 94 (26.5) 28(7.9) *4.30 (2.64,7.01) 32 (9.0) 26 (7.3) 1.26 (0.73,2.18)
Lateral extrusion (≥ 2) 4(1.1) 2 (0.6) 2.00 (0.37,10.92) 11(3.9) 2 (0.6) 5.50 (1.22,24.81) 11 (3.1) 2(0.6) 5.50 (1.22,24.81) 5 (1.4) 2 (0.6) 2.50 (0.49,12.89)
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*

statistically significant at p<0.01

The relevance of fluctuation and incidence of features over time for the development of incident radiographic OA was investigated by examining the time points at which a feature was never present (i.e., absent - as the referent group), variably present (i.e., fluctuating), incident, or always present (i.e., prevalent). In those knees where the presence of the feature was incident (e.g. not found at baseline but present for at least one subsequent time point and all subsequent time points from P-4 to P0) showed the most highly increased risk (e.g. odds ratio (OR) 12.09, 95% CI (4.33,33.77) for cartilage and OR 9.52, 95% CI (3.94,22.99) for Hoffa-synovitis) and a lesser risk for the group with all time points positive (e.g. odds ratio (OR) 3.53, 95% CI (1.92,6.49) for cartilage and OR 2.50, 95% CI (1.73,3.60) for Hoffa-synovitis). The details of this analysis are presented in Table 3.

Table 3.

Time points with presence of a positive feature

MRI biomarker Category 1 Cases
N (%)		 Controls
N (%)		 Odds ratio (95% confidence interval)
Hoffa-Synovitis
absent 125 (35.2) 208 (58.6) Reference
fluctuating 8 (2.3) 6 (1.7) 1.89 (0.56,6.41)
incident 39 (11.0) 10 (2.8) *9.52 (3.94,22.99)
prevalent 183 (51.6) 131 (36.9) *2.50 (1.73,3.60)
Effusion-synovitis
absent 87 (24.5) 166 (46.8) Reference
fluctuating 37 (10.4) 43 (12.1) 2.02 (1.15,3.55)
incident 94 (26.5) 51 (14.4) *4.54 (2.71,7.60)
prevalent 137 (38.6) 95 (26.8) *3.47 (2.23,5.41)
Bone marrow lesion
absent 147 (41.4) 222 (62.5) Reference
fluctuating 34 (9.6) 28 (7.9) 1.96 (1.11,3.45)
incident 78 (22.0) 38 (10.7) *3.18 (1.95,5.17)
prevalent 96 (27.0) 67 (18.9) *2.32 (1.53,3.52)
Cartilage
absent 20 (5.6) 62 (17.5) Reference
fluctuating 1 (0.3) 2 (0.6) 1.77 (0.15,21.01)
incident 36 (10.1) 10 (2.8) *12.09 (4.33,33.77)
prevalent 298 (83.9) 281 (79.2) *3.53 (1.92,6.49)
Medial meniscus morphology
absent 177 (49.9) 264 (74.4) Reference
fluctuating 0 (0.0) 1 (0.3) n/a
incident 63 (17.8) 6 (1.7) *14.01 (5.47,35.87)
prevalent 115 (32.4) 84 (23.7) *1.91 (1.31,2.79)
Lateral meniscus morphology
absent 283 (79.7) 312 (87.9) Reference
fluctuating 0 (0.0) 2 (0.6) n/a
incident 23 (6.5) 2 (0.6) *12.64 (2.81,56.81)
prevalent 49 (13.8) 39 (11.0) 1.62 (0.98,2.68)
Medial meniscus extrusion
absent 261 (73.5) 327 (92.1) Reference
fluctuating 0 (0.0) 0 (0.0) n/a
incident 76 (21.4) 5 (1.4) *36.33 (8.89,148.47)
prevalent 18 (5.1) 23 (6.5) 0.881 (0.45,1.72)
Lateral meniscus extrusion
absent 344 (96.9) 353 (99.4) Reference
fluctuating 0 (0.0) 0 (0.0) n/a
incident 7 (2.0) 0 (0.0) n/a
prevalent 4 (1.1) 2 (0.6) 2.00 (0.37,10.92)
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*

statistically significant at p<0.01

1

Categories: absent - knee that does not exhibit a feature at any of the time points; fluctuating - knee that shows feature at least at one of the time points including baseline but not all time points; incident - knee does not exhibit the feature at baseline but at least at one of the follow-up time points and all subsequent time points; prevalent - knee exhibits feature at all time points

We examined the impact of the concomitant presence of multiple structural features of joint damage. Increasing number of positive features markedly increased risk for radiographic OA particularly for the baseline visits, the visits two years and one year prior the case defining visit and the case defining visit itself. Thus, presence of five or six concomitant features two years prior the diagnosis increased risk almost six-fold and at one year prior almost 12-fold compared to knees with only one or without any feature present at the same time point. An increase in number of concomitant features was highly associated with an increased in risk of incident OA for the baseline, P-2, P-1 and P0 visits (p for trend <0.0001). The details of this analysis are presented in Table 4.

Table 4.

Risk of incident radiographic osteoarthritis in regard to number of MRI features present

Time point Number of features present per knee Cases
N (%)		 Controls
N (%)		 OR (95% CI)
Baseline N=710
0 and 1 69 (19.4) 113 (31.8) Reference
2 88 (24.8) 99 (27.9) 1.59 (1.01,2.51)
3 97 (27.3) 83 (23.4) *2.27 (1.41,3.65)
4 68 (19.2) 47 (13.2) *2.79 (1.68,4.63)
5 and 6 33 (9.3) 13 (3.7) *5.28 (2.35,11.86)
P for trend <.0001
P-4 N=100
0 and 1 11 (22.0) 13 (26.0) Reference
2 11 (22.0) 16 (32.0) 0.82 (0.26,2.54)
3 14 (28.0) 13 (26.0) 1.26 (0.40,3.98)
4 8 (16.0) 8 (16.0) 1.44 (0.38,5.43)
5 and 6 6 (12.0) 0 (0.0) n/a
P for trend 0.1042
P-3 N=292
0 and 1 30 (20.6) 38 (26.0) Reference
2 43 (29.5) 43 (29.5) 1.39 (0.67,2.92)
3 38 (26.0) 34 (23.3) 1.57 (0.72,3.42)
4 26 (17.8) 22 (15.1) 1.59 (0.74, 3.46)
5 and 6 9 (6.2) 9 (6.2) 1.40 (0.44,4.40)
P for trend 0.3105
P-2 N=436
0 and 1 40 (18.4) 68 (31.2) Reference
2 48 (22.0) 54 (24.8) 1.70 (0.91,3.20)
3 56 (25.7) 52 (23.9) 2.23 (1.21 4.10)
4 49 (22.5) 34 (15.6) *2.75 (1.47,5.16)
5 and 6 25 (11.5) 10 (4.6) *5.57 (2.13 14.57)
P for trend <.0001
P-1 N=660
0 and 1 39(11.8) 105 (31.8) Reference
2 74(22.4) 89(27.0) *2.80 (1.60,4.91)
3 89(27.0) 77(23.3) *4.57 (2.49,8.38)
4 85(25.8) 44(13.3) *7.43 (4.06,13.6)
5 and 6 43(13.0) 15(4.6) *11.93 (5.33,26.70)
P for trend <.0001
P0 N=670
0 and 1 24(7.2) 101 (30.2) Reference
2 50(14.9) 93(27.8) *2.58 (1.35,4.94)
3 81(24.2) 75(22.4) *7.57 (3.57,16.04)
4 81(24.2) 47(14.0) *11.46 (5.70,23.03)
5 and 6 99(29.6) 19(5.7) *38.48 (15.97,92.70)
P for trend <.0001
Open in a new tab
*

statistically significant at p<0.01

Discussion

This is the first investigation using a matched case-control design to examine structural predictors of incident radiographic OA over multiple time points from one to four years prior to incidence. Because the development of radiographic OA is a multifaceted process, we used several analytic approaches to assess the impact of presence of MRI-detected features at different time points in regard to risk of incident OA. Taking into account those different analyses, we found that knees exhibiting structural features in the two years prior to developing disease had an increased risk with the number of features present increasing the risk further, i.e., lesion load seems potentially more relevant than presence of any specific feature alone. In regard to baseline presence of features, it is noteworthy that presence of BMLs, of Hoffa- and effusion-synovitis and prevalent medial meniscal damage increased risk of OA while cartilage damage did not, although it was a common finding in both case and control knees at baseline. While our study design and the pre-defined annual follow-up visits within the OAI do not allow a definitive determination of the chronological order of the appearance of structural features, we showed that new presence and persistence of a feature prior to the case defining visit but not at baseline bears a higher risk than knees exhibiting that feature at every time point (prevalent findings), suggesting that incidence of new features over time might play a more important role than presence of any a given feature alone.

The latter finding in particular distinguishes our work from a recently published study also embedded within the OAI that looked specifically at incidence of symptoms and cartilage loss over time as outcome parameters but only analyzed baseline predictors, with baseline being defined as the 12-month OAI visit (8). Our study is unique in that we looked at all available time points prior to the diagnosis of radiographic OA in a well-defined matched case-control design with regard to gender, age, and baseline radiographic disease status in both knees, which was paramount to ensure maximum comparability between cases and controls.

While the observed hazard ratios are not easily comparable due to relatively large and overlapping confidence intervals, nonetheless our trajectory analysis allows several important conclusions. We observed that presence of MRI features seems to be particularly relevant closer to the diagnosis of radiographic OA, which underlines the relevance of fluctuation of these features, with some of these features observed far distant to the case defining visit (i.e. at P-4 and P-3) still potentially regressing and, thus, not contributing markedly to incident radiographic OA. An important finding was that at the visit two years prior to the case-defining visit (P-2), presence of Hoffa- and effusion-synovitis, medial BMLs and medial meniscal damage increased risk of OA but cartilage damage did not. This finding emphasizes the role of non-cartilaginous features in early disease as well as disease progression, as has been suggested previously (9, 13, 32). The highest risk of any of the features at one year prior to the case-defining visit (P-1) was the presence of medial BMLs (more than 6-fold), suggesting that the presence of BMLs may be important later in the disease trajectory when other features indicating structural damage are present.

At the time point of radiographic OA onset, knees that had developed radiographic OA were more likely to exhibit any of the MRI features but patello-femoral BMLs, which was of borderline significance. This proves that OA is not a disease with a clearly defined onset, i.e., radiographic OA being the starting point, but rather a slowly developing process that seems to be well established by the time radiography is able to define it (i.e. K-L grade 2). In addition, lesion load plays an important role, with the more features present the higher the risk of developing incident radiographic OA, which again was true particularly for the two time points prior the case-defining visit.

Our findings build on the existing literature and expand previous findings. Meniscal damage is a common finding in the elderly (11). Nonetheless, it has been reported that incidental meniscal damage is associated with a marked elevation in subsequent risk of radiographic OA (10). Our findings support an important role of meniscal damage, including tears and any type of maceration, i.e., meniscal substance loss, in disease initiation. Meniscal extrusion has also been reported as a separate risk factor for disease progression (17, 25), but our findings suggest that the role of extrusion does not seem to be as prominent in the onset of radiographic OA. We used a conservative cut-off for the definition of extrusion of 3 mm or more, which is in line with the radiologic literature (26, 27). A minor amount of extrusion might be within the physiologic range of normal and, thus, not play a relevant role for disease onset.

Our work emphasizes the role of the subchondral bone in the disease course as reflected by the highly increased risk for knees especially with medial BMLs. Again we used a relatively conservative cut-off with presence being defined as grade 2 or 3 lesions. BMLs are highly fluctuating but most of previous studies included smaller lesions in their analyses (33–35). The association of BMLs with pain has been particularly prominent for larger BMLs (35, 36). Others reported that fluctuation of these lesions is highly associated with fluctuations in pain (37). We found that although fluctuating BMLs are associated with increased risk of radiographic OA, persistent incident BMLs confer the greatest risk of radiographic OA. Microstructural changes within the subchondral bone alter local biomechanics and load distribution, eventually leading to articular surface deformity, incident cartilage damage and vice versa, emphasizing the close interrelation within the osteochondral unit (33, 38). The fact that cartilage damage played a lesser role for incident OA in our analyses supports the strategy of targeting the subchondral bone in early disease as an important treatment approach. We are acknowledging as a shortcoming that subchondral sclerosis and thickening could not be assessed using the OAI MRI dataset due to missing availability of a T1-weighted sequence. However, both features are manifestation of later disease stages and it is unlikely that sclerosis is common in knees without radiographic OA as sclerosis is one of the disease-defining features of the K-L scale.

OA is widely regarded as a biomechanically driven disease, with synovitis being a secondary phenomenon that further contributes to disease progression (39). We were not able to elucidate if synovial activation is the very first manifestation of OA preceding other structural alterations, but could confirm that inflammation plays an important role for later development of radiographic OA. The occurrence of incident Hoffa-synovitis conferred very high odds (more than nine-fold) of incident ROA. It has been shown previously that in knees without OA the risk for cartilage loss was markedly increased whenever effusion and synovitis were present (13). A concomitant appearance of structural features in early disease has been suggested previously, with an increased risk of synovial activation in knees observed for knees with meniscal damage and no signs of OA at all (i.e. K-L 0 knees) (40).

Limitations of our study include the absence of information on symptomatic OA. We do not know if subjects that developed radiographic OA also developed symptoms and if subjects developed symptoms prior the diagnosis of OA. Inclusion of these clinical parameters would have gone beyond the scope of this study but is highly important and needs to be explored further. Recent work by Sharma and colleagues suggests an important role of several of structural disease features for the development of symptoms (8). In addition, we included knees with both, Kellgren-Lawrence grades 0 and 1 in our analyses and can only speculate whether results for Kellgren-Lawrence 0 knees would differ from the results presented. We used cut-points for the different MRI features that were based on potential clinical relevance and tried to be conservative (i.e. defining mainly moderate and large lesions as “presence” of a given feature). Different cut-points might yield somewhat different results, which we acknowledge as a limitation. Performing multiple additional analyses using several cut-points would have gone beyond the focus of our study. In addition, we acknowledge that we were not able to contrast the findings of the MRI readings with a reference standard such as arthroscopy or histology. However, arthroscopy is able to visualize only the articular surface and misses evaluation of other important tissues such as the subchondral bone, and it is not feasible to invasively assess knee joints in an observational study over several time points. We applied a validated scoring system that was developed based on long-standing experience with other semiquantitative scoring instruments to assess structural joint damage in osteoarthritis (23, 41, 42). The readers were highly experienced in MRI assessment, and the reliability of the readings was excellent.

Knee OA is a major public health concern, with a recent report estimating the lifetime risk of primary total knee replacement as 7.0% for males and as 9.5% for females. Over half of the adults in the United States diagnosed with symptomatic knee OA will potentially undergo a total knee replacement during their life (43). The ultimate goal in any interventional approaches must be a reduction of these numbers in light of aging populations, and targeting early disease seems to be one of the most promising approaches. Prior to development and implementation of therapeutic strategies, the structural determinants of disease need to be fully understood in order to target the most relevant tissue in any individual being affected by the disease. We clearly acknowledge that OA is a multifactorial process and that disease onset may be triggered by pathology in multiple tissues that may be present or appearing in chronological order but also concomitantly.

Summarizing our findings, we demonstrated that knees exhibiting MRI features, especially within the two years prior disease onset, exhibiting several features concomitantly, and experiencing the new occurrence of these features at one or more time points are associated with increased risk for developing incident radiographic OA as compared to matched knees not exhibiting these features of structural damage.

Supplementary Material

Supp AppendixS1

Acknowledgments

Funding

The study and image acquisition were funded by the OAI, a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners of the OAI include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health.

The image analyses were funded by a contract with the University of Pittsburgh (Pivotal OAI MRI Analyses [POMA]: NIH/NHLBI Contract No. HHSN2682010000 21C), and in part by a vendor contract from the OAI coordinating center at University of California, San Francisco (N01-AR-2-2258). The statistical data analysis was funded by a contract with the University of Pittsburgh (Pivotal OAI MRI Analyses [POMA]: NIH/NHLBI Contract No. HHSN2682010000 21C).

Footnotes

Disclosures

None of the authors declare any potential conflicts of interest in regard to this manuscript. Potential conflicts outside of this work: Dr. Guermazi has received consultancies, speaking fees, and/or honoraria from OrthoTrophix, Genzyme, MerckSerono and TissueGene. and is President and shareholder of Boston Imaging Core Lab (BICL), LLC a company providing image assessment services. Dr. Roemer is Chief Medical Officer and shareholder of BICL, LLC. Dr. Kwoh has provided consulting services to Novartis and has received research support from Astra-Zeneca. Dr Eckstein is CEO of Chondrometrics GmbH, a company providing MR image analysis services to academic researchers and to industry. He provides consulting services to MerckSerono, Novartis, and Sanofi-Aventis, has received speaker honoraria from Merck, Glaxo-Smith-Kline, Genzyme, Medtronic, and Synthes, and has received research support from Pfizer, Eli Lilly, MerckSerono, Glaxo-Smith-Kline, Centocor R&D, Wyeth, Novartis, and Stryker. Dr. Hunter receives royalties from DJO.

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