1 INTRODUCTION

Anterior cruciate ligament (ACL) injury is a well-recognized risk factor for knee osteoarthritis (OA). Radiographic knee OA is evident in 50%–70% of individuals 10–15 years after an ACL injury, irrespective of surgical anterior cruciate ligament reconstruction (ACLR),1, 2 and associated with significant deterioration in knee symptoms over time.3 Evidence of OA and rapid cartilage loss was observed as early as 1–2 years following ACLR using magnetic resonance imaging (MRI).4, 5 Given the poor structural4, 6 and symptomatic prognosis7 of early post-traumatic OA features (e.g., cartilage and bone marrow lesions [BMLs]), identifying factors that contribute to these prevalent and worsening features and persistent pain is a priority to inform possible prevention strategies for OA before the development of the radiographic disease and reduction of quality of life.

The infrapatellar fat pad (IPFP) has the potential to contribute to the incidence and progression of early OA features and pain following ACLR. The IPFP (also known as Hoffa's fat pad) is intra-articular, yet extra-synovial, adipose tissue that is highly vascularized and innervated, and situated directly behind the patellar tendon and inferior pole of the patella.8-11 The IPFP is increasingly implicated as a source of OA-related nociception12 and might contribute to articular cartilage degeneration, through the release of inflammatory cytokines.13-17 Although conflicting evidence exists,18 a larger IPFP volume has been associated with radiographic OA19 and pain,19, 20 with a larger IPFP volume corresponding to worse cartilage quality.21

The IPFP may be particularly important in post-traumatic OA following ACL injury. Preliminary data from 26 patients with acute ACL rupture suggests that ACL rupture can damage the IPFP (increased hyperintense signal),22 and it is common for arthroscopic ACLR techniques to shave the IPFP to optimize intra-articular views. Indeed, the IPFP was significantly thinner in knees 3 months post-ACLR compared to uninjured contralateral knees.23 Synovitis and synovial proliferation of the IPFP (Hoffa-synovitis) assessed on non-contrast-enhanced MRI are also common following ACLR and may be associated with cartilage degradative biomarkers.22 Given the location of the IPFP, the patellofemoral joint may be particularly influenced by the IPFP, possibly contributing to the high rates of patellofemoral OA following ACLR.6, 24, 25 For example, larger IPFP volume was associated with the presence of symptomatic patellofemoral OA in older adults19 and more extensive IPFP fibrosis (scarring) 2 years after ACLR was associated with more patellofemoral cartilage lesions on second-look arthroscopy.26 Further understanding of the relationship of IPFP morphology and Hoffa-synovitis with prevalent and progressive early OA features and pain may assist with secondary OA risk profiling. Therefore, we aimed to (i) compare IPFP volume and Hoffa-synovitis between individuals 1-year post-ACLR and uninjured controls; (ii) determine the cross-sectional association of IPFP volume and Hoffa-synovitis to prevalent early OA features on MRI (i.e., cartilage and BMLs) and knee pain 1-year post-ACLR; and (iii) determine whether IPFP volume and Hoffa-synovitis measured at 1-year post-ACLR are associated with longitudinal changes in early OA features on MRI and knee pain at 5 years post-ACLR.

2 METHODS 2.1 Study design and participants

This Level II prospective study (Prognostic Risk Study Level of Evidence) evaluated MRIs of patients 1 and 5 years post-ACLR. We utilized data from an established cohort following ACLR.4, 27, 28 Consecutive patients aged 18–50 years from one of two orthopedic surgeons were eligible for inclusion at approximately 1 year (mean ± standard deviation 13 ± 1 months, range 11–15 months) following primary single-bundle hamstring-tendon autograft ACLR.4 Exclusion criteria included previous injury/surgery to the index knee before ACL rupture, and subsequent injury to (or follow-up surgery on) the index knee. Any patient with a condition other than ACLR that currently affected their function in daily living or reported a contraindication to MRI was also excluded. Control participants aged 18–50 years with no lower-limb injury/surgery history were recruited via word-of-mouth to match the age, sex, and activity level of those following ACLR.4 Activity level was defined as Level I (sports with frequent jumping, cutting, pivoting) to Level IV (sedentary).29 Ethical approval was obtained from The University of Melbourne (HREC 1136167), The University of Queensland (HREC 2012000567 and 20133001448), and La Trobe University (HEC 15-100) Human Research Ethics Committees. All participants provided written informed consent. Age, sex, height, and body mass were recorded at baseline, and body mass index calculated.

2.2 MRI acquisition

Unilateral knee MRI scans were acquired 1 and 5 years post-ACLR and at a single timepoint in uninjured controls using a single 3.0T system (Philips Achieva) as previously described.4, 6 Imaging sequences consisted of (i) 3D proton density-weighted isotropic VISTA sequence acquired at 0.35 mm isotropically (repetition time [TR]/echo time [TE] 1300 ms/27 ms, 150-mm2 field of view [FOV; acquisition time 6.18 min]). (ii) Sagittal Short Tau Inversion Recovery (STIR) sequence acquired at 2.5 mm thickness with 1.2 mm slice gap (inversion time of 180 ms was applied with TR/TE 3850 ms/30 ms, FOV 160 mm2 [acquisition time 3.18 min]). (iii) Axial proton density-weighted turbo spin–echo sequence acquired at 2.5 mm thickness with 2.0 mm slice gap (TR/TE 3850 ms/34 ms, FOV 140 mm2 (acquisition time 2.06 min).4

2.3 IPFP volume and Hoffa-synovitis

We assessed IPFP volume and Hoffa-synovitis from MRIs at 1-year post-ACLR and in uninjured controls. Two investigators (Ashish Vora and Ankit Doshi) independently measured IPFP volumes using the 3D proton density-weighted isotropic VISTA sagittal MRI sequence. The IPFP was segmented by manually digitizing IPFP boundaries (Figure 1) on each sagittal slice from the first to the last slice where IPFP was visible using commercially available software (3D Slicer Version 4.8.1, Surgical Planning Laboratory at Brigham and Women's Hospital and the MIT Artificial Intelligence Laboratory, Massachusetts). For each participant, all segmented slices were reconstructed and summed to obtain IPFP volumes. The number of sagittal slices that captured the IPFP (and therefore segmented) ranged from 28 to 40 for each participant depending on body size. The interrater reliability of IPFP volumes was confirmed using the same images used in the analysis (intraclass correlation [95% confidence interval]: 0.98 [0.97 to 0.99]). The mean IPFP volume values of the two investigators were used in the analysis. A musculoskeletal radiologist (Ali Guermazi), with 20 years of experience in the semi-quantitative evaluation of MRIs, assessed Hoffa-synovitis using the semi-quantitative MRI Osteoarthritis Knee Score (MOAKS).30 Hoffa-synovitis was graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) using the sagittal STIR sequence. Increased Hoffa-synovitis scores within the IPFP represent increased signal alterations. In the present study, presence of Hoffa-synovitis was defined as grade ≥ 1.

An example of unsegmented (left) and segmented (right) infrapatellar fat pad on sagittal 3D proton density-weighted isotropic VISTA magnetic resonance imaging (MRI) sequence [Color figure can be viewed at wileyonlinelibrary.com] 2.4 OA features on MRI

OA features on MRI at 1 and 5 years post-ACLR were evaluated using the MOAKS by one musculoskeletal radiologist who has established interrater and intra-rater reliability (κ, 0.61–0.80).30 The radiologist graded the participant's paired images presented in chronological order and was unaware of the IPFP volume and Hoffa synovitis results. The radiologist was blinded to the arthroscopic findings, any meniscal or chondral surgical intervention at the time of ACLR and clinical/radiographic information. The MOAKS divides the knee into 14 subregions, covering both the patellofemoral and tibiofemoral compartments, to score specific osteochondral features related to OA.30 For patellofemoral OA features, the medial and lateral femoral trochlea and patella were assessed. For tibiofemoral OA features, the central and posterior femoral subregions, and anterior, central, and posterior tibial subregions were assessed. Cartilage lesions were graded based on: (i) size relative to each subregion (where 0 = none, 1 ≤ 33%, 2 = 33%–66%, and 3 ≥ 66%); and (ii) depth, defined as the percentage of full-thickness cartilage loss (where 0 = no full thickness loss, 1 ≤ 10%, 2 = 10%–75%, and 3 ≥ 75%). BMLs were graded based on size relative to each subregion (0 = none, 1 ≤ 33%, 2 = 33%–66%, 3 ≥ 66%). Worsening of each patellofemoral and tibiofemoral OA feature was defined as any increase in the respective MOAKS score using reliable and sensitive criteria.31 Briefly, either progression or a new patellofemoral OA feature from 1 to 5 years was classified as worsening patellofemoral OA, and progression or a new tibiofemoral OA feature from 1 to 5 years was classified as worsening tibiofemoral OA. The rates of worsening OA features in this cohort were recently reported.6

2.5 Knee pain

Participants completed the Knee injury and Osteoarthritis Outcome Score (KOOS) and Anterior Knee Pain Scale (AKPS) at 1 and 5 years post-ACLR. The KOOS consists of five subscales: pain, symptoms, activities of daily living, function in sport and recreation, and quality of life.32 Knee pain was assessed using the KOOS-Pain subscale. Each of the nine KOOS-Pain items are scored from 0 (none) to 4 (extreme problems). A normalized score ranging from 0 to 100 is calculated, with lower scores indicating more pain. The KOOS has been validated for use in patients with ACL injuries and in those with posttraumatic OA.33 The 13-item AKPS is a valid and reliable measure of patellofemoral pain in adolescents and young adults.34 It is scored from 0 to 100, with lower scores indicating greater pain and disability.

2.6 Statistical analysis

Demographic and IPFP characteristics (i.e., volume and Hoffa-synovitis) of the ACLR and control participants were compared using independent t tests (after confirming normality with the Shapiro–Wilks test), or χ 2 tests, as appropriate. Univariate analysis was conducted to compare IPFP volumes between the two groups, while controlling for BMI. As one surgeon reported regularly shaving 10%–30% of the IPFP centrally, the other attempted not to shave the IPFP where possible; in sensitivity analyses, we adjusted for the surgeon to account for different approaches to the IPFP. We also conducted sensitivity analyses comparing IPFP volumes and Hoffa-synovitis between participants from either surgeon.

In the ACLR group, logistic regression analyses were used to assess the relation of IPFP volume and Hoffa-synovitis at 1-year post-ACLR to prevalent (1-year post-ACLR) and worsening (1–5 years post-ACLR) cartilage and BMLs in the patellofemoral and tibiofemoral compartments separately. Analyses were adjusted for age, sex, and BMI. Odds ratios and 95% confidence intervals (CIs) are presented. Linear regression analyses assessed whether IPFP volume and Hoffa-synovitis at 1 year were associated with knee pain scores at 1-year post-ACLR and 5 years post-ACLR. Analyses were adjusted for age, sex, BMI, and additionally for 1-year knee pain scores (for 5-year analyses only). Standardized and unstandardized coefficients are presented. We also conducted sensitivity analyses adjusting for the surgeon. Data were analyzed using the Statistical Package for the Social Sciences (SPSS Statistics Version 26; IBM Corporation).

3 RESULTS 3.1 Participants characteristics

We included all 111 participants following ACLR from the previously established cohort with MRI data available at 1-year post-ACLR and 20 uninjured controls.4 Participants were matched on sex (ACLR vs. controls: 36% female vs. 35% female), age (mean ± standard deviation: 30 ± 8 years vs. 30 ± 7 years), activity level (ACLR: Level I: 32%, Level II: 9%, Level III: 39%, Level IV: 21%; Control I: 45.0%, Control II: 15.0%, Control III: 40.0%, Control IV: 0%), but not BMI (26.1 ± 4.0 kg/m2 vs. 22.8 ± 1.8 kg/m2).4 At 5 years post-ACLR, 78 (70%) had MRI data available and 80 (72%) completed the follow-up knee pain questionnaires (Figure 2). As previously described, at 1-year post-ACLR, cartilage lesions were evident in 68% of participants (45% patellofemoral, 48% tibiofemoral) and BMLs in 46% (24% patellofemoral, 31% tibiofemoral).4 In the 78 participants with 5-year MRI data, worsening cartilage lesions were evident in 51% (44% patellofemoral, 21% tibiofemoral) and worsening BMLs in 30% (18% patellofemoral, 15% tibiofemoral).6

Data overview for uninjured control participants and participants 1 and 5 years following ACLR. *Missing IPFP volume (n = 5), Hoffa-synovitis (n = 1), and bone marrow lesion (n = 1) data due to poor image quality. ACLR, anterior cruciate ligament reconstruction; AKPS, Anterior Knee Pain Scale; IPFP, infrapatellar fat pad; KOOS, Knee injury and Osteoarthritis Outcome Score; OA, osteoarthritis

3.2 IPFP volume and Hoffa-synovitis: ACLR versus uninjured controls

The average IPFP volume did not differ between participants 1-year post-ACLR (mean ± SD: 34.72 ± 7.65 cm3) and controls (32.51 ± 6.82cm3) (mean difference [95% confidence interval]: 2.21 cm3 [−1.42 to 5.84]). When data were adjusted for BMI (ACLR: 34.39 ± 7.29 cm3, Control: 34.27 ± 7.56 cm3), similar results were observed (mean difference 0.12 cm3 [−3.56 to 3.80]). Sensitivity analyses adjusting for surgeon revealed similar results (p = .115). Hoffa-synovitis was evident in 61% of participants 1 year after ACLR (Grade 0 = 39%, Grade 1 = 52%, Grade 2 = 9%) and 80% of controls (Grade 0 = 20%, Grade 1 = 75%, Grade 2 = 5%; p = .159).

We also conducted sensitivity analyses to determine whether there were differences in IPFP volume and Hoffa-synovitis based on IPFP approach used by the surgeons. When data were adjusted for age, sex, and BMI, the average IPFP volume was smaller in participants whose IPFP was shaved during ACLR surgery compared with those IPFP was not shaved (mean difference [95% confidence interval]: 2.47cm3 [0.14 to 4.80]). There were no differences in Hoffa-synovitis (61% vs. 62%).

3.3 IPFP volume and Hoffa-synovitis: Association with MRI OA features

In those following ACLR, IPFP volume was not cross-sectionally associated with any OA feature at 1-year post-ACLR, except for patellofemoral BMLs (Table 1). Individuals with a larger IPFP volume had higher odds of BMLs in the patellofemoral compartment at 1-year post-ACLR (OR [95% CI]: 1.104 [1.016 to 1.200]) (Table 1) and worsening cartilage lesions in the tibiofemoral compartment at 5 years (OR: 1.234 [1.026 to 1.483]) (Table 2). Hoffa-synovitis at 1-year post-ACLR was not associated with prevalent OA features (Table 1), however, it was associated with worsening of patellofemoral BMLs (Table 2). Individuals with IPFP synovitis at 1-year post-ACLR had increased odds of BML worsening in the patellofemoral compartment at 5 years (OR: 7.465 [1.291 to 43.169]). Sensitivity analyses adjusting for surgeons revealed similar results.

Table 1. Relationship of IPFP volume and presence of Hoffa-synovitis to prevalence of knee osteoarthritis features on MRI 1 year after anterior cruciate ligament reconstruction Outcome frequency Unadjusted OR [95% CI] Adjusted OR [95% CI]a IPFP volume Tibiofemoral cartilage lesions 55/106 (52%) 0.998 [0.950 to 1.050] 0.966 [0.904 to 1.033] Patellofemoral cartilage lesions 51/106 (48%) 1.020 [0.970 to 1.073] 1.082 [0.999 to 1.171] Tibiofemoral bone marrow lesions 33/105 (31%) 1.012 [0.959 to 1.068] 0.993 [0.925 to 1.066] Patellofemoral bone marrow lesions 25/105 (24%) 1.051 [0.992 to 1.115] 1.104 [1.016 to 1.200] Hoffa-synovitis Tibiofemoral cartilage lesions 53/110 (48%) 0.958 [0.445 to 2.061] 0.959 [0.435 to 2.116] Patellofemoral cartilage lesions 50/110 (45%) 0.779 [0.371 to 1.725] 0.745 [0.315 to 1.760] Tibiofemoral bone marrow lesions 34/110 (31%) 0.739 [0.325 to 1.681] 0.728 [0.318 to 1.668] Patellofemoral bone marrow lesions 26/110 (24%) 1.607 [0.628 to 4.110] 1.670 [0.633 to 4.402] Note: Bolded values denote statistical signficance at the p < .05 level. Abbreviations: CI, confidence interval; IPFP, infrapatellar fat pad; MRI, magnetic resonance imaging; OR, odds ratio. Table 2. Relationship of IPFP volume and presence of Hoffa-synovitis at 1 year to worsening of osteoarthritis features on MRI 1–5 years after anterior cruciate ligament reconstruction Outcome frequency Unadjusted OR [95% CI] Adjusted OR [95% CI]a IPFP volume Worsening tibiofemoral cartilage lesions 14/74 (19%) 0.977 [0.903 to 1.057] 1.234 [1.026 to 1.483] Worsening patellofemoral cartilage lesions 33/74 (45%) 0.974 [0.916 to 1.035] 1.023 [0.939 to 1.114] Worsening tibiofemoral bone marrow lesions 12/74 (16%) 1.020 [0.943 to 1.103] 1.019 [0.915 to 1.134] Worsening patellofemoral bone marrow lesions 12/74 (16%) 0.961 [0.881 to 1.048] 1.027 [0.908 to 1.161] Hoffa-synovitis Worsening tibiofemoral cartilage lesions 16/78 (21%) 0.428 [0.140 to 1.306] 0.431 [0.132 to 1.413] Worsening patellofemoral cartilage lesions 34/78 (44%) 1.742 [0.686 to 4.424] 1.985 [0.727 to 5.418] Worsening tibiofemoral bone marrow lesions 12/78 (15%) 3.919 [0.796 to 19.296] 4.546 [0.861 to 23.989] Worsening patellofemoral bone marrow lesions 14/78 (18%) 4.971 [1.028 to 24.034] 7.465 [1.291 to 43.169] Note: Bolded values denote statistical signficance at the p < .05 level. Abbreviations: CI, confidence interval; IPFP, infrapatellar fat pad; MRI, magnetic resonance imaging; OR, odds ratio. 3.4 IPFP volume and Hoffa-synovitis: Association with knee pain

The average KOOS-Pain and AKPS scores were 91 ± 9 and 91 ± 8 at 1-year post-ACLR, respectively. At 5 years post-ACLR, the average KOOS-Pain was 94 ± 9 and the AKPS score was 93 ± 9.7 There was no evidence that IPFP volume or Hoffa-synovitis at 1-year post-ACLR were associated with knee pain at 1 or 5 years post-ACLR (Table 3). Sensitivity analyses adjusting for surgeons revealed similar results.

Table 3. Relationship of IPFP volume and Hoffa-synovitis size at 1 year to knee pain at 1 and 5 years after anterior cruciate ligament reconstruction Unadjusted Adjusteda β Unstandardized B [95% CI] β Unstandardized B [95% CI] IPFP volume KOOS-Pain at 1 year (n = 106) −0.044 −0.037 [−0.276 to 0.188] −0.058 −0.069 [−0.373 to 0.236] AKPS at 1 year (n = 106) 0.024 0.024 [−0.174 to 0.221] 0.034 0.034 [−0.201 to 0.269] KOOS-Pain at 5 years (n = 76)b 0.506 0.460 [0.278 to 0.641] 0.057 0.063 [−0.222 to 0.348] AKPS at 5 years (n = 76)b −0.005 −0.005 [−0.203 to 0.192] 0.167 0.168 [−0.088 to 0.425] Hoffa-synovitis KOOS-Pain at 1 year (n = 110) 0.052 0.750 [−1.985 to 3.486] 0.049 0.699 [−2.047 to 3.444] AKPS at 1 year (n = 110) 0.085 1.081 [−1.329 to 3.491] 0.079 1.005 [−1.222 to 3.232] KOOS-Pain at 5 years (n = 80)b 0.088 1.226 [−1.568 to 4.020] 0.101 1.421 [−1.258 to 4.100] AKPS at 5 years (n = 80)b −0.030 −0.428 [−3.214 to 2.359] −0.022 −0.307 [−2.975 to 2.361] Abbreviations: β, standardized coefficient; CI, confidence interval; AKPS, Anterior Knee Pain Scale (scores 0–100, 100 = no patellofemoral pain); KOOS, Knee injury and Osteoarthritis Outcome Score (scores 0–100, 100 = no knee pain); IPFP, infrapatellar fat pad. 4 DISCUSSION

Our findings provide no indication that individuals 1-year following ACLR have abnormal IPFP volume or prevalence of Hoffa-synovitis compared with uninjured controls. Yet, in those following ACLR, greater IPFP volume and synovitis appear to be associated with the presence and worsening of some early OA features in both the tibiofemoral and patellofemoral compartments, but not with knee pain. These findings suggest that that IPFP may be implicated in the early development and progression of post-traumatic OA.

Our finding that ACLR surgery does not compromise IPFP morphology is perhaps somewhat surprising given that the IPFP may be disrupted (e.g., shaved) to improve intra-articular view during ACLR. Of the two surgeons who performed all ACLR procedures, there was a mix of approaches to the IPFP intra-operatively, which increases the generalizability of our findings. While one surgeon reported regularly shaving the IPFP, the other attempted to preserve the IPFP. As anticipated, participants who had their IPFP shaved during surgery had smaller IPFP volume 1-year post-ACLR. Despite this, the IPFP volume observed following ACLR was of similar size to the uninjured controls when adjusting for the surgeon in the analyses. The IPFP volumes for both ACLR participants and uninjured controls were slightly higher (mean IPFP volume: ACLR 34.39 cm3, Control 34.27 ± 7.56 cm3) than previously reported in knee OA populations (ranging from 25.4 to 29.0 cm3).19, 35, 36 The larger volumes observed in our ACLR and control populations may reflect our cohort of mostly men (compared with the OA studies of mostly women), as men have significantly greater IPFP volume (normalized to body weight) than women.37 Our results also suggest that the prevalence of Hoffa-synovitis does not differ between ACLR populations and uninjured controls. A high percent of uninjured controls had IPFP synovitis (80%)—this is at the high end of IPFP synovitis prevalence observed in our systematic review of MRI features in asymptomatic uninjured adults (16%–80%).38 The prevalence of IPFP synovitis in patients following ACLR in the present study (61%) was similar to that reported in patients with radiographic knee OA (52%)39 and those with patellofemoral pain (61%).40

Our results indicate that IPFP volume and Hoffa-synovitis at 1-year post-ACLR appears to be associated with some important early post-traumatic OA features in both the patellofemoral and tibiofemoral compartments. For the patellofemoral compartment, greater IPFP volume and Hoffa-synovitis appear to increase the odds of BMLs at 1-year post-ACLR, and BML worsening (sevenfold) at 5 years, respectively. The odds of worsening patellofemoral cartilage in the presence of Hoffa-synovitis was also elevated and may be clinically meaningful (OR: 1.985 [0.727 to 5.418]), but wide confidence intervals in these estimates indicate statistical imprecision. For the tibiofemoral compartment, no cross-sectional associations were observed at 1-year post-ACLR, yet greater IPFP volume and Hoffa-synovitis appear to elevate the odds of worsening cartilage lesions at 5 years, but the point estimates were somewhat imprecise. The exact mechanism by which IPFP volume and Hoffa-synovitis increase the odds of prevalent and worsening early OA features is unclear but may relate to cytokines, adipokines, interleukins, and growth factors secreted by IPFP that can accelerate cartilage breakdown by increasing matrix metalloproteinases production.14 Our findings may also reflect that the IPFP changes we observed represent an early OA state of the whole knee rather than being on the causal pathway for cartilage and BML worsening as such. Given the important long-term implications of worsening cartilage and BMLs on radiographic OA outcomes,41, 42 the IPFP may represent an important marker of early disease status that warrants further investigation.

The IPFP is extensively innervated and can be a potent source of nociception.12 Given the intimate relationship of the IPFP structure with the patellofemoral compartment, we anticipated that IPFP volume and Hoffa-synovitis may be associated with the severity of knee (patellofemoral) pain. However, we found no evidence of associations between IPFP volume or Hoffa-synovitis and knee pain in patients at 1 or 5 years post-ACLR. Previous studies in individuals with knee OA have reported that IPFP volume and Hoffa-synovitis are associated with knee pain.19, 20, 43 Although some individuals reported moderate-to-severe knee pain in the present study, on average individuals reported mild pain at 1 year (mean KOOS-Pain = 91, range 44–100; mean AKPS = 91, range 63–100) and 5 years (mean KOOS-Pain = 94, range 47–100; mean AKPS = 93, range 55–100) after ACLR compared with participants from knee OA studies—for example, Ballegaard et al.20 reported mean KOOS-Pain score of 63 in participants with knee OA—which may somewhat explain the lack of associations between IPFP volume/Hoffa-synovitis and knee pain in our study.

A strength of our study is that we reliably assessed IPFP volume, which better represents IPFP size than the maximal IPFP cross-sectional area that others have assessed from MRI.44 There are a number of limitations of the study that should be acknowledged. Firstly, the 1 and 5 years MRIs were evaluated in pairs and unblinded to time point, which may have resulted in an overestimation of worsening scores; however, this approach overcomes the limitations of the innately crude grading system of the MOAKS.31 Secondly, we assessed Hoffa-synovitis in the present study, which is a surrogate measure of synovitis. Thus, findings may differ from direct assessment of the synovium using contrast-enhanced MRI. Thirdly, although our convenience sample of uninjured controls was recruited to match on age, sex, and activity level of those following ACLR, they were not matched on BMI. However, to account for this we adjusted the analyses for BMI.

In conclusion, IPFP volume and Hoffa-synovitis in younger adults following ACLR did not differ from uninjured controls. In individuals 1-year post-ACLR, greater IPFP volume and Hoffa-synovitis appear to be associated with the presence and worsening of some early OA features in the patellofemoral and tibiofemoral compartment, however not with knee pain. These findings suggest that that IPFP volume and Hoffa-synovitis may be relevant in the early development and progression of post-traumatic OA, however further research with a larger sample size and longer-term follow-up is required.

ACKNOWLEDGMENTS

Harvi F. Hart is a recipient of a Canadian Institutes of Health Research (430152) Fellowship. Adam G. Culvenor is a recipient of a National Health and Medical Research Council (NHMRC) of Australia Early Career Fellowship (Neil Hamilton Fairley Clinical Fellowship, APP1121173) and Brooke E. Patterson is a recipient of NHMRC post-graduate scholarship (APP1114296). The funders had no role in any part of the study or in any decision about publication.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to research design, or the acquisition, analysis, or interpretation of data; drafting the paper or revising it critically; and approved the final version to be submitted for publication.