Co-existing patterns of MRI lesions were differentially associated with knee pain at rest and on joint loading: a within-person knee-matched case-controls study

Pain at rest and pain on joint loading are two different manifestations of knee pain in osteoarthritis [1‐3]. Pain at rest has been a marker for more severe cases of knee OA and a criterion utilized for the recommendation of total knee replacement (TKR) [4, 5]. Pain on joint loading, e.g., pain with walking, is among the most commonly reported symptoms experienced by patients with knee OA [6], and consequently contributes to physical disability [7‐9]. These two types of pain are differentially associated with other clinical variables and response to treatment [3, 10, 11]. For example, neuropathic pain is more strongly associated with pain at rest than pain on joint loading among people with end-stage hip and knee OA [10]. Additionally, patients with higher knee pain at rest are more likely to have less favorable pain relief after TKR [3], whereas pain on joint loading is improved significantly compared with pain at rest among patients treated with TKR or placebo [3, 11]. Collectively, these findings suggest that pain at rest and pain on joint loading may have different underlying mechanisms and corresponding risk factors. However, to our knowledge, despite the different clinical relevance and impact on patients, differential risk factors for these two types of osteoarthritic knee pain are poorly understood.

Knee OA is a disease of the whole joint featured by structural changes in a number of tissues including cartilage, meniscus, synovium and subchondral bone. These lesions can be identified and assessed in a compartment-specific semi-quantitative way on MRI [12]. Studies on different MRI structural lesions have primarily focused on individual MRI lesions and knee OA outcomes [13]. Focusing on a single MRI feature or structural lesion may be overly simplistic as it does not give a comprehensive picture of the relation between MRI lesions and pain in this whole joint disease. For example, articular cartilage is incapable of directly generating pain because it is aneural. However, cartilage defects, in isolation from other tissues, have been reported to be associated with knee pain in OA [14, 15]. Such an association may limit insights into the pathogenesis of osteoarthritic knee pain.

Studying the relation of multiple MRI lesions to knee pain in OA is methodologically challenging. First, many factors that account for an individual’s pain response, such as central hypersensitivity, are either not collected or not controlled for in most observational studies [16]; thus the validity of study findings related to an individual’s pain could be affected by residual confounding. A within-person knee-matched case-control study design has been proposed to eliminate person-level confounders and improve the validity of study findings [17, 18]. Second, to include all MRI lesions into a multivariable regression model and obtain their “independent” effects may be problematic in the absence of knowledge regarding the temporal sequence among the occurrences of MRI lesions. Some effect estimates represent the total effect, and others direct effects, according to the chronology of the occurrence [19, 20]. An alternative strategy is to identify the patterns of co-existing MRI lesions and examine their relation to knee pain in OA [21], which is attractive because model building with many highly correlated predictors can be otherwise nearly impossible. To date, there are no published studies that have utilized these approaches to examine the associations of multiple MRI lesions with subtypes of osteoarthritic knee pain. Therefore, we conducted a within-person knee-matched case-control study to determine if distinct patterns of co-existing MRI lesions have differential associations with knee pain at rest and on joint loading using data collected from the Osteoarthritis Initiative (OAI).

Among 130 eligible participants whose MRI-lesion assessments were available, 60% were women, their mean age was 63.8 years, more than 80% of participants were White, and the mean BMI was 29.6 kg/m². Among 260 knees from 130 eligible participants, the prevalence of Kellgren/Lawrence grade 0, 1, 2, 3 and 4 was 15.8, 28.0, 19.7, 24.8 and 11.8%, respectively.

Among the OAI participants with or at high risk of knee OA, we identified five distinct patterns of co-existing MRI lesions that were differentially associated with subtypes of knee pain in OA. These findings not only allow a glimpse of distinct clinically relevant pathways leading to knee pain, but also provide insights into the pathogenesis of knee pain in OA.

When we compared subgroup III (moderate morphological lesions) with subgroup I (minimal lesions), the results suggested that morphologic lesions of cartilage and meniscus were not significantly associated with knee pain at rest or knee pain on joint loading. Aneural hyaline articular cartilage and the meniscus do not generate pain directly, or appear to have a limited role in the pathogenesis of pain. Although there is data that vascular penetration and nerve growth after a meniscal tear may be a source of pain [24], osteoarthritic knees with a meniscal tear are not more painful than those without a tear [25]. Therefore, meniscal tears are an unlikely immediate source of knee pain in OA [26], underlying the large body of evidence that arthroscopic surgery targetting meniscus was no better than conservative interventions such as exercise therapy in pain relief [27].

BMLs reflect increased focal loading in the subchondral bone [28]. Synovitis-effusion is thought to be an inflammatory reaction that could be triggered by structural damage. Consistent with the published study [21], we found that synovitis-effusion and TFJ-BML often coexisted, especially with TFJ-CartM. Meanwhile, the severity of these lesions correlated well in subgroups. In the current study, the difference between subgroup III (moderate morphological lesions) and subgroup IV (moderate multiple reactive lesions) that have the same level of TFJ-CartM mostly lies in the prevalence and severity of EFF, HFS and TFJ-BML. Knees of subgroup IV had a higher risk of greater knee pain at rest and on joint loading than knees of subgroup III, supporting other studies that have reported that synovitis-effusion and TFJ-BML may be the major sources of knee pain in OA [18, 29]. Given that pain is the key reason for seeking medical care [30], these lesions should be considered as clinically relevant markers of symtomatic knee OA. A recent study showed that improvement of synovitis on MRI following a transcatheter arterial embolization was associated with a significant reduction in WOMAC pain among patients with mild to moderate radiographic knee OA [31]. Studies have also shown that BMLs can be reduced by zoledronic acid or prostacyclin analogue iloprost [32, 33]. Our findings highlight the importance of modifying either synovitis-effusion or BMLs to reduce knee pain and consequent pain-related disability.

The role of PFJ in the surgical treatment of knee OA remains controversial [34‐37]. For example, there is evidence that preoperative PFJ OA or anterior knee pain does not compromise the outcome or survival of a medial unicompartmental knee replacement [34, 35]. Additionally, at the time of a TKR, patellar retention was not statistically significantly associated with the risk of incident postoperative anterior knee pain, compared with patellar resurfacing for patients receiving TKR [36]. Based on latent class analysis, we identified the co-existing pattern of BMLs and CartM that are located separately in PFJ and TFJ, allowing us to examine their differential contributions to osteoarthritic knee pain. We found that knees with greater TFJ-CartM could have lower prevalence and severity of PFJ-CartM and PFJ-BML (e.g., subgroup V versus subgroup IV, or subgroup III versus subgroup II). In contrast, subgroup V (severe lesions) had larger ORs of both knee pain at rest and on joint loading than subgroup IV (moderate multiple reactive lesions), suggesting that lesions in PFJ were not significantly associated with subtypes of knee pain (e.g., knee pain on stairs). Our findings, if confirmed, are informative for the management of patella during surgical treatment from the perspective of structural pathogenic source of pain.

In contrast to knee pain at rest that represents pain occurring without mechanical stimuli, knee pain on joint loading is a symptom in response to localized stress. Interestingly, joint loading can act as either a source of pain or a remedy for pain among individuals with knee OA [38]. Animal studies showed that joint loading may attenuate structural damage in OA, depending on the amount and frequency [39, 40]. Meanwhile, there is evidence from human studies indicates that exercise, such as land-based training, is effective in the management knee OA [41, 42]. In the present study, we observed larger and more skewed ORs for pain at rest than for pain on joint loading. When we compared the subgroup III (moderate morphological lesions) with the subgroup I (minimal lesions), the ORs of knee pain on joint loading were less than 1.0 (i.e., 0.7 for pain with walking and 0.8 for pain on stairs) whereas the ORs of knee pain at rest were over 2.0 (i.e., 2.2 for pain in bed at night and 3.1 for pain with sitting/lying down). Collectively, these findings may add additional evidence that mechanical loading may attenuate knee pain for patients with symptomatic knee OA. It should be noted that there are other explanations. For example, various methods of distraction potentially including physical activity can be used as a modifying tactic to reduce pain [43].

Our study has several strengths. We assessed knee pain at rest and knee pain on joint loading using four items of WOMAC pain sub-scale, allowing us to separately look at knee pain in response to different pathogenic sources. Since our study design allowed the assessment of the pain difference in two knees within the same person over a short period of time, we believe that participants should be able to tell a one-point difference. Moreover, in the absence of knowledge of the temporal sequence of MRI lesions, we fitted latent class analysis to identify subgroups representing distinct patterns of co-existing MRI lesions. Although our study is subjective to limitations of a case-control study such a selection bias, as an advance over previous studies [44, 45], we were able to examine the differential association of multiple MRI lesions localized in different compartments with knee pain occurring with or without joint loading. Finally, person-level confounders were eliminated using a within-person knee-matched case-control study design; thus, the validity of the study findings was improved.

Limitations of the present study should be noted. First, although we identified patterns of co-existing MRI lesions, we still cannot tell the temporal sequence of occurrence of these MRI lesions. For example, TFJ-BML often coexisted with synovitis-effusion in subgroups [21], making it difficult to sort out their differential contributions to knee pain. Second, uncertainty in subgroup membership assignment might lead to potentially biased effect estimate, albeit the maximum-probability approach. However, the lowest average posterior probability of membership was above 0.92 among all subgroups, suggesting that subgroup assignment was robust. Third, each WOMAC pain subscale item (0–5) that we used to identify case and control knees has not been validated separately from the pain subscale as a whole. Forth, we used the difference of ≥1 point for both pain at rest and pain on joint loading regardless of potentially different variance in the score for each item [46]. Finally, because we adopted a within-person case-control study design, we were not able to examine the association of person-level factors, such as central hypersensitivity and coping strategy, with knee pain in OA.

In conclusion, co-existing patterns of MRI lesions were identified and differentially associated with knee pain at rest and on joint loading in OA. Morphological lesions of cartilage and meniscus were not statistically significantly associated with pain. Synovitis-effusion and TJF-BML were highly correlated and appeared to be the major sources of pain. PFJ lesions had a limited role in the pathogenesis of osteoarthritic knee pain. These findings are informative for optimizing a treatment strategy targeting the pathogenic sources of osteoarthritic knee pain.