Structural phenotypes of knee osteoarthritis: potential clinical and research relevance

Abstract

A joint contains many different tissues that can exhibit pathological changes, providing many potential targets for treatment. Researchers are increasingly suggesting that osteoarthritis (OA) comprises several phenotypes or subpopulations. Consequently, a treatment for OA that targets only one pathophysiologic abnormality is unlikely to be similarly efficacious in preventing or delaying the progression of all the different phenotypes of structural OA. Five structural phenotypes have been proposed, namely the inflammatory, meniscus-cartilage, subchondral bone, and atrophic and hypertrophic phenotypes. The inflammatory phenotype is characterized by marked synovitis and/or joint effusion, while the meniscus-cartilage phenotype exhibits severe meniscal and cartilage damage. Large bone marrow lesions characterize the subchondral bone phenotype. The hypertrophic and atrophic OA phenotype are defined based on the presence large osteophytes or absence of any osteophytes, respectively, in the presence of concomitant cartilage damage. Limitations of the concept of structural phenotyping are that they are not mutually exclusive and that more than one phenotype may be present. It must be acknowledged that a wide range of views exist on how best to operationalize the concept of structural OA phenotypes and that the concept of structural phenotypic characterization is still in its infancy. Structural phenotypic stratification, however, may result in more targeted trial populations with successful outcomes and practitioners need to be aware of the heterogeneity of the disease to personalize their treatment recommendations for an individual patient. Radiologists should be able to define a joint at risk for progression based on the predominant phenotype present at different disease stages.

Keywords: Clinical trial; MRI; Osteoarthritis; Phenotypes; Structure.

Fig. 1

Phenotypic characterization. A The cartilage/meniscus phenotype is characterized by severe meniscal damage depicted in this example as partial meniscal maceration of the medial meniscal body (arrow) and is commonly associated with severe cartilage loss (arrows point to diffuse superficial cartilage damage of the medial tibia). There is severe meniscal extrusion (parallel lines and double-headed small arrow). In addition, there is diffuse superficial cartilage damage at the medial femur. Different definitions of a cartilage-meniscus phenotype have been proposed depending on the amount of cartilage damage and meniscal involvement (Roemer FW et al., Patterns of progression differ between Kellgren-Lawrence 2 and 3 knees fulfilling different definitions of a cartilage-meniscus phenotype in the Foundation for National Institutes of Health Osteoarthritis Biomarkers study (FNIH). Osteoarthritis and Cartilage Open 2022;4(3): 100284.). Depending on the definition, this knee may also fulfill the imaging requirements of an atrophic phenotype, characterized by advanced cartilage loss and little or no marginal osteophytes. B Bone phenotype. A large bone marrow lesion (BML) is present in the medial central subregion of the medial femur (grade 3, arrows). The size of the BML defines this knee as a bone phenotype. C The inflammatory phenotype is characterized by severe joint effusion-synovitis (asterisk). D So-called Hoffa-synovitis, a non-specific surrogate of whole knee synovitis, is another manifestation of inflammation and is considered for the classification of an inflammatory structural phenotype. E The atrophic phenotype is characterized by severe cartilage loss without relevant osteophyte formation. It can be diagnosed by radiography. Anterior–posterior radiograph shows severe medial joint space narrowing (arrows), defining this knee as Kellgren-Lawrence grade 3. There is, however, only a tiny, equivocal osteophyte at the lateral tibia (arrow). The discrepancy between joint space narrowing (a surrogate for cartilage and meniscal damage, and meniscal extrusion) defines this knee as having an atrophic phenotype. F The hypertrophic phenotype is characterized by large osteophytes with only minor cartilage loss and can be defined either radiographically based on joint space narrowing or by MRI based on cartilage integrity or damage. Coronal dual echo at steady state (DESS) reformatted image shows large osteophytes at the medial and lateral femoral joint margin (arrows) and moderate-sized osteophytes at the medial and lateral tibia (arrowheads). G Example of the hypertrophic phenotype as visualized by X-ray. Large marginal osteophytes are seen at the medial compartment (short arrows) but also laterally (arrowhead). The medial and lateral joint space is largely preserved (long arrows)

Fig. 2

Structural phenotypes may overlap and one joint may exhibit more than one phenotype. Sagittal intermediate-weighted fat suppressed image shows a large bone marrow lesion at the central subregion of the medial femur (arrows). In addition, there is a moderate-to-large joint effusion-synovitis (asterisk). This knee fulfills the definition for two phenotypes, i.e., the subchondral bone and the inflammatory phenotype