Strategic application of imaging in DMOAD clinical trials: focus on eligibility, drug delivery, and semiquantitative assessment of structural progression

Abstract

Despite decades of research efforts and multiple clinical trials aimed at discovering efficacious disease-modifying osteoarthritis (OA) drugs (DMOAD), we still do not have a drug that shows convincing scientific evidence to be approved as an effective DMOAD. It has been suggested these DMOAD clinical trials were in part unsuccessful since eligibility criteria and imaging-based outcome evaluation were solely based on conventional radiography. The OA research community has been aware of the limitations of conventional radiography being used as a primary imaging modality for eligibility and efficacy assessment in DMOAD trials. An imaging modality for DMOAD trials should be able to depict soft tissue and osseous pathologies that are relevant to OA disease progression and clinical manifestations of OA. Magnetic resonance imaging (MRI) fulfills these criteria and advances in technology and increasing knowledge regarding imaging outcomes likely should play a more prominent role in DMOAD clinical trials. In this perspective article, we will describe MRI-based tools and analytic methods that can be applied to DMOAD clinical trials with a particular emphasis on knee OA. MRI should be the modality of choice for eligibility screening and outcome assessment. Optimal MRI pulse sequences must be chosen to visualize specific features of OA.

Keywords: MRI; clinical trial; disease-modifying osteoarthritis drugs; imaging; knee osteoarthritis.

Figure 1.

Reproducibility limitations of radiography and superiority of magnetic resonance imaging (MRI) in depicting osteoarthritis as a whole-joint disease. (a) Baseline anterior–posterior (a.p.) radiograph shows a normal medial tibiofemoral joint space width (arrows). (b) At 2 years follow-up, there is apparent definitive joint space narrowing (arrowheads). Soft tissues are not assessable on the radiograph. (c) Baseline MRI of the same knee shows discrete superficial cartilage thinning of the medial tibia (arrowhead) while the cartilage of the medial femur is apparently normal. There is minimal medial meniscal extrusion of 2 mm still considered physiologic. (d) Two years later, no definite cartilage loss is observed (arrowheads) and meniscal extrusion has not progressed (arrow). Apparent progression on the a.p. radiograph is due to positioning errors with minimal change in beam angulation leading to false-positive joint space narrowing.

Figure 2.

Diagnoses of exclusion using MRI as an instrument to define patient eligibility. (a) Axial T2-weighted MRI shows a complete posterior root tear of the medial meniscus (arrows). (b) Corresponding coronal intermediate-weighted fat-suppressed image shows corresponding medial meniscal extrusion due to mechanical instability of the medial meniscus (arrow). Root tears are considered high-risk findings for rapid progression of cartilage loss and subsequent articular collapse. For this reason, patients exhibiting root tears should not be included in clinical DMOAD trials as joints exhibiting root tears are likely not amenable to any pharmacologic DMOAD effects. (c) Coronal intermediate-weighted fat-suppressed image shows articular collapse due to subchondral insufficiency fracture of the medial femoral condyle. There is an osteochondral depression at the fracture site (arrow) and corresponding large bone marrow edema (asterisk). In addition, there is a large nonspecific subchondral cyst (arrowhead). Bone cysts that potentially increase the risk for fracture are considered exclusionary at screening.

Figure 3.

Subchondral bone phenotype of knee osteoarthritis. Phenotypic stratification may help in selecting patients most likely to benefit from a specific candidate DMOAD molecule. Compounds targeting the subchondral bone may have an impact on bone marrow lesions. For this reason, knees with large bone marrow lesions or those with multiple lesions are included in such trials. (a) Sagittal intermediate-weighted fat-suppressed image shows a large bone marrow lesion in the medial femoral condyle fulfilling the definition of the subchondral bone phenotype (arrows). In addition, there is a minor subchondral cyst and widespread full-thickness cartilage damage. Note that knees with extensive widespread full-thickness cartilage loss are likely not responsive to any anti-catabolic mode of action as there is not sufficient cartilage to preserve and measure structural DMOAD effects. Phenotypes may overlap and one knee may exhibit more than one specific phenotype. This knee also exhibits large effusion-synovitis and thus fulfills the inflammatory phenotype, in addition. (b) Sagittal intermediate-weighted fat-suppressed MRI of another patient shows several tibial and femoral bone marrow lesions (arrows). In comparison with the bone marrow lesion in (a), these are smaller in size or volume but numerous and thus defining this knee as exhibiting the subchondral bone phenotype. Note that bone marrow lesions are nonspecific findings and multiple differential diagnoses apply. In this case, there is an identical-appearing signal change at the femoral metaphysis consistent with red marrow conversion in the typical location. In contrast, subchondral OA-related bone marrow lesions are localized directly adjacent to the subchondral plate.

Figure 4.

Relevance of sequence selection of feature-specific assessment. (a) Coronal intermediate-weighted fat-suppressed sequence shows the medial tibiofemoral compartment. There are large bone marrow lesions at the medial femur (arrows) and tibia (asterisk) reflected as areas of high signal intensity contrasting the normal fatty marrow that is depicted with low signal. In addition, there are other signs of advanced structural knee OA including widespread cartilage damage, marginal osteophytes, and meniscal extrusion. (b) Coronal fast low-angle shot (FLASH) with water excitation (WE) MRI, a 3D high-resolution sequence, is commonly used for cartilage quantification. This type of sequence, a gradient echo sequence, is prone to magnetic susceptibility and thus relatively insensitive to BMLs and will lead to underestimation of the lesion size as shown by the arrows. The tibial lesion is hardly depicted at all.

Figure 5.

Artificial intelligence applied to accelerate image acquisition. Trained convolutional neural networks (CNNs) are used for post hoc image reconstruction. The original MRI data set is undersampled and the missing structural information is re-created by the CNN resulting in almost equivalent image quality. (a) Example shows coronal intermediate weighed fat-suppressed images acquired with a 7T ultrahigh-field system. A super high-resolution matrix of 720 × 720 pixels is used with an in-plane resolution of 0.15 mm × 0.15 mm, 3 mm thickness, acquired in 9 min 30 s. (b) Fourfold undersampling with post-acquisition AI reconstruction results in a decrease in imaging acquisition time down to 2 min 22 s. The image overall exhibits a smoother image impression but the overall quality seems comparable. As CNNs always need extensive training data, the future will need to show if rare findings are depicted with confidence and determination of the ideal acceleration factor without losing relevant structural information needs to be shown in the future.

Figure 6.

Example of documentation of extra-articular injection. The documentation of an intra-articular route of administration is paramount and most easily achieved using air administered at the time of injection. (a) Lateral radiograph shows air within Hoffa’s fat pad but not intra-articularly (arrows). (b) Another lateral X-ray shows air in the prefemoral fat pad (arrow) but not within the joint cavity. (c) Another example shows an air collection in the subcutaneous tissue but not in the joint (arrows).

Figure 7.

Within-grade assessment. Semiquantitative MRI assessment is based on expert evaluation of MRIs applying validated scoring systems. While definitive visual change may be apparent, often lesions (particularly bone marrow lesions and cartilage alterations) do not fulfill the definition of a so-called full-grade change. For this reason, and particularly to increase sensitivity to change, so-called within-grade changes have been introduced that are able to document definite change despite not fulfilling a full-grade change. Within-grade changes have been shown to be clinically valid and to correspond to quantitative cartilage loss. (a) Coronal short tau inversion recovery (STIR) image shows a small bone marrow lesion at the central medial femur (arrow). (b) Follow-up MRI 1 year later shows a definite increase in size that does not fulfill the criteria for a full-grade change (arrowhead). This is a typical example of a within-grade increase of a subchondral bone marrow lesion.