Role of Advanced MRI in Treat-to-Target, Precision Medicine and Patient Phenotyping Strategies
A number of abstracts accepted for presentation at the European League Against Rheumatism annual meeting explore the role of advanced imaging in treat to target, precision medicine and patient phenotyping strategies (archive).
We wanted to explore the recent paper published in JAMA, 5 February 2019, Møller-Bisgaard et al, that reported on whether the integration of magnetic resonance imaging (MRI) into clinical rheumatology practice can enhance strategies for monitoring disease activity and determining whether the therapy being tested is effective in slowing down joint damage and disease progression 1.
The key objective of this study was to determine whether an MRI-guided treat-to-target strategy versus a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. The study was part of the IMAGINE-RA randomized clinical trial, conducted in nine hospitals in Denmark and supported by Abbvie. The presence of bone marrow edema (BME) in the wrist or MCP joints was used as a marker to escalate a predefined treatment algorithm versus a conventional clinical treat-to-target strategy can improve outcomes in patients with RA in clinical remission.
BME occurs in various forms of inflammatory and non-inflammatory arthritis and probably represents infiltration of inflammatory cells and vascular perfusion changes within the bone marrow. BME is common in early RA and is associated with erosive progression and poor functional outcomes 2. It is also well established that the location and extent of BME in psoriatic arthritis (PsA) is different from those seen in RA and osteoarthritis (OA) 3,4, suggesting that treatment monitoring strategies must incorporate MRI as a key biomarker.
However, the recent study by Møller-Bisgaard and colleagues showed that MRI-guided treat-to-target strategy using BME compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates and it did not reduce radiographic progression over 2 years in this particular patient cohort. Notably, their follow-up work, which will be presented at EULAR 2019 shows that ‘MRI Tenosynovitis and Osteitis are Independent Predictors of Radiographic and MRI Damage Progression In Rheumatoid Arthritis Patients In Clinical Remission’. This study demonstrates that novel MRI-based biomarkers for inflammation and damage during tenosynovitis independently predict both X-ray and MRI damage progression in rheumatoid arthritis (RA) patients in clinical remission. Details of the methods and discussion on predictive value of the imaging biomarkers for monitoring pathology of RA will be discussed during oral presentation at EULAR.
The JAMA published study’s conclusion offers exciting opportunities for future research. As stated earlier, it is established that inflammation and BME are important predictors of the disease progression in patients with inflammatory arthritis such as RA and PsA and can be better understood with more advanced imaging sequences such as Dynamic Contrast Enhanced (DCE)-MRI 5. This MR sequence of rapidly acquired images after the Gadolinium-based contrast agent injection was collected as a part of the IMAGINE-RA imaging protocol. Due to its dynamic as opposed to static nature, DCE-MRI visualises the vascularisation levels of the oedema lesions, thus looking into the oedema’s level of perfusion and inflammation, as though it was a heterogenous tumor.
Published work by Brown et al has provided compelling evidence to suggest that the best predictor of progressive erosion in RA is Doppler Ultrasound, implicating a key role for BME and perfusion in driving diseases progression6. As previously shown by Hodgson et al7,8, DCE-MRI can be used to quantify the perfusion and treatment changes in the bone compartment. This approach can potentially help to distinguish between inflammation, repair or trauma in the bone, which all look oedema-like on static MRI sequences and reveal treatment responses as measured with the AI-driven methodologies that are based on the objective quantitative assessment of DCE-MRI time vs intensity curves (DYNAMIKA, IAG) 5. It has been shown that the perfusion measured this way is predictive of treatment response, despite unchanged or persistent BME.
These studies and emerging evidence in the literature would seem to indicate an opportunity to use DCE-MRI datasets from the same or similar trials to explore the heterogeneity of BME and synovial perfusion/inflammation in order to better phenotype RA patients and show vascular responses following various treatment regimens that can complement the widespread and validated static scoring systems such as RAMRIS.
There is also a unique opportunity to examine the overlap between RA and cardiovascular diseases that impact on vascular perfusion, especially in bone, implicating endothelial dysfunction and angiogenesis impairment in the cardiovascular system 9 and the ageing vasculature of arthritic joints 10.
Another existing abstract that will be presented at EULAR19 explores how advanced imaging can be used in assessment of disease modifying properties of already approved treatments in PsA: ‘A Phase IV, Multicenter, Single-Arm, Open-Label Study to Evaluate the Impact of Apremilast on Hand and Whole-Body MRI Outcomes in Patients With Psoriatic Arthritis (MOSAIC): Rationale, Design, and Methods’. This new trial design speaks to the added value of advanced MRI-based early efficacy biomarkers in the assessment of Apremilast-based treatment of psoriatic arthritis.
An important abstract to mention is the first results from the ambitious work by Dr. Lipsky and colleagues where Lupus Nephritis is being understood through advanced imaging biomarkers, ‘Development of a Multi-Modality Imaging Approach to Evaluate Lupus Nephritis and Initial Results.’ This study presents the design of a novel imaging approach for the evaluation of the spectrum of pathologic changes in lupus nephritis. Multi-modality imaging performed in the study includes dynamic contrast enhanced MRI (DCE-MRI) applied to detect changes in vascularization and perfusion, Diffusion Weighted Imaging (DWI) applied to assess interstitial diffusion, T2*Map/BOLD applied to assess the tissue oxygenation and T1rho to evaluate fibrosis.
We believe that the inflammation within the joints (BME) or other organs is a site for important pathological changes that drive damage in RA and other diseases 11,12.
It has been proposed that imaging remission should only be selected as a target if it can be convincingly demonstrated that it can be treated and that the clinical outcome for patients will be improved by trying to achieve imaging remission in addition to clinical remission 13.
Our hypothesis is that different grades of BME and synovitis examined with DCE-MRI will be predictive of erosive progression regardless of treatment strategy in patients with RA in clinical remission and low disease activity. We would advocate the importance of using more sensitive imaging modalities such as DCE-MRI or multi-parametric MRI to test, in a more targeted way, precision treatments in RA and PsA.
We propose that existing and future treatments guided by imaging, biomarkers and deeper phenotyping of the patients will deliver better outcomes in smarter clinical trials and in the rheumatology clinics of the future.
We are confident that this concept will appeal to a broader audience in rheumatology research and clinical practice especially regarding the importance of using more sensitive measures and biomarker tools to better phenotype arthritic diseases and stratify patients for smarter clinical trials. Advances and new directions in the field of MRI 14 will reflect potential treatment changes in future RA treatments, guided by DCE-MRI or multi-parametric imaging processed using advanced algorithms.
We would like to thank our academic collaborators, industrial partners and members of our research teams for useful discussions about the integration of MRI into rheumatology research and clinical practice.
- Møller-Bisgaard, S. et al. Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial. JAMA 321, 461–472 (2019).
- McQueen, F. M. & Ostendorf, B. What is MRI bone oedema in rheumatoid arthritis and why does it matter? Arthritis Res. Ther. 8, 222 (2006).
- Totterman, S. M. S. Magnetic resonance imaging of psoriatic arthritis: insight from traditional and three-dimensional analysis. Curr Rheumatol Rep 6, 317–321 (2004).
- Link, T. M. & Li, X. Bone marrow changes in osteoarthritis. Semin Musculoskelet Radiol 15, 238–246 (2011).
- Boesen, M. et al. MR Imaging of Joint Infection and Inflammation with Emphasis on Dynamic Contrast-Enhanced MR Imaging. PET Clin 13, 523–550 (2018).
- Brown, A. K. et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum. 58, 2958–2967 (2008).
- Hodgson, R. et al. Dynamic contrast enhanced MRI of bone marrow oedema in rheumatoid arthritis. Ann. Rheum. Dis. 67, 270–272 (2008).
- Hodgson, R. J., O’Connor, P. & Moots, R. MRI of rheumatoid arthritis image quantitation for the assessment of disease activity, progression and response to therapy. Rheumatology 47, 13–21 (2008).
- Ungvari, Z. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat. Rev. Cardiol. 15, 555–565 (2018).
- Findlay, D. M. & Kuliwaba, J. S. Bone-cartilage crosstalk: a conversation for understanding osteoarthritis. Bone Res 4, 16028 (2016).
- Roemer, F. W. et al. MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthr. Cartil. 17, 1115–1131 (2009).
- Alliston, T., Hernandez, C. J., Findlay, D. M., Felson, D. T. & Kennedy, O. D. Bone marrow lesions in osteoarthritis: what lies beneath. J. Orthop. Res. 36, 1818–1825 (2017).
- van der Heijde, D. Remission by imaging in rheumatoid arthritis: should this be the ultimate goal? Ann. Rheum. Dis. 71 Suppl 2, i89-92 (2012).
- Borrero, C. G., Mountz, J. M. & Mountz, J. D. Emerging MRI methods in rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 85–95 (2011).