MRI/PET

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.

Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.1368

Abstract

BACKGROUND:
Phase III clinical trials have shown apremilast (APR) reduced PsA signs/symptoms and improved physical function,but no study has addressed its impact on structural disease progression. MRI is a highly sensitive, validated tool to assess inflammatory and structural changes, as it can detect soft tissue inflammation, bone marrow edema (BME) lesions, bone erosion and proliferation in peripheral joints and axial skeleton. Whole-body (WB)-MRI, a relatively novel technique in musculoskeletal studies, allows assessment of all peripheral/axial joints and entheses in 1 examination. Recent, consensus-based and semi-quantitative scoring methods were developed and validated. This study is the first to systematically use new state-of-the-art MRI scoring methodologies to assess PsA inflammatory and structural changes in a global clinical trial.

OBJECTIVES:
To assess APR efficacy on inflammatory indices and imaging outcome measures associated with PsA structural progression by conventional static MRI and dynamic contrast-enhanced (DCE)-MRI of the most affected hand and WB-MRI.

METHODS:
The study aims to enroll 120 biologic-naïve adults with PsA for ≥3 mos to ≤5 yrs and prior treatment with ≤2 conventional DMARDs. Subjects must have ≥3 swollen and ≥3 tender joints, hand involvement (≥1 swollen joint or ≥1 dactylitis) and ≥1 active enthesitis site. After 4-wk screening, all eligible patients will receive APR 30 mg twice daily (titrated during the first 5 days) as monotherapy or in combination with methotrexate for 48 wks, with a 4-wk observational follow-up. Conventional MRI and optional DCE-MRI of the most affected hand and WB-MRI of the entire body will be performed at Wks 0, 24 and 48. The primary endpoint is change from BL to Wk 24 in OMERACT PsA MRI (PsAMRIS) composite score of BME + synovitis + tenosynovitis. Other imaging endpoints include change from BL to Wk 48 in PsAMRIS composite score (BME + synovitis + tenosynovitis) and change from BL to Wks 24 and 48 in PsAMRIS composite score (BME + synovitis), PsAMRIS composite inflammation score (BME + synovitis + tenosynovitis + periarticular inflammation), PsAMRIS total damage score (erosion + bone proliferation), WB-MRI indices (including peripheral joint inflammation index and peripheral enthesis inflammation index), hip and knee inflammation MRI scores (HIMRISS, KIMRISS), OMERACT heel enthesitis MRI indices, axial inflammation indices (SPARCC, CanDen), DEMRIQ-Volume and DEMRIQ-Inflammation and other DCE-MRI–derived parameters. Clinical parameters will include SJC/TJC, cDAPSA, SPARCC Enthesitis Index, Leeds Enthesitis Index, Leeds Dactylitis Index, PASDAS, PtGA, PhGA, Patient’s Assessment of Pain, HAQ-DI, and BASDAI and impact of disease (PsAID12). Safety and tolerability also will be assessed.

RESULTS:
The study protocol was approved by an independent ethics committee and is now enrolling in the USA. Selected countries in Europe and Russia will also participate. MRI, clinical and patient-reported outcomes will be analyzed.

CONCLUSION:
This study will provide important evidence of APR’s impact on inflammatory/structural changes by assessing all PsA musculoskeletal domains (peripheral arthritis, enthesitis, dactylitis and axial disease). Furthermore, it will yield information on use of conventional MRI–, WB-MRI– and DCE-MRI–driven outcome measures in PsA clinical trials.

Less Severe Synovitis in Patients with Knee Osteoarthritis is Associated with Higher Self-Reported Pain Intensity 12 Months After Total Knee Arthroplasty- An Exploratory Cohort Study.

Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.5695

Abstract

BACKGROUND:
Synovitis is a pain generator in patients with osteoarthritis and associated with upregulation of pro-inflammatory cytokines, which have been found to lead to pain sensitivity and worse self-reported pain(1).

OBJECTIVES:
This study aimed to investigate the association between pre- and perioperative synovitis from imaging and histology and self-reported pain 12 months after total knee arthroplasty (TKA).

METHODS:
Preoperative synovitis was assessed from MRI data of the knee by 11 point synovitis score a.m Guermazi (2) using contrast enhanced MRI (CE-synovitis) and heuristic time intensity curve analysis of the dynamic contrast enhanced MRI (DCE-MRI) data using the DYNAMIKA® software (Image Analysis group, London) providing Dynamic Enhanced MR Quantification (DEMRIQ) Indices (3). Perioperative synovitis was also assessed from biopsies of the synovium in 6 predefined places graded histologically a.m Krenn (4). Worst pain within the last 24-hours (visual analog scale, VAS, 0-100) was assessed before and 12 months after TKA. Patients were divided into a low-pain (VAS≤30) and a high-pain (VAS>30) group based on 12-months postoperative VAS.

RESULTS:
Twenty-six patients had full pre- and postoperative data and were analysed. The high-pain group had significantly lower CE-synovitis (P=0.03), DCE-MRI inflammation indices (DEMRIQ-inflammation) (P<0.03) and a trend towards lower histologically assessed synovitis grades (P=0.077) compared to the low-pain group at baseline. Preoperative synovitis scores were also inversely correlated with pain 12-months after TKA, CE-synovitis (R = – 0.455, P = 0.022) and DCE-MRI inflammation (R = -0.528, P = 0.007), indicating that more severe preoperative synovitis is associated with less severe pain at 12-months.

CONCLUSION:
Higher preoperative synovitis scores are associated with less postoperative pain 12-months after TKA. Further, correlation analysis revealed that less severe preoperative synovitis was associated with worse pain 12-months after TKA, suggesting that CE and DCE-MRI synovitis quantification could be used as imaging markers for prediction of good surgical outcomes.

Magnetic Resonance Imaging Tenosynovitis and Osteitis are Independent Predictors of Radiographic and MRI Damage Progression in Rheumatoid Arthritis Patients In Clincial Remission

Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.2006

Abstract

BACKGROUND:
Progression of structural joint damage occurs in 20-30 % of patients with rheumatoid arthritis (RA) in clinical remission1. Magnetic resonance imaging (MRI)-detected synovitis and in particular osteitis/bone marrow edema (BME) are known predictors of structural progression in both active RA and in remission, but the predictive value of adding MRI tenosynovitis assessment as potential predictor in patients in clinical remission has not been investigated.

OBJECTIVES:
To investigate the predictive value of baseline MRI inflammatory and damage parameters on 2 year MRI and X-ray damage progression in an RA cohort in clinical remission, following MRI and conventional treat-to-target (T2T) strategies.

METHODS:
200 RA patients in clinical remission (DAS28-CRP<3.2 and no swollen joints) on conventional DMARDs, included in the randomized IMAGINE-RA trial2 (conventional DAS28 + MRI-guided T2T strategy targeting absence of BME vs conventional DAS28 guided T2T strategy) had baseline and 2 years contrast-enhanced MRIs of the dominant wrist and 2nd-5th MCP joints and X-rays of hands and feet performed, which were evaluated with known chronology by two experienced readers according to the OMERACT RAMRIS scoring system and Sharp/van der Heijde method, respectively.

The following potentially predictive baseline variables: MRI BME, synovitis, tenosynovitis, MRI and X-ray erosion and joint space narrowing (JSN) score, CRP, DAS28, smoking status, gender, age and patient group were tested in univariate logistic regression analyses with 2-year progression in MRI combined damage score, Total Sharp Score (TSS), and MRI and X-ray JSN and erosion scores as dependent variables. Variables with p<0.1, age, gender and patient group were included in multivariable logistic regression analyses with backward selection.

RESULTS:
Based on univariate analyses MRI BME, synovitis, tenosynovitis, x-ray erosion and JSN, gender and age were included in subsequent multivariable analyses. Independent MRI predictors of structural progression were BME (MRI progression) and tenosynovitis (MRI and X-ray progression), MRI combined damage score: sum score of MRI erosion and JSN scores.

CONCLUSION:
This trial is the first to report that MRI tenosynovitis independently predicts both X-ray and MRI damage progression in RA patients in clinical remission. Further studies are needed to confirm MRI-determined tenosynovitis as predictor of progressive joint destruction in RA clinical remission.

Impact of a Magnetic Resonance Imaging-Guided Treat-to-Target Strategy on Disease Activity and Progression in Patients with Rheumatoid Arthritis (The IMAGINE-RA Trial): Study Protocol for a Randomized Controlled Trial.

Copyright © Author(s) (or their employer(s)) 2015.
Trials. 2015 Apr;7(178)_suppl doi: 10.1186/s13063-015-0693-2
Trial registration: http://www.ClinicalTrials.gov identifier: NCT01656278 (5 July 2012)

Abstract

BACKGROUND:
Rheumatoid arthritis (RA) is a chronic, progressive joint disease, which frequently leads to irreversible joint deformity and severe functional impairment. Although patients are treated according to existing guidelines and reach clinical remission, erosive progression still occurs. This demonstrates that additional methods for prognostication and monitoring of the disease activity are needed. Bone marrow edema (BME) detected by magnetic resonance imaging (MRI) has proved to be an independent predictor of subsequent radiographic progression. Guiding the treatment based on the presence/absence of BME may therefore be clinically beneficial. We present the design of a randomized controlled trial (RCT) aiming to evaluate whether an MRI-guided treatment strategy compared to a conventional treatment strategy in anti-CCP-positive erosive RA is better to prevent progression of erosive joint damage and increase the remission rate in patients with low disease activity or clinical remission.

METHODS/DESIGN:
The study is a non-blinded, multicenter, 2-year RCT with a parallel group design. Two hundred anti-CCP-positive, erosive RA patients characterized by low disease activity or remission, no clinically swollen joints and treatment with synthetic disease-modifying antirheumatic drugs (DMARDs) will be included. Patients will be randomized to either a treatment strategy based on conventional laboratory and clinical examinations (control group) or a treatment strategy based on conventional laboratory and clinical examinations as well as MRI (intervention group). Treatment is intensified according to a predefined treatment algorithm in case of inflammation defined as a disease activity score (DAS28) >3.2 and at least one clinically swollen joint (control and intervention groups) and/or MRI-detected BME (intervention group only). The primary outcome measures are DAS28 remission (DAS28 < 2.6) and radiographic progression (Sharp/vdHeijde score).

DISCUSSION:
The perspectives, strengths and weaknesses of this study are discussed.

Osteoarthritis Phenotypes and Novel Therapeutic Targets.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Biochemical Pharmacology. 2019 Jul;37 doi: 10.1016/j.bcp.2019.02.037. Epub 2019 Mar 1.

Abstract

The success of disease-modifying osteoarthritis drug (DMOAD) development is still elusive. While there have been successes in preclinical and early clinical studies, phase 3 clinical trials have failed so far and there is still no approved, widely available DMOAD on the market. The latest research suggests that, among other causes, poor trial outcomes might be explained by the fact that osteoarthritis (OA) is a heterogeneous disease with distinct phenotypes. OA trials might be more successful if they would address and target a specific phenotype. The increasing availability of advanced techniques to detect particular OA characteristics expands the possibilities to distinguish between such potential OA phenotypes. Magnetic resonance imaging is among the key imaging techniques to stratify and monitor patients with changes in bone, cartilage and inflammation. Biochemical markers have mainly used as secondary parameters and could further delineate phenotypes. Moreover, post-hoc analyses of trial data have suggested the existence of distinct pain phenotypes and their relevance in the design of clinical trials. Although ongoing work in the field supports the concept of OA heterogeneity, this has not yet resulted in more effective treatment options. This paper reviews the current knowledge about potential OA phenotypes and suggests that combining patient clinical data, quantitative imaging, biochemical markers and utilizing data-driven approaches in patient selection and efficacy assessment will allow for more successful development of effective DMOADs.

Synovial Cellular and Molecular Signatures Stratify Clinical Response to csDMARD Therapy and Predict Radiographic Progression in Early Rheumatoid Arthritis Patients

Copyright © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.
Annals of the Rheumatic Diseases. 2019 Jun;78(6) doi: 10.1136/annrheumdis-2018-214539. Epub 2019 Mar 16.

Abstract

OBJECTIVES:
To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally.
METHODS:
144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.
RESULTS:
Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) d iffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.
CONCLUSIONS:
We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.

Imaging in Rheumatoid Arthritis: The Role of Magnetic Resonance Imaging and Computed Tomography.

Abstract

In suspected and diagnosed rheumatoid arthritis (RA), magnetic resonance imaging (MRI) allows detection of all relevant pathologies, such as synovitis, tenosynovitis, bone marrow edema (osteitis), bone erosion and cartilage damage. MRI is more sensitive than clinical examination for monitoring disease activity (i.e., inflammation) and more sensitive than conventional radiography and ultrasonography for monitoring joint destruction. In suspected RA, MRI bone marrow edema predicts development of RA, and in early RA patients, it predicts subsequent structural damage progression. CT is the standard reference imaging modality for visualizing bone damage, including bone erosions in RA, but lacks sensitivity for soft-tissue changes, including synovitis and tenosynovitis. CT has a minimal role in RA clinical trials and practice, except in selected patients where MRI is contraindicated or not available or if crystal arthritis such as gout or pseudo-gout is suspected. MRI has documented utility in diagnosis, monitoring and prognostication of patients with RA and is increasingly used for these purposes in clinical practice and particularly clinical trials.

MRI Findings of Rapidly Progressive Hepatocellular Carcinoma.

Copyright © Copyright 2010 Elsevier Inc. All rights reserved.
Magnetic Resonance Imaging. 2010 Jul;28(6) doi: 10.1016/j.mri.2010.03.005. Epub 2010 Apr 27.

Abstract

PURPOSE:
The purpose of this study is to determine the magnetic resonance imaging (MRI) and patient characteristics in subjects with hepatocellular carcinoma (HCC) that exhibit rapid progression.
MATERIALS AND METHODS:
In this unblinded retrospective study, initial and follow up MR images were reviewed, before and after rapid progression of HCC, respectively. Rapid progression was defined as a lesion <3 cm which exhibited >3 cm increase in one year or 2 cm increase in 6 months. Patient characteristics and MRI findings were determined using clinical information from the institution clinical information system and records from the Radiology and Pathology Departments, Hepatology Division and Liver Transplant Service of the Department of Medicine.
RESULTS:
Seven individuals were identified with HCC that showed rapid progression. Five of the patients had underlying hepatitis C, one had alcoholic hepatitis, and one had immunosuppression due to liver transplantation. On initial MRI, six patients had early intense ring enhancing lesions, which rapidly progressed in size. Five patients died within 6 months, one within 1 year after progression despite treatment. Six of the seven patients also had multiple other liver nodules on initial MRI; those that showed ring enhancement rapidly progressed but those without, did not show rapid progression.
CONCLUSION:
Patients with rapidly progressive HCC had underlying hepatitis C and intense ring enhancement on initial MRI. This group of patients should be evaluated further to determine if they might benefit from early intervention.

Richter Transformation of Chronic Lymphocytic Leukemia: A Review of Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography and Molecular Diagnostics

Copyright © 2017 © 2017, Shaikh et al.
Cureus. 2017 Jan;9(1) doi: 10.7759/cureus.968

Abstract

BACKGROUND:
Chronic lymphocytic leukemia (CLL) is a low-grade B-cell proliferative disease with a generally indolent course. In a few cases, it undergoes transformation and becomes a more aggressive malignancy, such as diffuse large B-cell lymphoma (DLBCL). This process, which is called Richter transformation (RT), is often detected too late and is associated with a poor prognosis. There are multiple molecular diagnostic approaches to detect RT in preexisting CLL. Metabolic imaging using 18-fluorine fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) can be a very useful tool for early detection of RT and which can hence allow for timely intervention, thereby improving the patient’s chances of survival.

Voxel-wise correlation of PET/CT with multiparametric MRI and histology of the prostate using a sophisticated registration framework.

OBJECTIVES:

To develop a registration framework for correlating positron emission tomography/computed tomography (PET/CT) images with multiparametric MRI (mpMRI) and histology of the prostate, thereby enabling voxel-wise analysis of imaging parameters.

PATIENTS AND METHODS:

In this prospective proof-of-concept study, nine patients scheduled for radical prostatectomy underwent mpMRI and PET/CT imaging prior to surgery. One had PET imaging using 18 F-fluoromethylcholine (FCH), five using 68 Ga-labelled prostate-specific membrane antigen (PSMA)-HBED-CC (PMSA-11) and three using a trial 68 Ga-labelled THP-PSMA tracer. PET/CT data was co-registered with mpMRI via the CT scan and an in vivo 3D T2w MRI, and then co-registered with ground truth histology data using ex vivo MRI of the prostate specimen. Maximum and mean standardised uptake values (SUVmax and SUVmean) were extracted from PET data using tumour annotations from histology, and Kolmogorov-Smirnov tests were carried out to compare between tumour and benign voxel values. Correlation analysis was performed between mpMRI and PET SUV tumour voxels using Pearson’s correlation coefficient and R squared statistics.

RESULTS:

PET/CT data from all nine patients were successfully registered with mpMRI and histology data. SUVmax and SUVmean ranged from 2.21 to 12.11 and 1.08 to 4.21, respectively. All patients showed the PET SUV values in benign and tumour voxels were from statistically different distributions. Correlation analysis showed no consistent trend between the T2w or ADC values and PET SUV. However, parameters from DCE MRI including the maximum enhancement (ME), volume transfer constant Ktrans and the initial area under the contrast agent concentration curve (iAUGC60) showed consistent positive correlations with PET SUV. Furthermore, R2* values from BOLD MRI showed consistent negative correlations with PET SUV voxel values.

CONCLUSION:

We have developed a novel framework for registering and correlating PET/CT data at a voxel-level with mpMRI and histology. Despite registration uncertainties, perfusion and oxygenation parameters from DCE MRI and BOLD imaging showed correlations with PET SUV. Further analysis will be performed on a larger patient cohort to quantify these proof-of-concept findings. Improved understanding of the correlation between mpMRI and PET will provide supportive information for focal therapy planning of the prostate.