Auto-Immune & Inflammatory

The Effects of Weight Loss on Imaging Outcomes in Osteoarthritis of the Hip or Knee in People who are Overweight or Obese: A Systematic Review

Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Osteoarthritis Cartilage. 2020 Jan;28(1):10-21. doi: 10.1016/j.joca.2019.10.013. Epub 2019 Nov 26.

Abstract

OBJECTIVE:
To evaluate the structural effects of weight loss on hip or knee osteoarthritis (OA) and to summarize which structural joint pathologies have been examined and the evidence for the outcome measurement instruments applied.
DESIGN:
Based on a pre-specified protocol (available: PROSPERO CRD42017065263), we conducted a systematic search of the bibliographic databases, Medline, Embase and Web of Science identifying longitudinal articles reporting the effects of weight loss on structural imaging outcomes in OA of the hip or knee in people who are overweight or obese.
RESULTS:
From 1625 potentially eligible records, 14 articles (from 6 cohorts) were included. 2 cohorts were derived from RCTs. Evaluated pathologies were: articular cartilage (n = 7), joint space width (n = 3), bone marrow lesions (n = 5), synovitis (n = 2), effusion (n = 1), meniscus (n = 3), bone marrow density (n = 1) and infrapatellar fat pad (IPFP; n = 2). Cartilage showed conflicting results when evaluating cartilage thickness by direct thickness measurements. Compositional dGEMRIC and T2 mapping measures in early knee OA showed trends towards reduced cartilage degeneration. Joint space width on conventional radiographs showed no change. Weight loss reduced the size of the IPFP. Synovitis and effusion were not affected. Following weight loss DXA showed bone loss at the hip.
CONCLUSION:
We did not find consistent evidence of the effects of weight loss on OA structural pathology in people who are overweight or obese. There is a need to achieve consensus on which structural pathologies and measurements to apply in weight loss and OA research.

The Role of Advanced MRI in the Development of Treat-to-Target Therapeutic Strategies, Patient Stratification and Phenotyping in Rheumatoid Arthritis

In this commentary we discuss the potential of advanced imaging, particularly Dynamic Contrast Enhanced (DCE) magnetic resonance imaging (MRI) for the objective assessment of disease progression in rheumatoid arthritis (RA). We emphasise the potential DCE-MRI in advancing the field and exploring new areas of research and development in RA. We believe that different grades of bone marrow edema (BME) and synovitis in RA can be examined and monitored in a more sensitive manner with DCE-MRI. Future treatments for RA will be significantly improved by enhanced imaging of BMEs and synovitis. DCE-MRI will also facilitate enhanced stratification and phenotyping of patients enrolled in clinical trials.

Development of a Multi-Modality Imaging Approach to evaluate Lupus Nephritis and initial results.

© Author(s) (or their employer(s)) 2019. Published by BMJ.
Annals of the Rheumatic Diseases. 2019 June;78(2)

Abstract

BACKGROUND:
Lupus nephritis (LN) remains a significant cause of morbidity and mortality in subjects with Systemic Lupus Erythematosus (SLE). The gold standard for evaluation of LN remains the kidney biopsy, whereas renal function is usually evaluated by eGFR and urinary protein:creatinine ratio. More effective and sensitive methodology is needed to assess LN and also the response to treatment. Functional imaging of the kidney using quantitative techniques has great potential, as it can assess kidney function and pathologic changes non-invasively by evaluating perfusion, oxygenation, cellular density and fibrosis.
OBJECTIVE:
To develop a multi-modality imaging approach for the evaluation of the spectrum of pathologic changes in LN.

METHODS:

In this multi-center study, subjects who were having a standard of care renal biopsy for LN were asked to participate in the imaging evaluation. Local Institutional Review Board approval was obtained, and subjects signed an Informed Consent Form. Dynamic contrast enhanced MRI (DCE-MRI) was employed to detect changes in vascularization and perfusion, Diffusion Weighted Imaging (DWI) to assess interstitial diffusion, T2*Map/BOLD – the tissue oxygenation and T1rho to evaluate fibrosis. The imaging scores will be compared to renal biopsy, including ISN/RPS classification of LN, activity index and chronicity index.

RESULTS:
Five patients have been evaluated to date and their imaging data assessed for quality. The initial results have demonstrated the feasibility of acquiring multi-modality imaging data, including dynamic imaging sequences, in the multi-center trial setting. Figure 1 illustrates scans from a representative patient. This study will determine whether multi-modality imaging could become an effective, non-invasive tool to assess renal function and pathology in LN.
CONCLUSION:
The initial assessment of 5 LN subjects has established the feasibility of multi-modality imaging as a tool to evaluate LN in a multi-center study. By assessing functional and structural MRI outcomes and correlating them to clinical data, this study will provide essential preliminary evidence on the value of multi-modality imaging in diagnosis and evaluating the response to treatment of LN patients.

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.

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.