Rheumatology

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.

Effect of Liraglutide on Body Weight and Pain in Patients with Overweight and Knee Osteoarthritis: Protocol for a Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Single-Centre Trial

Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
BMJ Open. 2019 May;9(5) doi: 10.1136/bmjopen-2018-024065

Abstract

INTRODUCTION:
With an increasing prevalence of citizens of older age and with overweight, the health issues related to knee osteoarthritis (OA) will intensify. Weight loss is considered a primary management strategy in patients with concomitant overweight and knee OA. However, there are no widely available and feasible methods to sustain weight loss in patients with overweight and knee OA. The present protocol describes a randomised controlled trial evaluating the efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide in a 3 mg/day dosing in patients with overweight and knee OA.

METHODS AND ANALYSIS:
150 volunteer adult patients with overweight or obesity and knee OA will participate in a randomised, double-blind, placebo-controlled, parallel-group and single-centre trial. The participants will partake in a run-in diet intervention phase (week −8 to 0) including a low calorie diet and dietetic counselling. At week 0, patients will be randomised to either liraglutide 3 mg/day or liraglutide placebo 3 mg/day for 52 weeks as an add-on to dietetic guidance on re-introducing regular foods and a focus on continued motivation to engage in a healthy lifestyle. The co-primary outcomes are changes in body weight and the Knee Injury and Osteoarthritis Outcome Score pain subscale from week 0 to week 52.

ETHICS AND DISSEMINATION:
The trial has been approved by the regional ethics committee in the Capital Region of Denmark, the Danish Medicines Agency and the Danish Data Protection Agency. An external monitoring committee (The Good Clinical Practice Unit at Copenhagen University Hospitals) will oversee the trial. The results will be presented at international scientific meetings and through publications in peer-reviewed journals.

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.

Magnetic Resonance Imaging in Rheumatology

Abstract

Magnetic resonance (MR) imaging has traditionally only played a small role in the clinical care of most patients with arthritis. However, with modern therapeutic strategies, early diagnosis is now more important than ever before. Consequently, advanced MRI techniques and applications now play a crucial role in managing an increasing proportion of rheumatology patients. This article reviews MR imaging techniques that are in widespread use and in development for detection and quantification of inflammation and structural damage in arthritis. It focuses on the role of MR imaging for diagnosis, management, and research in inflammatory arthropathies. Osteoarthritis and gout are briefly reviewed.

Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials

Abstract

Background Methotrexate (MTX) is considered the anchor drug in rheumatoid arthritis (RA) treatment, based on efficacy, safety, and its ability to increase the efficacy of biologic agents when used in combination. Both the “American College of Rheumatology” (ACR) and the “European League Against Rheumatism” (EULAR) recommend the use of biologic agents with concomitant MTX in RA. However, analyses from health care claims suggest that the MTX prescribed in conjunction with a biologic disease-modifying antirheumatic drug (bDMARD), is not collected at the pharmacy by more than half of the patients. Despite claims from pivotal trial data, the empirical evidence supporting combination MTX plus bDMARD in terms of the actual benefit-harm has not been evaluated extensively.

Objectives To review the evidence for benefit and harm associated with combining MTX with a biologic agent in RA patients.

Methods A systematic review and meta-analysis of randomised controlled trials (RCTs) was performed to identify all trials relating treatment of RA with MTX in combination with bDMARD compared to a bDMARD in monotherapy. Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals (RR, 95%CI) and inconsistency (I2, %) estimated using Review Manager. According to the protocol the major outcomes were ACR50 for benefit and withdrawals due to adverse events (AEs) for harm (PROSPERO: CRD42014014633).

Results From the 4,405 identified references, 14 trials were eligible for inclusion in the meta-analysis. The overall likelihood of responding to therapy (ie, RR according to ACR50) was 1.36 [1.24 to 1.49] – with a low degree of inconsistency (28%) – in favour of concomitant use of MTX when treating with a biologic (P<0.001). There was no reason to suspect that added value of MTX varied with the choice of bDMARD (Test for subgroup differences P=0.38): abatacept 1.27 [0.97 to 1.67], adalimumab 1.42 [1.24 to 1.61], etanercept 1.44 [1.22 to 1.69], golimumab 1.60 [1.13 to 2.27], infliximab 3.54 [1.38 to 9.08], rituximab 1.31 [0.74 to 2.32], and tocilizumab 1.24 [1.03 to 1.51]. The overall estimate of discontinuing therapy due to AEs from concomitant use of MTX was 1.17 [0.94 to 1.44] (P=0.16) compared to bDMARD in monotherapy – corresponding to a possible 17% increased risk.

Conclusions This systematic review and meta-analysis of RCTs provides empirical evidence about the clinical value of combining the prescribed bDMARD with the recommended concomitant use of MTX. Combination therapy increases the probability of achieving treatment success at the level of ACR50 by approximately 40% compared to patients using biologics in monotherapy. Although the precision around the estimate of concomitant MTX use does not rule out an increased risk of clinically important harms, these findings justify the recommendation that all patients prescribed biologics should be encouraged to continue MTX therapy.

Dual Energy CT Scanning: Variable Sensitivity for Gout in Non-Tophaceous and Tophaceous Disease and in Individual Erosions

Background/Purpose: Dual energy computed tomography (DECT) is emerging as a diagnostic tool for gout, but its sensitivity has not been established. We assessed the sensitivity of DECT for the detection of monosodium urate (MSU) deposits in both non-tophaceous and tophaceous gout.

Methods: Twenty-one patients with gout (per Wallace criteria) agreed to participate in this study funded by Siemens Medical Solutions and underwent DECT of their hands, wrists, elbows, knees, ankles, and feet. Eleven had non-tophaceous gout confirmed by the demonstration of MSU crystals in a joint aspirate. Ten patients had tophaceous gout (crystal-proven in 7), defined by the presence of palpable tophi (n=5), the presence of erosions of the first metatarsal head on radiograph (n=3), or gross MSU deposits in a surgical specimen (n=2). Scans were performed using a SOMATOM Definition Flash Dual Source CT scanner (Siemens Healthcare) with simultaneous acquisition of images at 80 and 140 kV. Post-processing was performed using Siemens software with predefined standard parameters; the threshold ratio parameter was set at 1.36. Sensitivity was defined as the percentage of gout patients who were correctly identified by DECT.

Results: The 21 patients included 17 men, with a mean age of 61 years (range, 43 – 83). Among the 11 patients with non-tophaceous gout, MSU deposits were only detected by DECT in the joint proven to be affected by aspiration in 2 (sensitivity=18%). However, the MSU deposits were evident in ≥1 joint area evaluated by DECT in 7 patients (overall sensitivity=64%), ≥1 clinically affected joint in 4 (57%) patients and ≥1 clinically unaffected joint in 6 (86%) patients. The number of MSU deposits correlated with the maximum recorded serum urate (r2=0.502, p=.022) but not with gout duration. Among the 10 patients with tophaceous gout, 9 had MSU deposits evident by DECT (sensitivity=90%). In an index case of tophaceous gout (Figure), we were surprised to see tophi evident by clinical examination (panel A), 3D volume rendering (Panel B), and bony erosion (panel C-little finger DIP), that were negative by DECT (panel C-lack of green deposits). This prompted us to evaluate the sensitivity of DECT for individual gouty erosions (defined by the presence of an overhanging edge in a joint not affected by severe joint space loss). In 3 patients with extensive foot involvement, MSU deposits were detected by DECT within or immediately adjacent to 13/26 (50%) erosions.

Conclusion: DECT detected MSU deposits in non-tophaceous gout, with 65% sensitivity on scanning of both upper and lower extremity joints and only 18% on scanning of the crystal-proven joint. The sensitivity was 90% in tophaceous gout, but remained inadequate when evaluated on the basis of individual erosive lesions. The detection of MSU deposits by DECT may relate to their density and this could potentially be improved with an adjustment of algorithm input parameters.

Intra-Operative Synovitis Predicts Worse Pain and Function 2 Years after Total Knee Arthroplasty for Osteoarthritis

Background/Purpose:

Total knee arthroplasty (TKA) is one of the most common elective
orthopedic procedures in the US.  However, up to 20% of patients have chronic
post-operative pain.  There is therefore an urgent need to identify modifiable
risk factors to improve patients’ outcomes. Inflammation is reversible, and has
been associated with pain in knee osteoarthritis (KOA). However, whether
inflammation is associated with chronic pain or other suboptimal outcomes after
TKR is unknown. Therefore, this study investigated the association between pre-operative
synovial inflammation and 2-year outcomes following TKA for KOA.

 

Methods:

We identified 33 KOA patients who underwent primary unilateral
TKA and had chronic pain (WOMAC ≤60; 100 =best) at 2 years. Patients were
matched 2:1 on surgeon and surgery date with TKA cases with little pain at 2
years, (WOMAC ≥70).   All patients provided demographic and pre-and
post-operative self-report data. Preoperative radiographs were graded by two blinded
evaluators for alignment and Kellgren and Lawrence score.  H+E slides of
intra-operative synovial tissue were reviewed and graded for inflammation
according to the validated Krenn Criteria. Prosthesis information, history of previous
surgery to the index knee, post-operative steroid injection and manipulations
were recorded from surgeons’ and inpatient charts.  Regression analyses were performed
to evaluate whether pre-operative inflammation was an independent predictor of
pain, function or stiffness 2 years after TKA.

Results:

Average age was 67 years, (±7.9), 65% were women and 91%
were Caucasian.  In a multivariate linear regression controlling for Krenn
Score, post-operative steroid injection, age, MCS, PCS, pre-operative WOMAC
pain and Euroqol, patients with greater inflammation (Krenn  ≥3) had more
pain at 2-years (WOMAC 65.01 vs. 76.14; p-value 0.03). Patients who had a
steroid injection soon after TKA (based on surgeon’s suspicion  of
tenosynovitis) were more likely to have worse 2 year WOMAC pain scores (60.3
vs. 80.9;  p-value = 0.0495).  Every 10 year increase in age was associated
with a 6.6 unit increase in 2-year WOMAC pain score,( i.e. less pain.). Separate
models showed a similar association between high Krenn score and worse 2-year
function, (WOMAC Function 70.2 vs. 81.1; p-value 0.01), but no association
between Krenn score and 2 year WOMAC stiffness. Neither radiographic findings nor
implant type were associated with 2-year outcomes.

Conclusion:

Increased synovial inflammation at the time of surgery
predicts worse WOMAC pain and function 2 years after TKA.  This is a
potentially modifiable risk factor which could be a target for future
interventional trials.