Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not ...respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive ...RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.
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•Deep phenotyping and RNA-seq of early rheumatoid arthritis individuals pre-treatment•Synovial plasma cell gene expression predicts future progressive joint damage on X-ray•Blood interferon gene signature associates with synovial B and plasma cell infiltration•Interactive website enables RNA-seq and clinical data to be fully explored
Lewis et al. use histology and RNA-seq of synovial biopsies from a cohort of early rheumatoid arthritis individuals to identify three histological pathotypes and reveal gene modules associated with disease severity and clinical response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To examine in a cohort of rheumatoid arthritis (RA) patients undergoing serial ultrasound (US)–guided biopsies of small joints in the context of clinical trials whether sufficient synovial ...tissue could be obtained at both baseline and second biopsy to: 1) accurately evaluate the synovial immune phenotype, 2) permit adequate RNA extraction to determine molecular signatures, and 3) sensitively detect change in the number of synovial sublining macrophages (CD68+) following effective therapy.
Methods
Synovial samples from RA patients undergoing US‐guided biopsy of small joints as part of 2 clinical trials (Barts Early Arthritis Cohort n = 18 and the Clinical and Pathological Response to Certolizumab Pegol (CLIP‐Cert) study n = 17) were examined, and the quality and quantity of histologic samples and RNA extracted per joint were determined and compared to synovial thickness and power Doppler scores determined by US before biopsy. Modulation of the number of CD68+ sublining macrophages was correlated with clinical response to treatment.
Results
Good quality synovial tissue that accurately reflected the synovial immune phenotype of the total joint was obtained in 80% of US‐guided procedures when synovial thickness (higher than grade 2) was documented before biopsy. In 100% of the procedures, sufficient RNA was extracted to permit molecular analysis. There was a significant correlation between change in CD68+ sublining macrophage number and clinical response to treatment.
Conclusion
This study provides minimum standards for sample retrieval for small joint biopsy. Furthermore, our findings confirm the clinical utility of the procedure in the largest reported cohort of US‐guided small joint biopsies. The demonstration that small joint synovial tissue can be readily accessed by a technically simple, minimally invasive procedure is likely to facilitate critical advancements in the knowledge of RA pathobiology and personalized health care.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Ultrasound (US) provides an indirect method of assessing synovial ...blood flow and has been shown to correlate with clinical disease activity in patients with Rheumatoid Arthritis. This study examines the relationship of US determined synovitis with synovial vascularity, angiogenic/lymphangiogenic factors and cellular mediators of inflammation in a cohort of patients with early Rheumatoid Arthritis (RA) patients prior to therapeutic intervention with disease modifying therapy or corticosteroids.
An ultrasound guided synovial biopsy of the supra-patella pouch was performed in 12 patients with early RA prior to treatment. Clinical, US and biochemical assessments were undertaken prior to the procedure. Ultrasound images and histological samples were obtained from the supra-patella pouch. Histological samples were stained for Factor VIII and a-SMA (a-smooth muscle actin). Using digital imaging analysis a vascular area score was recorded. QT-PCR (quantitative-PCR) of samples provided quantification of angiogenic and lymphangiogenic gene expression and immunohistochemistry stained tissue was scored for macrophage, T cell and B cell infiltration using an existing semi-quantitative score.
Power Doppler showed a good correlation with histological vascular area (Spearman r--0.73) and angiogenic factors such as vascular endothelial growth factor-A (VEGF-A), Angiopoietin 2 and Tie-2. In addition, lymphangiogenic factors such as VEGF-C and VEGF-R3 correlated well with US assessment of synovitis. A significant correlation was also found between power Doppler and synovial thickness, pro-inflammatory cytokines and sub-lining macrophage infiltrate. Within the supra-patella pouch there was no significant difference in US findings, gene expression or inflammatory cell infiltrate between any regions of synovium biopsied.
Ultrasound assessment of synovial tissue faithfully reflects synovial vascularity. Both grey scale and power Doppler synovitis in early RA patients correlate with a pro-angiogenic and lymphangiogenic gene expression profile. In early RA both grey scale and power Doppler synovitis are associated with a pro-inflammatory cellular and cytokine profile providing considerable validity in its use as an objective assessment of synovial inflammation in clinical practice.
Injection drug use is a leading transmission route of HIV and STDs, and disease prevention among drug users is an important public health concern. This study assesses cost-effectiveness of behavioral ...interventions for reducing HIV and STDs infections among injection drug-using women. Cost-effectiveness analysis was conducted from societal and provider perspectives for randomized trial data and Bernoullian model estimates of infections averted for three increasingly intensive interventions: (1) NIDA’s standard intervention (SI); (2) SI plus a well woman exam (WWE); and (3) SI, WWE, plus four educational sessions (4ES). Trial results indicate that 4ES was cost-effective relative to WWE, which was dominated by SI, for most diseases. Model estimates, however, suggest that WWE was cost-effective relative to SI and dominated 4ES for all diseases. Trial and model results agree that WWE is cost-effective relative to SI per hepatitis C infection averted ($109 308 for in trial, $6 016 in model) and per gonorrhea infection averted ($9 461 in trial, $14 044 in model). In sensitivity analysis, trial results are sensitive to 5 % change in WWE effectiveness relative to SI for hepatitis C and HIV. In the model, WWE remained cost-effective or cost-saving relative to SI for HIV prevention across a range of assumptions. WWE is cost-effective relative to SI for preventing hepatitis C and gonorrhea. WWE may have similar effects as the costlier 4ES.
To aid public health policymaking, we studied the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions for heroin dependence in Malaysia.
We estimated the cost-effectiveness ...ratios of three treatments for heroin dependence. We used a microcosting methodology to determine fixed, variable, and societal costs of each intervention. Cost data were collected from investigators, staff, and project records on the number and type of resources used and unit costs; societal costs for participants' time were estimated using Malaysia's minimum wage. Costs were estimated from a provider and societal perspective and reported in 2004 US dollars.
Muar, Malaysia.
126 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial in Malaysia (2003-2005) receiving counseling and buprenorphine, naltrexone, or placebo for treatment of heroin dependence.
Primary outcome measures included days in treatment, maximum consecutive days of heroin abstinence, days to first heroin use, and days to heroin relapse. Secondary outcome measures included treatment retention, injection drug use, illicit opiate use, AIDS Risk Inventory total score, and drug risk and sex risk subscores.
Buprenorphine was more effective and more costly than naltrexone for all primary and most secondary outcomes. Incremental cost-effectiveness ratios were below $50 for primary outcomes, mostly below $350 for secondary outcomes. Naltrexone was dominated by placebo for all secondary outcomes at almost all endpoints. Incremental treatment costs were driven mainly by medication costs, especially the price of buprenorphine.
Buprenorphine appears to be a cost-effective alternative to naltrexone that might enhance economic productivity and reduce drug use over a longer term.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Develop and apply new costing methodologies to estimate costs of opioid dependence treatment in countries worldwide.
Data Sources/Study Setting
Micro‐costing methodology developed and data ...collected during randomized controlled trial (RCT) involving 126 patients (July 2003–May 2005) in Malaysia. Gross‐costing methodology developed to estimate costs of treatment replication in 32 countries with data collected from publicly available sources.
Study Design
Fixed, variable, and societal cost components of Malaysian RCT micro‐costed and analytical framework created and employed for gross‐costing in 32 countries selected by three criteria relative to Malaysia: major heroin problem, geographic proximity, and comparable gross domestic product (GDP) per capita.
Principal Findings
Medication, and urine and blood testing accounted for the greatest percentage of total costs for both naltrexone (29–53 percent) and buprenorphine (33–72 percent) interventions. In 13 countries, buprenorphine treatment could be provided for under $2,000 per patient. For all countries except United Kingdom and Singapore, incremental costs per person were below $1,000 when comparing buprenorphine to naltrexone. An estimated 100 percent of opiate users in Cambodia and Lao People's Democratic Republic could be treated for $8 and $30 million, respectively.
Conclusions
Buprenorphine treatment can be provided at low cost in countries across the world. This study's new costing methodologies provide tools for health systems worldwide to determine the feasibility and cost of similar interventions.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background/Aims
The COVID-19 pandemic has hugely impacted on the structure of rheumatology services across the country and remote consultations have become a familiarity. It is important to ...understand the effectiveness of new patient consultations conducted over the telephone, whether there is a role to continue using teleconsultations to triage referrals and whether there is a difference in outcomes based on the type of initial consultation telephone or face-to-face (F2F).
Methods
All new referrals to our department that received an initial telephone consultation over a 2-month period (October-November 2020) were identified. The conversion rate to a F2F consultation and discharge rates were calculated. Referrals were also separated into two groups based on the referral details early inflammatory arthritis (EIA) and non-early inflammatory arthritis (non-EIA). Patients ultimately diagnosed with inflammatory arthritis (IA) were identified and separated into two groups according to their initial consultation; initial telephone consultation (October-November 2020) and initial F2F consultation (March-April 2021). The time from first encounter to disease-modifying antirheumatic drug (DMARD) initiation was calculated and compared between the two groups.
Results
October-November 2020: 154 new patient referrals had teleconsultation for their first appointment (44% were EIA referrals). 56% of the 154 patients were given a F2F appointment following the telephone consultation. The conversion rate was higher in the EIA group in comparison to the non-EIA group (69% vs 41%). 10 patients were diagnosed with IA (8 were EIA referrals) and the average time to initiation of DMARD was 55 days. 19% of the 154 patients were discharged following the initial telephone consultation, of which 72% were non-EIA referrals, with the most common diagnoses being mechanical/degenerative problems and fibromyalgia. These results were presented at a departmental meeting and it was agreed that all future new EIA referrals should have an initial F2F consultation to minimise the number of consultations and potential delays in treatment. March-April 2021: 319 patients had a F2F consultation for their first consultation. There were 39 patients with confirmed IA in this group (36 were EIA referrals). The average time to initiation of DMARD was 22 days, with 40% starting a DMARD on initial consultation.
Conclusion
There seems to be a role for teleconsultation for new patient referrals, as evidenced by a 19% discharge rate. However, high conversion rates to F2F appointment in the EIA group suggests that initial teleconsultations were not only ineffective but also led to slower DMARD initiation. One limitation of this project was that EIA patient sample sizes were small. As our specialty continues to utilise other modes of consultation beyond traditional F2F reviews, we must adapt and better identify which patients are most suitable for each particular mode of consultation.
Disclosure
Y. Man: None. S. Patel: None. N. Ng: None.
Abstract
Background/Aims
Psychiatric comorbidities are common in patients living with rheumatological conditions and are associated with poorer health outcomes and treatment response. The evidence ...base for psychological intervention is scarce and of poor quality. One trial has found CBT intervention early post-diagnosis of rheumatoid arthritis has small to medium effect sizes for depression and anxiety and no effect on disability. Acceptance and Commitment Therapy (ACT) is a psychological therapy with a good evidence base for a number of long term health conditions. The target process in ACT is psychological flexibility, which relates closely to a number of positive life outcomes including adaptive response to illness and trauma. Psychological inflexibility has been shown to be associated with poorer function and psychological wellbeing in chronic pain populations and more recently juvenile idiopathic arthritis specifically. We aimed to evaluate outcomes for a sample (n = 12) of newly diagnosed (within 3 years of diagnosis) patients with inflammatory arthritis who underwent an individualised ACT intervention using patient satisfaction data, qualitative feedback and measures of mood, quality of life and psychological flexibility.
Methods
Patients received up to 7 sessions of one to one therapy. Outcome measures included PHQ-9, GAD-7, compACT, and Brief Pain Inventory (BPI) and a satisfaction questionnaire with open questions inviting qualitative responses. Paired t-tests were conducted, and the Jacobson and Truax method used to calculate Reliable Change Index and Clinically Significant Change criteria. Effect sizes were calculated using Cohens’ d. Correlation analysis was conducted using Pearsons correlation coefficients.
Results
Patients who took part in the brief intervention showed significant improvement in depression, anxiety, quality of life and psychological flexibility. Effect sizes were large. Correlation analysis showed strong correlations between PF and both depression and quality of life. Changes in PF from baseline to end of therapy strongly correlated with changes in depression and disability, and moderately correlated with anxiety. Subanalyses will be presented to understand which particular components of PF most closely relate to improvements in outcomes on disability and mood.
Conclusion
A brief one to one ACT-based psychological intervention conferred good benefit for a rheumatology population. Results suggest PF is a key therapeutic target in psychological interventions for people with arthritis and that ACT is a viable, highly acceptable and promising alternative to CBT in this population. More studies are needed to understand whether this effect is generalisable and longer-term outcomes.
Disclosure
L. Maher-Edwards: None. N. Ng: None. D. Gillanders: None.
Abstract
Background
Psychiatric comorbidities are common in patients living with rheumatological conditions and are associated with poorer health outcomes and treatment response. The evidence-base ...for psychological intervention in this population is scarce. Acceptance- and mindfulness-based cognitive therapies are of increasing popularity. Acceptance and Commitment Therapy (ACT) is a psychological therapy with a robust evidence-base for mood disorders and long-term health conditions, in particular in chronic pain populations. ACT aims to help clients to develop skills to identify and let go of unhelpful patterns of symptom control and avoidance so that they can move towards important life areas (values) and goals. Research has consistently shown that higher levels of acceptance (a component of psychological flexibility) in chronic illness is associated with better quality of life and emotional well-being. No studies have looked at the effects of ACT-based interventions in rheumatology. This study aimed to: Develop and pilot I) a 6-week group and II) a brief (up to 6 sessions) one to one intervention based on Acceptance and Commitment Therapy (ACT) in a rheumatology population. Outcomes were evaluated using patient satisfaction data, qualitative feedback and quantitative outcomes using a range of questionnaires measuring mood, quality of life and psychological flexibility.
Methods
Patients attending a rheumatology psychology service received either group OR brief one to one intervention delivered by a qualified psychologist. Group consisted of 6 sessions; each session was 3 hours (18 hours total). The brief one to one intervention consisted of up to 6 one-hour face to face sessions (max 6 hours total). A range of outcome measures were administered pre- and post-treatment. Paired t-tests were conducted, and the Jacobson and Truax method used to calculate Reliable Change Index and Clinically Significant Change criteria. Effect sizes were calculated using Cohens’ d. For comparison published data in chronic pain populations were used.
Results
Patients responded well to ACT-based interventions: with improvements in mood, psychological flexibility and quality of life. All effect sizes were large and compared favourably to published trials in chronic pain populations. Group participants showed significant improvements in depression and psychological flexibility pre- to post- treatment. On the other hand, participants who received the brief one to one intervention showed significant improvements on all measures. Overall those who had group therapy showed smaller improvements in outcome measures, rated themselves as less improved and were less satisfied with their therapy than those that received up to 6 sessions of individualised therapy.
Conclusion
A brief one to one intervention of up to 6 sessions of ACT-based psychological therapy conferred good benefit for a rheumatology population and outperformed group therapy. More studies are needed to understand whether this effect is generalisable and longer-term outcomes.
Disclosures
L. Maher-Edwards None. A. Quigley None. D. Gillanders None. N. Ng None.
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