Influence of patient global assessment on the disease activity assessment in patients with rheumatoid arthritis: A meteor cross-sectional study

Background Disease activity indices (DAI) are used to guide immunosuppressive therapy in rheumatoid arthritis (RA). The inclusion of patient global assessment (PGA) in these indices has been questioned as it conveys mainly disease impact rather than disease activity.ObjectivesTo determine the influence of PGA on patient disease states and to determine PGA correlations with inflammatory parameters, disease impact, demographic, clinical and contextual factors

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required

Methods for high-dimensonal analysis of cells dissociated from cyropreserved synovial tissue

Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. Methods: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq. Results: Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified. Conclusions: We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers

The conundrum of indeterminate QuantiFERON-TB Gold results before anti-tumor necrosis factor initiation

Shahrad Hakimian,1 Yevgeniy Popov,1 Abbas H Rupawala,2 Karen Salomon-Escoto,3 Steven Hatch,4 Randall Pellish1,2 1Department of Medicine, 2Division of Gastroenterology, 3Division of Rheumatology, 4Division of Infectious Disease, UMass Memorial Medical Center, Worcester, MA, USA Background: Tumor necrosis factor alpha (TNFα) is a key cytokine in both the pathogenesis of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) and the host defense against tuberculosis (TB). Consequently, anti-TNFα medications result in an increased risk of latent TB infection (LTBI) reactivation. Here, we sought to evaluate the factors affecting the results of QuantiFERON-TB Gold In-Tube (QFT-GIT) assay as a screening tool for LTBI. Methods: We conducted an observational, retrospective study in patients with IBD and RA who underwent LTBI screening using QFT-GIT at UMass Memorial Medical Center between 2008 and 2016 prior to initiation of anti-TNF medications. Results: We included 107 and 89 patients with IBD and RA, respectively. We found that a higher proportion of IBD patients had indeterminate QFT-GIT result compared to RA patients. Furthermore, we found that the majority of patients with indeterminate results were tested during an acute flare of IBD (88%) and while taking corticosteroids. Of all patients receiving ≥20 mg equivalent prednisone dose (n=32), 63% resulted in indeterminate QFT-GIT, compared to only 6% indeterminate testing in patients receiving <20 mg of equivalent prednisone dose (n=164, P<0.001). There was no correlation between indeterminate results and age, gender, disease duration, or distribution, or smoking status within each population. Conclusion: We observed that high-dose corticosteroids may affect QFT-GIT outcomes leading to a high proportion of indeterminate results. We propose that IBD patients should be tested prior to initiation of corticosteroids to avoid equivocal results and prevent potential delays in initiation of anti-TNF medications. Keywords: indeterminate QuantiFERON-TB Gold, latent TB infection, inflammatory bowel disease, rheumatoid arthritis, corticosteroids, IBD flar

How to treat patients with rheumatoid arthritis when methotrexate has failed? The use of a multiple propensity score to adjust for confounding by indication in observational studies

Pathophysiology and treatment of rheumatic disease

Changes in physical function using three methods of scoring the Health Assessment Questionnaire in established active rheumatoid arthritis

Background: We investigated sensitivity to change of three scoring methods of the Health Assessment Questionnaire (HAQ) in relation to change in disease activity in patients with active rheumatoid arthritis (RA).Patients and Methods: Adult RA-patients with complete data in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database with respect to the 20 HAQ questions and disease activity score with 28-joint count using the erythrocyte sedimentation rate (DAS28-ESR) for 2 visits, at least 6-12 months apart, and high disease activity (DAS28-ESR >5.1) at visit 1. Changes in HAQ scored by the (1) conventional method (HAQ-8), (2) HAQ-Tomlin method (HAQ-T), and (3) HAQ-20-item method (HAQ-20) were analyzed in relation to the European League Against Rheumatism (EULAR) RA response criteria, dichotomized to good/moderate and no response.Results: In 421 patients, mean standard deviation (SD) DAS28-ESR declined significantly (6.1 [0.8]-4.8 [1.6], P = 0.22 was significantly higher in 47% of patients with EULAR good/moderate score compared to the no response patients (64% vs. 11%, P < 0.0001). Good/moderate EULAR response, higher baseline DAS28, and higher baseline HAQ (7.11, 1.55, and 1.06, respectively) were independent predictors of achieving a HAQ-MCII.Conclusion: Three HAQ scoring methods performed similarly in sensitivity to change with no advantage of alternative scoring methods compared to the conventional HAQ-8 method. A good/moderate EULAR response, despite long disease duration, was associated with a significant likelihood of achieving a HAQ-MCII.Pathophysiology and treatment of rheumatic disease

Country-level socioeconomic status relates geographical latitude to the onset of RA: a worldwide cross-sectional analysis in the METEOR registry

Objective:Age at rheumatoid arthritis (RA) onset varies by geographical latitude. We have investigated to what extent differences in patient-specific factors and country-level socioeconomic indicators explain this variability. Methods: Patients with RA from the worldwide METEOR registry were included. Bayesian multilevel structural equation models were used to study the relationship between the absolute value of (hospital) geographical latitude and age at diagnosis (as a proxy for age at RA onset). We examined to what extent this effect is mediated by individual patient characteristics and by country-specific socioeconomic indicators and disentangled whether the observed effects occurred at the patient, hospital, or country levels. Results: We included 37 981 patients from 93 hospitals in 17 geographically widespread countries. Mean age at diagnosis per country ranged from 39 (Iran) to 55 (Netherlands) years. Per degree increase in country latitude (between 9.9 degrees and 55.8 degrees), mean age at diagnosis increased by 0.23 years (95% credibility interval: 0.095 to 0.38) (reflecting >10 years difference in age at RA onset). For hospitals within a country, this latitude effect was negligible. Inclusion of patient-specific factors (eg, gender, anticitrullinated protein antibodies status) in the model augmented the main effect from 0.23 to 0.36 years. Inclusion of country-level socioeconomic indicators (eg, gross domestic product per capita) in the model almost effaced the main effect (from 0.23 to 0.051 (-0.37 to 0.38)). Conclusions: Patients living closer to the equator get RA at a younger age. This latitude gradient was not explained by individual patient characteristics, but rather by countries' socioeconomic status, providing a direct link between countries' level of welfare and the clinical onset of RA.Pathophysiology and treatment of rheumatic disease

Autoantibody status is not associated with early treatment response to first-line methotrexate in patients with early rheumatoid arthritis

Pathophysiology and treatment of rheumatic disease

Association of seventeen definitions of remission with functional status in a large clinical practice cohort of patients with rheumatoid arthritis

OBJECTIVE: To compare the association between different remission criteria and physical function in rheumatoid arthritis patients followed in clinical practice. METHODS: Longitudinal data from the METEOR database were used. Seventeen definitions of remission were tested: ACR/EULAR Boolean-based; Simplified/Clinical Disease Activity Index (SDAI/CDAI); and fourteen Disease Activity Score (DAS)-based definitions. Health Assessment Questionnaire (HAQ)≤0.5 was defined as good functional status. Associations were investigated using generalised estimating equations (GEE). Potential confounders were tested and sensitivity analyses performed. RESULTS: Data from 32,915 patients (157,899 visits) were available. The most stringent definition of remission was the ACR/EULAR Boolean-based definition (1.9%). The proportion of patients with HAQ≤0.5 was higher for the most stringent definitions, although it never reached 100%. However, this also meant that, for the most stringent criteria, many patients in non-remission had HAQ≤0.5. All remission definitions were associated with better function, with the strongest degree of association observed for the SDAI (adjusted OR (95% CI): 3.36 (3.01-3.74)). CONCLUSION: The seventeen definitions of remission confirmed their validity against physical function in a large international clinical practice setting. Achievement of remission, according to any of the indices may be more important than the use of a specific index. A multidimensional approach, targeted at wider goals than disease control, is necessary to help all patients achieve the best possible functional status