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

Background: Tumor necrosis factor alpha (TNFalpha) 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-TNFalpha 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 \u3e /=20 mg equivalent prednisone dose (n=32), 63% resulted in indeterminate QFT-GIT, compared to only 6% indeterminate testing in patients receiving \u3c 20 mg of equivalent prednisone dose (n=164, P \u3c 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

Body mass index and treatment survival in patients with RA starting treatment with TNFalpha-inhibitors: long-term follow-up in the real-life METEOR registry

OBJECTIVES: To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry. METHODS: Data from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI \u3c 18.5 kg/m(2); 46% normal weight, BMI 18.5-25 kg/m(2); 32% pre-obesity, BMI 25-30 kg/m(2); 13% obesity class I, BMI 30-35 kg/m(2); 3.4% obesity class II, BMI 35-40 kg/m(2); and 1.6% obesity class III, BMI \u3e 40 kg/m(2). Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan-Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days. RESULTS: Patients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found. CONCLUSION: Both underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients

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)). However, only minor differences were noted between definitions (range of adjusted OR 1.99 to 3.36). Sensitivity analyses yield similar results. Conclusions: 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

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

Assessment of control of rheumatoid arthritis disease activity

As very effective targeted biological therapies have become available to treat rheumatoid arthritis (RA), remission is now the goal of treatment. Since 1981, efforts have been undertaken to develop criteria for clinical remission in RA. Although several different measures of disease activity have been proposed, many issues remain unresolved. Active joint inflammation, even if involving only a few joints, negatively impacts a patient\u27s quality of life and may ultimately result in structural damage. Thus, a low disease activity state (LDAS), which has been adopted as the target in clinical trials of \u27treat to target\u27, may not be the optimal treatment target in clinical practice. Similarly, the definitions of remission used in clinical trials may not be appropriate for use in daily clinical practice because some allow for the presence of several tender and swollen joints. Measures of disease activity do not necessarily correlate with structural remission, which implies halting progression of radiographic evidence of damage over time. Because no single measure of RA disease activity fully quantifies the global burden of disease, rheumatologists must follow multiple parameters to assess disease activity thoroughly and to adjust treatment optimally

Inequity in access to bDMARD care and how it influences disease outcomes across countries worldwide: Results from the METEOR-registry

Objective: To establish in a global setting the relationships between countries' socioeconomic status (SES), measured biological disease modifying antirheumatic drug (bDMARD)-usage and disease outcomes. To assess if prescription and reimbursement rules and generic access to medication relates to a countries' bDMARD-usage. Methods: Data on disease activity and drug use from countries that had contributed at least 100 patients were extracted from the METEOR database. Mean disease outcomes of all available patients at the final visit were calculated on a per-country basis. A questionnaire was sent to at least two rheumatologists per country inquiring about DMARD-prices, access to treatment and valid regulations for prescription and reimbursement. Results: Data from 20 379 patients living in 12 different countries showed that countries' SES was positively associated with measured disease activity (meanDAS28), but not always with physical functioning (HAQ-score). A lower country's SES, stricter rules for prescription and reimbursement of bDMARDs as well as worse affordability of bDMARDs were associated with lower bDMARD-usage. bDMARD-usage was negatively associated with disease activity (although not with physical functioning), but the association was moderate at best. Conclusions: Disease activity in patients with rheumatoid arthritis as well as bDMARD-usage varies across countries worldwide. The (negative) relationship between countries' bDMARD-usage and level of disease activity is complex and under the influence of many factors, including - but not limited to - countries' SES, affordability of bDMARDs and valid prescription and reimbursement rules for bDMARDs

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis