Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.

BACKGROUND: In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. RESULTS: In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. CONCLUSIONS: Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Factors associated with atherosclerosis in radiographic and non-radiographic axial spondyloarthritis. A multicenter study on 838 patients.

OBJECTIVES: To identify disease-related factors associated with subclinical atherosclerosis and cardiovascular (CV) events in a large series of patients with axial spondyloarthritis (axSpA) and to identify possible differences in the effect of the potential pro-atherogenic factors between ankylosing spondylitis (AS) non-radiographic axSpA (nr-axSpA). METHODS: This is a cross-sectional observational study of the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Subclinical atherosclerosis determined by carotid ultrasound included assessment of carotid intima-media thickness (cIMT) and plaque detection. RESULTS: 639 AS and 167 nr-axSpA patients were recruited. CV risk factors (CRF) and several disease-related factors showed a statistically significant association with subclinical atherosclerosis in the crude analysis. After adjustment for age, sex, and smoking (model 1), associations remained statistically significant for spinal mobility, inflammatory bowel disease, use of prednisone, and Disease-modifying antirheumatic drugs (DMARD) when assessing carotid plaques and for acute phase reactants (APR) at diagnosis, use of prednisone, DMARD, and TNF-inhibitors when measuring cIMT. In model 2, which also included classic CRF as confounding factors to identify axSpA features with a potential independent pro-atherogenic effect, the functional status was the only variable significantly associated with plaques and the use of prednisone and APR at diagnosis with cIMT. No association differences were found between both subtypes of patients. Besides, APR at diagnosis were also associated with subsequent development of CV events that had occurred in 33 patients. CONCLUSION: Apart from CRF, atherosclerotic disease in AxSpA is associated with disease-related factors such as inflammatory response and disease severity, with no differences between AS and nr-axSpA.

Potential relation of cardiovascular risk factors to disease activity in patients with axial spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) patients are known to have a higher prevalence of several comorbidities, including, among others, an increased risk of atherosclerosis, hypertension, dyslipidemia, and diabetes. The purpose of the present study was to determine whether the sum of traditional cardiovascular (CV) risk factors is related to disease characteristics, such as disease activity, in patients with axSpA. METHODS: A cross-sectional study that encompassed 804 patients with axSpA was conducted. Patients were assessed for the presence of five traditional CV risk factors (diabetes mellitus, dyslipidemia, hypertension, obesity, and smoking status), and disease activity measurements. A multivariable regression analysis was performed to evaluate whether the number of classic CV risk factors was independently associated with specific features of the disease, to include disease activity. RESULTS: A multivariable analysis showed that Ankylosing Spondylitis Disease Activity Score-C reactive protein (ASDAS-CRP) activity score was significantly higher in patients with 1 [beta coefficient 0.3 (95% confidence interval (CI) 0.1-0.5), p = 0.001] and ⩾2 [beta coefficient 0.5 (95% CI 0.3-0.7), p = 0.000] CV risk factors compared with those without CV risk factors. Similarly, patients with 1 [OR 2.00 (95%CI 0.99-4.02), p = 0.053] and ⩾2 [OR 3.39 (95%CI 1.82-6.31), p = 0.000] CV risk factors had a higher odds ratio for the presence of high disease activity compared with the zero CV category. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) activity score was significantly associated with the number of CV risk factors, being higher in patients with more CV risk factors. These relationships showed a CV risk factor-dependent effect being beta coefficients and ORs higher for the effect of ⩾2 over 1 CV risk factor. CONCLUSION: Among patients with axSpA, as the number of traditional CV risk factors increased, disease activity similarly increases in an independent manner.

Long-term etanercept survival in patients with psoriatic arthritis: a multicenter retrospective analysis in daily clinical practice in Spain.

Although several randomized clinical trials and observational studies have evaluated the effectiveness, safety and drug survival of etanercept (ETN) in the treatment of psoriatic arthritis (PsA), long-term data regarding these aspects are currently scarce. For this reason, we sought to investigate the long-term survival and safety of ETN in PsA patients in 4 tertiary care Spanish hospitals over a 13-year observation period (from 2004 to 2017). The records of 85 PsA patients were reviewed. ETN showed an excellent survival profile, with rates of treatment discontinuation at 1, 3, 5 and 10 years of 15, 37, 46 and 59%, respectively. In our cohort, a trend toward longer drug survival in patients with shorter disease duration and those who were treated with ETN as their first biologic agent was observed. On the other hand, combination therapy with conventional disease-modifying antirheumatic drugs did not provide greater improvement on the long-term drug survival. Only 12% of the patients reported adverse events (AEs) during therapy, being most of them of mild to moderate intensity, and in only 7% AEs led to drug discontinuation. To the best of our knowledge, the present study shows the largest follow-up period of ETN-treated population analyzed in a real-life setting, and these results demonstrate the positive safety profile and long-term effectiveness of this biologic agent in the management of PsA patients.

Points to Consider in the Foundation of Multidisciplinary Units for Psoriatic Arthritis: A Delphi Study and a Systematic Review of the Literature.

INTRODUCTION: In numerous clinical practice guidelines, emphasis is placed on the need for coordinated care of psoriatic arthritis (PsA) between rheumatologists and the objective was to develop experience-based points to consider facilitating the implementation of multidisciplinary units (Dermatology/Rheumatology) for the management of patients with PsA. METHODS: A scientific committee of rheumatology and dermatology experts in the management of PsA, and with experience in joint care, discussed the critical aspects of multidisciplinary PsA Units. The discussion became the basis for a Delphi survey in two rounds submitted to a panel of 24 specialists in rheumatology and dermatology not involved in PsA units. The statements and practices that reached a consensus were summarized and further elaborated. RESULTS: After two Delphi rounds, agreement was reached for 49 of the 50 proposed statements. These included a justification of the units, objectives, and utilities, as well as operational aspects of the units, such as the minimal and ideal premises, referral criteria, and necessary resources. The statements were compiled in 11 points to consider. CONCLUSIONS: This consensus offers some points to consider, including premises and recommendations, for the development of specialized Units in the management of PsA based on expert opinion. We trust these guidelines may facilitate their implementation in the future. FUNDING: Pfizer.

Multi-examiner reliability of automated radio frequency-based ultrasound measurements of common carotid intima-media thickness in rheumatoid arthritis.

OBJECTIVES: To assess the reliability of the automated radio frequency (RF)-based US measurement of carotid intima-media thickness (IMT) performed by rheumatologists and to evaluate the variability between this method and the conventional B-mode US measurement of carotid IMT in RA patients. METHODS: Twelve rheumatologists measured in two blinded rounds the IMT of both common carotid arteries (CCAs) of seven RA patients with an automated RF-based method. At each round, a cardiologist measured both CCA-IMTs of the patients using an automated B-mode method. Inter-observer reliability for RF-based IMT measurements was evaluated by the intra-class correlation coefficient (ICC). Intra-observer reliability for RF-based IMT measurements was assessed using the root mean square coefficient of variation (RMS-CV), Bland-Altman method and ICC. Agreement between the two US methods was evaluated by the Bland-Altman method, ICC and RMS-CV. RESULTS: Inter-observer ICCs for the RF-based CCA-IMT measurements were 0.85 (95% CI 0.69, 0.94) for the first round, and 0.77 (95% CI 0.55, 0.91) for the second round. RMS-CVs for the RF-based CCA-IMT measurements varied from 5.6 to 11.7%. The mean intra-observer ICC for the RF-based CCA-IMT measurements was 0.61 (95% CI 0.46, 0.71). In the Bland-Altman analysis for agreement between RF-based and B-mode CCA-IMT measurements, the mean difference varied from -0.6 to -19.7 µm. Inter-method ICCs varied from 0.57 to 0.83 for 11 rheumatologists. Inter-method RMS-CVs varied from 11.3 to 13.7%. CONCLUSIONS: Our results suggest that automated RF-based CCA-IMT measurement performed by rheumatologists can be a reliable method for assessing cardiovascular risk in RA patients.