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.

Preventing organ damage in systemic lupus erythematosus: the impact of early biological treatment.

INTRODUCTION: One of the most important aims in the management of systemic lupus erythematosus (SLE) is to avoid or delay the accumulation of organ damage. The first five years after diagnosis are crucial for prognosis. AREAS COVERED: This manuscript reviews available data on organ damage accrual in SLE and early therapeutic intervention as a possible strategy to prevent its long-term accrual. EXPERT OPINION: Organ damage can be minimized by controlling disease activity and risk of flares, reducing the dose of glucocorticoids, and ensuring a proper therapeutic intervention with an early introduction of the right therapies. The current standard treatment cannot provide clinical remission in all patients with SLE. Therefore, there is a clinical need for introducing new therapeutic strategies able to achieve the main therapeutic objectives. The addition of biologic and other therapeutic agents to the standard of care is effective for controlling disease activity and for preventing severe flares, enabling a reduced use of glucocorticoids, and presumably reducing organ damage progression. Considering its efficacy and safety, early inclusion of biologic agents in the first lines of the treatment algorithm, at least in certain patients, could be considered as an innovative treatment approach to decrease disease burden in SLE patients.

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. FINDINGS: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. INTERPRETATION: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. FUNDING: The Instituto de Salud Carlos III.

Correlation of fatigue with other disease related and psychosocial factors in patients with rheumatoid arthritis treated with tocilizumab: ACT-AXIS study.

To assess the hypothesis if tocilizumab (TCZ) is effective on disease activity, and also its effect in fatigue and other clinical and psychological disease-related factors in patients with rheumatoid arthritis (RA) treated with TCZ.A 24-week, multicenter, prospective, observational study in patients with moderate to severe RA receiving TCZ after failure or intolerance to disease-modifying antirheumatic drugs or tumor necrosis factor-alpha was conducted.Of the 122 patients included, 85 were evaluable for effectiveness (85% female, 51.9 ±â€Š12.5 years, disease duration 8.7 ±â€Š7.4 years). Mean change in C-reactive protein level from baseline to week 12 was -11.2 ±â€Š4.0 (P < .001). Mean Disease Activity Index score (DAS28) decreased from 5.5 ±â€Š1.0 at baseline to 2.7 ±â€Š1.3 (P < .001) at week 24. Mean change in Functional Assessment of Chronic Illness Therapy score was -5.4 ±â€Š11.2 points at week 24. Multiple regression analysis showed that the improvement in DAS28, sleep, and depression explained 56% and 47% of fatigue variance at week 12 and 24, respectively.Tocilizumab is effective in reducing disease activity and results in a clinically significant improvement in fatigue, pain, swollen joint count, morning stiffness, sleepiness, depression, and DAS28; the last 3 were specifically identified as factors explaining fatigue variance with the use of TCZ in RA patients.