IL-6 Signaling Attenuates TNF-α Production by Plasmacytoid Dendritic Cells in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is characterized by autoimmune joint destruction with debilitating consequences. Despite treatment advancements with biologic therapies, a significant proportion of RA patients show an inadequate clinical response, and restoration of immune self-tolerance represents an unmet therapeutic need. We have previously described a tolerogenic phenotype of plasmacytoid dendritic cells (pDCs) in RA patients responding to anti-TNF-α agents. However, the molecular mechanisms involved in tolerogenic reprogramming of pDCs in RA remain elusive. In this study, guided by transcriptomic analysis of CD303+CD123+ pDCs from RA patients in remission, we revealed enhanced expression of IL-6R and its downstream signaling compared with healthy pDCs. Functional assessment demonstrated that IL-6R engagement resulted in marked reduction of TNF-α secretion by pDCs whereas intracellular TNF-α was significantly increased. Accordingly, pharmacologic inhibition of IL-6R signaling restored TNF-α secretion levels by pDCs. Mechanistic analysis demonstrated impaired activity and decreased lysosomal degradation of ADAM17 (a disintegrin and metalloproteinase 17) sheddase in pDCs, which is essential for TNF-α cleavage. Importantly, reduction of TNF-α secretion by IL-6-treated pDCs attenuated the inflammatory potential of RA patient-derived synovial fibroblasts. Collectively, these findings position pDCs as an important source of TNF-α in RA pathogenesis and unravel an anti-inflammatory mechanism of IL-6 by limiting the pDC-derived TNF-α secretion.

Distinct long-term disease activity trajectories differentiate early on treatment with etanercept in both rheumatoid arthritis and spondylarthritis patients: a prospective cohort study.

To characterize disease activity trajectories and compare long-term drug retention between rheumatoid (RA) and spondylarthritis (SpA) patients initiating tumor necrosis factor inhibitor (TNFi) treatment (etanercept). Prospective observational study of RA, axial (AxSpA) and peripheral SpA (PerSpA) patients initiating etanercept during 2004-2020. Kaplan-Meier plots were used for drug retention comparisons and multivariable Cox regression models for predictors of discontinuation. Long-term disease activity trajectories were identified by latent class growth models using DAS28-ESR or ASDAS-CRP as outcome for RA and AxSpA respectively. We assessed 711 patients (450 RA, 178 AxSpA and 83 PerSpA) with a median (IQR) follow-up of 12 (5-32) months. At 5 years, 22%, 30% and 21% of RA, AxSpA and PerSpA patients, respectively, remained on therapy. Etanercept discontinuation was independent of the diagnosis and was predicted by gender and obesity in both RA and SpA groups. Four disease activity (DA) trajectories were identified from 6th month of treatment in both RA and AxSpA. RA patients in remission-low DA groups (33.7%) were younger, had shorter disease duration, fewer comorbidities and lower baseline disease activity compared to moderate (40.6%) & high DA (25.7%) groups. In AxSpA 74% were in inactive-low DA and they were more often males, non-obese and had lower number of comorbidities compared to higher ASDAS-CRP trajectories. In RA and AxSpA patients, disease activity trajectories revealed heterogeneity of TNFi treatment responses and prognosis. Male gender, lower baseline disease activity and fewer comorbidities, characterize a favourable outcome in terms of disease burden accrual and TNFi survival.

A Peripheral Blood Signature of Increased Th1 and Myeloid Cells Combined with Serum Inflammatory Mediators Is Associated with Response to Abatacept in Rheumatoid Arthritis Patients.

Abatacept (CTLA4-Ig)-a monoclonal antibody which restricts T cell activation-is an effective treatment for rheumatoid arthritis (RA). Nevertheless, only 50% of RA patients attain clinical responses, while predictors of response are rather limited. Herein, we aimed to investigate for early biomarkers of response to abatacept, based on a detailed immunological profiling of peripheral blood (PB) cells and serum proteins. We applied flow cytometry and proteomics analysis on PB immune cells and serum respectively, of RA patients starting abatacept as the first biologic agent. After 6 months of treatment, 34.5% of patients attained response. At baseline, Th1 and FoxP3+ T cell populations were positively correlated with tender joint counts (p-value = 0.047 and p-value = 0.022, respectively). Upon treatment, CTLA4-Ig effectively reduced the percentages of Th1 and Th17 only in responders (p-value = 0.0277 and p-value = 0.0042, respectively). Notably, baseline levels of Th1 and myeloid cell populations were significantly increased in PB of responders compared to non-responders (p-value = 0.009 and p-value = 0.03, respectively). Proteomics analysis revealed that several inflammatory mediators were present in serum of responders before therapy initiation and strikingly 10 amongst 303 serum proteins were associated with clinical responses. Finally, a composite index based on selected baseline cellular and proteomics' analysis could predict response to abatacept with a high sensitivity (90%) and specificity (88.24%).

Baseline IgG-Fc N-glycosylation profile is associated with long-term outcome in a cohort of early inflammatory arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease for which prediction of long-term prognosis from disease's outset is not clinically feasible. The importance of immunoglobulin G (IgG) and its Fc N-glycosylation in inflammation is well-known and studies described its relevance for several autoimmune diseases, including RA. Herein we assessed the association between IgG N-glycoforms and disease prognosis at 2 years in an early inflammatory arthritis cohort. METHODS: Sera from 118 patients with early inflammatory arthritis naïve to treatment sampled at baseline were used to obtain IgG Fc glycopeptides, which were then analyzed in a subclass-specific manner by liquid chromatography coupled to mass spectrometry (LC-MS). Patients were prospectively followed and a favorable prognosis at 2 years was assessed by a combined index as remission or low disease activity (DAS28 < 3.2) and normal functionality (HAQ ≤ 0.25) while on treatment with conventional synthetic DMARDs and never used biologic DMARDs. RESULTS: We observed a significant association between high levels of IgG2/3 Fc galactosylation (effect 0.627 and adjusted p value 0.036 for the fully galactosylated glycoform H5N4F1; effect -0.551 and adjusted p value 0.04963 for the agalactosylated H3N4F1) and favorable outcome after 2 years of treatment. The inclusion of IgG glycoprofiling in a multivariate analysis to predict the outcome (with HAQ, DAS28, RF, and ACPA included in the model) did not improve the prognostic performance of the model. CONCLUSION: Pending confirmation of these findings in larger cohorts, IgG glycosylation levels could be used as a prognostic marker in early arthritis, to overcome the limitations of the current prognostic tools.

Τhe Complete Mitochondrial Genome of Bactrocera carambolae (Diptera: Tephritidae): Genome Description and Phylogenetic Implications.

Bactrocera carambolae is one of the approximately 100 sibling species of the Bactrocera dorsalis complex and considered to be very closely related to B. dorsalis. Due to their high morphological similarity and overlapping distribution, as well as to their economic impact and quarantine status, the development of reliable markers for species delimitation between the two taxa is of great importance. Here we present the complete mitochondrial genome of B. carambolae sourced from its native range in Malaysia and its invaded territory in Suriname. The mitogenome of B. carambolae presents the typical organization of an insect mitochondrion. Comparisons of the analyzed B. carambolae sequences to all available complete mitochondrial sequences of B. dorsalis revealed several species-specific polymorphic sites. Phylogenetic analysis based on Bactrocera mitogenomes supports that B. carambolae is a differentiated taxon though closely related to B. dorsalis. The present complete mitochondrial sequences of B. carambolae could be used, in the frame of Integrative Taxonomy, for species discrimination and resolution of the phylogenetic relationships within this taxonomically challenging complex, which would facilitate the application of species-specific population suppression strategies, such as the sterile insect technique.