Obesity reduces the real-world effectiveness of cytokine-targeted but not cell-targeted disease-modifying agents in rheumatoid arthritis.

OBJECTIVES: The effectiveness of TNF inhibitors in RA has been shown to be affected by obesity. No such effect has been found for abatacept and rituximab, while for tocilizumab results are ambiguous. Additionally, it remains unresolved whether sex is an effect modifier for obesity. We investigated the impact of obesity on the drug effectiveness of conventional synthetic or biologic DMARDs, taking into account potential sex-specific differences. METHODS: Data from 10 593 RA patients included in the German observational cohort study Rheumatoid Arthritis: oBservation of BIologic Therapy (RABBIT) since 2009 were analysed. Patients had to have a BMI ≥18.5 kg/m2, at least one follow-up and 6 months of observation time. The influence of obesity on drug effectiveness was investigated by regression analysis, adjusting for potential confounders. RESULTS: Obesity had a negative impact on improvement in the DAS with 28 joints using ESR as an inflammation marker of -0.15 (95% CI: -0.26; -0.04) units for women receiving conventional synthetic DMARDs, -0.22 (95% CI: -0.31; -0.12) units for women receiving TNF inhibitors, -0.22 (95% CI: -0.42; -0.03) units for women receiving tocilizumab and -0.41 (95% CI: -0.74; -0.07) units for men receiving tocilizumab. Overall, no negative obesity effects on the effectiveness of rituximab and abatacept were found. CONCLUSION: Obesity has a negative impact on the effectiveness of cytokine-targeted but not cell-targeted therapies in daily practice, affecting more outcomes and therapies in women than in men. Overall, no effects of obesity on treatment effectiveness were found for rituximab and abatacept.

SLAMF7 (CD319) on activated CD8+ T cells transduces environmental cues to initiate cytotoxic effector cell responses.

CD8+ T-cell responses are meticulously orchestrated processes regulated by intercellular receptor:ligand interactions. These interactions critically control the dynamics of CD8+ T-cell populations that is crucial to overcome threats such as viral infections or cancer. Yet, the mechanisms governing these dynamics remain incompletely elucidated. Here, we identified a hitherto unknown T-cell referred function of the self-ligating surface receptor SLAMF7 (CD319) on CD8+ T cells during initiation of cytotoxic T-cell responses. According to its cytotoxicity related expression on T effector cells, we found that CD8+ T cells could utilize SLAMF7 to transduce environmental cues into cellular interactions and information exchange. Indeed, SLAMF7 facilitated a dose-dependent formation of stable homotypic contacts that ultimately resulted in stable cell-contacts, quorum populations and commitment to expansion and differentiation. Using pull-down assays and network analyses, we identified novel SLAMF7-binding intracellular signaling molecules including the CRK, CRKL, and Nck adaptors, which are involved in T-cell contact formation and may mediate SLAMF7 functions in sensing and adhesion. Hence, providing SLAMF7 signals during antigen recognition of CD8+ T cells enhanced their overall magnitude, particularly in responses towards low-affinity antigens, resulting in a significant boost in their proliferation and cytotoxic capacity. Overall, we have identified and characterized a potent initiator of the cytotoxic T lymphocyte response program and revealed advanced mechanisms to improve CD8+ T-cell response decisions against weak viral or tumor-associated antigens, thereby strengthening our defense against such adversaries.

Golimumab improves patient-reported outcomes in daily practice of inflammatory rheumatic diseases in Germany.

Aim: To analyze the quality of life (QoL), work productivity and activity impairment (WPAI) and healthcare resource utilization (HCRU) in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients receiving golimumab under routine clinical settings in Germany. Materials & methods: Prospective observational study, GO-ART, analyzed changes in WPAI, QoL and HCRU during 24 months of golimumab therapy. Results: Seven hundred and forty-eight patients (RA = 250, PsA = 249 and AS = 249) were enrolled. Substantial improvements in WPAI scores presenteeism, activity impairment and total work productivity impairment and QoL were observed at month three and were maintained through month 24. Fewer patients had disease-related hospitalizations and consulted physician at month 24 than at the baseline. Conclusion: Golimumab induces sustained improvements in WPAI and QoL and reduces healthcare resource utilization in RA, PsA and AS.