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OBJECTIVE:Determine the contribution of joint and skin improvements to health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). METHODS:SPIRIT-P1 and SPIRIT-P2 are phase 3 trials investigating ixekizumab, an interleukin-17A antagonist, in the treatment of patients with active PsA. Patients were randomised to ixekizumab or placebo. Outcomes included the Disease Activity Index for Psoriatic Arthritis (DAPSA), the Psoriasis Area and Severity Index (PASI), the European Quality of Life-Five Dimensions (EQ-5D) Visual Analogue Score (VAS), the 36-Item Short-Form Health Survey (SF-36) and the Work Productivity and Activity Impairment (WPAI) Questionnaire. The contribution of joint and skin improvements to HRQoL was modelled using a smoothing spline method and depicted with response surface graphics. RESULTS:In this integrated analysis, 402 patients with PsA had baseline psoriasis of ≥3% of body surface area. We applied response surface modelling to this patient data set to investigate the relationship between DAPSA, PASI and HRQoL improvements at week 24. The greatest improvement in EQ-5D VAS was associated with the largest per cent improvements in both DAPSA and PASI together, rather than DAPSA or PASI alone. Similar observations were made in domains of SF-36 and WPAI. CONCLUSION:Optimal improvements in patients' HRQoL were dependent on successful treatment of both joint and skin symptoms.

Objective: To evaluate the effect of withdrawing ixekizumab in patients with psoriatic arthritis (PsA) in whom minimal disease activity (MDA) has been achieved after open‐label ixekizumab treatment. Methods: SPIRIT‐P3 was a multicenter, randomized, double‐blind withdrawal study of biologic treatment–naive adult patients with PsA who were treated with open‐label ixekizumab for 36 weeks (160 mg at week 0, then 80 mg every 2 weeks). Patients in whom MDA was sustained for >3 consecutive months were randomized 1:1, between weeks 36 and 64, to undergo blinded withdrawal of ixekizumab treatment (placebo) or to continue ixekizumab treatment every 2 weeks up to week 104. The primary efficacy end point was time to relapse (loss of MDA) for randomized patients. Patients who experienced a relapse were re‐treated with ixekizumab every 2 weeks up to week 104. Results: A total of 394 patients were enrolled and received open‐label ixekizumab every 2 weeks. Of those patients, 158 (40%) achieved sustained MDA and were randomized to undergo withdrawal of ixekizumab treatment (placebo every 2 weeks; n = 79) or to continue ixekizumab treatment every 2 weeks (n = 79). Disease relapse occurred more rapidly with treatment withdrawal (median 22.3 weeks [95% confidence interval (95% CI) 16.1–28.3]) compared to those who continued treatment with ixekizumab (median not estimable; P < 0.0001). Sixty‐seven patients (85%) compared to 30 patients (38%) experienced relapse in the placebo group and the continued treatment group, respectively. Median time to achieving MDA again with re‐treatment was 4.1 weeks (95% CI 4.1–4.3); in 64 of 67 patients (96%) who experienced relapse with treatment withdrawal, MDA was achieved again with re‐treatment. Safety was consistent with the known safety profile for ixekizumab. Conclusion: Continued ixekizumab therapy is superior to ixekizumab withdrawal in maintaining low disease activity in biologic treatment–naive patients with PsA. Re‐treatment with ixekizumab following a relapse may restore disease control in cases of treatment interruption. [ABSTRACT FROM AUTHOR]

IL-10 is an immunoregulatory cytokine that has broad effects across the immune system. In Th cell subsets, Th2 cells produce considerable amounts of IL-10. The transcription factors that regulate IL-10 production in Th2 cells are still incompletely described. In this study, we demonstrate that the ETS family transcription factor ETS variant (Etv)5 regulates IL-10 production in Th2 cells. T cell-specific Etv5-deficient and littermate control mice demonstrated that IL-10 production and gene expression were significantly decreased in the absence of Etv5. In an Aspergillus fumigatus extract-induced inflammation model, IL-10-producing CD4+ T cells in bronchoalveolar lavage and lung were significantly decreased in mice that lacked Etv5 in T cells, compared with control mice. We showed that Etv5 directly binds to the Il10 locus conserved noncoding sequence 3 site and that it activates gene expression in a luciferase reporter assay and following retroviral transduction. Etv5 deficiency did not affect the expression of other transcription factors known to be important for expression of IL-10, including Jun family members, GATA3, E4BP4, and IFN regulatory factor 4. However, in the absence of Etv5, binding of these transcription factors to the Il10 locus was dramatically reduced. Ectopic Etv5 expression in Th2 cells that lack Etv5 restored IL-10 production and the binding of IL-10-inducing transcription factors including E4BP4, IFN regulatory factor 4, and GATA3. Taken together, we conclude that Etv5 plays a crucial role in regulating IL-10 production in Th2 cells by facilitating the binding of IL-10-inducing transcription factors at the Il10 locus. [ABSTRACT FROM AUTHOR]

The IL-9-secreting Th9 subset of CD4 Th cells develop in response to an environment containing IL-4 and TGF-β, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report, we demonstrate that the ETS transcription factor ETS variant 5 (ETV5) promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct effects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) infection in the respiratory tract triggers robust innate and adaptive immune responses, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of ongoing inflammation and tissue repair occur during a distinct recovery period. B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV infection, but their potential role during recovery and resolution of inflammation is unknown. We found that antibody-mediated CD86 blockade in vivo after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in airways and lung interstitium, but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3+ regulatory T cells (Tregs), and adoptive transfer of Tregs into αCD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Specific depletion of Tregs late after infection mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Furthermore, we identified neutrophils as a target of Treg suppression since neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that Tregs, in a CD86 dependent mechanism, contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is a leading cause of respiratory tract disease worldwide. Anti-viral CD8+ T lymphocytes responding to IAV infection are believed to eliminate virally infected cells by direct cytolysis but may also contribute to pulmonary inflammation and tissue damage via the release of pro-inflammatory mediators following recognition of viral antigen displaying cells. We have previously demonstrated that IAV antigen expressing inflammatory cells of hematopoietic origin within the infected lung interstitium serve as antigen presenting cells (APC) for infiltrating effector CD8+ T lymphocytes; however, the spectrum of inflammatory cell types capable of serving as APC was not determined. Here, we demonstrate that viral antigen displaying neutrophils infiltrating the IAV infected lungs are an important cell type capable of acting as APC for effector CD8+ T lymphocytes in the infected lungs and that neutrophils expressing viral antigen as a result of direct infection by IAV exhibit the most potent APC activity. Our findings suggest that in addition to their suggested role in induction of the innate immune responses to IAV, virus clearance, and the development of pulmonary injury, neutrophils can serve as APCs to anti-viral effector CD8+ T cells within the infected lung interstitium. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) play a prominent role in the resolution of viral infections through their capacity both to mediate contact-dependent lysis of infected cells and to release soluble proinflammatory cytokines and chemokines. The factors controlling these antiviral effector activities in vivo at infection sites are ill defined. Using a mouse model of influenza infection, we observed that the expression of CTL effector activity in the infected lungs is dictated by the target cell type encountered. CD45(+) lung infiltrating inflammatory mononuclear cells, particularly CD11c(hi) dendritic cells, trigger both CTL cytotoxicity and release of inflammatory mediators, whereas CD45(-) influenza-infected respiratory epithelial cells stimulate only CTL cytotoxicity. CTL proinflammatory mediator release is modulated by co-stimulatory ligands (CD80 and CD86) expressed by the CD45(+) inflammatory cells. These findings suggest novel mechanisms of control of CTL effector activity and have potentially important implications for the control of excess pulmonary inflammation and immunopathology while preserving optimal viral clearance during respiratory virus infections.