Discontinuation and switching patterns of tumour necrosis factor inhibitors (TNFis) in TNFi-naive and TNFi-experienced patients with psoriatic arthritis: an observational study from the US-based Corrona registry.

Objective: To examine patterns of tumour necrosis factor inhibitor (TNFi) use in TNFi-naive and TNFi-experienced patients with psoriatic arthritis (PsA) in the USA. Methods: All patients aged ≥18 years with PsA enrolled in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry who initiated a TNFi (index therapy) between March 2013 and January 2017 and had ≥1 follow-up visit were included. Times to and rates of discontinuation/switch of the index TNFi were compared between TNFi-naive and TNFi-experienced cohorts. Patient demographics and disease characteristics at the time of TNFi initiation (baseline) were compared between cohorts and between patients who continued versus discontinued their index TNFi by the first follow-up visit within each cohort. Results: This study included 171 TNFi-naive and 147 TNFi-experienced patients (total follow-up, 579.2 person-years). Overall, 75 of 171 TNFi-naive (43.9%) and 80 of 147 TNFi-experienced (54.4%) patients discontinued their index TNFi; 33 of 171 (19.3%) and 48 of 147 (32.7%), respectively, switched to a new biologic. TNFi-experienced patients had a shorter time to discontinuation (median, 20 vs 27 months) and were more likely to discontinue (p=0.03) or switch (p Conclusions: The results of this real-world study can help inform treatment decisions when selecting later lines of therapy for patients with PsA

Restoration of CD28 Expression in CD28− CD8+ Memory Effector T Cells Reconstitutes Antigen-induced IL-2 Production

The control of many persistent viral infections by Ag-specific cytolytic CD8+ T cells requires a concurrent virus-specific CD4+ Th cell response. This reflects in part a requirement of activated effector CD8+ T cells for paracrine IL-2 production as a growth and survival factor. In human CMV and HIV infection, the majority of differentiated virus-specific CD8+ T cells notably lose the ability to produce IL-2 but also lose expression of CD28, a costimulatory molecule. Analysis of the fraction of memory CD8+ T cells that continue to express CD28 revealed these cells retain the ability to produce IL-2. Therefore, we examined if IL-2 production by CD28− CD8+ T cells could be restored by introduction of a constitutively expressed CD28 gene. Expression of CD28 in CD28− CD8+ CMV- and HIV-specific CD8+ T cells reconstituted the ability to produce IL-2, which could sustain an autocrine proliferative response after Ag recognition. These results suggest that the loss of CD28 expression during differentiation of memory/effector CD8+ T cells represents a decisive step in establishing regulation of responding CD8+ T cells, increasing the dependence on CD4+ Th for proliferation after target recognition, and has implications for the treatment of viral disease with adoptively transferred CD8+ T cells

Baseline patient characteristics associated with response to biologic therapy in patients with psoriatic arthritis enrolled in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry.

Objectives: To compare baseline characteristics between patients with psoriatic arthritis (PsA) who achieved and did not achieve minimal disease activity (MDA) with biologic therapy in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Methods: Patients with PsA aged ≥18 years enrolled between March 2013 and March 2016 who were receiving biologics at enrolment (baseline), not in MDA and had ≥2 follow-up visits were included. Patients were classified as those who remained on their index biologic and achieved MDA at the second follow-up visit (MDA achievers (MDA-A)) and those who did not (MDA non-achievers (MDA-NA)). Demographics, clinical characteristics, patient-reported outcomes and medication history were compared between groups. Results: Of 148 patients with PsA who met the inclusion criteria, 34 (23.0%) and 114 (77.0%) were classified as MDA-A and MDA-NA, respectively. At baseline, most patients (96.6%) were receiving tumour necrosis factor inhibitors, and both groups were similar in age, sex, race, medication history, enthesitis and dactylitis counts, disease duration and comorbidities. Compared with MDA-A, MDA-NA had significantly worse mean tender joint count (7.2 vs 3.4), patient-reported pain (51.2 vs 35.7), patient-reported fatigue (54.1 vs 42.4), physical function (Health Assessment Questionnaire, 1.0 vs 0.6), Bath Ankylosing Disease Activity Index (5.0 vs 3.4) and Bath Ankylosing Spondylitis Functional Index (4.0 vs 2.0) scores (all p\u3c0.05). Conclusions: Approximately one in four patients achieved MDA with their index biologic at the time of the second follow-up visit. Both groups were similar in several baseline demographic and clinical features; however, patients who did not achieve MDA generally had worse tender joint counts and patient-reported outcomes

Neuroimaging Correlates of Suicidality in Decision-Making Circuits in Posttraumatic Stress Disorder

In depression, brain and behavioral correlates of decision-making differ between individuals with and without suicidal thoughts and behaviors. Though promising, it remains unknown if these potential biomarkers of suicidality will generalize to other high-risk clinical populations. To preliminarily assess whether brain structure or function tracked suicidality in individuals with posttraumatic stress disorder (PTSD), we measured resting-state functional connectivity and cortical thickness in two functional networks involved in decision-making, a ventral fronto-striatal reward network and a lateral frontal cognitive control network. Neuroimaging data and self-reported suicidality ratings, and suicide-related hospitalization data were obtained from 50 outpatients with PTSD and also from 15 healthy controls, and all were subjected to seed-based resting-state functional connectivity and cortical thickness analyses using a priori seeds from reward and cognitive control networks. First, general linear models (GLM) were used to evaluate whether ROI-to-ROI functional connectivity was predictive of self-reported suicidality after false discovery rate (FDR)-correction for multiple comparisons and covariance of age and depression symptoms. Next, regional cortical thickness statistics were included as predictors of ROI-to-ROI functional connectivity in follow-up GLMs evaluating structure-function relationships. Functional connectivity between reward regions was positively correlated with suicidality (p-FDR ≤ 0.05). Functional connectivity of the lateral pars orbitalis to anterior cingulate/paracingulate control regions also tracked suicidality (p-FDR ≤ 0.05). Furthermore, cortical thickness in anterior cingulate/paracingulate was associated with functional correlates of suicidality in the control network (p-FDR < 0.05). These results provide a preliminary demonstration that biomarkers of suicidality in decision-making networks observed in depression may generalize to PTSD and highlight the promise of these circuits as transdiagnostic biomarkers of suicidality

A Prospective Study of the Impact of Transcranial Alternating Current Stimulation on EEG Correlates of Somatosensory Perception

The (8–12 Hz) neocortical alpha rhythm is associated with shifts in attention across sensory systems, and is thought to represent a sensory gating mechanism for the inhibitory control of cortical processing. The present preliminary study sought to explore whether alpha frequency transcranial alternating current stimulation (tACS) could modulate endogenous alpha power in the somatosensory system, and whether the hypothesized modulation would causally impact perception of tactile stimuli at perceptual threshold. We combined electroencephalography (EEG) with simultaneous brief and intermittent tACS applied over primary somatosensory cortex at individuals’ endogenous alpha frequency during a tactile detection task (n = 12 for EEG, n = 20 for behavior). EEG-measured pre-stimulus alpha power was higher on non-perceived than perceived trials, and analogous perceptual correlates emerged in early components of the tactile evoked response. Further, baseline normalized tactile detection performance was significantly lower during alpha than sham tACS, but the effect did not last into the post-tACS time period. Pre- to post-tACS changes in alpha power were linearly dependent upon baseline state, such that alpha power tended to increase when pre-tACS alpha power was low, and decrease when it was high. However, these observations were comparable in both groups, and not associated with evidence of tACS-induced alpha power modulation. Nevertheless, the tactile stimulus evoked response potential (ERP) revealed a potentially lasting impact of alpha tACS on circuit dynamics. The post-tACS ERP was marked by the emergence of a prominent peak ∼70 ms post-stimulus, which was not discernible post-sham, or in either pre-stimulation condition. Computational neural modeling designed to simulate macroscale EEG signals supported the hypothesis that the emergence of this peak could reflect synaptic plasticity mechanisms induced by tACS. The primary lesson learned in this study, which commanded a small sample size, was that while our experimental paradigm provided some evidence of an influence of tACS on behavior and circuit dynamics, it was not sufficient to induce observable causal effects of tACS on EEG-measured alpha oscillations. We discuss limitations and suggest improvements that may help further delineate a causal influence of tACS on cortical dynamics and perception in future studies

CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response

Autoreactivity and Exceptional CDR Plasticity (but Not Unusual Polyspecificity) Hinder Elicitation of the Anti-HIV Antibody 4E10

The broadly-neutralizing anti-HIV antibody 4E10 recognizes an epitope in the membrane-proximal external region of the HIV envelope protein gp41. Previous attempts to elicit 4E10 by vaccination with envelope-derived or reverse-engineered immunogens have failed. It was presumed that the ontogeny of 4E10-equivalent responses was blocked by inherent autoreactivity and exceptional polyreactivity. We generated 4E10 heavy-chain knock-in mice, which displayed significant B cell dysregulation, consistent with recognition of autoantigen/s by 4E10 and the presumption that tolerance mechanisms may hinder the elicitation of 4E10 or 4E10-equivalent responses. Previously proposed candidate 4E10 autoantigens include the mitochondrial lipid cardiolipin and a nuclear splicing factor, 3B3. However, using carefully-controlled assays, 4E10 bound only weakly to cardiolipin-containing liposomes, but also bound negatively-charged, non-cardiolipin-containing liposomes comparably poorly. 4E10/liposome binding was predominantly mediated by electrostatic interactions rather than presumed hydrophobic interactions. The crystal structure of 4E10 free of bound ligands showed a dramatic restructuring of the combining site, occluding the HIV epitope binding site and revealing profound flexibility, but creating an electropositive pocket consistent with non-specific binding of phospholipid headgroups. These results strongly suggested that antigens other than cardiolipin mediate 4E10 autoreactivity. Using a synthetic peptide library spanning the human proteome, we determined that 4E10 displays limited and focused, but unexceptional, polyspecificity. We also identified a novel autoepitope shared by three ER-resident inositol trisphosphate receptors, validated through binding studies and immunohistochemistry. Tissue staining with 4E10 demonstrated reactivity consistent with the type 1 inositol trisphosphate receptor as the most likely candidate autoantigen, but is inconsistent with splicing factor 3B3. These results demonstrate that 4E10 recognition of liposomes competes with MPER recognition and that HIV antigen and autoepitope recognition may be distinct enough to permit eliciting 4E10-like antibodies, evading autoimmunity through directed engineering. However, 4E10 combining site flexibility, exceptional for a highly-matured antibody, may preclude eliciting 4E10 by conventional immunization strategies

Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies

Understanding the association between skin involvement and joint activity in patients with psoriatic arthritis: experience from the Corrona Registry.

Objective: To compare the characteristics of patients with psoriatic arthritis among patient groups stratified by degree of skin and joint involvement, and to evaluate the relationship between skin severity and joint activity. Methods: Body surface area (BSA) and Clinical Disease Activity Index (CDAI) at enrolment were analysed. Patient characteristics were stratified by skin severity and joint activity. Baseline patient characteristics, clinical and disease characteristics and patient-reported outcomes were compared. The strength of the relationship of skin severity and joint activity was evaluated using methods for categorical variables (χ Results: 1542 adult patients in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry enrolled between 21 May 2013 and 20 September 2016 were analysed. Most patients in the BSA \u3e3%/CDAI moderate/high subgroup had worse clinical and patient-reported outcomes. A significant (p Conclusion: Skin severity is modestly correlated with joint activity, and patients with higher skin severity are two times more likely to have increased joint involvement. Clinicians need to address both skin severity and joint activity in treatment decisions