Rheumatoid Factor as a Potentiator of Anti–Citrullinated Protein Antibody–Mediated Inflammation in Rheumatoid Arthritis

Objective. The co-occurrence of rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods. In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti–cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results. Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P \u3c 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion. The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA

The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes

Immunoglobulins, antigens and complement can assemble to form immune complexes (IC). ICs can be detrimental as they propagate inflammation in autoimmune diseases. Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis. We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy. We find that the MPs in RA synovial fluid are highly heterogeneous in size. The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs. These mpICs frequently express the integrin CD41, consistent with platelet origin. Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor. Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs. Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils. Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs

Case Management as a Significant Component of Usual Care Psychotherapy for Youth with Disruptive Behavior Problems

Youth with disruptive behavior problems (DBPs) represent the majority of youth served in usual care (UC) psychotherapy, and are at high risk for maladaptive outcomes. Little is known about UC psychotherapeutic strategies utilized with this population. Researchers and clinicians suggest that case management (CM) is a major activity occurring in usual care. CM includes coordinating care with service providers and individuals, including schools, psychiatrists, and community-based services. This study assesses the prevalence and predictors of clinician use of CM in usual care. Results from this study suggest that CM is frequently used in UC psychotherapy with youth with DBPs. The extent of use of CM in UC may have implications for implementation of evidence-based practices in usual care psychotherapy

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1–12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis

How Has Dunsmuir Worked? A Legal- Empirical Analysis of Substantive Review of Administrative Decisions after Dunsmuir v. New Brunswick: Findings from the Federal Courts

This is the first in a series of three articles undertaking an in-depth study of Canadian judicial review and appeal decisions decided in English post-Dunsmuir. This article sets out the foundations of our research based on a set of 104 questions, focusing on both choice and application of standard of review and, applying that analytical structure, examines federal court decisions made between 2008 and 2015. We ask how those decisions reflect the key changes introduced by Dunsmuir, including: (a) the move to one deferential standard; (b) an analytical focus on applying rather than selecting the standard of review; (c) a description of reasonable decisions as ones where the reasoning is transparent, justifiable and intelligible, and the result falls within a reasonable range of outcomes, taking account of the law and the facts; and (d) a renewed emphasis on the centrality of deference

How Has Dunsmuir Worked? A Legal- Empirical Analysis of Substantive Review of Administrative Decisions after Dunsmuir v. New Brunswick: Findings from the Federal Courts

This is the first in a series of three articles undertaking an in-depth study of Canadian judicial review and appeal decisions decided in English post-Dunsmuir. This article sets out the foundations of our research based on a set of 104 questions, focusing on both choice and application of standard of review and, applying that analytical structure, examines federal court decisions made between 2008 and 2015. We ask how those decisions reflect the key changes introduced by Dunsmuir, including: (a) the move to one deferential standard; (b) an analytical focus on applying rather than selecting the standard of review; (c) a description of reasonable decisions as ones where the reasoning is transparent, justifiable and intelligible, and the result falls within a reasonable range of outcomes, taking account of the law and the facts; and (d) a renewed emphasis on the centrality of deference

Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity

<div><p>Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.0005) in symptom presentation. In particular, the T cell chemokines CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) were coordinately increased in the mediator-high group and levels of these chemokines could be associated with seroconversion status and elevated liver function tests (p = 0.027 and p = 0.021 respectively). There was also upregulation of acute phase proteins including CRP and serum amyloid A. Consistent with the role of CXCL9/CXCL10 in attracting immune cells to the site of infection, CXCR3+ CD4 T cells are reduced in the blood of early acute Lyme disease (p = 0.01) and the decrease correlates with chemokine levels (p = 0.0375). The levels of CXCL9/10 did not relate to the size or number of skin lesions but elevated levels of serum CXCL9/CXCL10 were associated with elevated liver enzymes levels. Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations.</p></div

Serum Amyloid A levels are associated with elevated liver function tests.

<p>Lyme patients were separated into two populations based on normal (n = 24) vs. elevated liver enzyme tests (n = 20) and the levels of Serum Amyloid A (Panel A) and CRP (Panel B) were compared at multiple time points relative to healthy controls (n = 23). Serum amyloid A (p = 0.036) and CRP (p = 0.017) levels are significantly different between Lyme patients with high liver function tests at the pre-treatment visit. Both groups are significantly different from controls at (p<0.0005), but are not different from each other or controls, at both the Post-treatment and 6 Month follow-up visits. There is no significant difference in CRP levels between high and normal liver function groups, however both are significantly different from controls (p<0.0005).</p

Elevated Immune Mediators in Lyme Disease.

<p>Serum samples from patients with diagnosed acute Lyme disease (n = 44, red) and healthy controls (n = 23, black) were assayed for the presence of 58 soluble mediators and 7 acute phase proteins using an optimized multiplex-based assay system. Displayed are those mediators that show significant changes (q<0.1%) in Lyme patients vs. controls. (Panel A) Results are displayed as a heat map to visualize differences in mediator levels in Acute Lyme patients relative to controls. (Panel B) Unsupervised hierarchical clustering of the results was performed, and the output displayed as a heatmap. This analysis resulted in the formation of two clusters, including a “mediator high” cluster that contains samples derived from patients with acute <i>B. burgdorferi</i> infection who exhibited elevated serum inflammatory mediators. The second “mediator low” cluster includes a subset of samples from acute <i>B. burgdorferi</i> infection as well as the matched healthy controls, both of which exhibited low levels of inflammatory mediators.</p