Pain and Health Status in ERA In collaboration with Pam Weiss (CHOP) and other Childhood Arthritis and Rheumatology Research Alliance (CARRA) investigators, we conducted a cross-sectional study using data from 2,571 children with JIA enrolled in the CARRA Registry to determine whether clinical characteristics of JIA were associated with pain intensity, physical function, and health status. Pain intensity, physical function, and health status differed significantly between JIA subtypes. Subjects with ERA reported worse pain and function in comparison to other categories of JIA. In multivariable analyses, higher active joint count and current use of nonsteroidal anti-inflammatory drugs (NSAIDs), biologics, or corticosteroids were associated with worse scores on all patient-reported measures. ERA subtypes and older age were associated with greater pain intensity and poorer health status. Enthesitis, sacroiliac tenderness, and NSAID use were independently associated with increased pain intensity in ERA, whereas systemic JIA and uveitis were significantly associated with worse health status. The correlation was low between physician global assessment of disease activity and patient-reported pain intensity, physical function, and health status. These data indicate that there are significant differences in pain intensity, physical function, and health status among JIA categories, and they suggest that current treatments may not be equally effective for particular disease characteristics more common in specific JIA categories, such as enthesitis or sacroiliac tenderness in ERA. Biological Effects of HLA-B27 Misfolding HLA-B27 misfolding can generate ER stress and activate the unfolded protein response (UPR), which promotes the production of certain cytokines including IL-23 and IFNβin macrophages. In rats transgenic for HLA-B27, SpA-like disease is strongly associated with expansion and activation of IL-23-responsive CD4+ Th17 T cells in the colon, joints, and draining lymph nodes. We are currently using this model to evaluate the role of HLA-B27 misfolding as an upstream innate immune stimulus in causing this disease. We recently demonstrated that TNF- alpha enhances the development of osteoclasts (OCs) 2.5-fold in transgenic rat monocytes expressing HLA-B27, but not HLA-B7, or cells from wild type rats. TNF-alpha-induced HLA-B expression, which exacerbated misfolding and resulted in ER stress and UPR activation in B27-expressing, but not B7-expressing, or wild type cells. ER stress and UPR activation was associated with enhanced IL-1-alpha and IFN- beta production. Interestingly, we found that these cytokines were promoting (IL-1-alpha) and inhibiting (IFN-beta) OC formation, with the net effect being greater osteoclastogenesis under the conditions studied. When IFN-beta was neutralized, OC formation was almost 4-fold higher in the HLA-B27 transgenic cells. We have additional preliminary data suggesting that rat osteoblasts expressing HLA-B27 become refractory to the inhibitory effects of TNF-alpha when they are also exposed to IFN-gamma. Mineralization is inhibited under these conditions in HLA-B7 and wild type osteoblasts, whereas HLA-B27 expressing cells mineralize normally. The biological effect is associated with robust UPR activation, but the molecular mechanism is still unclear. Together, these results implicate HLA-B27 misfolding in altering bone homeostasis in transgenic rats under pro-inflammatory conditions, and suggest that it may contribute to the unique SpA phenotype through downstream pathways such as altering the response of cells to TNF-alpha. Evidence for Autophagy in HLA-B27+ Ankylosing Spondylitis Francesco Ciccia and colleagues have shown previously that IL-23 is upregulated in ileal biopsy tissue samples from AS patients with chronic, but sub-clinical, gastrointestinal inflammation. Unlike Crohns disease, IL-23 upregulation is not associated with IL-17A overexpression, and they have some evidence that this may be due to a tissue protective effect of IL-22-expressing NKp44+ cells. In a collaborative effort we have recently shown that gene expression (ATG16L, IRGM, MAP1LC3A) and protein markers of autophagy (LC3II, ATG5, ATG12) are expressed in chronic inflammatory ileal lesions from AS patients, similar to Crohns disease, but that the UPR is not activated. HC-10 reactive (unfolded/misfolded) HLA class I heavy chains were prominent in the tissue samples from AS patients, and co-localized with HRD-1 (SYVN or synoviolin gene), a marker of ER-associated degradation (ERAD) that has been shown to assist in the removal of misfolded HLA class I heavy chains. These results provided strong evidence for in vivo HLA-B27 misfolding, and suggest a model where ongoing ERAD may not be sufficient and could lead to activation of autophagy pathways rather than UPR activation. The IL-23/IL-17 Axis in Spondyloarthritis This years efforts include an invited review article on HLA-B27 misfolding and AS published in part with a special series in Molecular Immunology on the pathogenesis of spondyloarthritis. This article highlights the contribution of protein misfolding and its consequences to the pathogenesis of this immune-mediated inflammatory disease, and in particular non-canonical pathways linking ER stress to activation of the IL-23/IL-17 axis. I also wrote an invited commentary (co-authored with Dr. Michael Ward, NIAMS) on a clinical trial being published in The Lancet providing the first evidence that targeting the IL-23/IL-17 axis may be beneficial in the treatment of AS. This is likely to represent the beginning of a number of papers that will appear over the next several years exploring the efficacy of biologics and small molecules that target components of the IL-23/IL-17 pathway in AS. We were the first to discover activation of this axis in the HLA-B27 transgenic model of SpA in a paper published in 2009, and moreover provided critical evidence linking HLA-B27 to this pathway.

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