Development of a Juvenile Spondyloarthritis Disease Activity Index In collaboration with Pam Weiss (CHOP), other Childhood Arthritis and Rheumatology Research Alliance (CARRA) investigators, we used the Pediatric Section of the American College of Rheumatology list-serve and an international list-serve to administer a modified Delphi consensus technique to establish potential parameters for measuring disease activity. Validation was performed retrospectively using a multicenter cohort of 243 children. In total, 106 physicians representing 14 countries completed the initial questionnaire, with >75% completion on subsequent questionnaires. Eighty percent consensus was reached on 10 items, with two removed after individual item analysis. Peripheral disease, axial disease, and uveitis were the 3 primary domains that explained 58% of the variance. The Juvenile SpA Disease Activity index (JSpADA) discriminated well between subjects with active versus inactive disease (p<0.001) and was responsive to worsening in disease activity over time (p<0.001). There were moderate correlations with the Juvenile Arthritis disease activity score (r=0.80), patient and physician assessments of disease activity (r=0.70 and 0.66, respectively), and the Childhood Health Assessment Questionnaire (r=0.56). This is the first disease activity index developed for JSpA. Future studies will be needed to validate the JSpADA index prospectively, and in multi-center cohorts. Ultrasound versus Dolorimetry for Enthesitis in Children with Enthesitis-Related Arthritis (ERA) We tested the accuracy of physical examination with a dolorimeter to detect enthesitis in children using ultrasound (US) as the reference standard, in collaboration with Pam Weiss and colleagues at CHOP. This was a cross-sectional study of 30 patients with ERA and 30 controls, focusing on tendon insertion sites at the lateral humeral epicondyle, medial humeral epicondyle, superior patellar pole, inferior patellar pole, Achilles, and plantar fascia at the calcaneus. The most common sites of abnormality by US were the superior patellar pole (18/60 sites or 30%), lateral humeral epicondyle (12%) and Achilles (10%). Intrarater reliability of US was kappa=0.78 (95% CI of 0.63-0.93), with interrater reliability at kappa=0.81 (95% CI of 0.670.95). Interrater reliability of enthesitis tenderness by physical exam using a dolorimeter was lower (kappa=0.49, with 95% CI of 0.33-0.65), and poorly predictive of US-confirmed enthesitis. ERA patients also had more pain and lower pain thresholds at every site, including control sites (p<0.001). Standardized dolorimeter examination for detection of enthesitis in children has poor accuracy and reliability, with lower pain thresholds possibly contributing to limited accuracy. The use of US to detect enthesitis needs to be further evaluated for diagnosis of ERA as well as prediction of disease progression and guiding therapeutics. HLA-B27 and the Microbiome The role of HLA-B27 in SpA continues to be an active area of investigation. It has been hypothesized that changes in the gut microbiome due to HLA-B27 may be an intermediary in the development of SpA. To investigate this possibility in a model system where many variables can be controlled, we examined HLA-B27 and human β2-microglobulin (hβ2m) transgenic rats (B27-Tg). In a collaborative effort, we examined cecal microbiota using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing of rats from different facilities and of different genotypes. Comparing B27-Tg and wild type (WT) rats we found significant differences by principle coordinates analysis, with increases in the relative abundance of Prevotella spp. and decreases in Rikenellaceae spp. Interestingly, BRISK analysis revealed increases in Bacteroides vulgatus abundance in B27-Tg and hβ2m compared to WT. This is the first demonstration that HLA-B27 is associated with altered gut microbiota, and will pave the way for future studies in this animal model and in humans to understand how the microbiome may influence SpA pathogenesis. Evidence for Autophagy in HLA-B27+ Ankylosing Spondylitis (AS) Ciccia and colleagues have shown previously that IL-23 is upregulated in ileal biopsy tissue samples from AS patients with chronic, sub-clinical gastrointestinal inflammation. Unlike Crohns disease, IL-23 upregulation is not associated with IL-17A overexpression in AS. In a collaborative project we demonstrated that gene expression and protein markers of autophagy are overexpressed in chronic inflammatory ileal lesions from AS patients. Unfolded/misfolded HLA class I heavy chains were prominent in the tissue samples from AS patients, and co-localized with HRD-1 (SYVN), 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. Population-Based Spinal Mobility Measures: The 2009-2010 US National Health and Nutrition Examination Survey (NHANES) The modified New York classification criteria for AS contain clinical parameters that include measures of spinal mobility. Despite the widespread clinical and research use of these criteria, normal population-based measures are lacking. Using data obtained from the 2009-2010 NHANES, the Spondyloarthritis Research and Treatment Network (SPARTAN) together with the Spondyloarthritis Association of America (SAA) established normal ranges for occiput-to-wall (OTW), thoracic expansion (TE), and anterior lumbar flexion (ALF). Only 3.8% of normal subjects had and an OTW measure greater than 0 cm, whereas 8.8% were out of range (based on previously established values) for TE at a threshold of 2.5 cm. New threshold (minimal) values based on the 5th percentile for TE (2.2 cm) and ALF (1.9 cm) were established, after excluding individuals with severe obesity (BMI >35kg/M2), which tends to lower TE and increase ALF measures. This study provides new values for mobility measures that are relevant to classification of axial SpA and AS. Functional Genomics of ERAP1 Ongoing efforts published only as abstracts to date are expected to come to fruition in the next year. These include evaluating the role of ERAP1 in the pathogenesis of HLA-B27-mediated rat SpA. ERAP1 variants confer susceptibility to AS in HLA-B27 positive individuals. To study this gene-gene interaction we created an ERAP1 null gene using TALEN-mediated genome editing. Currently, were are breeding animals to determine whether ERAP1 loss-of-function affects the biology of HLA-B27 and the development of SpA. Induced Pluripotent Stem Cells We have developed an active induced pluripotent stem (iPS) cell program to support functional genomics efforts in SpA. In particular, this enables us to study cell lineages that are not readily accessible from patients such as bone and fat forming osteoblasts and adipocytes, as well as early hematopoietic precursors that may be important in pathogenesis. We have derived several iPS cell lines from axial SpA patient fibroblasts by reprogramming them with cMYC, OCT4, KLF4, and SOX2, and demonstrated that they can be differentiated into cardiomyocytes, mesenchymal stem cells, osteoblasts, chondrocytes and adipocytes. We have also successfully developed immune cells including monocytes and dendritic cells from iPS cells. In preliminary studies, iPS-derived osteoblasts from axial SpA patients have an interesting phenotype that includes enhanced production of calcified matrix and resistance to cytokines that usually inhibit bone formation. These findings may be relevant to aberrant bone formation that characterizes this immune-mediated inflammatory disease.
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