The authors wish to make the following correction to this paper [...].
<p>Multiple studies have shown the microbiota to be abnormal in patients with spondyloarthritis (SpA). The purpose of this study was to explore the genetic contributions of these microbiota abnormalities. We analyzed the impact of HLA-B27 on the microbiota of children at risk for SpA and compared the microbiota of HLA-B27+ pediatric offspring of ankylosing spondylitis (AS) patients with that of HLA-B27+ children with SpA. Human DNA was obtained from the offspring for determination of HLA-B27 status and polygenic risk score (PRS). Fecal specimens were collected from both groups for sequencing of the V4 region of the 16S ribosomal RNA gene. Among the offspring of AS patients, there was slight clustering by HLA-B27 status. After adjusting for multiple comparisons, five operational taxonomic units (OTUs) representing three unique taxa distinguished the HLA-B27+ from negative children: and were lower in the HLA-B27+ offspring, while was higher. HLA-B27+ offspring without arthritis were compared to children with treatment-naïve HLA-B27+ SpA. After adjustments, clustering by diagnosis was present. A total of 21 OTUs were significantly associated with diagnosis state, including (higher in SpA patients) and (higher in controls). Thus, our data confirmed associations with and with juvenile SpA, and also suggest that the mechanism by which HLA-B27 is associated with SpA may not involve alterations of the microbiota.</p>
<p><strong>OBJECTIVES: </strong>To evaluate the current practices in management of patients with juvenile spondyloarthritis (JSpA) who failed anti-tumour necrosis factor agents (anti-TNF).</p>
<p><strong>METHODS: </strong>An online survey was distributed to Childhood Arthritis and Rheumatology Research Alliance (CARRA) members of the JIA workgroup. Data collection included estimated number of JSpA patients who have failed anti-TNF therapy over two-year period, reasons for discontinuing anti-TNF therapy and other medications used afterward. The JSpA population was de ned as the following subtypes: enthesitis-related arthritis, psoriatic arthritis, undifferentiated spondyloarthritis, juvenile ankylosing spondylitis (AS) i.e. meeting modi ed NY criteria for AS before age 16, and reactive arthritis. Findings were summarised using descriptive statistics.</p>
<p><strong>RESULTS: </strong>The survey response rate was 36% (n= 60/169). The majority of participants were paediatric rheumatologists (93%). Many physicians have JSpA patients who failed anti-TNF therapy (63%). The most common reason for changing anti-TNF therapy was secondary non-response (72%). Sacroiliitis was the most important factor considered when assessing response to an anti-TNF agent and the most common reason for primary non-response (45%). When assessing anti-TNF failure for sacroiliitis, many (65%) felt imaging of the sacroiliac joints was the most important aspect in their decision making. The majority try a second anti-TNF agent after initial anti-TNF failure (87%) and switch to another medication class after 2 anti-TNF agents have failed (62%).</p>
<p><strong>CONCLUSIONS: </strong>More than half of paediatric rheumatologists surveyed have at least one JSpA patient who failed anti-TNF therapy. The majority failed because of secondary non-response. Sacroiliitis is an important but challenging aspect to manage for patients with JSpA.</p>
<p><strong>BACKGROUND: </strong>The objective of this work was to describe magnetic resonance imaging (MRI) changes over time in inflammatory and structural lesions at the sacroiliac joint (SIJ) in children with spondyloarthritis (SpA) exposed and unexposed to tumor necrosis factor inhibitor (TNFi).</p>
<p><strong>METHODS: </strong>This was a retrospective, multicenter study of SpA patients with suspected or confirmed sacroiliitis who underwent at ≥2 pelvic MRI scans. Images were reviewed independently by 3 radiologists and scored for inflammatory and structural changes using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ inflammation score (SIS) and structural score (SSS). Longitudinal, quantitative changes in patient MRI scans were measured using descriptive statistics and stratified by TNFi exposure. We used an average treatment effects (ATE) regression model to explore the average effect of TNFi exposure over time on inflammatory and structural lesions, adjusting for baseline lesion scores.</p>
<p><strong>RESULTS: </strong>Forty-six subjects were evaluated using the SIS (n = 45) and SSS (n = 18). Median age at baseline imaging was 13.6 years, 63% were male and 71% were white. Twenty-three subjects (50%) were TNFi exposed between MRI studies. The median change in SIS in TNFi exposed and unexposed subjects with a baseline SIS ≥0 was - 20.7 and - 14.3, respectively (p = 0.09). Eleven (85%) TNFi exposed and 8 (89%) unexposed subjects with a baseline SIS ≥0 met the SIS minimal clinically important difference (MCID; ≥2.5). Using the ATE model adjusted for baseline SIS, the average effect of TNFi on SIS in patients with a baseline SIS ≥2 was - 14.5 (p < 0.01). Unadjusted erosion change score was significantly worse in TNFi unexposed versus exposed subjects (p = 0.03) but in the ATE model the effect of TNFi was not significant.</p>
<p><strong>CONCLUSION: </strong>This study quantitatively describes how lesions in the SIJs on MRI change over time in patients exposed to TNFi versus unexposed. Follow-up imaging in TNFi exposed patients showed greater improvement than the unexposed group by most metrics, some of which reached statistical significance. Surprisingly, a majority of TNFi unexposed children with a baseline SIS≥2 met the SIS MCID. Additional studies assessing the short and long-term effects of TNFi on inflammatory and structural changes in juvenile SpA are needed.</p>
<p><strong>OBJECTIVE: </strong>To describe characteristics of children with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.</p>
<p><strong>METHODS: </strong>All children with ERA and JPsA were identified. Demographics, clinical characteristics, and treatments were described. Those with and without sacroiliitis were compared. In those with sacroiliitis, the first visit with clinically active sacroiliitis (which came first in 72% of cases) was compared to the first visit without.</p>
<p><strong>RESULTS: </strong>Nine hundred two children with ERA or JPsA were identified. Children with ERA were older at diagnosis (10.8 vs. 8.2 years, p<0.01) and more likely male (56% vs. 38%, p<0.01). Polyarticular involvement was reported in 57% and 72% of those with ERA and JPsA. HLA-B27 was positive in 38% and 12% of those tested with ERA and JPsA. At least one biologic was taken by 72% and 64% of those with ERA and JPsA. Sacroiliitis (diagnosed clinically and/or by imaging) was reported in 28% (40% ERA and 12% JPsA). Of these, 54% were female, 36% were HLA-B27 positive, and 81% took at least one biologic. In children with sacroiliitis, the physician global, parent/patient global, and cJADAS 10 were all significantly worse at the first visit with clinically active sacroiliitis versus the first visit without active sacroiliitis.</p>
<p><strong>CONCLUSION: </strong>In this registry, there are over 900 children with ERA or JPsA. There was high biologic use in this population, especially in those with sacroiliitis. Further, there was equal sex representation in those with sacroiliitis.</p>
<p>Studies have identified abnormalities in the microbiota of patients with arthritis. To evaluate the pathogenicity of human microbiota, we performed fecal microbial transplantation from children with spondyloarthritis and controls to germ-free KRN/B6xNOD mice. Ankle swelling was equivalent in those that received patient vs. control microbiota. Principal coordinates analysis revealed incomplete uptake of the human microbiota with over-representation of two genera (Bacteroides and Akkermansia) among the transplanted mice. The microbiota predicted the extent of ankle swelling (R2 = 0.185, p = 0.018). The abundances of Bacteroides (r = -0.510, p = 0.010) inversely and Akkermansia (r = 0.367, p = 0.078) directly correlated with ankle swelling. Addition of Akkermansia muciniphila to Altered Schaedler's Flora (ASF) resulted in small but statistically significant increased ankle swelling as compared to mice that received ASF alone (4.0 mm, 3.9-4.1 vs. 3.9 mm, IQR 3.6-4.0, p = 0.041), as did addition of A. muciniphila cultures to transplanted human microbiota as compared to mice that received transplanted human microbiota alone (4.5 mm, IQR 4.3-5.5 vs. 4.1 mm, IQR 3.9-4.3, p = 0.019). This study supports previous findings of an association between A. muciniphila and arthritis.</p>
<p><strong>BACKGROUND: </strong>Prior studies have demonstrated abnormalities in the composition of the gastrointestinal microbiota in pediatric and adult patients with spondyloarthritis (SpA). In particular, diminished fecal abundance of Faecalibacterium prausnitzii and abnormalities in both directions in the abundance of the Bacteroides genus have been identified.</p>
<p><strong>METHODS: </strong>We obtained fecal specimens from 30 children with treatment-naïve enthesitis-related arthritis (ERA) and 19 healthy controls, as well as specimens from 11 adult patients with longstanding SpA and 10 adult healthy controls. All of the samples underwent sequencing of the 16S ribosomal DNA. A subset of the pediatric fecal samples was subjected to shotgun metagenomics sequencing.</p>
<p><strong>RESULTS: </strong>ERA patients had decreased abundance of the anti-inflammatory F. prausnitzii A2-165 strain (41 ± 28% versus 54 ± 20% of all sequences matching F. prausnitzii, p = 0.084) and an increased abundance of the control F. prausnitzii L2/6 strain (28 ± 28% versus 15 ± 15%, p = 0.038). Similar trends were observed in adults with longstanding SpA (n = 11) and controls (n = 10). In contrast, the fecal abundance of Bacteroides fragilis was increased in ERA subjects (2.0 ± 4.0% versus 0.45 ± 0.7% of all sequences, p = 0.045), yet was diminished in adult subjects (0.2 ± % versus 1.0 ± % of all sequences, p = 0.106). Shotgun metagenomics sequencing of the fecal DNA in the pediatric subjects revealed diminished coverage of the butanoate pathway (abundance normalized to controls of 1 ± 0.48 versus 0.72 ± 0.33 in ERA, p = 0.037).</p>
<p><strong>CONCLUSIONS: </strong>The anti-inflammatory F. prausnitzii A2-165 strain appears to be depleted in both pediatric and adult SpA. In contrast, B. fragilis may be depleted in adult disease yet abundant in pediatric SpA, suggesting developmental effects on the immune system.</p>
<p><strong>OBJECTIVE: </strong>Children with clinically diagnosed juvenile psoriatic arthritis (JPsA) who were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry (CARRA-JPsA) were classified according to pediatric International League of Associations for Rheumatology (ILAR) and adult criteria [Classification criteria for Psoriatic Arthritis (CASPAR)]. Data on demographic and clinical features at baseline and 1-year followup were analyzed and compared.</p>
<p><strong>METHODS: </strong>Cross-sectional analysis was performed of CARRA-JPsA patients enrolled between May 2010 and December 2013 and stratified according to age at disease onset (≤ or > 4 yrs). Features of patients fulfilling ILAR and CASPAR criteria were compared at baseline and followup using chi square, Fisher's exact, Mann-Whitney-McNemar, Wilcoxon signed rank, and t tests, as appropriate.</p>
<p><strong>RESULTS: </strong>Among 361 children enrolled as CARRA-JPsA, 72.02% had symptom onset at > 4 years of age, with a male predominance and high prevalence of enthesitis. At followup, statistically significant improvements were reported in arthritis, dactylitis, enthesitis, psoriasis, sacroiliitis, and nail pitting, but not in health questionnaire (HQ) scores. Of the patients, 80.5% fulfilled ILAR criteria for JPsA. Fifty-two patients, whose disease fulfilled CASPAR criteria but had not been included in the JPsA cohort, manifested more enthesitis, sacroiliitis, inflammatory bowel disease and uveitis and less psoriasis.</p>
<p><strong>CONCLUSION: </strong>The data support division of patients with JPsA into 2 clinical subgroups, according to age at disease onset. Improvement in objective findings did not correlate with changes in HQ scores. Pediatric rheumatologists currently do not diagnose JPsA in all children whose disease manifestations meet CASPAR criteria. Unification of adult and pediatric PsA classification criteria warrants consideration.</p>
<p><strong>OBJECTIVE: </strong>There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.</p>
<p><strong>METHODS: </strong>Case-based surveys were administered to CARRA members to identify prevailing treatments for new-onset systemic JIA. A 2-day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability.</p>
<p><strong>RESULTS: </strong>The initial case-based survey identified significant variability among current treatment approaches for new-onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership.</p>
<p><strong>CONCLUSION: </strong>Four standardized treatment plans were developed for new-onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA.</p>