ObjectiveThe Paediatric Rheumatology International Trials Organisation (PRINTO) recently undertook an effort to better harmonize the pediatric and adult arthritis criteria. These provisional criteria are being refined for optimal performance. We aimed to investigate differences between patients who did and did not fulfill these PRINTO criteria among youth diagnosed with juvenile spondyloarthritis (SpA) that met axial juvenile SpA (axJSpA) classification criteria.MethodsThis was a retrospective cross-sectional sample of youth diagnosed with juvenile SpA who met the axJSpA classification criteria. Demographics, clinical manifestations, and physician and patient-reported outcomes were abstracted from medical records. Magnetic resonance imaging (MRI) scans underwent central imaging review by at least two central raters. Differences between groups were compared using Wilcoxon signed-rank test or chi-square test, as appropriate.ResultsOf 158 patients who met axJSpA criteria, 107 patients (68%) met the PRINTO provisional criteria for enthesitis/spondylitis-related arthritis. A total of 41 patients (26%) did not fulfill any of the three major PRINTO criteria due to lack of peripheral disease manifestations. Demographics, prevalence of inflammatory or structural lesions on MRI, family history of SpA, and duration of pain were not statistically different between those who did and did not meet PRINTO criteria. Those who fulfilled the PRINTO criteria had significantly more peripheral arthritis, enthesitis, and HLA-B27 positivity but reported less sacral/buttock pain.ConclusionPhenotypic differences of children with axJSpA between those who were and were not classified by the PRINTO criteria were primarily due to peripheral disease manifestations and HLA-B27 positivity. Modification of the PRINTO provisional criteria may facilitate capture of youth with primarily axial disease.

Initial success with B cell-targeted chimeric antigen receptor (CAR) T cells for the treatment of systemic lupus erythematosus and other rheumatic diseases has generated enthusiasm for the broad application of this technology outside of the field of oncology. Paediatric patients with severe rheumatic diseases require lifelong therapy with a substantial toxicity burden and a high cost of care. Paradigm-shifting treatments, including CAR T cells, are desperately needed. Although CAR T cell therapy shows promise for paediatric rheumatic diseases, there are unique aspects of care compared with adults, which require careful consideration and expertise. In response, we established the Integrated Multidisciplinary Paediatric Autoimmunity and Cell Therapy (IMPACT) working group, comprising international experts in the fields of paediatric rheumatology, oncology and cellular therapy, immunology and nephrology, to address the challenges of introducing cell therapies to patients with paediatric-onset autoimmune diseases. Given the possible benefits, we advocate for the study of CAR T cells in paediatric patients with rheumatic diseases who carry a lifelong risk of morbidity and mortality from chronic illness and medication toxicity. As this patient population is relatively small, consensus around definitions of success, robust study of predictors of response and uniform assessment and reporting of toxicities are critical to advancing the field. In this Perspective, the authors and the members of the Integrated Multidisciplinary Paediatric Autoimmunity and Cell Therapy (IMPACT) working group discuss specific considerations for the use of chimeric antigen receptor (CAR) T cell therapies in paediatric patients with rheumatic diseases.

ObjectiveTo evaluate the influence of pelvic magnetic resonance imaging (MRI) findings on axial disease assessment in juvenile spondyloarthritis (JSpA).MethodsThis was a cross-sectional study of patients with JSpA with suspected axial disease. Three experts reviewed each case and rated their confidence (–3 to +3) in the presence of axial disease, first with clinical data and second with clinical and MRI data. Agreement was defined as ≥ 2/3 clinical experts with a rating of ≤ –1 or ≥ 1, and high confidence agreement as ≤ –2 or ≥ 2. The association of clinical features and both global assessments was tested with modified Poisson regression models.ResultsTwo hundred seventy-two of 303 cases (89.8%) achieved agreement with clinical data alone. Adding imaging data affected agreement in 38.9% (118/303) and directionality of agreement in 23.4% (71/303). Agreement was facilitated in 26/31 cases and lost in 21/272 cases. Of those 71 cases that changed directionality, 33 changed from axial disease being absent to present and 38 from present to absent. The final model had an area under the receiver-operating characteristic (AUROC) curve of 0.93 and 3 factors were independently associated with expert agreement (HLA-B27: relative risk [RR] 1.41, 95% CI 1.14-1.74; pain improvement with activity: RR 1.27, 95% CI 1.05-1.54; and bone marrow edema on MRI: RR 4.08, 95% CI 2.91-5.73).ConclusionThe addition of imaging data affected directionality and improved high confidence agreement of expert assessment of axial disease. These results underscore the integral role of MRI in the determination of axial disease in JSpA.

Axial Spondyloarthritis (AS) is an autoinflammatory disease with increased inflammation isolated to the sacroiliac joints and spine. As current treatments are not curative and globally suppress the immune system, research that determines mechanism of disease can improve patient quality of life by leading to therapies that avoid mass immunosuppression. It is well known that activation of immune cells causes a metabolic switch towards glycolysis, leading us to ask if immune cells are more glycolytic in people with AS and if this metabolic circuit is responsible for the enhanced inflammatory function. We found that bulk PBMCs from people with AS have significantly increased glycolytic flux. As glycolysis can feed the ETC, we also examined mitochondrial flux and found that AS PBMCs have increased mitochondrial flux as well. This increase yields enhanced superoxide (SO) within the mitochondria across CD14+ monocytes, CD19+ B cells, CD16+ cells, and CD4+and CD8+ T cells. Ultimately, this heightened metabolic flux yields increased abundance of ATP for energy utilization. These data illustrate the presence of a hyper metabolic state in people with AS. Our SO data suggest this phenotype penetrates multiple cell populations. Identifying the metabolic flux of individual populations will show if this metabolic dysregulation is cell specific or system wide. Determining the origin of this programming is the next step to understanding disease pathogenesis and potential therapeutic targets. This work is supported by the Shear Family Foundation, the University of Colorado Division of Rheumatology T32, and the Cleo Meador and George R. Scott Endowed Chair in Hematology Research. Immune Mechanisms of Human Disease (HUM)

HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs. This Review provides an update on the evidence for the three main hypotheses of HLA-B27 in the pathogenesis of spondyloarthritis. The authors discuss the current understanding of the effect of HLA-B27 on innate and adaptive immunity and how this drives disease.

The Spondylitis Association of America (SAA) and the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) convened a conference on the campus of the National Institutes of Health (NIH) on September 28 and 29, 2023, to identify unmet needs in spondyloarthritis (SpA) research. The conference featured presentations by experts in areas of disease endotypes, pain, innovative imaging in SpA, health disparities in rheumatic diseases, and therapeutics. Members of the conference planning committee moderated the sessions and led the development of manuscripts summarizing recommendations to address unmet research needs. Early career investigators were invited to submit abstracts, which were presented at a networking session during the conference. Here, we highlight each of the sessions comprising the conference in the form of manuscripts published together as a conference summary.

OBJECTIVE:The goal was to develop and validate classification criteria for axial juvenile spondyloarthritis (SpA; AxJSpA). METHODS:This international initiative consisted of four phases: (1) item generation, (2) item reduction, (3) criteria development, and (4) validation of the AxJSpA criteria by an independent team of experts in an internationally representative validation cohort. RESULTS:These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians, which collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included the following: imaging of active inflammation, imaging of structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% confidence interval [CI] 91.4%-99.7%), sensitivity of 64.3% (95% CI 54.9%-73.1%), and area under the receiver operating characteristic curve of 0.81 (95% CI 0.76%-0.86%). CONCLUSION:The new AxJSpA classification criteria require an entry criterion and a physician diagnosis of juvenile SpA and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.

Northrop Grumman Space Park (NGSP) introduced the Mini Cooler Plus (MCP) to their family of pulse tube cryocoolers in 2019 [1] and presented the details of its TRL6 qualification testing in 2022 [2]. The thermal mechanical unit (TMU) of the MCP is an extension of spacequalified pulse tube coolers, all of which are designed to provide a long life (ten-plus years) of delivering low-mass, high-cooling capacity for hyperspectral and infrared imaging payloads in tactical airborne and space applications. The cooler is of modular split configuration allowing flexibility in the compressor (wave generator) and cold head placements to meet the available envelope of packaging constraints. The cold head assembly can be oriented at any position relative to the compressor assembly, and the transfer line (length and shape) can be customized to individual applications. The TMU (thermo-mechanical unit) weighs less than 3kg and can lift 1.5 W at 45 K or 11 W at 110K with 150 W electrical input at 300 K reject. The thermal performance has been characterized as a function of input voltage and as a function of cold tip load and temperature at variety of heat sink temperatures of -20C, 0C, +20C and +40C. Functional testing of the MCP was performed to higher input powers and MCP performance data versus operating conditions were collected. An analytical expression for cold tip load (Q(c)), impedance (Z) and power factor (PF) as a function of reject temperature (T-rej), cold tip temperature (T-c), frequency (f), and input power (P-ac) were generated. These tests were repeated with third party control electronics. All results will be presented here.

HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human β2m (hβ2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3−/−), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10% of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58-0.73 (range: 0.36-0.88) for the joints, 0.65-0.81 (range: 0.39-0.95) for the entheses, and 0.62-0.75 (range: 0.60-0.76) for chronic nonbacterial osteomyelitis-like lesions.

OBJECTIVE:To validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA), and modified versions thereof, in a North American cohort of patients with enthesitis-related arthritis (ERA).METHODS:We utilized the Childhood Arthritis and Rheumatology Research Alliance Registry database ERA cohort to validate the JSpADA and its modifications (JSpADA6-no Schober, no C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR]; JSpADA7-no Schober; and JSpADA7-no CRP/ESR) using the Outcome Measures in Rheumatology principles of face validity, discriminative validity, and responsiveness to change.RESULTS:There were 51 subjects (64 visits) with complete JSpADA data with a mean age of 13.7 years and disease duration of 30.9 months. Subjects were predominantly White (84.3%), and 56.9% were male and 50% were HLA-B27 positive. The JSpADA showed high correlation with the clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10; r = 0.81), moderate-to-high correlation with physician global assessment (PGA; r = 0.69), and low-to-fair correlation with Childhood Health Assessment Questionnaire (CHAQ; r = 0.22). The modifications of the JSpADA (JSpADA7-no Schober; JSpADA7-no CRP/ESR; and JSpADA6-no Schober, no CRP/ESR) performed similarly with high correlation with cJADAS10 (r = 0.81, 0.79, and 0.80, respectively), moderate-to-high correlation with PGA (r = 0.65, 0.67, 0.64, respectively), and low-to-fair correlation with CHAQ (r = 0.35, 0.34, 0.39, respectively). All modified versions of JSpADA had good responsiveness to change. All versions of JSpADA had excellent discriminative validity.CONCLUSION:We propose the term modified JSpADA for the modification of JSpADA with 6 elements (JSpADA6-no Schober, no CRP/ESR). This shorter disease activity index may improve implementation of JSpADA in both clinical practice and research trials.

HLA-B27 allele is a major risk factor for the development of spondyloarthritis ( SpA) and induces an SpA- like disease when expressed in rats, although the mechanism remains incompletely understood. Endoplasmic reticulum aminopeptidase 1 (ERAP1) modifies the effects of HLA-B27 on the risk of developing SpA, indicating a gene-gene interaction, with loss-of-function or reduced expression of ERAP1 acting in a protective manner. Since the principal function of ERAP1 is to optimize peptides for presentation by HLA class I proteins, its protective effect has been assumed to be a consequence of how ERAP1 shapes the repertoire of peptides presented by HLA-B27. Tran and colleagues explored the interaction between HLA- B27 and ERAP1 in HLA-B27 transgenic (Tg) rats by extinguishing ERAP1 protein expression using genome editing. ERAP1-deficient HLA-B27-expressing rats were protected from developing arthritis without a reduction in gut inflammation. Since the presentation of peptides by HLA- B27 to CD8+ T cells is not implicated in the development of SpA in rats, they further explored how ERAP1 deficiency affected HLA-B27. Surprisingly, ERAP1 deficiency promoted more efficient HLA-B27 folding and reduced misfolding, as well as attenuated the development of ER stress and its consequences in macrophages. In contrast, in the absence of ERAP1, the folding and assembly of HLA-B7 was substantially reduced, consistent with known effects of ERAP1 on the generation of optimal peptides for loading onto HLA class I alleles. These findings continue to implicate aberrant folding of HLA-B27 in the generation of disease and provide a model to further explore arthritogenic mechanisms.

OBJECTIVE:Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. METHODS:The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. RESULTS:The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. CONCLUSION:This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long-term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long-term follow-up.

Patients with classical melorheostosis exhibit exuberant bone overgrowth in the appendicular skeleton, resulting in pain and deformity with no known treatment. Most patients have somatic, mosaic mutations in MAP2K1 (encoding the MEK1 protein) in osteoblasts and overlying skin. As with most rare bone diseases, lack of affected tissue has limited the opportunity to understand how the mutation results in excess bone formation. The aim of this study was to create a cellular model to study melorheostosis. We obtained patient skin cells bearing the MAP2K1 mutation (affected cells), and along with isogenic control normal fibroblasts reprogrammed them using the Sendai virus method into induced pluripotent stem cells (iPSCs). Pluripotency was validated by marker staining and embryoid body formation. iPSCs were then differentiated to mesenchymal stem cells (iMSCs) and validated by flow cytometry. We confirmed retention of the MAP2K1 mutation in iMSCs with polymerase chain reaction (PCR) and confirmed elevated MEK1 activity by immunofluorescence staining. Mutation-bearing iMSCs showed significantly elevated vascular endothelial growth factor (VEGF) secretion, proliferation and collagen I and IV secretion. iMSCs were then differentiated into osteoblasts, which showed increased mineralization at 21 days and increased VEGF secretion at 14 and 21 days of differentiation. Administration of VEGF to unaffected iMSCs during osteogenic differentiation was sufficient to increase mineralization. Blockade of VEGF by bevacizumab reduced mineralization in iMSC-derived affected osteoblasts and in affected primary patient-derived osteoblasts. These data indicate that patient-derived induced pluripotent stem cells recreate the elevated MEK1 activity, increased mineralization, and increased proliferation seen in melorheostosis patients. The increased bone formation is driven, in part, by abundant VEGF secretion. Modifying the activity of VEGF (a known stimulator of osteoblastogenesis) represents a promising treatment pathway to explore. iPSCs may have wide applications to other rare bone diseases. © 2023 American Society for Bone and Mineral Research (ASBMR).

During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance. Here, we show that the pro-inflammatory cytokines IFNγ and TNF together rapidly induce glucose uptake, glycolysis, and glycolytic capacity in cultured keratinocytes. Furthermore, we found that acute IFNγ and TNF stimulation induces glucose transporter 4 (GLUT4) translocation to the plasma membrane and engages AMPK-dependent intracellular signaling. Together, these findings suggest acute cytokine-induced glucose metabolism in keratinocytes could contribute to inflammation in psoriatic disease, and that GLUT4 is involved in these processes.