Musculoskeletal misdiagnoses in pediatric patients with spinal tumors.

OBJECTIVE: Childhood spinal tumors often present with musculoskeletal symptoms, potentially causing a misdiagnosis and delays in diagnosis and treatment. This study aims to identify, characterize, and compare children with spinal tumors who had prior musculoskeletal misdiagnoses to those without, analyzing clinical presentation, diagnostic interval, and outcome. STUDY DESIGN: This retrospective cohort study evaluated all children aged 0-14 years diagnosed with a spinal tumor in Denmark from 1996 to 2018. The cohort was identified through the Danish Childhood Cancer Registry, and the registry data were supplemented with data from medical records. The survival was compared using the Kaplan-Meier method. RESULTS: Among 58 patients, 57% (33/58) received musculoskeletal misdiagnoses before the spinal tumor diagnosis. Misdiagnoses were mostly nonspecific (64%, 21/33), involving pain and accidental lesions, while 36% (12/33) were rheumatologic diagnoses. The patients with prior misdiagnosis had less aggressive tumors, fewer neurological/general symptoms, and 5.5 months median diagnostic interval versus 3 months for those without a misdiagnosis. Those with prior misdiagnoses tended to have a higher 5-year survival of 83% (95% confidence interval [CI]: 63%-92%) compared to 66% (95% CI: 44%-82%) for those without (p = .15). CONCLUSION: Less aggressive spinal tumors may manifest as gradual skeletal abnormalities and musculoskeletal symptoms without neurological/general symptoms, leading to misdiagnoses and delays.

Quantification of temporomandibular joint space in patients with juvenile idiopathic arthritis assessed by cone beam computerized tomography.

OBJECTIVE: To describe a method to calculate the total intra-articular volume (inter-osseous space) of the temporomandibular joint (TMJ) determined by cone-beam computed tomography (CBCT). This could be used as a marker of tissue proliferation and different degrees of soft tissue hyperplasia in juvenile idiopathic arthritis (JIA) patients. MATERIALS AND METHODS: Axial single-slice CBCT images of cross-sections of the TMJs of 11 JIA patients and 11 controls were employed. From the top of the glenoid fossa, in the caudal direction, an average of 26 slices were defined in each joint (N = 44). The interosseous space was manually delimited from each slice by using dedicated software that includes a graphic interface. TMJ volumes were calculated by adding the areas measured in each slice. Two volumes were defined: Ve-i and Vi , where Ve-i is the inter-osseous space, volume defined by the borders of the fossa and Vi is the internal volume defined by the condyle. An intra-articular volume filling index (IF) was defined as Ve-i /Vi , which represents the filling of the space. RESULTS: The measured space of the intra-articular volume, corresponding to the intra-articular soft tissue and synovial fluid, was more than twice as large in the JIA group as in the control group. CONCLUSION: The presented method, based on CBCT, is feasible for assessing inter-osseus joint volume of the TMJ and delimits a threshold of intra-articular changes related to intra-articular soft tissue proliferation, based on differences in volumes. Intra-articular soft tissue is found to be enlarged in JIA patients.

Inflammatory Biomarkers Can Differentiate Acute Lymphoblastic Leukemia with Arthropathy from Juvenile Idiopathic Arthritis Better Than Standard Blood Tests.

OBJECTIVE: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN: In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS: In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.

Performance of the 2016 ACR-EULAR myositis response criteria in juvenile dermatomyositis therapeutic trials and consensus profiles.

OBJECTIVES: The 2016 ACR-EULAR Response Criteria for JDM was developed as a composite measure with differential weights of six core set measures (CSMs) to calculate a Total Improvement Score (TIS). We assessed the contribution of each CSM, representation of muscle-related and patient-reported CSMs towards improvement, and frequency of CSM worsening across myositis response criteria (MRC) categories in validation of MRC. METHODS: Data from JDM patients in the Rituximab in Myositis trial (n = 48), PRINTO JDM trial (n = 139), and consensus patient profiles (n = 273) were included. Observed vs expected CSM contributions were compared using Sign test. Characteristics of MRC categories were compared by Wilcoxon tests with Bonferroni adjustment. Spearman correlation of changes in TIS and individual CSMs were examined. Agreement between physician-assessed change and MRC categories was evaluated by weighted Cohen's kappa. RESULTS: Of 457 JDM patients with IMACS CSMs and 380 with PRINTO CSMs, 9-13% had minimal, 19-23% had moderate and 41-50% had major improvement. The number of improved and absolute percentage change of CSMs increased by MRC improvement level. Patients with minimal improvement by MRC had a median of 0-1 CSM worsened, and those with moderate/major improvement had a median of zero worsening CSMs. Of patients improved by MRC, 94-95% had improvement in muscle strength and 93-95% had improvement in ≥1 patient-reported CSM. IMACS and PRINTO CSMs performed similarly. Physician-rated change and MRC improvement categories had moderate-to-substantial agreement (Kappa 0.5-0.7). CONCLUSION: The ACR-EULAR MRC perform consistently across multiple studies, supporting its further use as an efficacy end point in JDM trials.

The role of liver transaminase levels in methotrexate intolerance in juvenile idiopathic arthritis-a cross-sectional study.

Methotrexate (MTX) plays a key role when treating juvenile idiopathic arthritis (JIA), but MTX-intolerance is challenging. MTX-treatment might affect the liver, causing elevated levels of alanine aminotransferase (ALT), yet the role of ALT-levels in MTX-intolerance in JIA remains unclear. Our study aimed to investigate the association between ALT-levels during MTX-treatment and MTX-intolerance in JIA. Children (> 9 years old) diagnosed with JIA and treated with MTX (> 6 weeks) were eligible for enrollment. MTX-intolerance was assessed using the Methotrexate Intolerance Severity Score (MISS), completed by the parents, and defined as MISS ≥ 6 with at least 1 point for a behavioral/anticipatory/associative symptom. ALT-levels were determined at enrollment. A total of 118 children were enrolled (80 girls; 38 boys). MTX-intolerance was registered in 61%. ALT-levels did not differ between the MTX-intolerant group (median = 17.0 U/L [IQR: 14.0-26.0]) and the MTX-tolerant group (median = 20.5 U/L [IQR: 16.0-27.5]; p = 0.17). MTX-intolerance was prevalent in around 60% of both boys and girls. Nine out of 50 MTX-intolerant girls had elevated ALT-levels compared to 0/22 MTX-intolerant boys, however, there was no difference in median ALT levels between the two groups. Furthermore, the MTX-intolerant girls had a higher MISS (median = 14.0 [IQR: 9.3-17]) than the MTX-intolerant boys (median = 10.0 [IQR: 7.3-12]; p = 0.009). Our study did not find a difference in ALT-levels between MTX-intolerant and MTX-tolerant children. However, only MTX-intolerant girls and no MTX-intolerant boys showed elevated ALT-levels.

Musculoskeletal Diagnoses before Cancer in Children: A Danish Registry-Based Cohort Study.

OBJECTIVE: To identify the prevalence of musculoskeletal diagnoses recorded 6 months before the diagnosis of cancer and to evaluate whether preceding musculoskeletal diagnoses affected survival. STUDY DESIGN: We performed a nationwide registry-based cohort study including all children under 15 years of age diagnosed with cancer in Denmark over a 23-year period (1996-2018). The Danish National Patient Registry was used to identify musculoskeletal diagnoses and associated dates recorded within 6 months preceding the diagnosis of cancer. We compared the characteristics of children with and without a prior musculoskeletal diagnoses using prevalence ratios and 95% CI and diagnostic interval as median with IQR. We compared survival using Kaplan-Meier and Cox proportional hazards regression analysis adjusting for age, sex, and presence of metastasis at diagnosis. RESULTS: Of 3895 children with all types of cancer, 264 (7%) had a total of 451 hospital visits with musculoskeletal diagnosis within 6 months preceding the diagnosis of cancer; however, survival was not affected. The overall median diagnostic interval from first musculoskeletal diagnosis (within 6 months before cancer diagnosis) to cancer diagnosis was 15 days (IQR, 7-47 days). A diagnosis of juvenile idiopathic arthritis, unspecified arthritis, and arthropathy each accounted for 5% of the contacts, primarily in children with acute lymphoblastic leukemia, bone sarcomas, or neuroblastomas. CONCLUSIONS: A preliminary musculoskeletal diagnosis occurred in 7% of children with cancer, but did not affect the overall survival.

Uveitis in Juvenile Idiopathic Arthritis: 18-Year Outcome in the Population-based Nordic Cohort Study.

PURPOSE: To assess the long-term outcome of uveitis in juvenile idiopathic arthritis (JIA). DESIGN: Population-based, multicenter, prospective JIA cohort, with a cross-sectional assessment of JIA-associated uveitis (JIA-U) 18 years after the onset of JIA. PARTICIPANTS: A total of 434 patients with JIA, of whom 96 had uveitis, from defined geographic areas of Denmark, Finland, Norway, and Sweden. METHODS: Patients with onset of JIA between January 1997 and June 2000 were prospectively followed for 18 years. Pediatric rheumatologists and ophthalmologists collected clinical and laboratory data. MAIN OUTCOME MEASURES: Cumulative incidence of uveitis and clinical characteristics, JIA and uveitis disease activity, ocular complications, visual outcome, and risk factors associated with the development of uveitis-related complications. RESULTS: Uveitis developed in 96 (22.1%) of 434 patients with JIA. In 12 patients (2.8%), uveitis was diagnosed between 8 and 18 years of follow-up. Systemic immunosuppressive medication was more common among patients with uveitis (47/96 [49.0%]) compared with patients without uveitis (78/338 [23.1%]). Active uveitis was present in 19 of 78 patients (24.4%) at the 18-year visit. Ocular complications occurred in 31 of 80 patients (38.8%). Short duration between the onset of JIA and the diagnosis of uveitis was a risk factor for developing ocular complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8). Patients with a diagnosis of uveitis before the onset of JIA all developed cataract and had an OR for development of glaucoma of 31.5 (95% CI, 3.6-274). Presence of antinuclear antibodies (ANAs) was also a risk factor for developing 1 or more ocular complications (OR, 3.0; 95% CI, 1.2-7.7). Decreased visual acuity (VA) <6/12 was found in 12 of 135 eyes (8.9%) with uveitis, and 4 of 80 patients (5.0%) with JIA-U had binocular decreased VA <6/12. CONCLUSIONS: Our results suggest that uveitis screening should start immediately when the diagnosis of JIA is suspected or confirmed and be continued for more than 8 years after the diagnosis of JIA. Timely systemic immunosuppressive treatment in patients with a high risk of developing ocular complications must be considered early in the disease course to gain rapid control of ocular inflammation.

Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant.

OBJECTIVES: Here we investigated a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema to uncover the genetic and immunological basis of the disease. METHODS: On suspicion of an autoinflammatory condition, Sanger sequencing of nucleotide-binding oligomerization domain-like, leucine-rich repeat pyrin domain containing 1 (NLRP1) was performed and combined with an in vitro inflammasome reconstitution assay to measure caspase-1-mediated IL-1ß cleavage, stimulation of patient peripheral blood mononuclear cells (PBMCs) and whole blood to measure IL-1ß, IL-18 production and quantification of apoptosis-associated speck-like protein containing CARD (ASC) speck formation as a measure of inflammasome activation by flow cytometry. RESULTS: Sanger sequencing revealed a novel mutation (c.175G>C, p.A59P; NM_33004.4) in the inflammasome molecule NLRP1 segregating with disease, although with incomplete penetrance, in three generations. We found that patient PBMCs produced increased IL-1ß in response to inflammatory stimuli, as well as increased constitutive levels of IL-18. Moreover, we demonstrate that expression of the identified NLRP1 A59P variant caused spontaneous IL-1ß cleavage to mature IL-1ß. In addition, patient PBMCs responded to NLRP1 stimulation with increased ASC speck formation as a reflection of elevated inflammasome activity. CONCLUSION: We demonstrate that this novel NLRP1 A59P variant caused increased activation of the NLRP1 inflammasome, resulting in constitutively and inducibly elevated IL-1ß and IL-18 synthesis. We suggest the NLRP1 mutation underlies the pathogenesis of this rare autoinflammatory dyskeratotic disease inherited in an autosomal dominant manner with incomplete penetrance in the patient and within the family for several generations.

Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation.

OBJECTIVES: We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors. METHODS: Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants. RESULTS: WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1ß and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission. CONCLUSION: For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1ß and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.

Coping strategies and anxiety in association with methotrexate-induced nausea in juvenile idiopathic arthritis.

The aim of this study is to investigate whether methotrexate-induced nausea is associated with anxiety or the use of coping strategies in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). This is an observational study of children diagnosed with JIA (ILAR criteria), treated with MTX and aged 9 years or above. MTX-induced nausea was determined by the children's completion of a nausea diary and the parents' completion of the Methotrexate Intolerance Severity Score (MISS). Anxiety was assessed by the Beck Youth Inventories-Anxiety Inventory (BYI-A) and coping strategies were evaluated by an adapted Nausea Coping Questionnaire. Enrolled were 121 children (82 girls: 39 boys) with a median age (IQR) of 13.3 (11.3-15.1) years. The median MTX-dose (IQR) was 9.7 (9.0-10.9) mg/m2/week. The median treatment duration (IQR) was 340 (142-766) days. The MISS was completed for 120 children; 77 children completed the nausea diary for at least 7 days. MTX-induced nausea was present in 61% (73/120) of the children according to the MISS and in 73% (56/77) of the children according to the nausea diary. MTX-induced nausea was associated with a more frequent use of the coping strategy internalizing/catastrophizing (MISS, p = 0.012; diary, p < 0.0001) and higher BYI-A raw scores (diary, p = 0.016). MTX-induced nausea was associated with anxiety and the use of coping strategies in children with JIA. These psychological factors may be part of the mechanism behind the inter-individual variation in the level of nausea to MTX treatment.