Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on ...153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 74% (95% CI, 52-90%) was higher than that of CA125 alone 65% (95% CI, 43-84%) at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model 94% (95% CI, 85-98%) was significantly better than that of CA125 alone 52% (95% CI, 39-65%). These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.
ObjectivesJuvenile idiopathic arthritis (JIA) is a common chronic childhood disease and chronic pain is a debilitating feature. A strong link has been shown between poor sleep and pain in JIA. ...However, the causal direction is unknown. This study’s aim was to determine if, in adolescents with JIA, a recommended healthful sleep duration leads to reductions in pain when compared with the restricted sleep (RS) duration that is commonly seen.MethodsPatients with JIA (12–18 years old; pain score of ≥1 on a visual analogue scale) participated in a randomised, crossover sleep manipulation protocol. The 3-week protocol comprised a baseline week (BL), a week with healthy sleep duration (HSD; 9.5 hours in bed/night) and a RS week (RS; 6.5 hours in bed/night). After BL, participants were randomly assigned to either HSD or RS, and then crossed over to the other condition. Pain was self-assessed using the iCanCope with Pain app. We used Bayesian hierarchical models to estimate the effect of sleep duration on pain.ResultsParticipants (n=31; mean age=15.0±1.8 years) averaged 1.4 (95% credible interval (CrI) 1.2–1.6) more hours of sleep per night during HSD relative to RS. Compared with RS, HSD resulted in a favourable effect on pain scores (OR 0.61, 95% CrI 0.39–0.95).ConclusionIt is possible to have adolescents with childhood arthritis get a healthier sleep duration, and this longer sleep results in reduced pain. These findings complement prior correlational studies and confirm a causal relationship between reduced sleep duration and increased pain.Trial registration numberNCT04133662.
Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of ...malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course.
6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease.
The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.
To compare the clinical features and outcome between patients with juvenile psoriatic arthritis (JPsA) and non-JPsA juvenile idiopathic arthritis (JIA).
Fifty-three children with JPsA, 32 with < 5 ...joints in the first 6 months of disease (oligo-JPsA) and 21 (> or = 5 joints) polyarticular-onset (poly-JPsA) were compared to 53 patients with JIA who were matched by sex, age, date of diagnosis, and articular onset pattern.
There was no difference in the percentage of patients between the oligoarticular groups who developed extended oligoarthritis or in the percentage of patients who were positive for antinuclear antibodies. The only differences were that 25% of patients with oligo-JPsA had dactylitis compared to 0% of patients with oligo-JIA (p < 0.01) and 50% had nail pitting as compared to 18.7% (p < 0.05). In polyarticular patients the percentages with dactylitis were similar (19% vs 38%; p = 0.25). The frequency of uveitis was identical in the oligoarticular patients but a higher rate was seen in poly-JPsA compared to poly-JIA (23.8% vs 0%; p = 0.02), while contractures were more frequent in poly-JIA compared to poly-JPsA during the course of the illness (47.6% vs 14.3%; p = 0.03) but not at last followup (14.3% vs 4.7%; p = 0.6). At last followup the mean Childhood Health Assessment Questionnaire scores were similar in both the polyarticular and oligoarticular groups.
There were only a few differences between patients with JPsA and JIA regarding disease onset, disease course, and outcome. We suggest that large, longterm prospective studies are required to accurately determine whether subdividing JIA according to psoriasis is worthwhile.
To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments.
Children newly diagnosed with JIA at 16 ...Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan-Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments.
In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46-57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA.
Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.
Abstract Objective To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing 2005–2010 and 2017–2021 inception cohorts. Methods Patients enrolled within ...three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan–Meier survival analysis and multivariable Cox regression. Results The 2005–2010 and 2017–2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005–2010 and 26% (23, 30) in the 2017–2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for good health-related quality of life (≥9/10). Conclusion Although baseline disease characteristics were comparable in the 2005–2010 and 2017–2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient-reported outcomes were smaller than improvements in disease activity.
To describe probabilities and characteristics of disease flares in children with juvenile idiopathic arthritis (JIA) and to identify clinical features associated with an increased risk of flare.
We ...studied children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) prospective inception cohort. A flare was defined as a recurrence of disease manifestations after attaining inactive disease and was called significant if it required intensification of treatment. Probability of first flare was calculated with Kaplan-Meier methods, and associated features were identified using Cox regression.
1146 children were followed up a median of 24 months after attaining inactive disease. We observed 627 first flares (54.7% of patients) with median active joint count of 1, physician global assessment (PGA) of 12 mm and duration of 27 weeks. Within a year after attaining inactive disease, the probability of flare was 42.5% (95% CI 39% to 46%) for any flare and 26.6% (24% to 30%) for a significant flare. Within a year after stopping treatment, it was 31.7% (28% to 36%) and 25.0% (21% to 29%), respectively. A maximum PGA >30 mm, maximum active joint count >4, rheumatoid factor (RF)-positive polyarthritis, antinuclear antibodies (ANA) and receiving disease-modifying antirheumatic drugs (DMARDs) or biological agents before attaining inactive disease were associated with increased risk of flare. Systemic JIA was associated with the lowest risk of flare.
In this real-practice JIA cohort, flares were frequent, usually involved a few swollen joints for an average of 6 months and 60% led to treatment intensification. Children with a severe disease course had an increased risk of flare.
Joint inflammation is the common feature underlying juvenile idiopathic arthritis (JIA). Clinicians recognize patterns of joint involvement currently not part of the International League of ...Associations for Rheumatology (ILAR) classification. Using unsupervised machine learning, we sought to uncover data-driven joint patterns that predict clinical phenotype and disease trajectories.
We analyzed prospectively collected clinical data, including joint involvement using a standard 71-joint homunculus, for 640 discovery patients with newly diagnosed JIA enrolled in a Canada-wide study who were followed serially for five years, treatment-naïve except for nonsteroidal anti-inflammatory drugs (NSAIDs) and diagnosed within one year of symptom onset. Twenty-one patients had systemic arthritis, 300 oligoarthritis, 125 rheumatoid factor (RF)-negative polyarthritis, 16 RF-positive polyarthritis, 37 psoriatic arthritis, 78 enthesitis-related arthritis (ERA), and 63 undifferentiated arthritis. At diagnosis, we observed global hierarchical groups of co-involved joints. To characterize these patterns, we developed sparse multilayer non-negative matrix factorization (NMF). Model selection by internal bi-cross-validation identified seven joint patterns at presentation, to which all 640 discovery patients were assigned: pelvic girdle (57 patients), fingers (25), wrists (114), toes (48), ankles (106), knees (283), and indistinct (7). Patterns were distinct from clinical subtypes (P < 0.001 by χ2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q2 = 0.55 for patterns; 0.35 for groups). Some patients matched multiple patterns. To determine whether their disease outcomes differed, we further subdivided the 640 discovery patients into three subgroups by degree of localization-the percentage of their active joints aligning with their assigned pattern: localized (≥90%; 359 patients), partially localized (60%-90%; 124), or extended (<60%; 157). Localized patients more often maintained their baseline patterns (P < 0.05 for five groups by permutation test) than nonlocalized patients (P < 0.05 for three groups by permutation test) over a five-year follow-up period. We modelled time to zero joints in the discovery cohort using a multivariate Cox proportional hazards model considering joint pattern, degree of localization, and ILAR subtype. Despite receiving more intense treatment, 50% of nonlocalized patients had zero joints at one year compared to six months for localized patients. Overall, localized patients required less time to reach zero joints (partial: P = 0.0018 versus localized by log-rank test; extended: P = 0.0057). Potential limitations include the requirement for patients to be treatment naïve (except NSAIDs), which may skew the patient cohorts towards milder disease, and the validation cohort size precluded multivariate analyses of disease trajectories.
Multilayer NMF identified patterns of joint involvement that predicted disease trajectory in children with arthritis. Our hierarchical unsupervised approach identified a new clinical feature, degree of localization, which predicted outcomes in both cohorts. Detailed assessment of every joint is already part of every musculoskeletal exam for children with arthritis. Our study supports both the continued collection of detailed joint involvement and the inclusion of patterns and degrees of localization to stratify patients and inform treatment decisions. This will advance pediatric rheumatology from counting joints to realizing the potential of using data available from uncovering patterns of joint involvement.
Objective
To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest ...study population assembled to date.
Methods
Single‐nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA–associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA–associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.
Results
We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10–4). Systemic JIA–associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 95% confidence interval 3.2–255.8).
Conclusion
In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin‐1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.
Objective
Identification of the incidence of juvenile idiopathic arthritis (JIA)–associated uveitis and its risk factors is essential to optimize early detection. Data from the Research in Arthritis ...in Canadian Children Emphasizing Outcomes inception cohort were used to estimate the annual incidence of new‐onset uveitis following JIA diagnosis and to identify associated risk factors.
Methods
Data were reported every 6 months for 2 years, then yearly to 5 years. Incidence was determined by Kaplan‐Meier estimators with time of JIA diagnosis as the reference point. Univariate log‐rank analysis identified risk factors and Cox regression determined independent predictors.
Results
In total, 1,183 patients who enrolled within 6 months of JIA diagnosis met inclusion criteria, median age at diagnosis of 9.0 years (interquartile range IQR 3.8–12.9), median follow‐up of 35.2 months (IQR 22.7–48.3). Of these patients, 87 developed uveitis after enrollment. The incidence of new‐onset uveitis was 2.8% per year (95% confidence interval 95% CI 2.0–3.5) in the first 5 years. The annual incidence decreased during follow‐up but remained at 2.1% (95% CI 0–4.5) in the fifth year, although confidence intervals overlapped. Uveitis was associated with young age (<7 years) at JIA diagnosis (hazard ratio HR 8.29, P < 0.001), positive antinuclear antibody (ANA) test (HR 3.20, P < 0.001), oligoarthritis (HR 2.45, P = 0.002), polyarthritis rheumatoid factor negative (HR 1.65, P = 0.002), and female sex (HR 1.80, P = 0.02). In multivariable analysis, only young age at JIA diagnosis and ANA positivity were independent predictors of uveitis.
Conclusion
Vigilant uveitis screening should continue for at least 5 years after JIA diagnosis, and priority for screening should be placed on young age (<7 years) at JIA diagnosis and a positive ANA test.
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