Clinical and associated inflammatory biomarker features predictive of short-term outcomes in non-systemic juvenile idiopathic arthritis.

OBJECTIVE: To identify early predictors of disease activity at 18 months in JIA using clinical and biomarker profiling. METHODS: Clinical and biomarker data were collected at JIA diagnosis in a prospective longitudinal inception cohort of 82 children with non-systemic JIA, and their ability to predict an active joint count of 0, a physician global assessment of disease activity of ≤1 cm, and inactive disease by Wallace 2004 criteria 18 months later was assessed. Correlation-based feature selection and ReliefF were used to shortlist predictors and random forest models were trained to predict outcomes. RESULTS: From the original 112 features, 13 effectively predicted 18-month outcomes. They included age, number of active/effused joints, wrist, ankle and/or knee involvement, ESR, ANA positivity and plasma levels of five inflammatory biomarkers (IL-10, IL-17, IL-12p70, soluble low-density lipoprotein receptor-related protein 1 and vitamin D), at enrolment. The clinical plus biomarker panel predicted active joint count = 0, physician global assessment ≤ 1, and inactive disease after 18 months with 0.79, 0.80 and 0.83 accuracy and 0.84, 0.83, 0.88 area under the curve, respectively. Using clinical features alone resulted in 0.75, 0.72 and 0.80 accuracy, and area under the curve values of 0.81, 0.78 and 0.83, respectively. CONCLUSION: A panel of five plasma biomarkers combined with clinical features at the time of diagnosis more accurately predicted short-term disease activity in JIA than clinical characteristics alone. If validated in external cohorts, such a panel may guide more rationally conceived, biologically based, personalized treatment strategies in early JIA.

Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials.

OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: Patients (2-19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population. RESULTS: 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed. CONCLUSION: Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab. TRIAL REGISTRATION NUMBERS: NCT00886769, NCT00889863, NCT00426218 and NCT00891046.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.

OBJECTIVES: To describe the efficacy, safety, and exposure-response relationship of canakinumab in a subgroup of patients with systemic juvenile idiopathic arthritis (SJIA) aged ≥16 years, representative of adult-onset Still's disease (AOSD) patients, and to compare this subgroup with those of children and young adolescents with SJIA by pooling clinical data collected during the development programme of canakinumab. METHODS: Safety and efficacy data on canakinumab-treated patients were pooled from 4 SJIA studies (NCT00426218, NCT00886769, NCT00889863, and NCT00891046). In the majority of patients, canakinumab was administered at 4 mg/kg every 4 weeks. Efficacy parameters (adapted American College of Rheumatology [aACR] paediatric and juvenile idiopathic arthritis [JIA] ACR responses), quality of life, C-reactive protein levels, safety, and exposure-response relationship were assessed over 12 weeks in 3 age groups (children 2-<12, young adolescents 12-<16 and older adolescents and young adults ≥16 years). RESULTS: Efficacy outcomes were analysed in 216 children, 56 young adolescents and 29 older adolescents and young adults. Efficacy parameters across 3 age groups were largely comparable. At Day 15, at least 50% of patients from each age group exhibited aACR ≥70 and ACR responses. The safety profile of canakinumab was similar across age groups. One death was reported. CONCLUSIONS: Pooled analyses from SJIA studies indicate that older adolescents and young adults SJIA patients show similar efficacy, safety, and exposure-response relationship on a weight-based dosing regimen as observed in children and adolescent SJIA patients. These analyses suggest that canakinumab may be an effective therapy in young adults with Still's disease.

A curious case of growth failure and hypercalcemia: Questions.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis presenting with renal failure and hypercalcemia. CASE DIAGNOSIS/TREATMENT: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (≪3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 µmol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease. CONCLUSIONS: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.

A curious case of growth failure and hypercalcemia: Answers.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis, presenting with renal failure and hypercalcemia. CASE DIAGNOSIS/TREATMENT: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (<<3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 umol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease. CONCLUSIONS: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Systemic onset juvenile idiopathic arthritis and exposure to fine particulate air pollution.

OBJECTIVES: Fine particulate matter (PM2.5) is a measurable component of ambient pollution, and positive associations of short-term PM2.5 exposure with the clinical presentation of systemic onset juvenile idiopathic arthritis (SJIA) in young children have been described in a regional cohort. Our objective was to further establish associations between short-term pollution exposures and the reported clinical event of SJIA onset in cases residing from multiple metropolitan regions. METHODS: A case-crossover study design was used to analyse associations of short-term PM2.5 exposures with the event of SJIA symptom onset from cases residing in five metropolitan regions. Time trends, seasonality, month, and weekday were controlled for by matching. Selected exposure windows (to 14 days) of PM2.5 were examined. RESULTS: Positive, statistically significant associations between PM2.5 concentrations and elevated risk of SJIA were not observed. The most positive associations of short-term PM2.5 exposure with SJIA were in children <5.5 years (RR 1.75, 95% CI 0.85-3.62). An ad hoc extended pooled analysis including previously reported cases from Utah's metropolitan areas identified an increased risk of SJIA for children <5.5 years (RR = 1.76, 95% CI 1.07-2.89 per 10 µg/m3 increase in 3-day lagged moving average PM2.5). CONCLUSIONS: In this multi-city, multi-period study small, statistically insignificant PM2.5-SJIA associations are observed. However, as found in prior study, the PM2.5-SJIA association is most suggestive in preschool aged children. Larger numbers of SJIA cases spatially located in geographic areas which experience a greater day to day ambient particulate burden may be required by the analysis to demonstrate effects.

Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. METHODS: We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension. RESULTS: At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range. CONCLUSIONS: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1ß monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort.

OBJECTIVE: To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Later-onset rheumatoid factor negative polyarticular juvenile idiopathic arthritis (JIA): a unique patient group?

OBJECTIVES: To determine the two-year outcome of patients with later-onset polyarticular rheumatoid factor (RF) negative (-) juvenile idiopathic arthritis (JIA), and predictors of outcome. METHODS: All patients ages 10 to16 years diagnosed and followed in the Rheumatology Clinic at SickKids Hospital with the diagnosis of polyarticular RF- JIA were eligible for study. A retrospective chart analysis was performed and number of active joints, medications, laboratory information and childhood health assessment questionnaire scores were recorded at diagnosis, and 6, 12, and 24 months following diagnosis. RESULTS: As early as 6 months after diagnosis the mean number of active joints decreased from 16 to < 10, with 50% of the patients having < 5 active joints. The predominant joints affected were the wrist, knee, and small joints of the hand. The only predictor of active joint count at the 2-year follow-up was initial presenting active joint count as classified as mild, moderate, or severe. Sex, age, and laboratory results at presentation did not show any correlation with active joint count at 2 years. Majority of patients were treated with non-steroidal anti-inflammatory drugs (98%) and at least one disease-modifying anti-rheumatic drug (56%). CONCLUSIONS: The two-year outcome of patients with late-onset RF- polyarticular JIA was very good with the majority of patients having minimally active disease at last follow-up. Presence of significant polyarthritis at presentation was the only feature associated with long-term joint activity. Sex and lab results did not show any correlation with active joint in this cohort of RF-JIA patients.

Evaluation of perceived collaborative behaviour amongst stakeholders and clinicians of a continuing education programme in arthritis care.

Successful implementation of new extended practice roles which transcend conventional boundaries of practice entails strong collaboration with other healthcare providers. This study describes interprofessional collaborative behaviour perceived by advanced clinician practitioner in arthritis care (ACPAC) graduates at 1 year beyond training, and relevant stakeholders, across urban, community and remote clinical settings in Canada. A mixed-method approach involved a quantitative (survey) and qualitative (focus group/interview) evaluation issued across a 4-month period. ACPAC graduates work across heterogeneous settings and are on teams of diverse size and composition. Seventy per cent perceived their team as actively working in an interprofessional care model. Mean scores on the Bruyère Clinical Team Self-Assessment on Interprofessional Practice subjective subscales were high (range: 3.66-4.26, scale: 1-5 = better perception of team's interprofessional practice), whereas the objective scale was lower (mean: 4.6, scale: 0-9 = more interprofessional team practices). Data from focus groups (ACPAC graduates) and interviews (stakeholders) provided further illumination of these results at individual, group and system levels. Issues relating to ACPAC graduate role recognition, as well as their deployment, integration and institutional support, including access to medical directives, limitation of scope of practice, remuneration conflicts and tenuous funding arrangements were barriers perceived to affect role implementation and interprofessional working. This study offers the opportunity to reflect on newly introduced roles for health professionals with expectations of collaboration that will challenge traditional healthcare delivery.

Lengthening sleep reduces pain in childhood arthritis: a crossover randomised controlled trial.

OBJECTIVES: Juvenile 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. METHODS: Patients 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. RESULTS: Participants (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). CONCLUSION: It 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 NUMBER: NCT04133662.

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

Nailfold capillary density is importantly associated over time with muscle and skin disease activity in juvenile dermatomyositis.

OBJECTIVES: To investigate the longitudinal association of nailfold capillary density (NCD; as a potential marker of activity) with various other clinical measures of disease activity and to evaluate baseline NCD as a predictor of disease outcome in children with JDM. METHODS: Data from 809 clinic visits from 92 JDM patients were prospectively collected at each clinic visit over a time period of 5.5 years. The number of capillaries per millimetre at the distal nailfold was scored using a stereomicroscope. Disease activity was determined using the Childhood Myositis Assessment Scale (CMAS) and a modification of the validated disease activity score (DAS), which included three skin (SDAS) and three muscle (MDAS) criteria. An inception cohort subgroup (n=28) with a baseline visit at diagnosis was analysed separately. RESULTS: Both DAS subscores, MDAS (ß = -0.04437, P < 0.0001) and SDAS (ß = -0.1589, P < 0.0001), as well as the CMAS (ß = 0.02165, P < 0.0001) were significantly associated with loss of end row nailfold capillary over time (multiple regression mixed-model analysis). All patients in the inception subcohort showed a reduced baseline NCD (diagnostic sensitivity = 100%) that improved as the disease improved, but this did not predict longer term outcome or course of disease. CONCLUSION: NCD is a marker of skin and muscle disease activity, and is an important measure of disease activity changes from visit to visit. Determination of capillary density may be useful when making treatment decisions. A decrease in NCD may be considered for inclusion in the diagnostic criteria due to its high sensitivity.

Sleep and fatigue and the relationship to pain, disease activity and quality of life in juvenile idiopathic arthritis and juvenile dermatomyositis.

OBJECTIVES: To determine and compare the prevalence of disturbed sleep in JIA and JDM and the relationship of sleep disturbance to pain, function, disease activity and medications. METHODS: One hundred fifty-five patients (115 JIA, 40 JDM) were randomly sampled and were mailed questionnaires. Sleep disturbance was assessed by the sleep self-report (SSR) and the children's sleep habits questionnaire (CSHQ). Fatigue, pain and function were assessed by the paediatric quality of life inventory (PedsQL) and disease activity by visual analogue scales (VASs). Joint counts were self-reported. RESULTS: Eighty-one per cent responded, of whom 44% reported disturbed sleep (CSHQ > 41); there were no differences between disease groups. Poor reported sleep (SSR) was highly correlated with PedsQL fatigue (r = 0.56, P < 0.0001). Fatigue was highly negatively correlated with quality of life (r = -0.77, P < 0.0001). The worst pain intensity in the last week was correlated to sleep disturbance (r = 0.32, P = 0.0005). Fatigue was associated with prednisone and DMARD use. CONCLUSIONS: Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly associated with increased pain and decreased quality of life. Strategies aimed at improving sleep and reducing fatigue should be studied as possible ways of improving quality of life for children with rheumatic illness.

Kawasaki Disease and Systemic Juvenile Idiopathic Arthritis - Two Ends of the Same Spectrum.

Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (sJIA) are two distinct systemic inflammatory diseases of childhood. Each diagnosis is based on criteria, but numerous clinical features are overlapping. As no specific diagnostic tests are available, differentiation between both disease entities can be challenging. Here, we describe the disease course of patients with co-diagnosis of both KD and sJIA (KD/sJIA). All our KD (n = 1765) and sJIA (n = 112) cases were critically reviewed for co-diagnosis of KD/sJIA. Eight KD/sJIA cases were identified and their clinical presentation, treatment regimens, coronary artery outcome and complications are herein described. Each KD/sJIA patient fulfilled diagnostic criteria for KD and for sJIA. Ongoing fever, rash and arthritis were present in each patient. The KD/sJIA patients had recalcitrant KD requiring multiple doses of intravenous immunoglobulin and steroids. Five patients had coronary artery dilatation at KD diagnosis, which resolved in all by 6 weeks. Pericardial effusion was present in 5 patients. One KD/sJIA patient developed macrophage activation syndrome. In conclusion, a small proportion (0.5%) of our KD patients evolved into sJIA, and 7% of our sJIA population presented initially as KD. KD/sJIA patients were characterized by a recalcitrant KD course and a high prevalence of coronary artery dilatation. Patients with co-diagnoses may provide a clue to potentially shared immunopathology in KD and sJIA, leading us to posit that both entities may be part of the same clinical spectrum.

Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study.

OBJECTIVE: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). METHODS: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. RESULTS: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. CONCLUSION: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response.