Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: There is no standardized approach to the treatment of pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Because of the rarity of pediatric AAV, randomized trials have not been feasible. The present study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) was undertaken to establish consensus treatment plans (CTPs) for severe pediatric AAV to enable the future study of comparative effectiveness and safety. METHODS: A workgroup of CARRA members (rheumatologists and nephrologists) formed the AAV Workgroup. This group performed a literature review on existing evidence-based treatments and guidelines for the management of AAV. They determined that the target population for CTP development was patients <18 years of age with new-onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal-limited AAV (eosinophilic GPA was excluded), with presentation confined to those with severe disease (i.e., organ- or life-threatening). Face-to-face consensus conferences employed nominal group techniques to identify treatment strategies for remission induction and remission maintenance, data elements to be systematically collected, and outcomes to be measured over time. RESULTS: The pediatric AAV Workgroup developed 2 CTPs for each of the remission induction and remission maintenance of severe AAV. A glucocorticoid-weaning regimen for induction and maintenance, a core data set, and outcome measures were also defined. A random sample of CARRA membership voted acceptance of the CTPs for remission induction and remission maintenance, with a 94% (75 of 80) and 98% (78 of 80) approval rate, respectively. CONCLUSION: Consensus methodology established standardized CTPs for treating severe pediatric AAV. These CTPs were in principle accepted by CARRA-wide membership for the evaluation of pragmatic comparative effectiveness in a long-term registry.

Identifying Candidate Biomarkers of Ionizing Radiation in Human Pulmonary Microvascular Lumens Using Microfluidics-A Pilot Study.

The microvasculature system is critical for the delivery and removal of key nutrients and waste products and is significantly damaged by ionizing radiation. Single-cell capillaries and microvasculature structures are the primary cause of circulatory dysfunction, one that results in morbidities leading to progressive tissue and organ failure and premature death. Identifying tissue-specific biomarkers that are predictive of the extent of tissue and organ damage will aid in developing medical countermeasures for treating individuals exposed to ionizing radiation. In this pilot study, we developed and tested a 17 µL human-derived microvascular microfluidic lumen for identifying candidate biomarkers of ionizing radiation exposure. Through mass-spectrometry-based proteomics, we detected 35 proteins that may be candidate early biomarkers of ionizing radiation exposure. This pilot study demonstrates the feasibility of using humanized microfluidic and organ-on-a-chip systems for biomarker discovery studies. A more elaborate study of sufficient statistical power is needed to identify candidate biomarkers and test medical countermeasures of ionizing radiation.

Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma.

OBJECTIVE: The aim of this study was to evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS). METHODS: A prospective, multicentre, 6-month observational study was performed. The data collected included disease features, global assessments, and subject symptoms. Bivariate and linear multilevel regression analyses were performed. RESULTS: A total of 86 jLS subjects (80% female, 80% Caucasian), median age of disease onset 7.7 years, were evaluated. Most had linear scleroderma or mixed morphea. Of the 86 subjects, 49 (57%) had 125 extracutaneous problems {median 2 [interquartile range (IQR) 1, 3] per subject} from nine organ systems. Most of these subjects had multiple musculoskeletal problems. ECI was associated with more extensive cutaneous involvement, higher number of symptoms, family history of autoimmunity, and ANA and RF positivity. Subjects with ECI had higher scores for physician global assessment of damage (PGA-D), and parental global assessment of disease impact, but not baseline physician global assessment of disease activity (PGA-A). Although subjects with ECI received more MTX and glucocorticoid treatment, they had a slower reduction in PGA-A scores and symptoms over time, suggesting a poorer response to treatment. In logistic regression modelling, female sex had the largest effect on parental impact scores. CONCLUSION: ECI occurred in the majority of subjects with jLS, and was associated with more medication use, longer treatment duration, higher PGA-D scores, and higher parental assessment of disease impact. Our findings suggest that jLS subjects with ECI have greater overall disease burden, both cutaneous and extracutaneous, and poorer response to treatment. More study of the treatment needs of this population is warranted.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Plasma exosomes from children with juvenile dermatomyositis are taken up by human aortic endothelial cells and are associated with altered gene expression in those cells.

BACKGROUND: The pathology of juvenile dermatomyositis (JDM) is characterized by prominent vessel wall and perivascular inflammation. This feature of the disease has remained unexplained and under-investigated. We have hypothesized that plasma exosomes, which play an important role in inter-cellular communication, may play a role in the vascular injury associated with JDM. OBJECTIVE: To characterize the circulating exosomes of children with JDM and determine whether the small RNA cargoes within those exosomes are capable of altering transcriptional programs within endothelial cells. DESIGN/METHODS: We purified exosomes from plasma samples of children with active, untreated JDM (n = 6) and healthy controls (n = 9). We characterized the small RNA cargoes in JDM and control exosomes by RNA sequencing using the Illumina HiSeq 2500 platform. We then incubated isolated exosomes from healthy controls and children with JDM with cultured human aortic endothelial cells (HAEC) for 24 h. Fluorescence microscopy was used to confirm that both control and JDM exosomes were taken up by HAEC. RNA was then purified from HAEC that had been incubated with either control or JDM exosomes and sequenced on the Illumina platform. Differential expression of mRNAs from HAEC incubated with control or JDM exosomes was ascertained using standard computational methods. Finally, we assessed the degree to which differential gene expression in HAEC could be attributed to the different small RNA cargoes in JDM vs control exosomes using conventional and novel analytic methods. RESULTS: We identified 10 small RNA molecules that showed differential abundance when we compared JDM and healthy control exosomes. Fluorescence microscopy of labeled exosomes confirmed that both JDM and control exosomes were taken up by HAEC. Differential gene expression analysis revealed 59 genes that showed differential expression between HAEC incubated with JDM exosomes vs HAEC incubated with exosomes from controls. Statistical analysis of gene expression data demonstrated that multiple miRNAs exerted transcriptional control on multiple genes with HAEC. CONCLUSIONS: Plasma exosomes from children with active, untreated JDM are taken up by HAEC and are associated with alterations in gene expression in those cells. These findings provide new insight into potential mechanisms leading to the targeting of vascular tissue by the immune system in JDM.

New Features for Measuring Disease Activity in Pediatric Localized Scleroderma.

OBJECTIVE: To identify clinical features that define disease activity in pediatric localized scleroderma (LS), and determine their specificity and importance. METHODS: We conducted a multicenter prospective study of patients with active and inactive LS skin lesions. A standardized evaluation of a single designated study lesion per subject was performed at 3 visits. We evaluated the pattern and correlation between assessed features and physician's global assessments of activity (PGA-A). RESULTS: Ninety of 103 subjects had evaluable data; 66 had active and 24 inactive disease. Subjects had similar age of onset, sex, and disease patterns. Linear scleroderma was the most common subtype. Features specific for active disease included erythema, violaceous color, tactile warmth, abnormal skin texture, and disease extension. Scores for these variables changed over time and correlated with PGA-A of the lesion. Active and inactive lesions could not be distinguished by the presence or level of skin thickening, either of lesion edge or center. However, in active lesions, skin thickening scores did correlate with PGA-A scores. Regression analysis identified the combination of erythema, disease extension, violaceous color, skin thickening, and abnormal texture as predictive of PGA-A at study entry. Damage features were common irrespective of activity status. CONCLUSION: We identified variables strongly associated with disease activity, expanding upon those used in current measures, and determined their relative importance in physician activity scoring. Skin thickening was found to lack specificity for disease activity. These results will help guide development of a sensitive, responsive activity tool to improve care of patients with LS.

Systemic Lupus Erythematosus, Sjögren Syndrome, and Mixed Connective Tissue Disease in Children and Adolescents.

Juvenile systemic lupus erythematosus (jSLE), mixed connective tissue disease (jMCTD), and Sjögren syndrome (jSS) are systemic autoimmune and inflammatory disorders with distinct patterns of organ involvement. All are characterized by autoantibody formation, with antinuclear (ANA) and anti-double-stranded DNA common in jSLE, ANA with high-titer ribonucleoprotein antibody in jMCTD, and Sjögren syndrome A and Sjögren syndrome B antibodies + ANA in jSS. Recognition, monitoring, and management for primary care providers are discussed, focusing on the role of primary physicians in recognizing and helping maintain optimal health in children with these potentially life-threatening diseases.

Mycophenolic acid induces senescence of vascular precursor cells.

OBJECTIVE: Endothelial dysfunction is central to the pathogenesis of many rheumatic diseases, typified by vascular inflammation and damage. Immunosuppressive drugs induce disease remission and lead to improved patient survival. However, there remains a higher incidence of cardiovascular disease in these patients even after adequate disease control. The purpose of this study was to determine the effect of mycophenolic acid (MPA), a commonly used immunosuppressive drug in rheumatology, on blood vessel or circulating endothelial colony forming cell number and function. METHODS: We tested whether mycophenolic acid exerts an inhibitory effect on proliferation, clonogenic potential and vasculogenic function of endothelial colony forming cell. We also studied potential mechanisms involved in the observed effects. RESULTS: Treatment with MPA decreased endothelial colony forming cell proliferation, clonogenic potential and vasculogenic function in a dose-dependent fashion. MPA increased senescence-associated ß-galactosidase expression, p21 gene expression and p53 phosphorylation, indicative of activation of cellular senescence. Exogenous guanosine supplementation rescued diminished endothelial colony forming cell proliferation and indices of senescence, consistent with the known mechanism of action of MPA. CONCLUSION: Our findings show that clinically relevant doses of MPA have potent anti-angiogenic and pro-senescent effects on vascular precursor cells in vitro, thus indicating that treatment with MPA can potentially affect vascular repair and regeneration. This warrants further studies in vivo to determine how MPA therapy contributes to vascular dysfunction and increased cardiovascular disease seen in patients with inflammatory rheumatic disease.

Malignancy in Pediatric-onset Systemic Lupus Erythematosus.

OBJECTIVE: To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population. METHODS: Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year-specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI. RESULTS: A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974-2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26-6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96-13.67). SIR were increased for both male and female patients, and across age groups. CONCLUSION: Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.

Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey.

BACKGROUND: Because pediatric antineutrophil cytoplasmic antibody-associated vasculitis is rare, management generally relies on adult data. We assessed treatment practices, uptake of existing clinical assessment tools, and interest in pediatric treatment protocols among rheumatologists caring for children with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: A needs-assessment survey developed by an international working group of pediatric rheumatologists and two nephrologists was circulated internationally. Data were summarized with descriptive statistics. Pearson's chi-square tests were used in inferential univariate analyses. RESULTS: The 209 respondents from 36 countries had collectively seen ~1600 children with GPA/MPA; 144 had seen more than two in the preceding 5 years. Standardized and validated clinical assessment tools to score disease severity, activity, and damage were used by 59, 63, and 36%, respectively; barriers to use included lack of knowledge and limited perceived utility. Therapy varied significantly: use of rituximab rather than cyclophosphamide was more common among respondents from the USA (OR = 2.7 [1.3-5.5], p = 0.0190, n = 139), those with >5 years of independent practice experience (OR = 3.8 [1.3-12.5], p = 0.0279, n = 137), and those who had seen >10 children with GPA/MPA in their careers (OR = 4.39 [2.1-9.1], p = 0.0011, n = 133). Respondents who had treated >10 patients were also more likely to continue maintenance therapy for at least 24 months (OR = 3.0 [1.4-6.4], p = 0.0161, n = 127). Ninety six percent of respondents believed in a need for pediatric-specific treatment guidelines; 46% supported adaptation of adult guidelines while 69% favoured guidelines providing a limited range of treatment options to allow comparison of effectiveness through a registry. CONCLUSIONS: These data provide a rationale for developing pediatric-specific consensus treatment guidelines for GPA/MPA. While pediatric rheumatologist uptake of existing clinical tools has been limited, guideline uptake may be enhanced if outcomes of consensus-derived treatment options are evaluated within the framework of an international registry.

Transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate.

Objective: The mechanisms that determine the efficacy or inefficacy of MTX in JIA are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. Methods: RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Results: A signature of 99 differentially expressed genes (Bonferroni-corrected P < 0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 × 10-10). Conclusion: Variability in clinical response to MTX in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response.

The catastrophic antiphospholipid syndrome in children.

PURPOSE OF REVIEW: To review the difficult syndrome of catastrophic antiphospholipid syndrome, emphasizing new developments in the diagnosis, pathogenesis and treatment. RECENT FINDINGS: Few recent publications directly address pediatric catastrophic antiphospholipid syndrome (CAPS). Most articles are case reports or are data from adult and pediatric registries. The major factors contributing to most pediatric catastrophic antiphospholipid syndrome include infection and the presence of antiphospholipid antibodies, but complement activation also is important in creating diffuse thrombosis in the microcirculation. Treatment of the acute emergency requires anticoagulation, suppression of the hyperinflammatory state and elimination of the triggering infection. Inhibition of complement activation appears to improve outcome in limited studies, and suppression of antiphospholipid antibody formation may be important in long-term management. SUMMARY: CAPS, an antibody-mediated diffuse thrombotic disease of microvasculature, is rare in childhood but has high mortality (33-50%). It requires prompt recognition and aggressive multimodality treatment, including anticoagulation, anti-inflammatory therapy and elimination of inciting infection and pathogenic autoantibodies.

Malignancy incidence in 5294 patients with juvenile arthritis.

OBJECTIVE: To determine cancer incidence in a large clinical juvenile-onset arthritis population. METHODS: We combined data from 6 existing North American juvenile-onset arthritis cohorts. Patients with juvenile-onset arthritis were linked to regional cancer registries to detect incident cancers after cohort entry, defined as first date seen in the paediatric rheumatology clinic. The expected number of malignancies was obtained by multiplying the person-years observed (defined from cohort entry to end of follow-up) by the geographically matched age, sex and calendar year-specific cancer rates. The standardised incidence ratios (SIR; ratio of cancers observed to expected) were generated, with 95% CIs. RESULTS: The 6 juvenile arthritis registries provided a total of 5294 patients. The mean age at cohort entry was 8.9 (SD 5.0) years and 68% of participants were female. The mean duration of follow-up was 6.8 years with a total of 36 063 person-years spanning 1978-2012. During follow-up, 9 invasive cancers occurred, compared with 10.9 expected (SIR 0.82, 95% CI 0.38 to 1.5). 3 of these were haematological (Hodgkin's, non-Hodgkin's lymphoma and leukaemia). 6 of the patients with cancer were exposed to disease-modifying drugs; 5 of these had also been exposed to biological agents. CONCLUSIONS: We did not clearly demonstrate an increase in overall malignancy risk in patients with juvenile-onset arthritis followed for an average of almost 7 years. 3 of the 9 observed cancers were haematological. 5 of the cancers arose in children exposed to biological agents. Longer follow-up of this population is warranted, with further study of drug effects.

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults.

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.

National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

The National Institutes of Health (NIH) Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was cosponsored by the NIH Office of Disease Prevention and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the NIH Office of Disease Prevention Web site for 4 weeks for public comment.

Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis.

OBJECTIVE: To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup. METHODS: Children were treated as per provider's discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years. RESULTS: Forty-eight children were followed for a mean of 28 months (range 12-42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician's global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events. CONCLUSION: Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.

Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors.

OBJECTIVE: To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). METHODS: Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. RESULTS: Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. CONCLUSION: Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.

Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus.

OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation.