To date only 38 cases of childhood-onset eosinophilic granulomatosis with polyangiitis (cEGPA; formerly Churg-Strauss syndrome) have been reported. Additional patients with cEGPA could enhance the ...understanding of this rare and life-threatening condition. Our objectives were (1) to determine the frequency of specific organ system involvement; (2) to examine initial therapeutic regimen; and (3) to document disease and therapy-related morbidity in a contemporary cohort of patients with cEGPA.
Retrospective review of patients evaluated at the Cleveland Clinic between 2003 and 2011 who met either American College of Rheumatology or Lanham criteria for EGPA and whose age was < 18 years at symptom onset.
Nine patients (8 female; 7 white) were identified. Median age at onset of rhinitis/asthma symptom was 13 years and median age at diagnosis of cEGPA was 15 years. All patients demonstrated eosinophilia, upper airway disease (allergic rhinitis, chronic sinusitis, and/or nasal polyps), and pulmonary involvement. Other frequently involved organ systems included musculoskeletal (67%), gastrointestinal (67%), cutaneous (67%), neurologic (56%), and cardiac (44%). Antineutrophil cytoplasmic antibody (ANCA) serologies were negative in all patients. The medications used most frequently for initial therapy included oral (44%) or intravenous corticosteroids (56%) and azathioprine (67%). Disease or therapeutic complications occurred in half of the cohort and included heart failure, stroke, and sequela from longterm, high-dose steroids.
Eosinophilia, in combination with upper airway, pulmonary, musculoskeletal, neurologic, and cardiac manifestations, is frequently observed in cEGPA. ANCA titers are often negative. Steroids are the mainstay of initial therapy but steroid-related side effects occur regularly.
Objective
To assess the efficacy and safety of rilonacept, an interleukin‐1 inhibitor, in a randomized, double‐blind, placebo‐controlled trial.
Methods
An initial 4‐week double‐blind placebo phase ...was incorporated into a 24‐week randomized multicenter design, followed by an open‐label phase. Seventy‐one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria.
Results
The time to response was shorter in the rilonacept arm than in the placebo arm (χ2 = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study.
Conclusion
Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA.
Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory ...cytokine in FMF.
To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF.
Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907).
6 U.S. sites.
Patients with FMF aged 4 years or older with 1 or more attacks per month.
One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo.
Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo.
8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 95% CI, -3.4 to -0.1; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days -0.5 and 2.4 days in the first and third quartiles, respectively; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month medians of -4 and 0 in the first and third quartiles, respectively; P = 0.047), but no differences were seen in other adverse events.
Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations.
Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF.
U.S. Food and Drug Administration, Office of Orphan Products Development.
To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments' clinimetric property and effect on quality of life (QOL).
A 3-phase study was conducted. The ...first phase involved 15 patients with LS and 14 examiners who assessed LoSSI surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E) twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children's Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.
Interrater reliability was excellent for ER intraclass correlation coefficient (ICC) 0.71, ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners' experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman's rho = 0.71-0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.
mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.
Takayasu Arteritis is an idiopathic, chronic, large vessel vasculitis involving the aorta and its primary branches. Few studies have been done in pediatric patients to date with the largest case ...series of US patients published in 2003 consisting of only 6 patients.
A retrospective chart review was performed on all patients seen at Cleveland Clinic Children's up until 2012 who met EULAR/PRINTO/PRES classification criteria for childhood Takayasu Arteritis.
Twenty-one patients with a mean follow up of 2.3 years were studied. Weight loss, fatigue, and anorexia were the most common presenting complaints. 57.1% of patients were hypertensive at first visit. The most common examintation finding was diminished pulses (61.9%), followed by bruits, and then murmurs. Thoracic aorta stenosis was the most common vascular abnormality. Seven of twenty-one patients responded well to methotrexate and prednisone alone. Ten of twenty-one patients required an additional medication for symptom and disease control (infliximab most commonly). About two-thirds of patients required at least one anti-hypertensive medication. Eight of the twenty-one patients required surgical intervention for severe disease refractory to medications (renal artery stenosis being the most common indication). Almost all patients reported symptomatic improvement after surgical intervention. Two of the eight patients required a second surgery for return of symptoms. Disease sequelae included arterial aneurysms, resolved heart failure, and hypertensive emergencies.
Our study emphasizes that constitutional symptoms coupled with objective findings of diminished pulses, bruits, and hypertension should raise clinical suspicion for Takayasu Arteritis in pediatric patients. Pharmacologic therapy alone can be successful in controlling disease progression, however surgery was successful in minimizing symptoms when medical therapies failed.
Recent warnings from scientists suggest there is limited time to enact policies to avert wide‐ranging ecological and social damage from climate change. In the United States, discussions about ...comprehensive national policies to avert climate change have begun, with “Green New Deal” proposals and climate plans put forth by members of Congress and presidential candidates. Oceans are largely absent or separate from these nascent policy proposals. Here, we highlight a policy framework to develop terrestrial and ocean‐integrated policies that can complement and enhance terrestrial‐focused initiatives focused on four specific sectors: 1) energy; 2) transportation; 3) food security; and 4) habitat restoration. Given political friction and constrained budgets, an integrated policy framework offers greater potential to achieve a portfolio of mitigation and adaptation goals in a cost‐effective manner, beyond what could be realized with marine or terrestrial policy solutions alone.
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).
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.
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.
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.
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.
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.
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.
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.
Objective
Granulomatosis with polyangiitis (Wegener's) (GPA) is a necrotizing granulomatous vasculitis affecting the upper and lower respiratory tract, kidneys, and other small vessels throughout ...multiple organ systems. Recently, classification criteria for childhood GPA have been proposed and include the addition of airway stenosis. Airway inflammation occurs more frequently in children than adults and often proves difficult to diagnose and treat. Our objectives were to 1) determine the frequency of airway involvement in a cohort of children with GPA as defined by the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Pediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria, 2) document the frequency of specific airway findings, and 3) review our treatment approach to children with GPA‐related airway disease.
Methods
A retrospective chart review was performed on patients ages <18 years with a diagnosis of vasculitis evaluated at the Cleveland Clinic between 2004 and 2010.
Results
Twenty‐eight patients fulfilling the EULAR/PRINTO/PRES classification criteria for the diagnosis of childhood GPA were included in the analysis. There was a mean followup time of 3.1 years. The overall prevalence of any airway disease was 86%, with upper airway involvement in 86% and laryngotracheobronchial (LTB) disease in 50% of patients. LTB disease was present at diagnosis in 36%, while in the remaining 14% it developed on immunosuppressive therapy. Ten patients underwent a successful endoscopic intervention.
Conclusion
Airway manifestations frequently occur in childhood GPA. Inflammatory changes can occur at any point in the disease course, necessitating diligent surveillance. Endoscopic interventions for LTB stenotic lesions represent a safe and effective therapeutic option.
Objective
The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant ...levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA.
Methods
DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti–tumor necrosis factor (anti‐TNF) therapy. Recombinant His‐tagged full‐length DEK protein (1–375 amino acids aa) and the 187–375‐aa and 1–350‐aa His‐tagged DEK fragments made in a baculovirus system were used for enzyme‐linked immunosorbent assay (ELISA) and immunoblotting. The C‐terminal 25‐aa fragment of DEK was expressed in a glutathione S‐transferase–tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule.
Results
DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti‐TNF therapy. Immunoblotting against the C‐terminal 25‐aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain.
Conclusion
DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti‐TNF therapy. The C‐terminal 25‐aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.
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