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Rina Mina,
Marisa S Klein-Gitelman,
Shannen Nelson,
B Anne Eberhard, Gloria Higgins,
Nora G Singer,
Karen Onel,
Lori Tucker,
Kathleen M O'Neil,
Marilynn Punaro,
Deborah M Levy,
Kathleen Haines,
Alberto Martini,
Nicolino Ruperto,
Daniel Lovell,
Hermine I Brunner
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ABSTRACT: 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.
Annals of the rheumatic diseases 01/2013; · 8.11 Impact Factor
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Kimberly Morishita,
Jaime Guzman,
Peter Chira,
Eyal Muscal,
Andrew Zeft,
Marisa Klein-Gitelman,
America G Uribe,
Leslie Abramson,
Susanne M Benseler,
Anne Eberhard, [......],
Andreas Reiff,
Margalit Rosenkranz,
Kenneth N Schikler,
Rosie Scuccimarri,
Nora G Singer,
Anne M Stevens,
Heather van Mater,
Dawn M Wahezi,
Andrew J White,
David A Cabral
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ABSTRACT: OBJECTIVE: To determine whether adult disease severity subclassification systems for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are concordant with the decision to treat pediatric patients with cyclophosphamide (CYC). METHODS: We applied the European Vasculitis Study (EUVAS) and Wegener's Granulomatosis Etanercept Trial (WGET) disease severity subclassification systems to pediatric patients with AAV in A Registry for Childhood Vasculitis (ARChiVe). Modifications were made to the EUVAS and WGET systems to enable their application to this cohort of children. Treatment was categorized into 2 groups, "cyclophosphamide" and "no cyclophosphamide." Pearson's chi-square and Kendall's rank correlation coefficient statistical analyses were used to determine the relationship between disease severity subgroup and treatment at the time of diagnosis. RESULTS: In total, 125 children with AAV were studied. Severity subgroup was associated with treatment group in both the EUVAS (chi-square 45.14, p < 0.001, Kendall's tau-b 0.601, p < 0.001) and WGET (chi-square 59.33, p < 0.001, Kendall's tau-b 0.689, p < 0.001) systems; however, 7 children classified by both systems as having less severe disease received CYC, and 6 children classified as having severe disease by both systems did not receive CYC. CONCLUSION: In this pediatric AAV cohort, the EUVAS and WGET adult severity subclassification systems had strong correlation with physician choice of treatment. However, a proportion of patients received treatment that was not concordant with their assigned severity subclass.
The Journal of Rheumatology 08/2012; 39(10):2012-2020. · 3.69 Impact Factor
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Kimberly Morishita,
Suzanne C Li,
Eyal Muscal,
Steven Spalding,
Jaime Guzman,
America Uribe,
Leslie Abramson,
Kevin Baszis,
Susanne Benseler,
Suzanne Bowyer, [......],
Lorien Nassi,
Kathleen M O'Neil,
Egla Rabinovich,
Suzanne E Ramsey,
Andreas Reiff,
Margalit Rosenkranz,
Kenneth Schikler,
Anne Stevens,
Dawn Wahezi,
David A Cabral
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ABSTRACT: There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician's global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool (www.vasculitis.org). Spearman's rank correlation coefficient (r(s)) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR.
A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0-40). The BVAS v.3 correlations were r(s) = 0.379 (95% CI 0.233 to 0.509) with PGA, r(s) = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and r(s) = 0.403 (95% CI 0.253 to 0.533) with ESR.
Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.
The Journal of Rheumatology 02/2012; 39(5):1088-94. · 3.69 Impact Factor
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Edward H Giannini,
Norman T Ilowite,
Daniel J Lovell,
Carol A Wallace,
C Egla Rabinovich,
Andreas Reiff, Gloria Higgins,
Beth Gottlieb,
Yun Chon,
Nan Zhang,
Scott W Baumgartner
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ABSTRACT: To evaluate the effects of long-term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA).
We conducted a 3-year, open-label, nonrandomized registry of 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts.
Statistically significant increases in the mean height percentiles from baseline were observed in etanercept-treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept-plus-methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6-13.8 percentile points) and the etanercept-plus-methotrexate group (range 2.1-5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate-only group.
Etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.
Arthritis & Rheumatism 11/2010; 62(11):3259-64. · 7.87 Impact Factor
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ABSTRACT: We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA).
Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction.
In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month.
Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.
Pediatric Rheumatology 12/2009; 7:21. · 1.44 Impact Factor
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David A Cabral,
América G Uribe,
Susanne Benseler,
Kathleen M O'Neil,
Philip J Hashkes, Gloria Higgins,
Andrew S Zeft,
Daniel J Lovell,
Daniel J Kingsbury,
Anne Stevens, [......],
Suzanne C Li,
Thomas Mason,
Esi Morgan Dewitt,
Eyal Muscal,
Lorien Nassi,
Andreas Reiff,
Kenneth Schikler,
Nora G Singer,
Dawn Wahezi,
Amy Woodward
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ABSTRACT: To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG.
Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.
MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6).
The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.
Arthritis & Rheumatism 11/2009; 60(11):3413-24. · 7.87 Impact Factor
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ABSTRACT: Abstract
Purpose
We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA).
Methods
Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction.
Results
In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month.
Conclusions
Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.
Pediatric Rheumatology. 01/2009;
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Daniel J Lovell,
David Glass,
Julie Ranz,
Sandy Kramer,
Bin Huang,
Rosa I Sierra,
Carol J Henderson,
Murray Passo,
Brent Graham,
Suzanne Bowyer, Gloria Higgins,
Robert Rennebohm,
Kenneth N Schikler,
Edward Giannini
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ABSTRACT: To examine the effects of daily supplementation with calcium (Ca) in combination with vitamin D on total body and lumbar spine bone mineral density (BMD) in patients with juvenile rheumatoid arthritis (JRA) who had not taken corticosteroids for at least 3 months prior to the beginning of the study.
One hundred ninety-eight children and adolescents (141 girls and 57 boys) with JRA, ages 6 to 18 years, with a mean +/- SD age of 11.7 +/- 3.3 years and a mean +/- SD disease duration of 5.6 +/- 3.8 years at the beginning of the study, were enrolled in this randomized double-blind, placebo-controlled trial to receive either daily oral supplements of 1,000 mg of Ca and 400 IU of vitamin D (n = 103) or matched placebo tablets and 400 IU of vitamin D (n = 95) for 24 months. Total body BMD (TBBMD) was measured by dual x-ray absorptiometry at baseline and every 6 months for 24 months.
At baseline, the mean +/- SD TBBMD was 0.89 +/- 0.14 gm/cm2 among patients randomized to the Ca group and 0.87 +/- 0.14 gm/cm2 among those randomized to placebo (P = 0.445). At 24 months, the mean +/- SD TBBMD among those receiving Ca was 0.95 +/- 0.13 gm/cm2, compared with 0.92 +/- 0.14 gm/cm2 among those receiving placebo. A longitudinal random-effects mixed model analysis that controlled for differences in the subject's initial BMD, sex, Tanner stage, adherence to the study medication regimen, and body composition revealed significantly higher TBBMD among patients who received Ca compared with patients who received placebo during the study period (P = 0.03).
Ca supplementation resulted in a small, but statistically significant, increase in TBBMD compared with placebo in children with JRA.
Arthritis & Rheumatism 08/2006; 54(7):2235-42. · 7.87 Impact Factor
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ABSTRACT: . To assess the efficacy and safety of etanercept in a large cohort of children with refractory systemic onset juvenile rheumatoid arthritis (SOJRA).
Standardized questionnaires were sent to US pediatric rheumatologists about patients with SOJRA treated with etanercept. Data were collected at baseline and at the last visit on etanercept. Response to treatment was assessed and compared to baseline as the mean percentage reduction in the following: acute phase reactants, prednisone dose, active joint count, and physician global assessment of disease activity. Response was defined as poor if the mean reduction was < 30%, fair if 30% to < 50%, good if 50% to < 70%, and excellent if > 70%.
We analyzed data obtained by survey of 82 SOJRA patients treated with etanercept for a mean of 25 months. Poor response to treatment was observed in 45% of the children, fair response in 9%, good in 13%, and excellent in 33%. Baseline steroid therapy could be discontinued in 27/59 (46%) patients. One or more disease flares occurred in 45% of all patients. Twenty-nine patients (35%) discontinued therapy, mostly due to lack of response or flare. There were 32 adverse event reports, most not considered serious, except for 2 cases of macrophage activation syndrome.
In this cohort of children with SOJRA, 46% had a good or excellent response, and most were able to reduce concomitant corticosteroid doses. The response to etanercept was fair or poor in more than half our study population, and disease flares were common. Due to the unique cytokine profile of SOJRA, tumor necrosis factor blockade may not be the optimal therapeutic approach for children with treatment-resistant SOJRA.
The Journal of Rheumatology 05/2005; 32(5):935-42. · 3.69 Impact Factor
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ABSTRACT: The aims of this study were: (1) to assess functional status, emotional well-being and quality of life in patients with polyarticular and systemic juvenile rheumatoid arthritis (JRA) treated with etanercept, and (2) to determine the prevalence and significance of adverse events associated with etanercept therapy.
All JRA patients (n = 21) who received etanercept in our rheumatology clinic over a 14-month period were evaluated. Patient demo-graphics, type of arthritis, dosing regimens, family history, measures of joint function and laboratory parameters were obtained for each patient. A questionnaire that comprised validated functional assessment and quality-of-life measures (the Childhood Health Assessment Questionnaire [CHAQtrade mark], the Juvenile Arthritis Function Assessment Report [JAFAR 5trade mark] and the Pediatric Quality of Life Inventory Version 4 [PedsQL Generic Scaletrade mark] scales) was administered to patients and parents to assess physical and emotional function, pain, adverse drug events and quality of life at each clinic visit.
Functional status and quality of life improved in patients with poly-articular and systemic disease. A significant difference between pre- and post-etanercept functional assessment (JAFARtrade mark and CHAQtrade mark) and quality-of-life assessment by parents and patients was found (p = 0.009, p = 0.002, p </= 0.001, p </= 0.001, respectively). The JAFARtrade mark results concurred with those of the CHAQtrade mark test, and did not distinguish between patients with polyarticular and systemic disease. Laboratory parameters indicative of toxicity did not differ between patients with polyarticular and systemic JRA and the number of adverse events reported was low. Underlying disease did not appear to predict improvement.
Etanercept appeared to improve functional status, emotional well-being, quality of life and activity level with minimal toxicity in patients with polyarticular and systemic JRA.
Clinical Drug Investigation 01/2003; 23(8):511-8. · 1.82 Impact Factor
