Suzanne C. Li

Development of consensus treatment plans for juvenile localized scleroderma: A roadmap toward comparative effectiveness studies in juvenile localized scleroderma

Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS.

Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma.

To evaluate the construct validity of 2 proposed measures (the Ultrasound Disease Activity [U‐DA] and the Tissue Thickness Score [TTS]) for evaluating sonographic differences in juvenile localized scleroderma skin lesions.

Increased sensitivity of the European medicines agency algorithm for classification of childhood granulomatosis with polyangiitis.

Objective. Granulomatosis with polyangiitis (Wegener’s; GPA) and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare in childhood and are sometimes difficult to discriminate. We compared use of adult-derived classification schemes for GPA against validated pediatric criteria in the ARChiVe (A Registry for Childhood Vasculitis e-entry) cohort, a Childhood Arthritis and Rheumatology Research Alliance initiative. Methods. Time-of-diagnosis data for children with physician (MD) diagnosis of AAV and unclassified vasculitis (UCV) from 33 US/Canadian centers were analyzed. The European Medicines Agency (EMA) classification algorithm and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) and American College of Rheumatology (ACR) criteria for GPA were applied to all patients. Sensitivity and specificity were calculated (MD-diagnosis as reference). Results. MD-diagnoses for 155 children were 100 GPA, 25 microscopic polyangiitis (MPA), 6 ANCA-positive pauciimmune glomerulonephritis, 3 Churg-Strauss syndrome, and 21 UCV. Of these, 114 had GPA as defined by EMA, 98 by EULAR/PRINTO/PRES, and 87 by ACR. Fourteen patients were identified as GPA by EULAR/PRINTO/PRES but not by ACR; 3 were identified as GPA by ACR but not EULAR/PRINTO/PRES. Using the EMA algorithm, 135 (87%) children were classifiable. The sensitivity of the EMA algorithm, the EULAR/PRINTO/PRES, and ACR criteria for classifying GPA was 90%, 77%, and 69%, respectively, with specificities of 56%, 62%, and 67%. The relatively poor sensitivity of the 2 criteria related to their inability to discriminate patients with MPA. Conclusion. EULAR/PRINTO/PRES was more sensitive than ACR criteria in classifying pediatric GPA. Neither classification system has criteria for MPA; therefore usefulness in discriminating patients in ARChiVe was limited. Even when using the most sensitive EMA algorithm, many children remained unclassified.

Assessing the performance of the Birmingham vasculitis activity score at diagnosis for Children with antineutrophil cytoplasmic antibody-associated vasculitis in a registry for childhood vasculitis (ARChiVe)

Objective. 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). Methods. 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 (rs) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR. Results. 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 rs = 0.379 (95% CI 0.233 to 0.509) with PGA, rs = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and rs = 0.403 (95% CI 0.253 to 0.533) with ESR. Conclusion. 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.

Do adult disease severity subclassifications predict use of cyclophosphamide in children with ANCA-associated vasculitis? An analysis of ARChiVe study treatment decisions.

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.

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

To characterize the early disease course in childhood‐onset antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and the 12‐month outcomes in children with AAV.

Durometry as an Outcome Measure in Juvenile Localized Scleroderma

DEAR EDITOR, Localized scleroderma (LS), or morphoea, is an autoimmune, inflammatory and fibrotic disease affecting the skin and subdermal tissues. One of the main cutaneous outcome variables used in LS to monitor disease is skin thickness, with scoring adapted from systemic sclerosis. Although validated, the utility of clinician skin-thickness scoring is limited by the need for training and ongoing practice. The durometer, an instrument used to measure material hardness, shows potential as a surrogate, or a tool that can augment the skinthickness score by providing a more objective measure. This study examines the validity and reliability of using the durometer in paediatric patients with LS. For the validity study, patients were recruited from three specialized paediatric LS clinics with baseline and follow-up visits. One lesion from each patient was chosen as the ‘study lesion’, and was graded for skin thickness by the physician using the modified Rodnan Skin Score (mRSS) technique and for skin hardness using the durometer. Study lesions were marked and photographed at the initial visit to improve the consistency of measurements at subsequent visits. A Rex durometer (Rex Gauge, Buffalo Grove, IL, U.S.A.) was used with a 0to 100-point scale, with results given in durometer units (DU). The durometer was placed in a vertical position (perpendicular to the lesion) and allowed to rest by gravity, while the body site being measured was supported so that the musculature was relaxed (Fig. 1). Both edges and the centre of the study lesion were measured by skin-thickness assessment based on mRSS and the durometer. An area of unaffected skin in the same body area, typically contralateral, was measured as a control. By definition, the unaffected skin had a skin-thickness score of 0. In addition, the physicians also completed the modified Localized Scleroderma Severity Index (mLoSSI) and the modified Localized Scleroderma Damage Index (mLoSDI). These are cutaneous measures used to capture new or expanding lesions, erythema and skin thickness of the edge (mLoSSI); and dermal atrophy, subcutaneous atrophy, dyspigmentation and skin thickness at the centre of the lesion (mLoSDI). In order to compare the durometer readings of a single study lesion, mLoSSI and mLoSDI scores were calculated for only the body site containing the study lesion. The same lesion was measured in the same manner at a second study visit, which occurred 25–53 weeks after the initial visit, to determine responsiveness to change. Data for an inter-rater reliability study were collected from a separate LS sample recruited from one of the paediatric LS clinics (University of Pittsburgh). Two physicians, an experienced (K.T.) and inexperienced durometer user (S.P.), evaluated the edges and centre of a single study lesion, as well as a contralateral area of unaffected skin, in a single clinic visit using the same durometer. The first observer marked the precise spot for each measure while the second observer was out of the room. Triplicate measures were obtained on the edges and centre and were averaged to obtain a single value. All data analysis was performed using SPSS software version 21 (IBM, Armonk, NY, U.S.A.). Paired-samples t-tests were used to detect any significant differences between the durometer measures of the study lesions and the unaffected skin. Spearman’s correlations examined the relationships between durometer readings and mLoSSI and mLoSDI. For responsiveness analysis, changes in durometer readings between two visits were calculated, and independent-samples t-tests were used to determine significant differences in durometer change scores between two defined ‘change’ groups. The two definitions of ‘change’ used were as

Description of the localized scleroderma subgroup of CARRAnet.

Results Data were available on 44 children. 81.8% were female and 88.6% were Caucasian, of which 13.6% were Latino. Mean age at onset was 8.2 years (± 4.0), yet first evaluation by a pediatric rheumatologist was 9.9 years (± 4.2). Reported subtypes were: 34 linear scleroderma (LiScl: 25 trunk/limbs, 9 face/neck), 7 with circumscribed morphea (CM: 5 deep, 2 superficial), 6 with generalized morphea (GenM), 3 with eosinophilic fasciitis (EF), and 1 with pansclerotic morphea. There were 5 cases of mixed morphea (2 CM and LiScl, 1 with facial LiScl and GM, 2 with EF and linear lesions). Eight subjects had new lesions at time of enrollment. Features of active lesions included extension of existing lesions (13), warmth (13), erythematous/violacious color (13), and skin induration at lesion perimeter (10). Damage included subcutaneous atrophy (36), hyperpigmentation (35), dermal atrophy (31), hypopigmentation (19), hair loss (17), muscle atrophy (13), joint contracture (10), limb shortening (5), and hemifacial atrophy(1). Only three patients had extracutaneous manifestations, including two with arthritis. ANA positivity was found in 45% of tested patients, otherwise there were no consistent laboratory or imaging abnormalities. Table 1. Mean physician global assessment was 1.61 (range 08) and mean CHAQ score was 0.19 (0-1.13). On a visual analog scale (0-10), mean parent/subject score of overall well-being was 1.80 (± 1.66) and pain was 1.41 (±2.03). Health related quality of life was reported as excellent in 13, very good in 22, good in 7, and poor in 2 subjects. A worst ever and current ACR functional class > I was reported in 33% and 20.5%, respectively. Medications used are listed in table 2.

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions.

To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies.

Physicians’ perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome

To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset <5 years, 33% did not require regular intervals between episodes, and 79% did not require the concomitant signs of aphthous stomatitis, adenitis, or pharyngitis during episodes as long as episodes were regular. Over half (58%) considered episode resolution with steroids to be diagnostic of PFAPA. Corticosteroids, antipyretics, tonsillectomy, and cimetidine were the most commonly prescribed treatments, while steroids and tonsillectomy were most effective. Subspecialists in pediatric rheumatology and infectious diseases showed limited adherence to the complete published criteria for diagnosing PFAPA suggesting heterogeneity in the characteristics of patients diagnosed with the disorder. These findings emphasize the need to develop consensus diagnostic and treatment guidelines in well-characterized patient populations.