Performance of Birmingham Vasculitis Activity Score and disease extent index in childhood vasculitides.

OBJECTIVES: To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) v3 and the Disease Extent Index (DEI) for the assessment of disease activity in 4 primary childhood (c-) systemic vasculitides. METHODS: Patients fulfilling the EULAR/PRINTO/PRES (Ankara) c-vasculitis classification criteria for Henoch-Schönlein purpura (HSP), childhood (c) polyarteritis nodosa (c-PAN), c-Wegener's granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) with disease duration at the time of diagnosis ≤3 months were extracted from the PRINTO database. The performance of the BVAS and DEI were examined by assessing convergent validity, the pattern of disease involvement, and responsiveness. We also evaluated alternative unweighted scoring methods for both tools. RESULTS: The analysis set included 796 patients with 669 HSP, 80 c-PAN, 25 c-WG and 22 c-TA. The median age at diagnosis was 6.9 years (6.6-12) and median delay in making the diagnosis from the onset of signs/symptoms was 0.01 (0.003-0.027) years. A strong correlation was found between the BVAS and DEI (rs=0.78) while correlation with the physician global assessment was moderate (rs=0.48) with BVAS and poor with DEI (rs=0.25). Both the BVAS and DEI sub-scores and total scores were able to descrive the disease involvement in the 4 childhood vasculitides. Responsiveness was large (>1.5) for both tools. The performance characteristics of the BVAS and DEI with the unweighted methods were comparable. CONCLUSIONS: This study demonstrates that both the BVAS and DEI are valid tools for the assessment of the level of disease activity in a large cohort of childhood acute and chronic vasculitides.

Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study.

OBJECTIVE: To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM). METHODS: The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were <18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported "as observed" and in the intent-to-treat (ITT) population. RESULTS: Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the "as observed" analysis, 57.9% of the patients with recent-onset juvenile DM and 36.4% of the patients experiencing disease flare (P<0.001) reached at least a 70% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4% and 51.2%, respectively (P<0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months. CONCLUSION: Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease.

Criteria to define response to therapy in paediatric rheumatic diseases.

PURPOSE: In this review we describe the general methodology and the results of the international projects, conducted by the Paediatric Rheumatology International Trials Organisation (PRINTO), in collaboration with the Paediatric Rheumatology Collaborative Study Group (PRCSG). The aim of these projects were to identify and validate criteria for the evaluation of response to therapy in clinical trials and in daily clinical practice in patients with the three major paediatric rheumatic diseases (PRD): juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE). METHODS: The methodological approach to identify and validate outcome measures can be divided into three main phases: (1) the development of a preliminary core set of measures to evaluate the outcome (e.g. response to therapy, remission criteria, disease activity or damage etc.) through literature review and consensus techniques; (2) a large-scale data collection for a prospectively evidence-based validation of the preliminary findings; (3) the final development of a validated criteria for the evaluation of the outcome. RESULTS: The core sets for three diseases included domains that are common to all diseases (physician's global assessment of disease activity; parent's global assessment of the overall patient's well-being; disability and/or health-related quality of life) plus additional domains that are specific for each disease. In order to be classified as a responder to a given treatment, a patient should demonstrate a different minimum level of improvement (≥30% in JIA, ≥20% in JDM, and ≥50% in JSLE) with no more than one of the remaining variables worsening by more than 30%. CONCLUSIONS: The proposed core sets and definitions of improvement incorporate clinically meaningful change in a composite endpoint for the evaluation of global response to therapy in the major PRD. The definitions are proposed for use in PRD clinical trials and may help physicians to decide if a child has responded adequately to therapy.

Budd-Chiari syndrome in children: experience with therapeutic radiological intervention.

OBJECTIVES: Budd-Chiari syndrome (BCS) in children is not uncommon. Published literature on therapy for this condition is scarce. We therefore attempted radiological interventions in these patients to determine their efficacy and safety. PATIENTS AND METHODS: Fourteen of 16 children with a median age of 22 months diagnosed as having BCS were subjected to an inferior vena cava/hepatic venogram with the aim to establish a normal antegrade flow in at least 1 hepatic vein (HV). RESULTS: A normal antegrade flow in at least 1 of the HVs could be established in 11 children. Three patients had angioplasty of the HV (vein size or=5 mm), and 6 had transjugular intrahepatic porta systemic shunt ([TIPSS] total occlusion of all 3 HVs or veno-occlusive disease). The youngest child undergoing a successful stenting was 7 months of age and the child undergoing TIPSS was 3 years of age. One patient had reversal of fulminant liver failure following a successful TIPSS. Postprocedure, 2 patients developed reversible encephalopathy and 1 had a neck hematoma. There was no procedure-related mortality. The procedure was successful in both patients with stenting (100%), 5 of the 6 patients with TIPSS (80%), and only 1 of the 4 patients (25%) with angioplasty. The median follow-up was 31 months. CONCLUSIONS: Radiological therapeutic intervention is feasible and safe in children with BCS. The overall results of stenting/TIPSS are better than with angioplasty; however, long-term results of these interventions need to be evaluated.

Development of neoplasms in pediatric patients with rheumatic disease exposed to anti-tumor necrosis factor therapies: a single Centre retrospective study.

BACKGROUND: Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. FINDINGS: 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. CONCLUSIONS: The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.

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.

Blau arteritis resembling Takayasu disease with a novel NOD2 mutation.

OBJECTIVE: To put forward a new concept--Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome. METHODS: We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene. RESULTS: The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described. CONCLUSION: Blau arteritis can be observed in the context of both typical and atypical (incomplete) Blau syndrome. The associated mutation in the NOD2 gene raises the question of the potential importance of this gene among patients with "primary" forms of Takayasu arteritis.