Jürgen Brunner

EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria

Objectives To validate the previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.

The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/european League Against Rheumatism Disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: A prospective validation study†‡

OBJECTIVE To validate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile dermatomyositis (DM). METHODS In 2001, a preliminary consensus-derived core set for evaluating response to therapy in juvenile DM was established. In the present study, the core set was validated through an evidence-based, large-scale data collection that led to the enrollment of 294 patients from 36 countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, concordance in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response. RESULTS The following clinical measures were found to be feasible, and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physicians global assessment of disease activity, 2) muscle strength, 3) global disease activity measure, 4) parents global assessment of patients well-being, 5) functional ability, and 6) health-related quality of life. CONCLUSION The members of the Paediatric Rheumatology International Trials Organisation, with the endorsement of the American College of Rheumatology and the European League Against Rheumatism, propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a child with juvenile DM has responded adequately to therapy.

Premature aging of the immune system in children with juvenile idiopathic arthritis

OBJECTIVE Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence. METHODS To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation. RESULTS JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age-matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki-67-positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04). CONCLUSION Our findings suggest that age-inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies.

Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS)

Background Rare chronic childhood vasculitides lack a reliable disease activity assessment tool. With emerging new treatment modalities such a tool has become increasingly essential for both clinical practice and therapeutic trials to reproducibly quantify change in disease state. Objective To develop and validate a paediatric vasculitis activity assessment tool based on modification of the Birmingham Vasculitis Activity Score (BVASv.3). Methods A paediatric vasculitis registry was reviewed to identify clinical features missing in the BVASv.3. A modified nominal group technique was used to develop a working version of the Paediatric Vasculitis Activity Score (PVAS). Prospective validation provided tool reliability, reproducibility and responsiveness to change. Training of assessors was done according to the BVAS principles. Results BVAS items were redefined (n=22) and eight paediatric items added in Cutaneous (n=4), Cardiovascular (n=3) and Abdominal (n=1) sections. The final PVAS has 64 active items in nine categories. The principles of new/worse and persistently active disease were retained as were the overall score and weighting of categories. The median PVAS in 63 children with systemic vasculitis was 4/63 (0–38/63). There was a high interobserver agreement for the overall as well as for subsystem scores (linear-weighted-κ ≥0.87). PVAS correlated with physicians global assessment (p<0.01); treatment decision (p=<0.01) and erythrocyte sedimentation rate (ESR) (p=0.01). In response to treatment, 15/19 patients assessed demonstrated a significant fall in PVAS (p=0.002), with good agreement among assessors for this change. Conclusions The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research.

Chitotriosidase as a marker of disease activity in sarcoidosis

Sarcoidosis is a chronic granulomatous inflammation. The clinical spectrum in childhood is heterogeneous. Angiotensin converting enzyme activity is used as a marker for disease activity. Human chitotriosidase is produced in macrophages. In this study, serum chitotriosidase levels were significantly higher in active sarcoidosis than in inactive disease or healthy controls. Serum chitotriosidase concentrations may be a useful marker for monitoring disease activity in sarcoidosis.

Successful treatment of severe juvenile microscopic polyangiitis with rituximab

Microscopic polyangiitis (MPA) previously called hypersensitivity angiitis is a systemic necrotizing vasculitis affecting predominantly small vessels. MPA involves multiple organ systems including the lung, the kidneys, the joints, and the skin. MPA mostly affects adults in their fourth and fifth decade of life. MPA and Wegener`s granulomatosis are grouped together as ANCA-associated vasculitis. MPA is associated with high titre of myeloperoxidase antineutrophil cytoplasmic antibodies (MPO)-ANCA. We present a 14-year-old female patient presented with MPA. She was treated with steroids and cyclophosphamide. After the complication of severe lung involvement, rituximab was administered as immune-modulating treatment. The MPA came to remission. This is the first report of a pediatric patient with MPA treated with rituximab. Rituximab might be a potential therapeutic option for relapsing ANCA associated vasculitis in childhood.

A novel therapeutic approach for LPIN1 mutation-associated rhabdomyolysis--The Austrian experience.

Introduction: Lipin 1 gene (LPIN1) mutations lead to cellular energy deficiency and cause up to 50% of the rhabdomyolysis episodes seen in pediatric patients. These episodes are associated with poor prognosis, as treatment options have been limited. We propose a novel therapeutic strategy based on prevention and early treatment of catabolism. Methods: Five patients were diagnosed with LPIN1 mutations. They were instructed to maintain high caloric intake in situations possibly leading to catabolism such as viral infections or excessive physical activity. When an episode of rhabdomyolysis occurred, patients were treated with intravenous high‐concentration glucose at first symptoms. Results: The therapeutic strategies described limited the number of rhabdomyolyis episodes, and the duration of episodes was reduced from 7–10 days, as reported in the literature, to 5 days. Conclusion: In this small series, patients with LPIN1 mutations appear to have benefited from prevention and early treatment of catabolism. Muscle Nerve 52:437–439, 2015

PAEDIATRIC VASCULITIS DAMAGE INDEX: A NEW TOOL FOR STANDARDISED DISEASE ASSESSMENT

Background Standardised assessment of disease damage is one of the main components of the OMERACT core set of outcome measures in adult ANCA-associated vasculitis. There is no validated tool to assess disease damage in children with vasculitis. While paediatric vasculitis shares many features with adult disease scoring tools validated for use in adults may miss some childhood specific damage. The Paediatric Vasculitis Outcome working group gathers physicians interested in childhood vasculitis from the PReS Vasculitis Working Group and the North American CARRA Vasculitis Committee. In collaboration with EUVAS, adaptation of adult vasculitis assessment tools was considered appropriate for paediatric disease. Vasculitis damage tool development followed our publication of the Paediatric Vasculitis Activity Score (PVAS).1 Objectives To develop a paediatric modification of the Vasculitis Damage Index (VDI).2 Methods Invited paediatric specialists and the group members reviewed existing items of the VDI and some additional items. Using nominal group technique consensus was obtained on damage items and their definitions for use in a paediatric modification of VDI (PVDI). Feasibility, face and content validity were assessed by paper case evaluations. Results Vasculitis damage is defined as the presence of irreversible features present for at least 3 months since the onset of vasculitis. While the VDI is an inventory of 64 items grouped into 11 organ systems, PVDI contains 72 items in 10 systems: musculoskeletal, skin/mucous membranes, ocular, ENT, chest, cardiovascular, abdominal, renal, nervous and “other”. A detailed PVDI glossary was produced. A separate assessment of school absence was added to the one-page form. Each item can be scored as “present” or “no longer present”(NLP), in order to address the potential reversibility of items that fulfil the definition of damage by duration and psychosocial impact but may completely resolve (e.g. growth delay). Every scored item always receives only one point, whether scored “present” or “NLP”, in order to retain compatibility with the VDI. Conclusions PVDI development is an important step towards better disease assessment in children which together with the PVAS allows paediatric vasculitis clinical trials and collaborative studies to gather reliable data on these rare diseases. The PVDI has yet to complete the validation process by its prospective use in real patients, which is currently underway. We aim to ensure that it remains a dynamic data-driven tool reflecting ongoing developments in the field of adult vasculitis damage assessment. References Dolezalova P, Price-Kuehne FE, Özen S et al. Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). Ann Rheum Dis 2013 Oct;72(10):1628-33. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the Vasculitis Damage Index (VDI) for the standardised clinical assessment of damage in the systemic vasculitides. Arthritis Rheum 1997;40:371-80 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5893

Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration

BackgroundRheumatic diseases in children are associated with significant morbidity andpoor health-related quality of life (HRQOL). There is no health-relatedquality of life (HRQOL) scale available specifically for children with lesscommon rheumatic diseases. These diseases share several features withsystemic lupus erythematosus (SLE) such as their chronic episodic nature,multi-systemic involvement, and the need for immunosuppressive medications.HRQOL scale developed for pediatric SLE will likely be applicable tochildren with systemic inflammatory diseases.FindingsWe adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters(SMILEY©) to Simple Measure of Impact of Illness in Youngsters(SMILY©-Illness) and had it reviewed by pediatric rheumatologists forits appropriateness and cultural suitability. We tested SMILY©-Illnessin patients with inflammatory rheumatic diseases and then translated it into28 languages.Nineteen children (79% female, n=15) and 17 parents participated. The meanage was 12±4 years, with median disease duration of 21 months (1-172months). We translated SMILY©-Illness into the following 28 languages:Danish, Dutch, French (France), English (UK), German (Germany), German(Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil),Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish(Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans,Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian,Japanese, Romanian, Serbian and Xhosa.ConclusionSMILY©-Illness is a brief, easy to administer and score HRQOL scale forchildren with systemic rheumatic diseases. It is suitable for use acrossdifferent age groups and literacy levels. SMILY©-Illness with itsavailable translations may be used as useful adjuncts to clinical practiceand research.

Disease activity in paediatric vasculitis: development of a generic assessment tool - PVAS

Methods The PRINTO vasculitis classification registry was reviewed for the presence of items not included in the original nine organ systems in BVAS3; items that were present in ≥ 20% of patients were added. Critical review of these items by a working group of paediatric rheumatologists with an interest in vasculitis resulted in the first version of PVAS. During consensus meetings content and face validity was established, resulting in minor modifications to the PVAS and its glossary. The score weightings were unchanged from BVAS3 resulting in the same range of numeric scores: 0-63, where zero indicates no vasculitis disease activity. Twenty paediatric paper training cases were prepared for the initial tool assessment.