%0 Journal Article %J Ann Rheum Dis %D 2017 %T ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. %A Caorsi, Roberta %A Penco, Federica %A Grossi, Alice %A Insalaco, Antonella %A Omenetti, Alessia %A Alessio, Maria %A Conti, Giovanni %A Marchetti, Federico %A Picco, Paolo %A Tommasini, Alberto %A Martino, Silvana %A Malattia, Clara %A Gallizi, Romina %A Podda, Rosa Anna %A Salis, Annalisa %A Falcini, Fernanda %A Schena, Francesca %A Garbarino, Francesca %A Morreale, Alessia %A Pardeo, Manuela %A Ventrici, Claudia %A Passarelli, Chiara %A Zhou, Qing %A Severino, Mariasavina %A Gandolfo, Carlo %A Damonte, Gianluca %A Martini, Alberto %A Ravelli, Angelo %A Aksentijevich, Ivona %A Ceccherini, Isabella %A Gattorno, Marco %K Adenosine Deaminase %K Adolescent %K Age of Onset %K Case-Control Studies %K Child %K Child, Preschool %K DNA Mutational Analysis %K Female %K Heterozygote %K Homozygote %K Humans %K Immunoglobulins %K Immunosuppressive Agents %K Infant %K Intercellular Signaling Peptides and Proteins %K Italy %K Livedo Reticularis %K Male %K Pedigree %K Polyarteritis Nodosa %K Stroke %K Thalidomide %K Tumor Necrosis Factor-alpha %K Young Adult %X

OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

%B Ann Rheum Dis %V 76 %P 1648-1656 %8 2017 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/28522451?dopt=Abstract %R 10.1136/annrheumdis-2016-210802 %0 Journal Article %J Lancet %D 2017 %T Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial. %A Ravelli, Angelo %A Davì, Sergio %A Bracciolini, Giulia %A Pistorio, Angela %A Consolaro, Alessandro %A van Dijkhuizen, Evert Hendrik Pieter %A Lattanzi, Bianca %A Filocamo, Giovanni %A Verazza, Sara %A Gerloni, Valeria %A Gattinara, Maurizio %A Pontikaki, Irene %A Insalaco, Antonella %A De Benedetti, Fabrizio %A Civino, Adele %A Presta, Giuseppe %A Breda, Luciana %A Marzetti, Valentina %A Pastore, Serena %A Magni-Manzoni, Silvia %A Maggio, Maria Cristina %A Garofalo, Franco %A Rigante, Donato %A Gattorno, Marco %A Malattia, Clara %A Picco, Paolo %A Viola, Stefania %A Lanni, Stefano %A Ruperto, Nicolino %A Martini, Alberto %K Adrenal Cortex Hormones %K Arthritis, Juvenile %K Humans %K Injections, Intra-Articular %K Italy %K Methotrexate %K Prospective Studies %K Treatment Outcome %X

BACKGROUND: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

METHODS: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

FINDINGS: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

INTERPRETATION: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

FUNDING: Italian Agency of Drug Evaluation.

%B Lancet %V 389 %P 909-916 %8 2017 03 04 %G eng %N 10072 %1 http://www.ncbi.nlm.nih.gov/pubmed/28162781?dopt=Abstract %R 10.1016/S0140-6736(17)30065-X %0 Journal Article %J Arthritis Rheum %D 2011 %T 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. %A Hasija, Rachana %A Pistorio, Angela %A Ravelli, Angelo %A Demirkaya, Erkan %A Khubchandani, Raju %A Guseinova, Dinara %A Malattia, Clara %A Canhao, Helena %A Harel, Liora %A Foell, Dirk %A Wouters, Carine %A De Cunto, Carmen %A Huemer, Christian %A Kimura, Yukiko %A Mangge, Harald %A Minetti, Carlo %A Nordal, Ellen Berit %A Philippet, Pierre %A Garozzo, Rosaria %A Martini, Alberto %A Ruperto, Nicolino %K Adolescent %K Adrenal Cortex Hormones %K Child %K Dermatologic Agents %K Dermatomyositis %K Female %K Humans %K Longitudinal Studies %K Male %K Methotrexate %K Prospective Studies %K Treatment Outcome %X

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.

%B Arthritis Rheum %V 63 %P 3142-52 %8 2011 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21647864?dopt=Abstract %R 10.1002/art.30475 %0 Journal Article %J Ann Rheum Dis %D 2010 %T EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation. %A Ruperto, Nicolino %A Ozen, Seza %A Pistorio, Angela %A Dolezalova, Pavla %A Brogan, Paul %A Cabral, David A %A Cuttica, Ruben %A Khubchandani, Raju %A Lovell, Daniel J %A O'Neil, Kathleen M %A Quartier, Pierre %A Ravelli, Angelo %A Iusan, Silvia M %A Filocamo, Giovanni %A Magalhães, Claudia Saad %A Unsal, Erbil %A Oliveira, Sheila %A Bracaglia, Claudia %A Bagga, Arvind %A Stanevicha, Valda %A Manzoni, Silvia Magni %A Pratsidou, Polyxeni %A Lepore, Loredana %A Espada, Graciela %A Kone-Paut, Isabella %A Paut, Isabelle Kone %A Zulian, Francesco %A Barone, Patrizia %A Bircan, Zelal %A Maldonado, Maria del Rocio %A Russo, Ricardo %A Vilca, Iris %A Tullus, Kjell %A Cimaz, Rolando %A Horneff, Gerd %A Anton, Jordi %A Garay, Stella %A Nielsen, Susan %A Barbano, Giancarlo %A Martini, Alberto %K Adolescent %K Biopsy %K Child %K Delphi Technique %K Granulomatosis with Polyangiitis %K Humans %K International Cooperation %K Internet %K Polyarteritis Nodosa %K Purpura, Schoenlein-Henoch %K Reproducibility of Results %K Takayasu Arteritis %X

OBJECTIVES: To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria.

METHODS: The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis

RESULTS: A total of 1183/1398 (85%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a kappa-agreement of 0.96 for HSP (95% CI 0.84 to 1), 0.88 for c-WG (95% CI 0.76 to 0.99), 0.84 for c-TA (95% CI 0.73 to 0.96) and 0.73 for c-PAN (95% CI 0.62 to 0.84), with an overall kappa of 0.79 (95% CI 0.73 to 0.84).

CONCLUSION: EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

%B Ann Rheum Dis %V 69 %P 790-7 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20388738?dopt=Abstract %R 10.1136/ard.2009.116624 %0 Journal Article %J JAMA %D 2010 %T Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. %A Foell, Dirk %A Wulffraat, Nico %A Wedderburn, Lucy R %A Wittkowski, Helmut %A Frosch, Michael %A Gerss, Joachim %A Stanevicha, Valda %A Mihaylova, Dimitrina %A Ferriani, Virginia %A Tsakalidou, Florence Kanakoudi %A Foeldvari, Ivan %A Cuttica, Ruben %A Gonzalez, Benito %A Ravelli, Angelo %A Khubchandani, Raju %A Oliveira, Sheila %A Armbrust, Wineke %A Garay, Stella %A Vojinovic, Jelena %A Norambuena, Ximena %A Gamir, María Luz %A García-Consuegra, Julia %A Lepore, Loredana %A Susic, Gordana %A Corona, Fabrizia %A Dolezalova, Pavla %A Pistorio, Angela %A Martini, Alberto %A Ruperto, Nicolino %A Roth, Johannes %K Adolescent %K Antirheumatic Agents %K Arthritis, Juvenile %K ATP-Binding Cassette Transporters %K Calgranulin B %K Child %K Child, Preschool %K Female %K Humans %K Infant %K Male %K Methotrexate %K Predictive Value of Tests %K Prospective Studies %K Recurrence %K Remission Induction %X

CONTEXT: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.

OBJECTIVES: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.

DESIGN, SETTING, AND PATIENTS: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.

INTERVENTION: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.

MAIN OUTCOME MEASURES: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.

RESULTS: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90).

CONCLUSIONS: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18186313.

%B JAMA %V 303 %P 1266-73 %8 2010 Apr 7 %G eng %N 13 %1 http://www.ncbi.nlm.nih.gov/pubmed/20371785?dopt=Abstract %R 10.1001/jama.2010.375 %0 Journal Article %J Ann Rheum Dis %D 2010 %T Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial. %A Vilca, Iris %A Munitis, Pablo Garcia %A Pistorio, Angela %A Ravelli, Angelo %A Buoncompagni, Antonella %A Bica, Blanca %A Campos, Lucia %A Häfner, Renate %A Hofer, Michael %A Ozen, Seza %A Huemer, Christian %A Bae, Sang Cheol %A Sztajnbok, Flavio %A Arguedas, Olga %A Foeldvari, Ivan %A Huppertz, Hans Iko %A Gamir, María Luz %A Magnusson, Bo %A Dressler, Frank %A Uziel, Yosef %A van Rossum, Marion A J %A Hollingworth, Peter %A Cawkwell, Gail %A Martini, Alberto %A Ruperto, Nicolino %K Adolescent %K Antibodies, Antinuclear %K Antirheumatic Agents %K Arthritis, Juvenile %K Child %K Child, Preschool %K Disability Evaluation %K Female %K Follow-Up Studies %K Humans %K Immunosuppressive Agents %K Male %K Methotrexate %K Prognosis %K Treatment Outcome %X

OBJECTIVES: To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis.

METHODS: Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria.

RESULTS: In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration > 1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index > 1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index > 1.14 (OR 2.18) and a parent's evaluation of child's overall well-being < or = 4.69 (OR 2.2).

CONCLUSION: The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.

%B Ann Rheum Dis %V 69 %P 1479-83 %8 2010 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20525842?dopt=Abstract %R 10.1136/ard.2009.120840