Browsing by Author "Ravelli, Angelo"

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    Defining Criteria for Disease Activity States in Systemic Juvenile Idiopathic Arthritis Based on the Systemic Juvenile Arthritis Disease Activity Score
    (2024-09) Rosina, Silvia; Rebollo-Giménez, Ana I; Tarantola, Letizia; Pistorio, Angela; Vyzhga, Yulia; El Miedany, Yasser; Lotfy, Hala M; Abu-Shady, Hend; Eissa, Mervat; Osman, Naglaa S; Hassan, Waleed; Mahgoub, Marwa Y; Fouad, Nermeen A; Mosa, Doaa M; Adel, Yasmin; Mohamed, Sheren E M; Radwan, Ahmed R; Abu-Zaid, Mohamed H; Tabra, Samar A A; Shalaby, Radwa H; Nasef, Samah I; Khubchandani, Raju; Khan, Archana; Maldar, Naziya P; Ozen, Seza; Bayindir, Yagmur; Alsuweiti, Motasem; Alzyoud, Raed; Almaaitah, Hiba; Vilaiyuk, Soamarat; Lerkvaleekul, Butsabong; Alexeeva, Ekaterina; Dvoryakovskaya, Tatyana; Kriulin, Ivan; Bracaglia, Claudia; Pardeo, Manuela; De Benedetti, Fabrizio; Licciardi, Francesco; Montin, Davide; Robasto, Francesca; Minoia, Francesca; Filocamo, Giovanni; Rossano, Martina; Simonini, Gabriele; Marrani, Edoardo; Abu-Rumeileh, Sarah; Kostik, Mikhail M; Belozerov, Konstantin E; Pal, Priyankar; Bathia, Jigna N; Katsicas, María M; Villarreal, Giselle; Marino, Achille; Costi, Stefania; Sztajnbok, Flavio; Silva, Rodrigo M; Maggio, Maria C; El-Ghoneimy, Dalia H; El Owaidy, Rasha; Civino, Adele; Diomeda, Federico; Al-Mayouf, Sulaiman M; Al-Sofyani, Fuad; Dāvidsone, Zane; Patrone, Elisa; Saad-Magalhães, Claudia; Consolaro, Alessandro; Ravelli, Angelo
    OBJECTIVE: Our objective was to develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist. METHODS: The cutoff definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, six methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, the Youden index, 90% specificity, maximum agreement, and receiver operating characteristic curve analysis. Sixty percent of the patients were assigned to the definition cohort, and 40% were assigned to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. RESULTS: The sJADAS10 cutoffs that separated ID from MDA, MDA from MoDA, and MoDA from HDA were ≤2.9, ≤10, and >20.6, respectively. The cutoffs discriminated strongly among different levels of pain, between patients with and without morning stiffness, and among patients whose parents judged their disease status as remission or persistent activity or flare or were satisfied or not satisfied with current illness outcome. CONCLUSION: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts and are therefore suitable for use in clinical trials and routine practice.
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    Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission a randomized clinical trial
    (2010-04-07) Foell, Dirk; Wulffraat, Nico; Wedderburn, Lucy R.; Wittkowski, Helmut; Frosch, Michael; Gerß, Joachim; Stanevicha, Valda; Mihaylova, Dimitrina; Ferriani, Virginia; Tsakalidou, Florence Kanakoudi; Foeldvari, Ivan; Cuttica, Ruben; Gonzalez, Benito; Ravelli, Angelo; Khubchandani, Raju; Oliveira, Sheila; Armbrust, Wineke; Garay, Stella; Vojinovic, Jelena; Norambuena, Ximena; Gamir, María Luz; García-Consuegra, Julia; Lepore, Loredana; Susic, Gordana; Corona, Fabrizia; Dolezalova, Pavla; Pistorio, Angela; Martini, Alberto; Ruperto, Nicolino; Roth, Johannes; Rīga Stradiņš University
    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, medicationwithdrawal 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 myeloidrelated 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, 320-1110] 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.
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    Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
    (2014-10-01) Davì, Sergio; Minoia, Francesca; Pistorio, Angela; Horne, Annacarin; Consolaro, Alessandro; Rosina, Silvia; Bovis, Francesca; Cimaz, Rolando; Gamir, Maria Luz; Ilowite, Norman T.; Kone-Paut, Isabelle; Feitosa De Oliveira, Sheila Knupp; McCurdy, Deborah; Silva, Clovis Artur; Sztajnbok, Flavio; Tsitsami, Elena; Unsal, Erbil; Weiss, Jennifer E.; Wulffraat, Nico; Abinun, Mario; Aggarwal, Amita; Apaz, Maria Teresa; Astigarraga, Itziar; Corona, Fabrizia; Cuttica, Ruben; D'Angelo, Gianfranco; Eisenstein, Eli M.; Hashad, Soad; Lepore, Loredana; Mulaosmanovic, Velma; Nielsen, Susan; Prahalad, Sampath; Rigante, Donato; Stanevicha, Valda; Sterba, Gary; Susic, Gordana; Takei, Syuji; Trauzeddel, Ralf; Zletni, Mabruka; Ruperto, Nicolino; Martini, Alberto; Cron, Randy Q.; Ravelli, Angelo; Rīga Stradiņš University
    Results The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections. Conclusion The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA. Objective To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection. Methods International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present.
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    The PRINTO evidence-based proposal for glucocorticoids tapering/discontinuation in new onset juvenile dermatomyositis patients
    (2019-05-22) Giancane, Gabriella; Lavarello, Claudio; Pistorio, Angela; Oliveira, Sheila K.; Zulian, Francesco; Cuttica, Ruben; Fischbach, Michel; Magnusson, Bo; Pastore, Serena; Marini, Roberto; Martino, Silvana; Pagnier, Anne; Soler, Christine; Stanevicha, Valda; Ten Cate, Rebecca; Uziel, Yosef; Vojinovic, Jelena; Fueri, Elena; Ravelli, Angelo; Martini, Alberto; Ruperto, Nicolino
    BackgroundPrednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation.MethodsNew onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation.ResultsBased on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1mg/kg/day in the first two months from onset if any of the CSM decreased by 50-94%, and from 1 to 0.2mg/kg/day in the following 4months if any CSM further decreased by 8-68%, followed by discontinuation in the ensuing 18months. The achievement of PRINTO JDM 50-70-90 response after 2months of treatment (ORs range 4.5-6.9), an age at onset >9years (OR 4.6) and the combination therapy PDN+MTX (OR 3.6) increase the probability of achieving clinical remission (p<0.05).ConclusionsThis is the first evidence-based proposal for glucocorticoid tapering/discontinuation based on the change in JDM CSM of disease activity.
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    The PRINTO evidence-based proposal for glucocorticoids tapering/discontinuation in new onset juvenile dermatomyositis patients
    (2019-05-22) Giancane, Gabriella; Lavarello, Claudio; Pistorio, Angela; Oliveira, Sheila K.; Zulian, Francesco; Cuttica, Ruben; Fischbach, Michel; Magnusson, Bo; Pastore, Serena; Marini, Roberto; Martino, Silvana; Pagnier, Anne; Soler, Christine; Stanevicha, Valda; Ten Cate, Rebecca; Uziel, Yosef; Vojinovic, Jelena; Fueri, Elena; Ravelli, Angelo; Martini, Alberto; Ruperto, Nicolino
    BackgroundPrednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation.MethodsNew onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation.ResultsBased on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1mg/kg/day in the first two months from onset if any of the CSM decreased by 50-94%, and from 1 to 0.2mg/kg/day in the following 4months if any CSM further decreased by 8-68%, followed by discontinuation in the ensuing 18months. The achievement of PRINTO JDM 50-70-90 response after 2months of treatment (ORs range 4.5-6.9), an age at onset >9years (OR 4.6) and the combination therapy PDN+MTX (OR 3.6) increase the probability of achieving clinical remission (p<0.05).ConclusionsThis is the first evidence-based proposal for glucocorticoid tapering/discontinuation based on the change in JDM CSM of disease activity.
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    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
    (2008-01-15) Ruperto, Nicolino; Ravelli, Angelo; Pistorio, Angela; Ferriani, Virginia; Calvo, Immaculada; Ganser, Gerd; Brunner, Jurgen; Dannecker, Guenther; Silva, Clovis Arthur; Stanevicha, Valda; Ten Cate, Rebecca; Van Suijlekom-Smit, Lisette W.A.; Voygioyka, Olga; Fischbach, Michel; Foeldvari, Ivan; Hilario, Odete; Modesto, Consuelo; Saurenmann, Rotraud K.; Sauvain, Marie Josephe; Scheibel, Iloite; Sommelet, Danièle; Tambic-Bukovac, Lana; Barcellona, Roberto; Brik, Riva; Ehl, Stephan; Jovanovic, Mirjana; Rovensky, Jozef; Bagnasco, Francesca; Lovell, Daniel J.; Martini, Alberto; Rīga Stradiņš University
    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) physician's global assessment of disease activity, 2) muscle strength, 3) global disease activity measure, 4) parent's global assessment of patient's 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.