Consolaro, Alessandro

Minoia, Francesca

Ravelli, Angelo

English

Archivio istituzionale della ricerca - Università di Genova

The Journal of Rheumatology Volume 45, no. 1Idiopathic ArthritisFilling the Gap: Toward a Disease Activity Tool for Systemic JuvenileFRANCESCA MINOIA, ALESSANDRO CONSOLARO and ANGELO RAVELLI http://www.jrheum.org/content/45/1/3J Rheumatol 2018;45;3-5 http://www.jrheum.org/alerts   1. Sign up for TOCs and other alerts  http://jrheum.com/faq   2. Information on Subscriptions  http://jrheum.com/reprints_permissions   3. Information on permissions/orders of reprints in rheumatology and related fields. Silverman featuring research articles on clinical subjects from scientists working  is a monthly international serial edited by Earl D.The Journal of Rheumatology of RheumatologyThe Journal on August 20, 2019 - Published by www.jrheum.orgDownloaded from 3Minoia, et al: EditorialPersonal non-commercial use only. The Journal of Rheumatology Copyright © 2018. All rights reserved.EditorialFilling the Gap: Towarda Disease Activity Toolfor Systemic JuvenileIdiopathic ArthritisSystemic juvenile idiopathic arthritis (sJIA) accounts for5%–15% of all children with chronic arthritis seen in Europeand North America, but is much more common in Asia, withreported frequency in India and Japan as high as 25% and50%, respectively1. It is rather distinct from the other formsof JIA, owing to the association of arthritis with peculiarextraarticular symptoms, which include high-spiking fever,erythematous macular rash, diffuse lymphadenopathy,hepatosplenomegaly, and serositis, especially pleuritis andpericarditis2,3. Arthritis may be absent at onset and developduring the disease course, weeks, months, or rarely, yearsafter the occurrence of systemic manifestations. Character-istic laboratory features include anemia (usually hypo-chromic and microcytic), leukocytosis, thrombocytosis,elevated immunoglobulins, increased erythrocyte sedimen-tation rate (ESR) and C-reactive protein (CRP), and hypoal-buminemia. Children with sJIA are uniquely susceptible todevelop a potentially fatal hyperinflammatory complicationknown as macrophage activation syndrome4.    Regular measurement of the level of disease activity inchildren with sJIA through the application of well-establishedtools is important in monitoring the disease course over timeand in assessing the effectiveness of therapeutic interven-tions. However, clinical instruments specifically validated foruse in sJIA are lacking. In recent randomized controlled trialsof sJIA, the American College of Rheumatology Pediatric 30criteria have been adapted for measuring therapeutic responseby adding, besides the 6 core set variables, the demonstrationof the resolution of fever (≥ 38°C) during the week precedingthe evaluation5,6 or of the absence of fever (≥ 38.5°C) in theprevious 2 weeks, and the reduction of systemic cortico-steroid dosage by at least 10% from baseline in patientstaking these medications7. Published criteria for clinicallyinactive disease8,9 and minimal disease activity10 are suitablefor use in sJIA. However, they are intended to define aparticular disease activity state and do not allow quantitativeestimation. In the last decade, the Juvenile Arthritis DiseaseActivity Score (JADAS) has gained increasing popularityfor the measurement of the level of disease activity inchildren with JIA11,12,13. However, although the JADAS hasbeen used in studies of sJIA14, it has been validated only inchildren with oligoarthritis and polyarthritis, including sJIAwithout extraarticular features, but not in children with sJIAand active systemic manifestations15.    Because systemic symptoms have a major influence on achild’s well-being and play a key role in driving therapeuticdecisions, any instrument used to assess the level of diseaseactivity in sJIA must incorporate their assessment. Althoughthese manifestations are partially recorded by the physician’sand parent’s/child’s global assessment scales, there iscurrently no tool that enables their specific measurement. Inthe past, quantitative systemic feature scores have beendevised16,17 (Table 1), but none have been widely embraced.    In this issue of The Journal, Limenis, et al18 report theresults of the final phase of a 3-step process aimed to developa tool to measure disease activity in sJIA. In the first step,292 items relevant to disease activity were generated throughinterviews with 14 children with sJIA and their parents. Thesecond stage consisted of a Delphi survey of internationalexperts, which led to identification of the 29 most importantindicators of disease activity in sJIA. The final step describedin the present article was organized into the following 3parts: (1) scrutiny of the metrologic performances of the 29items in 57 patients recruited in 3 Canadian centers; (2)resurvey of experts with review of the data obtained in thevalidation study; and (3) proposal of a core set of diseaseactivity measures.    A very detailed methodology was used to score diseaseactivity in the study patients, which included an 18-itempatient questionnaire, a 12-item parent questionnaire, theChildhood Health Assessment Questionnaire of physicaldisability, and a series of physician evaluations, consistingof the global assessment of disease activity (PGA)measured on a 10-cm visual analog scale (VAS), 10 clinicalSee sJIA disease activity measures, page 115 of RheumatologyThe Journal on August 20, 2019 - Published by www.jrheum.orgDownloaded from and laboratory items, and questions regarding changes tomedications.    The PGA was used as a criterion standard for the study,and for some analyses patients were dichotomized into thosewith mildly active or inactive disease and with moderately toseverely active disease, based on whether the VAS for thePGA was < 1.5 or ≥ 1.5, respectively. This cutoff was chosenarbitrarily because it was meant to be “clinically sensible”and allowed dividing the patients into 2 roughly equal groups.     For continuous variables (e.g., active joint count), thestrength of association with the criterion standard was firstdetermined by calculating Pearson correlation coefficient.Then, receiver-operating characteristic curves (ROC) werecreated for each item to calculate the optimal cutoff value andthe overall diagnostic value. For dichotomous variables (e.g.,presence or absence of rash), sensitivity and specificity werecomputed in relation with the dichotomized criterionstandard. The results of this analysis were used to calculatethe likelihood ratios for a positive test.    The results of the validation study were subsequentlysubmitted to the same group of international experts surveyedin the earlier step of the process. Based on the review of thesedata and their own judgment, the experts were asked to selectthe 10 items that they felt were most relevant to diseaseactivity. The PGA was excluded from the survey because itwas used as a criterion standard. The response rate of 154/187(82%) was remarkable.     The final core set of items for measuring disease activityin sJIA was set up by selecting the outcome variables thatwere assigned the highest number of expert votes and had aminimum Pearson correlation of 0.5 with the criterionstandard. The core set includes 6 clinical measures (PGA,child’s and parent’s global assessments, active joint count,rash, and fever) and 3 laboratory tests (ESR, CRP, andhemoglobin). For continuous variables, the cutoff pointscalculated with the ROC method in validation analyses thatcorrespond to moderately or severely active disease areprovided.    The outcome variables included in the core set proposedby Limenis, et al appear appropriate because they are part ofthe classic indicators of disease activity in sJIA and wereagreed upon by a large number of international expertpediatric rheumatologists. There is, however, a problem withthe cutoff points for moderate/high disease activity, whichseem too mild for a highly inflammatory illness such as sJIA.Examples are the values for CRP (> 5.5 mg/l), hemoglobin(< 119 g/l), and parent’s and child’s global assessments (> 0.9 cm and > 0.4 cm, respectively).     This shortcoming is partly due to the study design and thecharacteristics of the study population. Patients wererecruited in routine followup visits rather than at initialpresentation or during times of disease flare, and as a resulthad a low prevalence of systemic manifestations. Indeed,only 3 of them had fever, only 7 had rash, and chest pain,lymphadenopathy, splenomegaly, and hepatomegaly wereeach detected in only 1 patient (although all differentpatients). The paucity of extraarticular symptoms explainsthe poor sensitivity of these variables for higher diseaseactivity. Another limitation of the Limenis, et al analysis isthe use of a 2-week time frame to assess fever and rash,which appears too lengthy to evaluate these features inconjunction with disease activity at a particular clinic visit.In our opinion, a 1-week time frame would be more appro-priate. As discussed, the cutoff chosen to dichotomize thePGA is arbitrary and subjective and not supported by liter-ature evidence. A further problem with the proposed core setis that it only enables distinction of patients with inactivedisease or mild disease activity from those with moderate orhigh disease activity, but is not suitable to quantify theabsolute level of disease activity.    Despite these limitations, the authors are to becommended for accomplishing a valuable research effort and4 The Journal of Rheumatology 2018; 45:1; doi:10.3899/jrheum.170703Personal non-commercial use only. The Journal of Rheumatology Copyright © 2018. All rights reserved.Table 1. Composition and scoring of systemic feature scores published in the literature. Woo, et al16                                                         Vojinovic, et al 17Feature                                                      Score                Feature                                                          ScoreFever*                                                                              1                    Fever†                                                                                   1Rash                                                             1                    Rash                                                                 1Cervical lymphadenopathy                          1                    Lymphadenopathy                                           1Axillary lymphadenopathy                          1                    Hepatomegaly or splenomegaly                      1Inguinal lymphadenopathy                          1                    Serositis**                                                                           1Hepatomegaly                                              1                    ESR ≥ 20 mm/h                                               1Splenomegaly                                              1                    CRP ≥ 10 mg/l                                                 1Serositis**                                                                      1                    WBC count ≥ 12 × 109/l                                  1                                                                                          Hemoglobin ≤ 11 g/dl                                      1                                                                                          Platelet count ≥ 400 × 109/l                             1Score range                                                0–8                  Score range                                                   0–10*At the assessment visit or in the 24 hours preceding the assessment visit. ** Pericarditis, pleuritis, or peritonitis.† As documented in a diary. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; WBC: white bloodcell. of RheumatologyThe Journal on August 20, 2019 - Published by www.jrheum.orgDownloaded from for providing a core set of disease activity measures that mayconstitute the basis for the future development of responsecriteria specific for sJIA. A further important initiative in thisarea of research, which is currently in progress, is the inter-national collaborative effort aimed to devise a JADASversion for sJIA. In the study plan, a modification of theoriginal instrument has been envisioned to enable thequantification of extraarticular symptoms, with an approachsimilar to that of the systemic feature scores reported in Table1. A key objective of the project is the establishment of thecutoffs in the new score that correspond to the states ofinactive disease and low, moderate, and high disease activityin sJIA.FRANCESCA MINOIA, MD,Istituto Giannina Gaslini;ALESSANDRO CONSOLARO,MD, PhD, Istituto Giannina Gaslini and Università degli Studi di Genova;ANGELO RAVELLI, MD,Istituto Giannina Gaslini and Università degli Studi di Genova,Genoa, Italy.Address correspondence to Prof. A. Ravelli, Pediatria II-Reumatologia, Istituto Giannina Gaslini, Via G. Gaslini 5, 16147Genoa, Italy. E-mail: angeloravelli@gaslini.orgREFERENCES   1.    Consolaro A, Ravelli A. Unraveling the phenotypic variability ofjuvenile idiopathic arthritis across races or geographic areas—key tounderstanding etiology and genetic factors? J Rheumatol2016;43:683-5.   2.    Martini A. Systemic juvenile idiopathic arthritis. Autoimmun Rev2012;12:56-9.   3.    De Benedetti F, Schneider R. Systemic juvenile idiopathic arthritis.In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors.Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier;2016:205–16.   4.    Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al.Clinical features, treatment, and outcome of macrophage activationsyndrome complicating systemic juvenile idiopathic arthritis: amultinational, multicenter study of 362 patients. ArthritisRheumatol 2014;66:3160-9.   5.    Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N,Horneff G, et al. Two randomized trials of canakinumab in systemicjuvenile idiopathic arthritis. N Engl J Med 2012;367:2396-406.   6.    De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S,Calvo I, et al. Randomized trial of tocilizumab in systemic juvenileidiopathic arthritis. N Engl J Med 2012;367:2385-95.   7.    Ilowite NT, Prather K, Lokhnygina Y, Schanberg LE, Elder M,Milojevic D, et al. Randomized, double-blind, placebo-controlledtrial of the efficacy and safety of rilonacept in the treatment ofsystemic juvenile idiopathic arthritis. Arthritis Rheumatol2014;66:2570-9.   8.    Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinicalremission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290-4.   9.    Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. AmericanCollege of Rheumatology provisional criteria for defining clinicalinactive disease in select categories of juvenile idiopathic arthritis.Arthritis Care Res 2011;63:929-36. 10.    Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N,Palmisani E, et al. Development and validation of a preliminarydefinition of minimal disease activity in patients with juvenileidiopathic arthritis. Arthritis Rheum 2008;59:1120-7. 11.    Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S,Filocamo G, et al. Development and validation of a compositedisease activity score for juvenile idiopathic arthritis. ArthritisRheum 2009;61:658-66. 12.    Consolaro A, Bracciolini G, Ruperto N, Pistorio A, Magni-ManzoniS, Malattia C, et al. Remission, minimal disease activity, andacceptable symptom state in juvenile idiopathic arthritis: definingcriteria based on the juvenile arthritis disease activity score.Arthritis Rheum 2012;64:2366-74. 13.    Consolaro A, Ruperto N, Bracciolini G, Frisina A, Gallo MC,Pistorio A, et al. Defining criteria for high disease activity injuvenile idiopathic arthritis based on the juvenile arthritis diseaseactivity score. Ann Rheum Dis 2014;73:1380-3. 14.    De Benedetti F, Brunner H, Ruperto N, Schneider R, Xavier R,Allen R, et al. Catch-up growth during tocilizumab therapy forsystemic juvenile idiopathic arthritis: results from a phase III trial.Arthritis Rheumatol 2015;67:840-8. 15.    Consolaro A, Ravelli A. Defining criteria for disease activity statesin juvenile idiopathic arthritis. Rheumatology 2016;55:595-6. 16.    Woo P, Southwood TR, Prieur AM, Doré CJ, Grainger J, David J, etal. Randomized, placebo-controlled, crossover trial of low-dose oralmethotrexate in children with extended oligoarticular or systemicarthritis. Arthritis Rheum 2000;43:1849-57. 17.    Vojinovic J, Damjanov N, D’Urzo C, Furlan A, Susic G, Pasic S, etal. Safety and efficacy of an oral histone deacetylase inhibitor insystemic-onset juvenile idiopathic arthritis. Arthritis Rheum2011;63:1452-8. 18.    Limenis E, Feldman BM, Achonu C, Batthish M, Lang B, MclimontM, et al. Proposed core set of items for measuring disease activity insystemic juvenile idiopathic arthritis. J Rheumatol 2018;45:115-21.J Rheumatol 2017;44:3–5; doi:10.3899/jrheum.1707035Minoia, et al: EditorialPersonal non-commercial use only. The Journal of Rheumatology Copyright © 2018. 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Filling the Gap: Toward a Disease Activity Tool for Systemic Juvenile Idiopathic Arthritis

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Filling the Gap: Toward a Disease Activity Tool for Systemic Juvenile Idiopathic Arthritis

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