Objectives The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a ‘window of opportunity’ to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases.
Methods Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst ) or polyarticular disease (SJIA poly ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst , n=45; SJIA poly , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays.
Results Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly ) and 77% (SJIA syst vs infection) of all cases.
Conclusions Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.
- phenotype classification
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Handling editor Josef S Smolen
Collaborators Antje Hellige; Andreas Urban; Aleš Janda; Annette Jansson; Bernd-Ulrich Keck; Boris Hügle; Eggert Lilienthal; Elisabeth Weißbarth-Riedel; Frank Weller-Heinemann; Gerd Ganser; Gerd Horneff; Gert Reutter-Simon; Gertrud Wannenmacher; Gregor Dückers; Gundula Böschow; Hans-Iko Huppertz; Hartwig Lehmann; Jeannine Rettschlag; Jens Berrang; Johannes-Peter Haas; Jürgen Brunner; Markus Knuf; Kirsten Mönkemöller; Klaus Tenbrock; Markus Hufnagel; Prasad Thomas Oommen; Rainer Berendes; Sandra Hansmann; Thomas Berger; Toni Hospach.
Contributors DF, OF and SRP designed and planned the study. FG, DH, CP, CK, SdR, AM, MJ, NC and SRP performed experiments. FG, AM, MJ, BH, CP, CK, EL, SJV, SdR, DF and SRP analysed data. FG, AM, MJ, BH, NC, MM-G, CK, ML, EL, SJV, SdR, OF, DH, SRP and DF participated in data interpretation and discussion. All authors were involved in writing the manuscript and all made substantial contributions to the content and approved the final manuscript. Collaborators provided clinical data and samples (full details listed in online supplementary material).
Funding FG was supported by the EU FP7 EUTRAIN (European Translational Training for Autoimmunity and Immune manipulation Network) project grant (ref. 289903) until December 2016. FG, AM, NC, ML, SdR, SRP and DF received funding from the EU FP7 MIAMI (Monitoring innate Immunity in Arthritis and Mucosal Inflammation) project grant (ref. 305266). BH is funded by the HRB (Health Research Board) ref. LP-HSR-2017-021. The AID-Net was funded by the German Ministry of Research and Education (BMBF 01GM1512A/D). The UCD Conway Institute and Proteome Research Centre is funded by the Programme for Research in Third Level Institutions, as administered by Higher Education Authority of Ireland.
Competing interests OF declares the receipt of research grants and personal fees from Pfizer, Abbott and personal fees from Roche, Amgen, UCB, Celgene and Lilly. DF declares the receipt of research grant support and honoraria from Pfizer, Novartis, Sobi and Chugai-Roche. SRP declares honoraria from Celgene and is founder of Atturos, a UCD spin-out company developing advanced diagnostic tests. The other authors declare no conflicts of interest.
Patient consent for publication Not required.
Ethics approval University of Münster (reference 2009-031-f-S and 2014-637-f-S).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data relevant to the study are included in the article or uploaded as supplementary information.