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Biological classification of childhood arthritis: roadmap to a molecular nomenclature

A Publisher Correction to this article was published on 29 March 2021

This article has been updated


Chronic inflammatory arthritis in childhood is heterogeneous in presentation and course. Most forms exhibit clinical and genetic similarity to arthritis of adult onset, although at least one phenotype might be restricted to children. Nevertheless, paediatric and adult rheumatologists have historically addressed disease classification separately, yielding a juvenile idiopathic arthritis (JIA) nomenclature that exhibits no terminological overlap with adult-onset arthritis. Accumulating clinical, genetic and mechanistic data reveal the critical limitations of this strategy, necessitating a new approach to defining biological categories within JIA. In this Review, we provide an overview of the current evidence for biological subgroups of arthritis in children, delineate forms that seem contiguous with adult-onset arthritis, and consider integrative genetic and bioinformatic strategies to identify discrete entities within inflammatory arthritis across all ages.

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Fig. 1: The epidemiology of juvenile idiopathic arthritis.
Fig. 2: The evolution of classification criteria for childhood-onset arthritis.
Fig. 3: Current arthritis classification in children and adults.
Fig. 4: Biological fault lines in arthritis.
Fig. 5: Proposed subdivisions within arthritis: PRINTO and the four-cluster model.

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The work of P.A.N. is funded by US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) awards 2R01 AR065538, R01 AR075906, R01 AR073201, P30 AR070253 and R21 AR076630, the US National Heart, Lung, and Blood Institute award R21 HL150575, the Fundación Bechara, the Arbuckle Family Fund for Arthritis Research, and the Samara Jan Turkel Center for Pediatric Autoimmune Diseases at Boston Children’s Hospital. The work of R.A.C. is supported by the NIAMS Intramural Research Program Z01AR041184. The work of V.M.H. is funded by US National Institutes of Health grants UH2 AR067681, U01 AI101981, U01 AI130830, U01 HL152405, R01 DK125823, R01 AR051749 and UM2 AR067678, as well as investigator-initiated grants from Janssen R&D (ICD845278), Q32 Bio (SRA-001) and Pfizer (WI237571). The work of S.D.T. is supported by NIAMS (P30 AR070549), the US National Institute of Child Health and Human Development (R01 HD089928), the US National Eye Institute (EY030521) and the Center for Pediatric Genomics at Cincinnati Children’s Hospital Medical Center. The work of L.R.W. is supported by the UK Research and Innovation Medical Research Council (MR/R013926/1), Versus Arthritis (grants 22084 and 21593), Great Ormond Street Hospital (GOSH) Children’s Charity and the UK National Institute for Health Research Biomedical Research Centre at GOSH. The work of R.S.M.Y. is supported by the Hak-Ming and Deborah Chiu Chair in Paediatric Translational Research at the Hospital for Sick Children, University of Toronto, and by grants from the Canadian Institutes for Health Research (grant 381280), Genome Canada, the Netherlands Organization for Health Research and Development, Reumafonds, The Arthritis Society, Province of Ontario, Genome Alberta, Childhood Arthritis and Rheumatology Research Alliance, Alberta Children’s Hospital Research Institute and the Hospital for Sick Children Foundation.

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All authors researched data for the article. All authors contributed substantially to discussion of the content. P.A.N. and A.M. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Peter A. Nigrovic or Alberto Martini.

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P.A.N. declares support from investigator-initiated research grants from AbbVie, BMS, Novartis, Pfizer, and Sobi; consulting fees from BMS, Cerecor, Miach Orthopedics, Novartis, Pfizer, Quench Bio, Sigilon, Simcere, Sobi, and XBiotech; royalties from UpToDate Inc. and the American Academy of Pediatrics; and salary support from the Childhood Arthritis and Rheumatology Research Alliance. V.M.H. declares acting as a current or recent consultant to BMS, Celgene, Janssen R&D, and Q32 Bio, and support from research grants from Janssen R&D and Q32 Bio. S.O. declares receipt of consultancy or speaker fees from Novartis and Sobi. N.R. declares receipt of honoraria for consultancies or speaker bureaus in the past 3 years from Ablynx, AstraZeneca/MedImmune, Biogen, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GSK, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharm, Sanofi, Servier, Sinergie, and Sobi. The IRCCS Istituto Giannina Gaslini, where N.R. works as a full-time public employee, has received contributions in the past 3 years from BMS, Eli Lilly, F. Hoffmann-La Roche, GSK, Janssen, Novartis, Pfizer, and Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties. L.R.W. declares support from AbbVie, GSK, Pfizer, Sobi, and UCB to the CLUSTER Consortium. R.S.M.Y. declares one-time consulting fees from Eli-Lilly and Novartis. A.M. declares receipt of honoraria for consultancies from Aurinia, BMS, Eli-Lilly, EMD Serono, Janssen, and Pfizer. All other authors declare no competing interests.

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Nature Reviews Rheumatology thanks R. Khubchandani, B. Prakken and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nigrovic, P.A., Colbert, R.A., Holers, V.M. et al. Biological classification of childhood arthritis: roadmap to a molecular nomenclature. Nat Rev Rheumatol 17, 257–269 (2021).

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