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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Myasoedova, E., Crowson, C. S., Kremers, H. M., Therneau, T. M. & Gabriel, S. E. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 62, 1576–1582 (2010).
Eriksson, J. K. et al. Incidence of rheumatoid arthritis in Sweden: a nationwide population-based assessment of incidence, its determinants, and treatment penetration. Arthritis Care Res. 65, 870–878 (2013).
Taurog, J. D., Chhabra, A. & Colbert, R. A. Ankylosing spondylitis and axial spondyloarthritis. N. Engl. J. Med. 374, 2563–2574 (2016).
Nigrovic, P. A. & Schneider, R. in Textbook of Autoinflammation (eds Hashkes, P. J., Laxer, R. M. & Simon, A.) 587–616 (Springer Nature, 2019).
Ravelli, A. & Martini, A. Juvenile idiopathic arthritis. Lancet 369, 767–778 (2007).
Consolaro, A. et al. Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. Lancet Child. Adolesc. Health 3, 255–263 (2019).
Still, G. F. On a form of chronic joint disease in children. Med. Chir. Trans. 80, 47–60 (1897).
Ansell, B. M. & Bywaters, E. G. Prognosis in Still’s disease. Bull. Rheum. Dis. 9, 189–192 (1959).
Bywaters, E. G. Heberden Oration, 1966. Categorization in medicine: a survey of Still’s disease. Ann. Rheum. Dis. 26, 185–193 (1967).
Ansell, B. M. Heberden Oration, 1977. Chronic arthritis in childhood. Ann. Rheum. Dis. 37, 107–120 (1978).
Criteria for the classification of juvenile rheumatoid arthritis. Bull. Rheum. Dis. 23, 712-719 (1972).
Brewer, E. J. Jr et al. Current proposed revision of JRA Criteria. JRA criteria subcommittee of the diagnostic and therapeutic criteria committee of the american rheumatism section of The Arthritis Foundation. Arthritis Rheum. 20, 195–199 (1977).
Cassidy, J. T. et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum. 29, 274–281 (1986).
Wood, P. H. N. in The Care of Rheumatic Children (ed. Munthe, E.) 47–50 (EULAR Publishers, 1978).
Woo, P. & Wedderburn, L. R. Juvenile chronic arthritis. Lancet 351, 969–973 (1998).
Rosenberg, A. M. & Petty, R. E. A syndrome of seronegative enthesopathy and arthropathy in children. Arthritis Rheum. 25, 1041–1047 (1982).
Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31, 390–392 (2004).
Nigrovic, P. A., Raychaudhuri, S. & Thompson, S. D. Genetics and the classification of arthritis in adults and children. Arthritis Rheumatol. 70, 7–17 (2018).
Martini, A. Are the number of joints involved or the presence of psoriasis still useful tools to identify homogeneous disease entities in juvenile idiopathic arthritis? J. Rheumatol. 30, 1900–1903 (2003).
Martini, A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann. Rheum. Dis. 71, 1437–1439 (2012).
European Commission. Commission to the European Parliament and the Council. State of Paediatric Medicines in the EU: 10 years of the EU Paediatric Regulation. https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_report_en.pdf (2017).
Ruperto, N. & Martini, A. Current and future perspectives in the management of juvenile idiopathic arthritis. Lancet Child. Adolesc. Health 2, 360–370 (2018).
Schaller, J. G. The history of pediatric rheumatology. Pediatr. Res. 58, 997–1007 (2005).
Beukelman, T. & Nigrovic, P. A. Juvenile idiopathic arthritis: an idea whose time has gone? J. Rheumatol. 46, 124–126 (2019).
Martini, A. et al. Toward new classification criteria for juvenile idiopathic arthritis: first steps, pediatric rheumatology international trials organization international consensus. J. Rheumatol. 46, 190–197 (2019).
Nigrovic, P. A. et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 63, 545–555 (2011).
Ter Haar, N. M. et al. Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a five-year follow-up study. Arthritis Rheumatol. 71, 1163–1173 (2019).
Behrens, E. M., Beukelman, T. & Cron, R. Q. Juvenile idiopathic arthritis classification criteria: loopholes and diagnosis software. J. Rheumatol. 34, 234 (2007).
DeWitt, E. M. et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res. 64, 1001–1010 (2012).
Rumsey, D. G. & Laxer, R. M. The challenges and opportunities of classifying childhood arthritis. Curr. Rheumatol. Rep. 22, 4 (2020).
Guzman, J., Burgos-Vargas, R., Duarte-Salazar, C. & Gomez-Mora, P. Reliability of the articular examination in children with juvenile rheumatoid arthritis: interobserver agreement and sources of disagreement. J. Rheumatol. 22, 2331–2336 (1995).
van Gulik, E. C. et al. Juvenile idiopathic arthritis: magnetic resonance imaging of the clinically unaffected knee. Pediatric Radiol. 48, 333–340 (2018).
Magni-Manzoni, S. et al. Ultrasound-detected synovial abnormalities are frequent in clinically inactive juvenile idiopathic arthritis, but do not predict a flare of synovitis. Ann. Rheum. Dis. 72, 223–228 (2013).
Al-Matar, M. J. et al. The early pattern of joint involvement predicts disease progression in children with oligoarticular (pauciarticular) juvenile rheumatoid arthritis. Arthritis Rheum. 46, 2708–2715 (2002).
Hinks, A. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat. Genet. 45, 664–669 (2013).
Hinks, A. et al. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann. Rheum. Dis. 76, 765–772 (2017).
Hollenbach, J. A. et al. Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects. Arthritis Rheum. 62, 1781–1791 (2010).
Huemer, C. et al. Patterns of joint involvement at onset differentiate oligoarticular juvenile psoriatic arthritis from pauciarticular juvenile rheumatoid arthritis. J. Rheumatol. 29, 1531–1535 (2002).
Stoll, M. L. et al. Patients with juvenile psoriatic arthritis comprise two distinct populations. Arthritis Rheum. 54, 3564–3572 (2006).
Stoll, M. L., Nigrovic, P. A., Gotte, A. C. & Punaro, M. Clinical comparison of early-onset psoriatic and non-psoriatic oligoarticular juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 29, 582–588 (2011).
Eng, S. W. M. et al. Patterns of joint involvement in juvenile idiopathic arthritis and prediction of disease course: a prospective study with multilayer non-negative matrix factorization. PLoS Med. 16, e1002750 (2019).
Ritchlin, C. T., Colbert, R. A. & Gladman, D. D. Psoriatic arthritis. N. Engl. J. Med. 376, 957–970 (2017).
Stoll, M. L., Lio, P., Sundel, R. P. & Nigrovic, P. A. Comparison of Vancouver and International League of Associations for Rheumatology classification criteria for juvenile psoriatic arthritis. Arthritis Rheum. 59, 51–58 (2008).
Landré-Bouvais, A. J. Doit-on Admettre Une Nouvelle Espèce de Goutte Sous la dénomination d Goutte Asthenique Primitive? PhD thesis, École de Médecine de Paris (1800).
Garrod, A. B. On gout and rheumatism: the differential diagnosis, and the nature of the so-called rheumatic gout. Med. Chir. Trans. 37, 181–220 (1854).
Garrod, A. E. A Treatise on Rheumatism and Rheumatoid Arthritis (Charles Griffin & Co., 1890).
Waaler, E. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. Acta Pathol. Microbiol. Scand. 17, 172–188 (1940).
Rose, H. M. et al. Differential agglutination of normal and sensitized sheep erythrocytes by sera of patients with rheumatoid arthritis. Proc. Soc. Exp. Biol. Med. 68, 1–6 (1948).
Wright, V. Psoriasis and arthritis. Ann. Rheum. Dis. 15, 348–356 (1956).
Moll, J. M., Haslock, I., Macrae, I. F. & Wright, V. Associations between ankylosing spondylitis, psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and Behcet’s syndrome. Medicine 53, 343–364 (1974).
Schlosstein, L., Terasaki, P. I., Bluestone, R. & Pearson, C. M. High association of an HL-A antigen, W27, with ankylosing spondylitis. N. Engl. J. Med. 288, 704–706 (1973).
Stastny, P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N. Engl. J. Med. 298, 869–871 (1978).
Ball, J. Enthesopathy of rheumatoid and ankylosing spondylitis. Ann. Rheum. Dis. 30, 213–223 (1971).
Nienhuis, R. L. & Mandema, E. A new serum factor in patients with rheumatoid arthritis; The antiperinuclear factor. Ann. Rheum. Dis. 23, 302–305 (1964).
Schellekens, G. A., de Jong, B. A., van den Hoogen, F. H., van de Putte, L. B. & van Venrooij, W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).
Klareskog, L., Ronnelid, J., Lundberg, K., Padyukov, L. & Alfredsson, L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26, 651–675 (2008).
Chang, M. H. & Nigrovic, P. A. Antibody-dependent and -independent mechanisms of inflammatory arthritis. JCI Insight 4, e125278 (2019).
Schett, G. et al. Enthesitis: from pathophysiology to treatment. Nat. Rev. Rheumatol. 13, 731–741 (2017).
Simon, D. et al. Structural entheseal lesions in patients with psoriasis are associated with an increased risk of progression to psoriatic arthritis. Arthritis Rheumatol. https://doi.org/10.1002/art.41239 (2020).
Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).
Cuthbert, R. J. et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 69, 1816–1822 (2017).
Gracey, E. et al. Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat. Rev. Rheumatol. 16, 193–207 (2020).
Healy, P. J., Groves, C., Chandramohan, M. & Helliwell, P. S. MRI changes in psoriatic dactylitis–extent of pathology, relationship to tenderness and correlation with clinical indices. Rheumatology 47, 92–95 (2008).
Tuttle, K. S., Vargas, S. O., Callahan, M. J., Bae, D. S. & Nigrovic, P. A. Enthesitis as a component of dactylitis in psoriatic juvenile idiopathic arthritis: histology of an established clinical entity. Pediatr. Rheumatol. Online J. 13, 7 (2015).
Taylor, W. et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54, 2665–2673 (2006).
Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000).
Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).
Pekin, T. J. Jr. & Zvaifler, N. J. Hemolytic complement in synovial fluid. J. Clin. Invest. 43, 1372–1382 (1964).
Ruddy, S. & Austen, K. F. The complement system in rheumatoid synovitis. I. An analysis of complement component activities in rheumatoid synovial fluids. Arthritis Rheum. 13, 713–723 (1970).
Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).
Fischer, J. et al. IL-21+ CD4+ T helper cells co-expressing IFN-gamma and TNF-alpha accumulate in the joints of antinuclear antibody positive patients with juvenile idiopathic arthritis. Clin. Immunol. 217, 108484 (2020).
Holers, V. M. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat. Rev. Rheumatol. 14, 542–557 (2018).
Trouw, L. A., Rispens, T. & Toes, R. E. M. Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 331–339 (2017).
Nigrovic, P. A., Lee, P. Y. & Hoffman, H. M. Monogenic autoinflammatory disorders: conceptual overview, phenotype, and clinical approach. J. Allergy Clin. Immunol. 146, 925–937 (2020).
Ombrello, M. J. et al. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc. Natl Acad. Sci. USA 112, 15970–15975 (2015).
Nigrovic, P. A. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc. Natl Acad. Sci. USA 112, 15785–15786 (2015).
Colbert, R. A., Navid, F. & Gill, T. The role of HLA-B*27 in spondyloarthritis. Best Pract. Res. Clin. Rheumatol. 31, 797–815 (2017).
Frisell, T. et al. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 65, 2773–2782 (2013).
Langefeld, C. D. et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat. Commun. 8, 16021 (2017).
Gensler, L. S. et al. Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort. Ann. Rheum. Dis. 67, 233–237 (2008).
Prahalad, S. et al. Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. Arthritis Rheum. 64, 925–930 (2012).
Ferucci, E. D. et al. Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum. 52, 239–246 (2005).
Hinks, A. et al. Brief report: the genetic profile of rheumatoid factor-positive polyarticular juvenile idiopathic arthritis resembles that of adult rheumatoid arthritis. Arthritis Rheumatol. 70, 957–962 (2018).
Nigrovic, P. A. & White, P. H. Care of the adult with juvenile rheumatoid arthritis. Arthritis Rheum. 55, 208–216 (2006).
Weiss, P. F., Xiao, R., Biko, D. M. & Chauvin, N. A. Assessment of sacroiliitis at diagnosis of juvenile spondyloarthritis by radiography, magnetic resonance imaging, and clinical examination. Arthritis Care Res. 68, 187–194 (2016).
Colbert, R. A. Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond. Nat. Rev. Rheumatol. 6, 477–485 (2010).
Southwood, T. R. et al. Psoriatic arthritis in children. Arthritis Rheum. 32, 1007–1013 (1989).
Nigrovic, P. A. Juvenile psoriatic arthritis: bathwater or baby? J. Rheumatol. 36, 1861–1863 (2009).
Stoll, M. L. & Mellins, E. D. Psoriatic arthritis in childhood: a commentary on the controversy. Clin. Immunol. 214, 108396 (2020).
Ravelli, A. et al. Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum. 52, 826–832 (2005).
Ravelli, A. et al. Antinuclear antibody-positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis. Arthritis Rheum. 63, 267–275 (2011).
Nigrovic, P. A., Martinez-Bonet, M. & Thompson, S. D. Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification. Curr. Opin. Rheumatol. 31, 401–410 (2019).
Frisell, T. et al. Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden. Ann. Rheum. Dis. 75, 183–189 (2016).
Yamaguchi, M. et al. Preliminary criteria for classification of adult Still’s disease. J. Rheumatol. 19, 424–430 (1992).
Bywaters, E. G. Still’s disease in the adult. Ann. Rheum. Dis. 30, 121–133 (1971).
Vastert, S. J. et al. Anakinra in children and adults with Still’s disease. Rheumatology. 58, vi9–vi22 (2019).
De Benedetti, F. et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2385–2395 (2012).
Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2406 (2012).
Russo, R. A. & Katsicas, M. M. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J. Rheumatol. 40, 329–334 (2013).
Shimizu, M., Nakagishi, Y. & Yachie, A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. 61, 345–348 (2013).
Gattorno, M. et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 58, 1505–1515 (2008).
Oen, K. et al. Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J. Rheumatol. 29, 1989–1999 (2002).
Fantini, F. et al. Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J. Rheumatol. 30, 579–584 (2003).
Murray, K. J. et al. Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arthritis Rheum. 42, 1843–1853 (1999).
Barnes, M. G. et al. Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis. Arthritis Rheum. 62, 3249–3258 (2010).
Gregorio, A. et al. Lymphoid neogenesis in juvenile idiopathic arthritis correlates with ANA positivity and plasma cells infiltration. Rheumatology 46, 308–313 (2007).
Finnegan, S., Clarke, S., Gibson, D., McAllister, C. & Rooney, M. Synovial membrane immunohistology in early untreated juvenile idiopathic arthritis: differences between clinical subgroups. Ann. Rheum. Dis. 70, 1842–1850 (2011).
Albers, H. M. et al. Clinical course and prognostic value of disease activity in the first two years in different subtypes of juvenile idiopathic arthritis. Arthritis Care Res. 62, 204–212 (2010).
Guzman, J. et al. Predicting which children with juvenile idiopathic arthritis will have a severe disease course: results from the ReACCh-Out Cohort. J. Rheumatol. 44, 230–240 (2017).
Heiligenhaus, A. et al. Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany. Arthritis Res. Ther. 22, 81 (2020).
Ombrello, M. J. et al. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann. Rheum. Dis. 76, 906–913 (2017).
Cannizzaro, E., Schroeder, S., Muller, L. M., Kellenberger, C. J. & Saurenmann, R. K. Temporomandibular joint involvement in children with juvenile idiopathic arthritis. J. Rheumatol. 38, 510–515 (2011).
MacRae, V. E., Farquharson, C. & Ahmed, S. F. The pathophysiology of the growth plate in juvenile idiopathic arthritis. Rheumatology 45, 11–19 (2006).
Angeles-Han, S. T. et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the screening, monitoring, and treatment of juvenile idiopathic arthritis-associated uveitis. Arthritis Rheumatol. 71, 864–877 (2019).
Cassidy, J. T., Levinson, J. E. & Brewer, E. J. Jr. The development of classification criteria for children with juvenile rheumatoid arthritis. Bull. Rheum. Dis. 38, 1–7 (1989).
Robinson, E. et al. Towards stratified medicine in juvenile idiopathic arthritis. Pediatric Rheumatol. Online J. 15, 53–54 (2017).
Yeung, R. S. M. et al. Enhancing translational research in paediatric rheumatology through standardization. Nat. Rev. Rheumatol. 12, 684–690 (2016).
Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).
Lewis, M. J. et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 28, 2455–2470.e2455 (2019).
Scher, J. U., Ogdie, A., Merola, J. F. & Ritchlin, C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat. Rev. Rheumatol. 15, 153–166 (2019).
Sikora, K. A. et al. Germline gain-of-function myeloid differentiation primary response gene-88 (MYD88) mutation in a child with severe arthritis. J. Allergy Clin. Immunol. 141, 1943–1947.e1949 (2018).
Wakil, S. M. et al. Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 67, 288–295 (2015).
Moroldo, M. B., Tague, B. L., Shear, E. S., Glass, D. N. & Giannini, E. H. Juvenile rheumatoid arthritis in affected sibpairs. Arthritis Rheum. 40, 1962–1966 (1997).
Moroldo, M. B. et al. Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance. Arthritis Rheum. 50, 1928–1934 (2004).
Prahalad, S. et al. Twins concordant for juvenile rheumatoid arthritis. Arthritis Rheum. 43, 2611–2612 (2000).
McIntosh, L. A. et al. Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci. Arthritis Rheumatol. 69, 2222–2232 (2017).
Kirino, Y. & Remmers, E. F. Genetic architectures of seropositive and seronegative rheumatic diseases. Nat. Rev. Rheumatol. 11, 401–414 (2015).
Li, G. et al. High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction. Nat. Genet. 50, 1180–1188 (2018).
Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).
Terao, C. et al. Distinct HLA associations with rheumatoid arthritis subsets defined by serological subphenotype. Am. J. Hum. Genet. 105, 616–624 (2019).
Eng, S. W., Duong, T. T., Rosenberg, A. M., Morris, Q. & Yeung, R. S. The biologic basis of clinical heterogeneity in juvenile idiopathic arthritis. Arthritis Rheumatol. 66, 3463–3475 (2014).
Rezaei, E. et al. Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories. Rheumatol. 59, 1066–1075 (2020).
Saurenmann, R. K. et al. Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis. Arthritis Rheum. 62, 1824–1828 (2010).
Qiu, J., Soderlund-Venermo, M. & Young, N. S. Human parvoviruses. Clin. Microbiol. Rev. 30, 43–113 (2017).
Jadon, D. R., Shaddick, G., Jobling, A., Ramanan, A. V. & Sengupta, R. Clinical outcomes and progression to orthopedic surgery in juvenile- versus adult-onset ankylosing spondylitis. Arthritis Care Res. 67, 651–657 (2015).
Webb, R. et al. Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients. Ann. Rheum. Dis. 70, 151–156 (2011).
Webber, D. et al. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE. Rheumatology 59, 90–98 (2020).
Scott, I. C. et al. Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking. PLoS Genet. 9, e1003808 (2013).
Simon, A. K., Hollander, G. A. & McMichael, A. Evolution of the immune system in humans from infancy to old age. Proc. Biol. Sci. 282, 20143085 (2015).
Ercan, A. et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2, e89703 (2017).
Laver-Rudich, Z. & Silbermann, M. Cartilage surface charge. A possible determinant in aging and osteoarthritic processes. Arthritis Rheum. 28, 660–670 (1985).
Alpizar-Rodriguez, D. & Finckh, A. Environmental factors and hormones in the development of rheumatoid arthritis. Semin. Immunopathol. 39, 461–468 (2017).
Prisco, L. C., Martin, L. W. & Sparks, J. A. Inhalants other than personal cigarette smoking and risk for developing rheumatoid arthritis. Curr. Opin. Rheumatol. 32, 279–288 (2020).
Derrien, M., Alvarez, A. S. & de Vos, W. M. The gut microbiota in the first decade of life. Trends Microbiol. 27, 997–1010 (2019).
Horton, D. B. et al. Antibiotic exposure and juvenile idiopathic arthritis: a case-control study. Pediatrics. 136, e333–e343 (2015).
Arvonen, M., Virta, L. J., Pokka, T., Kroger, L. & Vahasalo, P. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group’s greater susceptibility to infections? J. Rheumatol. 42, 521–526 (2015).
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.
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.
Peer review information
Nature Reviews Rheumatology thanks R. Khubchandani, B. Prakken and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41584-021-00590-6
Frontiers in Medicine (2021)