Biological classification of childhood arthritis: roadmap to a molecular nomenclature

Abstract

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.

Figure 1.. Epidemiology of juvenile idiopathic arthritis.

Age of onset in 1081 children with arthritis evaluated in the Pediatric Rheumatology Clinic at The Hospital for Sick Children, Toronto, Canada. Note the paucity of JIA onset in the first year of life; the incidence peak in girls between age 1 and 4; and the relatively balanced gender ratio of arthritis that begins in adolescence. Modified from ref .

Figure 2.. Evolution of classification criteria for childhood-onset arthritis.

Since 1959, juvenile and adult arthritis have been distinguished by an age cutoff at the 16^th birthday. Nomenclature has evolved through the American Rheumatism Association’s juvenile rheumatoid arthritis (JRA) and EULAR’s juvenile chronic arthritis (JCA) to ILAR’s current juvenile idiopathic arthritis (JIA) system, for which a provisional revision has been proposed by PRINTO.

Figure 3.. Current arthritis classification in children and adults.

A. Major diagnostic categories of idiopathic inflammatory arthritis beginning in childhood (before the 16^th birthday) according to the ILAR nomenclature. B. Major diagnostic categories of idiopathic inflammatory arthritis beginning in adulthood (age 16 and onward). Adapted from refs ^,. Note to illustrator – for PRINTO, the early-onset ANA-positive category includes some seroneg polys, some of each oligo category, and some psoriatics. Other/unclassified includes others in each of these categories plus some psoriatics.

Figure 4.. Biological “Fault lines” in arthritis.

Studies in murine models and in humans identify three central dichotomies in arthritis biology: synovitis vs. enthesitis, antibody-related vs. antibody-independent, and autoimmune vs. autoinflammatory. Distinct forms of arthritis may be characterized by understanding where they reside on each spectrum.

Figure 5.. Proposed subdivisions within arthritis: PRINTO and the four-cluster model.

A. Provisional PRINTO JIA categories for childhood-onset arthritis. B. Four-cluster model defining mechanistic subgroups within arthritis across the age spectrum (modified from ). These two models represent hypotheses with differing methodology and purposes. The PRINTO model reflects an ongoing effort based on consensus methodology to provide preliminary criteria defining clinically homogeneous entities to enable structured validation studies as well as biological research. The four-cluster model integrates clinical and biological data to define groups that exhibit pathophysiologic similarity, irrespective of age of onset. These models exhibit more resemblance than difference, recognizing seropositive arthritis, spondyloarthritis, and systemic/Still’s disease as distinct entities. Early-onset ANA-positive children may or may not form a distinct subset within seronegative arthritis.