The pain trajectory of juvenile idiopathic arthritis (JIA): translating from adolescent patient report to behavioural sensitivity in a juvenile animal model

Abstract

Background While pain is a common symptom in JIA patients, it remains unclear why some JIA patients develop ongoing or persistent pain. Complex clinical and social settings confound analysis of individual factors that may contribute to this pain. To address this, we first undertook a retrospective analysis of pain reports in a JIA patient cohort with the aim of identifying potential factors contributing to persistent pain. We then carried out an experimental laboratory study, using joint inflammatory pain behaviour in rodents, to validate the role of these factors in the onset of persistent pain under controlled conditions. Methods Patients: Retrospective analysis of anonymised pain visual analogue scale (VAS) scores and accompanying clinical scores from 97 JIA patients aged 13–19 (mean: 16.40 ± 1.21) collected over 50 weeks. Rats: Experimental study of pain behaviour following intra-articular microinjection of complete Freund’s adjuvant (CFA) in adolescents ( n = 25) and young adults ( n = 43). Some animals ( n = 21) had been previously exposed to joint inflammation in infancy or adolescence. Results Patients: Cluster analysis of patient pain VAS scores revealed three trajectories over 50 weeks: consistently low pain ( n = 45), variable pain ( n = 30) and persistently high pain ( n = 22). Number of actively inflamed joints did not differ in the three groups. High pain at a single visit correlated with greater physician global assessment of disease activity, while a high pain trajectory over 50 weeks was associated with more limited joints but fewer actively inflamed joints. Rats: Rodents administered ankle joint CFA also exhibit low, medium and high joint pain sensitivities, independent of joint inflammation. Prolonged inflammatory pain behaviour was associated with high background pain sensitivity, following joint inflammation at an earlier stage in life. Conclusions Both JIA patients and rodents differ in their individual pain sensitivity independent of the concurrent joint inflammation. Using experimental animal models allows us to isolate physiological factors underlying these differences, independently of social or clinical factors. The results suggest that a history of prior arthritic activity/joint inflammation may contribute to high pain sensitivity in adolescents with JIA. Electronic supplementary material The online version of this article (10.1186/s12969-019-0360-3) contains supplementary material, which is available to authorized users.

Spinal interleukin-6 contributes to central sensitisation and persistent pain hypersensitivity in a model of juvenile idiopathic arthritis

“…Juvenile idiopathic arthritis is a heterogeneous group of musculoskeletal diseases affecting around 0.1% of children in the UK ( Manners and Bower, 2002 ). While the treatment of JIA has been revolutionised by the introduction of biologics ( Learoyd et al, 2019 , Lomholt et al, 2013 , Shiff, 2017 ), pain remains a major problem ( Cornelissen, 2014 , de Lalouvière et al, 2014 , Schaible, 2009 ). Electronic diary entries of JIA patients showed virtually no pain-free periods, and 86% of patients suffered from high levels of pain at least once a month ( Shiff, 2017 , Cornelissen, 2014 ).…”

“…An analysis of pain severity in JIA reveals that one in 10 patients have concerning pain trajectories in the 24 months post diagnosis, but that initial active joint counts does not always reflect these trajectories ( Shiff, 2017 ). Rodent models of JIA display a similar dissociation of joint inflammation and pain behaviour providing a basis for isolating biological mechanisms, independent of social or clinical factors ( Learoyd et al, 2019 ).…”

Altered sensory innervation and pain hypersensitivity in a model of young painful arthritic joints: short- and long-term effects

“…The results are relevant to the re-inflammation pain of adolescent and adult patients with JIA [ 13 ] as it is well-documented that many JIA patients suffer from re-inflammation in adulthood [ 57 ]. Furthermore, while many factors, such as age, [ 8 – 11 ] sex, [ 8 , 12 , 13 ] events [ 4 ], and dysfunctional health beliefs [ 15 , 16 ] have all been implicated as possible contributors to prolonged pain in adolescent JIA patients, our data suggest that while joint inflammation in childhood may not be very painful, re-inflammation of the joint at a later stage in life, will result in greater hyperinnervation and greater pain. Furthermore, we suggest that a better understanding of the mechanisms underlying joint hyperinnervation and the potential for priming in early life, may facilitate more targeted treatment of arthritis related pain.…”

“…A considerable number of children and adolescents suffer from joint pain associated with juvenile rheumatic disease; persistent pain is the most common and distressing symptom of juvenile idiopathic arthritis (JIA) [1]. Both clinical and experimental studies have highlighted the extent of this pain in young patients despite good disease control [1][2][3][4][5]. In the 5 years from disease onset, a subset of children with JIA (10-20%) develop persistent pain [4,[6][7][8] and there are indications that those with particularly poor pain outcomes might be identifiable at an earlier stage of the disease [6].…”

“…Both clinical and experimental studies have highlighted the extent of this pain in young patients despite good disease control [1][2][3][4][5]. In the 5 years from disease onset, a subset of children with JIA (10-20%) develop persistent pain [4,[6][7][8] and there are indications that those with particularly poor pain outcomes might be identifiable at an earlier stage of the disease [6]. A wide range of factors appear to influence persistent pain in inflammatory joint disease [1,9] but the measurable spread of this pain beyond diseased joints in both patients [3,10,11] and animal models [12] indicates an underlying biological mechanism of prolonged and widespread sensitization of pain circuitry within the central nervous system, driven by aberrant input from the joints or by central neuroimmune dysfunction [12][13][14].…”