Understanding juvenile idiopathic arthritis : a multidimensional approach

The overarching objective of this doctoral thesis is to enhance the understanding of Juvenile Idiopathic Arthritis (JIA), a complex autoimmune disease affecting children. With the aim of filling the knowledge gaps in JIA, we conducted a comprehensive study on biomarkers with distinct biological implications, including genetic variations, autoantibodies, and plasma and synovial fluid proteins, in individuals with JIA and controls.

The goal for Study I was to investigate the genetics of JIA by employing a case control genome-wide association analysis within a Swedish JIA cohort and controls. This study identified relations between specific Human Leukocyte Antigen (HLA) alleles and the presence of autoantibodies, namely anti-nuclear antibodies (ANA). We found that HLA-DRB1-DQA1-DQB1 haplotype was strongly associated with increased JIA risk in the overall cohort which HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. We also found that the ANA-positive JIA has a stronger association with this haplotype. Further logistic analysis revealed that HLA- DRB1*08 and DRB1*11 alleles, female sex, and lower age at onset all contribute to ANA-positivity in JIA.

Study II explored the involvement of LACC1 gene polymorphisms in non-systemic JIA for the first time. We detected significant associations of the LACC1 gene polymorphisms with JIA as well as for inflammatory bowel disease (IBD) suggesting mutual mechanisms linking different autoimmune conditions.

The goal of study III was to examine the prevalence of antibodies against citrullinated proteins/peptides (ACPA) in the plasma of Swedish JIA patients and juvenile control cohort for the first time and investigate the genetic predispositions underpinning ACPA presence in JIA. We also set to specify the ACPA reactivity profiles through utilization of a multiplex microarray platform, which facilitates the simultaneous detection of multiple reactivities. Anti-CCP antibodies were detected in 6.2% of JIA patients and 2% of controls and ACPAs with a variety of different reactivities were detected with high frequency in anti-CCP-positive patients as well as anti-CCP-negative patients although with a lower frequency. Anti-CCP antibodies correlated with rheumatoid factor, HLA-DRB1 shared epitope, RF-positive polyarthritis subtype and older age at onset.

Our core focus in the Study IV was to assess levels of biomarkers for early joint degradation in JIA compared to healthy children or juveniles with knee injuries, extending the potential for early detection and tracking of joint damage but also for distinguishing of molecular signatures associated with joint destruction in JIA. We assessed triple-paired synovial fluid, plasma and urine samples from JIA patients compared to plasma samples from healthy children and synovial fluid from knee-injured juveniles. We found that plasma levels of ARGS, C2C, COMP, and TRAP5b were elevated in children JIA when compared to healthy children. When comparing JIA patients to juveniles with knee injuries, we observed increased levels of synovial fluid C2C and TRAP5b in JIA, but decreased levels of ARGS and COMP. Among JIA patients, we discovered positive correlations between local (synovial fluid) and systemic (plasma/urine) levels of bone biomarkers. Additionally, we observed negative correlations between age and plasma levels of C2C and TRAP5b. However, we did not find any correlations between these biomarkers and gender, the number of affected joints, disease duration, or medication use.

Our investigation of diverse biomarkers and potential mechanisms in JIA has demonstrates novel insights into the multifaceted pathological profile of the disease. These findings not only show relevance to clinical phenotypes but also transcend current disease classification criteria. This thesis contributes to the advancement of our understanding of these intricate mechanisms, underscoring the pivotal roles of genetics and autoimmunity in the development of disease subtypes within JIA.

List of scientific papers

I. Genetic association of antinuclear antibodies with HLA in JIA patients. RAYA SALEH, Erik Sundberg, Katarina Tengvall, Lars Alfredsson, Ingrid Kockum, Leonid Padyukov*, Helena Erlandsson Harris*. *These authors share last authorship. [Manuscript]

II. LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis. G Assadi, R SALEH, F Hadizadeh, L Vesterlund, F Bonfiglio, J Halfvarson, L Törkvist, AS Eriksson, HE Harris, E Sundberg and M D’Amato. Genes and Immunity. (2016), 1–4.
https://doi.org/10.1038/gene.2016.17

III. Presence and reactivities of antibodies directed to citrullinated peptides in a Swedish JIA cohort. RAYA SALEH, Erik Sundberg, Monika Hansson, Linda Mathsson-Alm, Karl Skriner, Guy Serre, Karin Lundberg, Leonid Padyukov, Helena Erlandsson Harris. [Manuscript]

IV. Juvenile idiopathic arthritis patients have a distinct cartilage and bone biomarker profile that differs from healthy and knee-injured children. André Struglics*, RAYA SALEH*, Erik Sundberg, Mia Olsson, Helena Erlandsson Harris, Cecilia Aulin. Clin Exp Rheumatol. 2020 Mar-Apr;38(2):355-365. *These authors share first authorship.
https://doi.org/10.55563/clinexprheumatol/ck090i