Complement Activation Profiles in Patients with Juvenile Idiopathic Arthritis

Abstract

Objectives: Besides T- and B-cells also the innate immunity is playing an effective role in the
pathogenesis of Juvenile idiopathic arthritis (JIA) reported in literature. The complement system (CS)
is activated by the three different ways classical pathway (CP), lectin pathway (LP) and alternative
pathway (AP). This is a controlled prospective observational single center study focused on the three
pathways of CS and its effector, the terminal complement complex (TCC), associated with disease
activity in all clinical JIA subgroups.

Methods: Peripheral blood (PB) samples (n=159) of 60 JIA patients (partially also longitudinal visits)
were analyzed for specific complement pathway activation (COMPL300 ELISA), complement factor H
(CFH)-autoantibodies (CFHAb ELISA), and the soluble TCC (sC5b-9 ELISA) in serum (S) and EDTA
plasma (P). TCC was also analyzed in synovial fluid (SF) of JIA patients (n=9) controlled with samples
of healthy adults (n=12) obtained by arthroscopy (primarily gonarthrosis). As healthy controls (HC)
adults (n=100) and children (n=18) without inflammatory diseases were tested. The JADAS10 defined
the acute phase of the disease.

Results: We compared the elevated serum TCC levels of JIA patients in the acute phase of the disease
(13.32 IQR 8.09-19.48; p<0,001) with the controls' levels (7.78 IQR 4.93-10.31). Subgroup analyses
showed statistically significant (s.s.) elevation in PArf+, OAper, and OAext. COMPL300 analyses
revealed that JIA patients with acute disease had lower CP (82% IQR 37-97% vs 105% IQR 98-115%;
p<0.001), LP (31% IQR 2-86% vs 80% IQR 20-101%; p<0.001), and AP (25% IQR 2-88% vs 85% IQR
70-98%; p<0.001) capacity compared to the HC average due to chronic activation in all three pathways.
Both TCC and COMPL300 analyses during acute phase and remission showed a clear tendency,
especially in PArf+ but only s.s. in the individual course. Remarkable sJIA patients neither in TCC nor
in COMPL300 analyses showed complement activation. No evidence of CFH-autoantibodies was found
in our study group. The TCC levels in SF showed a median of 2.48 IQR 1.71-2.76 AU/ml in JIA patients
and surprisingly high levels in HC with 6.7 IQR 3.9-9.24 AU/ml.

Conclusion: Specific subgroups of JIA patients (extOA, PARf+, ERA) showed increased CS activation
in TCC in PB in the acute course of the disease. Furthermore, the decreased CS capacity, especially in
the CP and AP, confirms the consumption of complement components as an additional contributor to the
disease pathogenesis and acute course. Due to the CS activation throughout all disease activity states, we
could not determine s.s. between the acute and remission phases in our cohort. However, COMPL300 in
combination with TCC seems to be a helpful acute disease biomarker in the individual course.
The pharmacological modulation of CS components might be a valid alternative approach in treatmentresistant
patients, although further investigations are needed.