Abstract
BackgroundSigns of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade. This suggests a possible role for CNS inflammation in arthritis that may be affected by TNF blockade. We therefore investigated the effects of TNF blockade on the arthritis CSF proteome and how candidate proteins related to clinical measures of disease activity and inflammation.MethodsMass spectrometry-based quantitative proteomic analysis was performed on CSF from seven polyarthritis patients before and during infliximab treatment. Treatment-associated proteins were identified using univariate (Wilcoxon signed rank test) and multivariate (partial least squares discriminant analysis (PLS-DA)) strategies. Relations between selected candidate proteins and clinical measures were investigated using the Spearman correlations. Additionally, selected proteins were cross-referenced to other studies investigating human CSF in a thorough literature search to ensure feasibility of our results.ResultsUnivariate analysis of arthritis CSF proteome revealed a decrease of 35 proteins, predominantly involved in inflammatory processes, following TNF blockade. Seven candidate proteins, Contactin-1 (CNTN1), fibrinogen gamma chain (FGG), hemopexin (HPX), cell adhesion molecule-3 (CADM3), alpha-1B-glycoprotein (A1BG), complement factor B (CFB), and beta-2-microglobulin (B2M), were selected for further studies based on identification by both univariate and multivariate analyses and reported detection in human CSF and known associations to arthritis. Decreased levels of FGG and CFB in CSF after treatment showed strong correlations with both erythrocyte sedimentation rate and disability scores, while CNTN1 and CADM3 were associated with pain.ConclusionSeveral immune-related proteins in the CSF of arthritis patients decreased during TNF blockade, including FGG and CFB that both correlated strongly with systemic inflammation. Our findings stress that also intrathecal inflammatory pathways are related to arthritis symptoms and may be affected by TNF blockade.
Highlights
Signs of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade
Short-term infliximab-induced effects on the CSF proteome of arthritis patients identified by proteomic profiling Intrathecal effects of TNF-blockade on CSF proteome in patients with polyarthritis at the baseline and after 8 weeks of infliximab treatment (n = 7) were investigated
Univariate Wilcoxon signed rank test revealed that intrathecal levels of 31 of the 306 identified proteins were significantly altered after infliximab treatment (p < 0.05) (Additional file 1: Table S1)
Summary
Signs of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade. This suggests a possible role for CNS inflammation in arthritis that may be affected by TNF blockade. We have previously detected elevated inflammatory mediators in cerebrospinal fluid (CSF) of rheumatoid arthritis (RA) patients, where increased interleukin-1beta (IL-1β) levels correlated positively with fatigue [4]. Arthritis is associated with disturbed central pain regulation as reviewed by Walsh et al [5] Together, this indicates a connection between arthritis, central nervous mechanisms and global CNS symptoms. Little else is known about the effects of TNF blockade in the human intrathecal compartment or the relationship between CSF effects, CNS-related arthritis symptoms and peripheral inflammation
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