Involvement of the Circadian Rhythm and Inflammatory Cytokines in the Pathogenesis of Rheumatoid Arthritis

Abstract

Among the symptoms of patients with rheumatoid arthritis (RA), joint stiffness is influenced by diurnal rhythm and reaches peak in the morning, which is a common complaint and reflects the circadian nature of disease manifestation. In addition, inflammatory cytokines, which reach peak secretion early in the morning are major players causing the morning stiffness. In this review, we explore the link between the circadian clock and inflammation, focusing on the interactions of various clock genes with the immune-pathways underlying the pathology of rheumatoid arthritis.

Pharmacodynamic biomarkers and differential effects of TNF‐ and GM‐CSF‐targeting biologics in rheumatoid arthritis

“…The RNA‐sequencing study identified 3853 (2463 up, 1390 down) genes in DMARD‐IR patients and 2827 (1666 up, 1161 down) genes in anti‐TNF‐IR patients with dysregulated expression concentrations in comparison with healthy controls (Benjamini‐Hochberg P < 0.05). Ingenuity pathway analysis demonstrated that mitochondrial dysfunction and circadian rhythm signaling were disrupted in both disease populations, consistent with their reported roles in RA pathogenesis . Interestingly, multiple immunologic pathways were enriched in dysregulated genes of anti‐TNF‐IR patients but not DMARD‐IR patients, including signaling pathways in T cells, macrophages, and neutrophils ().…”

Evaluation of humoral and cellular immune responses to a DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats

“…2 Thus, these results are critical for the potential use of this vaccine in the treatment of RA as the imbalance between pro-inflammatory Th1-cytokines and anti-inflammatory Th2 and/or Th3 cytokines which has been shown to be a major player in the immunopathogenesis of RA. 6,27,28 To design the most effective DNA vaccines, it is important to understand the types of immune responses required to prevent infection or alleviate autoimmune diseases. 16,19 In these cases, adaptive cellular immune responses comprising Tc, Ts, Treg, Th1/Th2, Th17, and CD4 C CD29 C T-cell subsets have been shown to be critical for maintaining normal immune function, Table 3.…”

Resetting the clock on arthritis

“…Typically, an association is observed between increased pain during the night which keeps them awake, or increased stiffness in the morning [5]. While the exact mechanisms by which this occurs remains elusive, it has been suggested that the circadian clock differentially regulates inflammatory processes in relation to the wake/sleep cycle [6]. Transgenic mouse models have begun to shed light on the role of circadian clock rhythm in bone and joint development, maturation, and homeostasis, as mice with deficient clock regulation display abnormal joint morphology and increased susceptibility to inflammatory arthritis [7,8].…”