Cytokine inhibitors: soluble tumor necrosis factor receptor 1 and interleukin-1 receptor antagonist in Behçet’s disease

Abstract

Serum levels of proinflammatory cytokines, interleukin-1 beta (IL-1beta), tumor necrosis factor alpha, (TNF-alpha), and their inhibitors, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor 1 (sTNFR1), were determined by enzyme-linked immunosorbent assay in 104 patients with Behçet's disease (65 active, 39 inactive) and 40 healthy controls. The levels of IL-1beta and IL-1ra were significantly higher in both active and inactive patients than in control subjects (P<0.01 and P< 0.01, respectively). The concentrations of TNF-alpha and sTNFR1 were found to be higher in active patients than in controls (P< 0.01 and P< 0.001, respectively). There were no significant differences in the serum levels of these cytokines and their inhibitors between active and inactive patients. Significant increases in mean C-reactive protein level and erythrocyte sedimentation rate were found in patients with active vs inactive disease (P< 0.001 and P< 0.05, respectively). C-reactive protein values correlated with erythrocyte sedimentation rate but not with cytokines or their inhibitors. Our conclusion is that elevated serum TNF-alpha and sTNFR1 seem to be important inflammatory mediators in Behcet's disease. The statistically significant increase in these levels may arise from the severity of inflammation in the tissue or organ involved.

Etiology, Immunopathogenesis and Biomarkers in Behçet’s disease

“…A proof-of-concept study by Güll et al strongly implicated IL1β and BD with significant improvement seen especially in patients with uveitis treated with IL1β-regulating antibody [47]. Recently Tugal-Tutkun et al demonstrated rapid control of uveitis in BD patients without the need for high-dose corticosteroid in a prospective, open-label, randomized phase II trial [48] supporting several other previous studies of the proven efficacy of IL1β to induce stable clinical remission among BD patients [49][50][51][52].…”

“…Evidence from the GWASs further implicated several cytokines underlying the pathogenesis of BD [17,18,[22][23][24][25][26]. Moreover, the successful use of various anti-cytokine therapies in BD patients provides additional evidence that cytokines play a crucial role in its pathogenesis [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. These overall observations highlight the fundamental role of cytokines as key players in the pathogenesis of BD.…”

“…Levels have been shown to be elevated in studies from different populations [49,69,[78][79][80][81][82][83]. Metaanalysis by Touma et al [84] found TNF (-238A/G, -1031C/T, and -857T/C) polymorphisms are associated with susceptibility to BD, while an updated meta-analysis by Zhang et al confirmed a significant association between the TNF−308A/G polymorphism and BD susceptibility [85].…”

“…Among the 11 cytokines in the family, IL1β is the principal pro-inflammatory cytokine, leading to the expression of many chemokines and secondary mediators of inflammation and upregulating innate immunity in response to infectious agents [66]. The levels of IL1β have been shown to be elevated in several studies [45,46,49,67,68], including in synovial fluids of BD patients [45,46]. A proof-of-concept study by Güll et al strongly implicated IL1β and BD with significant improvement seen especially in patients with uveitis treated with IL1β-regulating antibody [47].…”

Ocular Manifestations of Behçet’s Disease

“…In autoinflammatory disorders, IL-1 blockage results in a rapid and continuous reduction of disease manifestations. Serum levels of IL-1β and IL-1 receptor antagonist were found to be significantly higher in Behçet patients [38,73,74].…”