Paradoxical Inflammation in IBD Patients Treated with Anti-Tumor Necrosis Factor Alpha Therapy

Review Article

Austin J Gastroenterol. 2017; 4(2): 1081.

Paradoxical Inflammation in IBD Patients Treated with Anti-Tumor Necrosis Factor Alpha Therapy

Münger C¹, Juillerat P¹ and Niess JH1,2*

¹Department of Gastroenterology, University Clinic of Visceral Surgery and Medicine, Switzerland

²Department of Gastroenterology and Hepatology, University Hospital of Basel, Switzerland

*Corresponding author: Niess JH, Department of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland

Received: February 07, 2017; Accepted: April 03, 2017; Published: May 03, 2017


The development of tumor necrosis factor (TNF) antagonists has revolutionized the treatment of inflammatory bowel disease (IBD). Paradoxically, TNF antagonists can also induce inflammation, such as psoriasis induced by TNF antagonists. The mechanisms by which TNF antagonists induce paradoxical inflammation, has remained largely unresolved. In this review we will focus on the immunologic effects of the therapy with TNF antagonists and give an overview of TNF antagonist-induced immunologically mediated diseases.

Keywords: Ulcerative colitis; Crohn’s disease; Tumor necrosis factor; Paradoxical inflammation


cIAP1: Cellular Inhibitor of Apoptosis Protein 1; cIAP2: Cellular Inhibitor of Apoptosis Protein 2; CKI: Intracellular Casein Kinase I; CRH: Corticotropin Releasing Hormone; EGFR: Epidermal Growth Factor Receptor; FcγRI: Fc-Gamma Receptor I; FcγRIII/II: Fc-Gamma Receptor III/II; FLIPL: FLICE-like Inhibitory Protein; G-CSF: Granulocyte Colony Stimulating Factor; HS: Hidradenitis Suppurativa; IKK: IκB Kinase; IBD: Inflammatory Bowel Disease; JNK: JUN N-terminal Kinase; LPS: Lipopolysaccharide; MLKL: Mixed Lineage Kinase Domain-Like (1); NF–κß: Nuclear Factor �Kappa-Light-Chain-Enhancer’ of Activated B-Cells; RIPK: Receptor- Interacting Serine/Threonine-Protein Kinase 1; sTNF: Soluble Tumor Necrosis Factor; TAB2: TGFß-Activated Kinase 2; TAB3: TGFß-Activated Kinase 3; TACE: TNF-Alpha-Converting Enzyme; tmTNF: Transmembrane Tumor Necrosis Factor; TNF: Tumor Necrosis Factor; TNFR1: Tumor Necrosis Factor Receptor 1; TNFR2: Tumor Necrosis Factor Receptor 2; TNFSF: Tumor Necrosis Factor Superfamily; TNFSRF: Tumor Necrosis Factor Receptor Superfamily; TRADD: TNFR1-Associated Death Domain Protein; TRAF2: TNFRAssociated Factor 2; TRAF5: TNFR-Associated Factor 5; UV: Ultraviolet


The tumor necrosis factor (TNF) antagonists are potent therapies for patients with inflammatory bowel disease (IBD) and other immune-mediated diseases. TNF plays a key role in a complex network of cytokines in initiating inflammatory reactions by activation of NF- κB, induction of apoptosis and necroptosis [1-3]. Forward signaling is induced by binding of soluble TNF to the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), whereas reverse signaling is induced by binding of the respective receptors to membrane-bound TNF [1,4]. This leads to pleiotropic effects, such as the release of the corticotropin releasing hormone (CRH) by the hypothalamus [5], suppression of appetite [6], release of acute phase proteins by the liver, such as C reactive protein, stimulation of phagocytes, attraction of neutrophils, increase of insulin resistance by serine-phosphorylation of insulin receptor substrate-1 in the liver an peripheral tissues [7-12]. Activation of TNF pathways can hence induce shock-like symptoms [12]. Prolonged exposition of low TNF concentrations can lead to cachexia as observed in cancer patients. Interfering with these complex processes is an attractive target to treat auto-inflammatory diseases, in which elevated TNF concentrations have been reported [13,14]. However, the pharmacological interference with TNF can also have unexpected effects. For example, the application of these substances can lead to immunologic side effects, either by the induction of antidrug antibodies, which can lead to a loss of response or infusion reactions or by a shift in the complex cytokine network which can paradoxically lead to other immune-mediated diseases such as psoriasis, arthritis and sarcoidosis that usually respond well to the treatment with TNF antagonists [15-18]. A nomenclature for the adverse events of biologicals analogue to the established nomenclature for adverse events induced by traditional drugs has been suggested (Table 1) [19]. We hence searched the literature using the key words “paradoxical reaction”, “IBD”, “ulcerative colitis”, “Crohn’s disease”, “anti-tumor necrosis factor-alpha”, “infliximab”, “adalimumab, “etanercept”, “golimumab”, “certolizumab”, “psoriasis”, “psoriatic arthritis”, “alopecia”, “arthritis”, “vasculitis”, “sarcoidosis”, and “hidradenitis suppurativa”. In this review we will first give an overview of the current concepts of TNF signaling pathways and then focus on paradoxical immunologic side effects of TNF antagonists.