Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

Abstract

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients' leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options.

Keywords: AA amyloidosis; IL-1inhibitors; TNF inhibitors; TNFR1; autoinflammatory disorders; misfolding disease; tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Figure 1

Schematic representation of variants in the TNFRSF1 gene associated with tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Pathogenic variants are found predominately in the first two cysteine-rich domains, CRD1 and CRD2. The numbering system for TNFR1 (tumor necrosis factor receptor 1) begins at amino acid residue methionine 1. The CRD domains are defined based on the UniProtKB database [9].

Figure 2

Summary of proposed pathogenic mechanisms in TRAPS. Binding of TNFα to TNFR1 leads to the assembly of the signaling pathway that ultimately upregulates the gene expression of many pro-inflammatory cytokines. There are multiple mechanisms that contribute to the pathogenesis of TRAPS. Heterozygous variants affect the structure of the extracellular domain and impact its ability to bind to the TNF ligand. Mutant receptors fail to shed from the cell surface to generate soluble TNFR1 proteins, which function to attenuate signaling through the TNFR1 receptor. Mutated misfolded proteins accumulate in the cells and cause endoplasmic stress (ER), upregulation in the unfolded protein response (UPR), and increased production of mitochondrial reactive oxygen species (ROS). The UPR initiates ER membrane stress sensors, including inositol-requiring protein (IRE1)α, to restore protein folding and homeostasis in the ER. In the ER stress, activation of IRE1α leads to splicing of transcription factor X-box binding protein 1 (XBP1) into its active form sXBP1, which acts as a transcription factor that can upregulate expression of many target genes. Autophagy is responsible for clearance of intracellular TNFR1. However, in patients with TRAPS, autophagy is defective and mutated proteins are not efficiently cleared from cells. MicroRNA can regulate gene expression at the transcriptional and post-transcriptional levels by binding to the complementary mRNA sequence. MicroRNAs can be detected in serum and various miRNAs can serve as biomarkers of the disease activity.

Figure 3

Summary of most common clinical manifestations in TRAPS. Organ-specific clinical manifestation of 209 TRAPS patients with variants validated as pathogenic and likely pathogenic in the Infevers database. * Not all reports contained an explicit description of these symptoms and they may be present in a larger proportion of patients than reported here [6,22,57,61,62,63].