IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients.

Sławomir Jeka,Renata Sokolik,Katarzyna Kolossa,Milena Iwaszko,Bartosz Bugaj,Katarzyna Bogunia-Kubik,Monika Chaszczewska-Markowska,Jerzy Świerkot,Joanna Wielińska

doi:10.3389/fimmu.2021.631603

Abstract

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

Highlights

Inflammatory arthritis comprises a diverse group of rheumatic diseases characterized by inflammation of synovial joints and systemic manifestations
The following demographic and clinical data were collected from all studied patients: gender, body mass index (BMI), disease onset, disease duration, medications received, C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (STC), rheumatoid factor (RF) levels, anti-cyclic citrullinated peptide antibody levels, HLA-B27 status, Disease Activity Score-28 (DAS28), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the visual analog scale (VAS, ranging from 0 to 100 mm) of pain, and health assessment questionnaires (HAQs) and global health assessments were used
The frequency of the genotypes and alleles of the IL-33 rs10975519, rs16924159, or rs7044343 did not differ between the Rheumatoid arthritis (RA) patients and controls, and no significant differences were found between the controls and ankylosing spondylitis (AS) or psoriatic arthritis (PsA) patients (Table 2)

Summary

Introduction

Inflammatory arthritis comprises a diverse group of rheumatic diseases characterized by inflammation of synovial joints and systemic manifestations. IL-33 is a dualfunction protein, acting both as an endogenous danger signal and a nuclear factor [3, 4]. This cytokine is constitutively expressed in the nuclei of endothelial and epithelial cells, acts as a nuclear repressor factor, and is involved in gene transcription regulation [5,6,7]. In response to cellular damage, full-length IL-33 is rapidly released into the extracellular matrix, initiating an inflammatory response [8, 9] This cytokine functions as an alarmin, alerting the immune system and triggering the inflammatory process [8, 10]

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Results

Conclusion