TNF-α Gene Polymorphisms: Association with Disease Susceptibility and Response to Anti-TNF-α Treatment in Psoriatic Arthritis

Abstract

The tumor necrosis factor-α (TNF-α) gene has been proposed as a major candidate gene in psoriatic arthritis (PsA). TNF-α is a therapeutic target for patients responding poorly to conventional treatments. We investigated the role of single-nucleotide polymorphisms (SNPs) at positions -238, -308, and +489 of the TNF-α gene in the genetic susceptibility to PsA, in the severity of the disease, and, finally, in the response to TNF-α inhibitors (adalimumab, etanercept, or infliximab). Fifty-seven Caucasian PsA patients and 155 healthy matched controls were studied. The SNP +489 variant allele A was significantly associated with PsA susceptibility (P=0.0136) and severity of clinical (Psoriasis Area and Severity Index score, American College of Rheumatology criteria, Disease Activity Score 28, and Disability Index Health Assessment Questionnaire) and laboratory (C-reactive protein and erythrocyte sedimentation rate) parameters (P-values ranging from 0.016 to 2.908 × 10(-12)). The difference in severity was accounted for by the differences between the AA and GA genotypes with respect to the GG genotype. The SNP +489A allele shows a trend of association with the response to PsA treatment with etanercept. These findings suggest a role of the SNP +489A allele in the susceptibility and severity of PsA.

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

“…However, although a monotherapy with anti-TNF-a is an established successful therapy in a number of autoimmune diseases (15)(16)(17), anti-TNF-a is not effective in T1D treatment (18)(19)(20)(21)(22)(23). Anti-TNF-a neutralizes TNF-a, produced by the immune cells infiltrating the target organ during the inflammatory process (11,14,15,45), and the combination of anti-TNF-a with anti-TCR also prevents the release of IL-1b, the other critical proinflammatory cytokine for the disease process (3), from the activated T cells (25).…”

“…Anti-TNF-a therapy is therefore an established therapeutic principle (14)(15)(16) in rheumatoid arthritis, inflammatory bowel diseases, lupus erythematosus, Sjögren syndrome, psoriasis, and Hashimoto thyroiditis (10,15,17).…”

Genetic, Epigenetic and Pharmacogenetic Aspects of Psoriasis and Psoriatic Arthritis

“…PsA patients with the TNFa -308 GG genotype responded better to TNF-a inhibitors than those with the AA or AG genotypes, 141 and the TNF-a 1489A allele showed a trend of association with the response to PsA treatment with etanercept, although there is as yet no evidence for a causal relationship. 142 The TNFRSF10A CC genotype (rs20575) was associated with European League Against Rheumatism (EULAR) response to infliximab at 6 months, whereas the TNFR1A AA genotype (rs767455) was associated with a better EULAR response at 3 months in PsA patients. 143 This finding is consistent with evidence that TNFRSF10A is expressed in PsA patients, where it can induce cell cycle arrest of proinflammatory cells and apoptosis in arthritic synovium.…”

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

“…Moreover, PsA individuals with HLA-B*27 or DQB1*02 were shown to have an increased risk of developing the most severe form of PsA, arthritis mutilans [38]. Recent studies of the single-nucleotide polymorphism +489A allele of the tumor-necrosis factor (TNF)α gene shows a trend of association with the response to PsA treatment with neutralizing antibodies to TNFα (etanercept), suggesting a role for the SNP +489A allele in the susceptibility and severity of PsA [39]. Moreover,gene-expression profiling of peripheral blood cells suggests that innate immunity may be important in the pathogenesis of PsA, involving Toll-like receptor (TLR) signaling, NF-κB, and various chromatin-remodeling complexes, and potential biomarkers of PsA in Ps patients being identified, such as NOTCH2NL , HAT1 , CXCL10 and SETD2 , which were associated with PsA irrespective of clinical differences between patients [40].…”