Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis

• Published in: Annals of the rheumatic diseases Vol. 62; no. 6; pp. 526 - 529
• Main Authors: Padyukov, L, Lampa, J, Heimbürger, M, Ernestam, S, Cederholm, T, Lundkvist, I, Andersson, P, Hermansson, Y, Harju, A, Klareskog, L, Bratt, J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.06.2003; BMJ; BMJ Publishing Group LTD
• Subjects: ACR; Adult; Aged; American College of Rheumatology; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Clinical medicine; Cytokines; Cytokines - genetics; DAS; disease activity score; disease modifying antirheumatic drug; DMARD; Etanercept; Extended Report; Female; Gangrene; Genes; Genetic Markers; genetics; Genotype; Genotype & phenotype; Humans; Immunoglobulin G - therapeutic use; interleukin; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Patient Selection; Patients; Pharmacology. Drug treatments; Polymorphism, Genetic; Prognosis; Receptors, Tumor Necrosis Factor - therapeutic use; Recombinant Fusion Proteins - therapeutic use; Rheumatoid arthritis; Rheumatology; Statistical analysis; Studies; Surveillance; TGF; TNF; TNF inhibitors; transforming growth factor; Treatment Outcome; Tumor necrosis factor-TNF; tumour necrosis factor; Sweden; Human; Immunopathology; Genetic marker; Treatment efficiency; Cytokine; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Immunomodulator; Chemotherapy; Chronic; Treatment; Etanercept; Tumor necrosis factor; Rheumatoid arthritis; Genetics; Predictive factor; Polymorphism; Receptors; Research Support; Genetic; Arthritis; Tumor Necrosis Factor/therapeutic use; Rheumatoid/drug therapy/genetics; Non-U.S. Gov't
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.62.6.526

Background: Rheumatoid arthritis (RA) is a genetically complex disease where the response to different treatments varies greatly between different patients. This is the case with the tumour necrosis factor (TNF) blocking agents, where 20–40% of patients have been described as non-responders. No predictive markers exist as yet for the prognosis of response. Objective: To analyse whether polymorphisms of several cytokine genes are associated with the responsiveness to TNF blockade with etanercept. Methods: 123 patients with active RA were treated with etanercept and response rates were determined after three months using American College of Rheumatology (ACR)20 and disease activity score (DAS)28 response criteria. Genotyping was done for TNF (−308 TNFA), interleukin (IL)10 (−1087 IL10), transforming growth factor (TGF)β1 (codon 25 TGFB1), and IL1 receptor antagonist (intron 2 IL1RN). Results: 24 patients (20%) were defined as non-responders owing to their failure to fulfil any of the ACR20 or DAS28 response criteria. None of the recorded alleles was alone significantly associated with responsiveness to treatment. However, a certain combination of alleles (−308 TNF1/TNF1 and −1087 G/G) was associated with good responsiveness to etanercept (p<0.05). In addition, a combination of alleles influencing interleukin 1 receptor antagonist (IL1Ra) and TGFβ1 production (A2 allele for IL1RN and rare C allele in codon 25 of TGFB1 gene) was associated with non-responsiveness (p<0.05). Conclusion: Genetic polymorphisms, which may influence the balance of pro- and anti-inflammatory cytokines of relevance for the course of RA, are associated with clinical responsiveness to etanercept treatment.