title: The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.
abstract: OBJECTIVE
  A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs).
  
  
  METHODS
  Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed.
  
  
  CONCLUSIONS
  A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients.
  
  
  CONCLUSIONS
  This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.
authors.affiliation: Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Hopkins
authors.forename: C E
authors.initials: CE
authors.lastname: O'Doherty
authors.forename: D J R
authors.initials: DJ
authors.lastname: Foster
authors.forename: V
authors.initials: V
authors.lastname: Suppiah
authors.forename: R N
authors.initials: RN
authors.lastname: Upton
authors.forename: L D
authors.initials: LD
authors.lastname: Spargo
authors.forename: L G
authors.initials: LG
authors.lastname: Cleland
authors.forename: S M
authors.initials: SM
authors.lastname: Proudman
authors.forename: M D
authors.initials: MD
authors.lastname: Wiese
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use* / Q000633:toxicity; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use* / Q000633:toxicity; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D013021:South Australia; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D007555:Isoxazoles; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D000077339:Leflunomide
keywords: PTPN22; leflunomide; pharmacogenomics; polymorphism; rheumatoid arthritis