Killer-cell immunoglobulin-like receptor gene polymorphisms and susceptibility to psoriatic arthritis.

OBJECTIVES: We conducted a case-control study to determine the association between KIR2D and KIR3D gene polymorphisms and their interaction with HLA alleles in PsA. METHODS: A total of 678 subjects with PsA and 688 healthy controls were studied. Differences between cases and controls in the frequency of individual KIR polymorphisms were tested for significance by an asymptotic χ(2) test and Fisher's exact test. Trends for increasing susceptibility to PsA from combined genotypes (HLA-KIR and HLA) were evaluated by the Cochran-Armitage trend test. Multigene logistic regression analysis was conducted to identify independent associations and interactions. RESULTS: In univariate analyses, KIR2DL2 and KIR2DS2 polymorphisms were significantly associated with PsA. Only KIR2DS2 was associated with PsA compared with healthy controls in multivariate analysis [odds ratio (OR) 1.25, 95% CI 1.01, 1.54, P = 0.044]. The presence of HLA-C group 2 alleles was associated with a higher risk of PsA (trend test P = 0.006). The risk of PsA is higher when KIR2DS2 is present with the HLA-C ligands (C group 1) for the corresponding inhibitory KIRs, and is highest when KIR2DS2 is present in the absence of HLA-C ligands for homologous inhibitor KIRs, compared with the state when KIR2DS2 is absent (trend test P = 0.027). The presence of HLA-C alleles that have high cell surface expression was also associated with a higher risk of PsA (trend test P < 0.001). HLA-B Bw4 and HLA-B Bw4 80ile allele groups were associated with a higher PsA risk (trend test P < 0.0001 for both analyses). CONCLUSION: This study confirms the association of the KIR2DS gene, especially KIR2DS2, with PsA.

High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis.

OBJECTIVE: Psoriatic arthritis (PsA) has a clear familial predisposition, the major histocompatibility complex (MHC) region being the strongest genetic locus. The study primary objective was to identify single nucleotide polymorphisms (SNPs) independent of known human leucocyte antigen (HLA) alleles within the MHC region that are associated with PsA using a high-density SNP map. METHOD: In all, 914 samples were assessed, including 427 PsA cases from 2 well established PsA cohorts and 487 controls from Canada. The genotype data consisted of 2521 SNPs from 2 Illumina Goldengate MHC panels, spanning 4.9 Mb of chromosome 6 with an average spacing of 2 kb. Classical HLA alleles were genotyped in all subjects using sequence-specific oligonucleotide probes or sequence-specific primers. A conditioning approach was used to distinguish between new associations and those in linkage disequilibrium (LD) with known HLA alleles. RESULTS: Unconditional association analysis revealed 43 markers with p<7.26×10(-5) (calculated experiment-wide significance threshold). In the conditional analysis, 10 SNPs showed statistically significant association at a threshold of p<7.26×10(-5). Seven SNPs were in strong LD in the study data (pairwise r(2) >0.77 in the controls) reflecting one association signal. These SNPs spanned a 1.6 Mb region. SNP rs1150735 is 1.5 kb upstream from ring finger protein 39 (RNF39). RNF39 SNPs have been associated with HIV1 disease progression and set point CD4 T cell count. CONCLUSION: Four new loci for either psoriasis or PsA in the MHC region that are independent of known HLA alleles have been identified. The effect size of these variants is modest. Replication of these variants in multiple larger populations is necessary.

Soluble biomarkers differentiate patients with psoriatic arthritis from those with psoriasis without arthritis.

OBJECTIVE: Biomarkers may be helpful in screening patients with psoriasis for PsA. Our purpose was to identify serum biomarkers for psoriasis and PsA. METHODS: Fifty-two patients with psoriasis (26 satisfying CASPAR classification criteria for PsA) and 26 healthy controls were recruited for our study. Patients with psoriasis and PsA were group matched for age, sex and psoriasis duration, whereas controls were matched for age and sex. Blood samples were drawn at the time of assessment and serum was analysed for the following: IL-12, IL-12p40, IL-17, TNF super family member 14 (TNFSF14), MMP-3, RANK ligand (RANKL), osteoprotegerin (OPG), cartilage oligomeric matrix protein (COMP), C-propeptide of Type II collagen (CPII), collagen fragment neoepitopes Col2-3/4(long mono) (C2C) and Col2-3/4(short) (C1-2C) and highly sensitive CRP (hsCRP). Data were analysed using logistic regression and receiver operating characteristic curves were plotted. RESULTS: Fifty-two patients with psoriatic disease had a mean age of 46 years and psoriasis duration of 16.8 years. Compared with controls, increased serum levels of RANKL, TNFSF14, MMP-3 and COMP independently associated with psoriatic disease (P < 0.05). Twenty-six PsA patients (mean swollen and/or tender joint count 16, swollen joint count 5) were then compared with 26 patients who had psoriasis alone. Increased levels of hsCRP, OPG, MMP-3 and the CPII : C2C ratio were independently associated with PsA (P < 0.03). CONCLUSION: This pilot study indicates that hsCRP, OPG, MMP-3 and the CPII : C2C ratio are biomarkers for PsA in patients with psoriasis.

Human leukocyte antigen alleles and susceptibility to psoriatic arthritis.

OBJECTIVE: Our purpose was to determine associations between HLA alleles and psoriatic arthritis (PsA). METHODS: 678 PsA cases and 688 healthy controls were analyzed in a case-control design. The difference in the proportion of cases and controls with at least 1 copy of HLA alleles were tested for significance using χ(2) test and Fisher's exact test. Association analyses of haplotypes inferred by the Expectation-Maximization algorithm were performed. In the family-based association study, data from 283 families were analyzed. RESULTS: Univariate analysis revealed that cases were more likely to be carriers of HLA-C*01, -C*02, -C*06, -C*12, -B*27, -B*38 and -B*57, whereas controls were more likely to be carriers of HLA-C*03, -C*07, -B*07, -B*51, -DRB1*15 and -DQB1*0602. In haplotype analyses, PsA cases were more likely to be carriers of the HLA haplotypes -C*01/-B*27, -C*02/-B*27, -C*12/-B*38, and -C*06/-B*57, while controls were more likely to be carriers of the haplotypes -C*07/-B*07 and -C*15/-B*51. In the family-based association analysis, the HLA alleles -A*02, -B*27 and -DRB1*07 were preferentially transmitted to cases, whereas the alleles -A*03, -A*28, -B*51, -DRB1*11 and -DQB1*0301 were under transmitted. CONCLUSION: This large case-control and family based association study shows that HLA-C*12/B*38, HLA-B*27 and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA. However, since patients with PsA also have psoriasis it is difficult to determine whether the primary association is with arthritis or psoriasis.

Soluble biomarkers associated with response to treatment with tumor necrosis factor inhibitors in psoriatic arthritis.

OBJECTIVE: To identify soluble biomarkers associated with response to therapy with tumor necrosis factor inhibitors (TNFi) in patients with psoriatic arthritis (PsA). METHODS: The study was conducted at a PsA clinic where patients are assessed every 6 months, and serum samples are collected and stored once a year at the time of clinical assessment. Forty patients with active PsA who gave serum samples prior to treatment with TNFi and after at least 3 months of therapy were identified. Patients were classified as TNFi responders if tender joint count was < 3, swollen joint count was 0, and Psoriasis Area and Severity Index score was < 4 at the time the second sample was collected. The following biomarkers were tested by ELISA: TNF superfamily 14, matrix metalloprotease-3 (MMP-3), receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, cartilage oligomeric matrix protein (COMP), CPII, C2C and C1-2C, CS-846, and highly sensitive C-reactive protein. Paired t tests and logistic regression was used for statistical analyses. RESULTS: After a mean treatment duration of 11 months with TNFi (etanercept 28 patients, adalimumab 6, golimumab 4, infliximab 2), 29 patients were classified as TNFi responders. Baseline level of MMP-3 was independently associated with responder status (OR 1.067 for each 1-unit increase, p = 0.045). A reduction in MMP-3 levels with therapy increased the odds of achieving response (OR 1.213 for each 1-unit change, p = 0.030), whereas a reduction in COMP decreased the odds (OR 0.587, for each 100-unit increase, p = 0.039). None of the other biomarkers was associated with response. CONCLUSION: Baseline as well as reduction in serum MMP-3 and increase in serum COMP are independently associated with response to TNFi therapy in patients with PsA.

Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis.

OBJECTIVE: To determine the association between folate pathway gene polymorphisms and the effectiveness, toxicity, and drug survival of methotrexate (MTX) in psoriatic arthritis (PsA). METHODS: Data were obtained from a longitudinal cohort of PsA patients evaluated according to a standard protocol. Data on duration of drug therapy, dose, side effects, and reasons for discontinuation are systematically recorded. Patients treated with MTX after clinic admission who had > or = 3 swollen joints prior to initiating MTX therapy were selected for evaluation of effectiveness. Response to MTX treatment was assessed at 6 months. Data from all patients treated in the clinic with MTX were used in evaluation of toxicity and drug survival. The following single-nucleotide polymorphisms (SNP) were measured using the Sequenom platform: MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), DHFR -473T>C (rs1650697), DHFR 35289A>G (rs1232027), and RFC 80G>A (rs1051266). Fisher's exact test, logistic regression, and Cox proportional hazard analyses were used to determine association. RESULTS: Two hundred eighty-one patients were identified from the database. All patients were included in the analysis for side effects and drug survival, and 119 patients were included in the effectiveness analysis. The minor A allele of DHFR gene at +35289 was the only SNP demonstrating association with response to MTX therapy (OR 2.99, p = 0.02). Patients homozygous for the minor allele of MTHFR 677C/T (677TT) had more liver toxicity (Fisher exact test, p = 0.04). CONCLUSION: Polymorphisms of the DHFR gene may be associated with MTX efficacy. MTHFR 677TT may have a relationship with MTX-induced liver toxicity in PsA.