Association of variably expressed KIR3dl1 alleles with psoriatic disease.

The purpose of this study is to examine the genetic interaction of variably expressed killer cell immunoglobulin-like receptor (KIR) 3DL1 alleles with their cognate ligand, human leukocyte antigen (HLA)-Bw4, in susceptibility to psoriatic disease (PsD). A novel allelic typing system was developed to differentiate KIR3DL1 alleles (*High, *Low, *Null expression, and 3DS1), in PsD patients, including those with psoriatic arthritis (PsA) and cutaneous psoriasis without arthritis (PsC) and healthy controls. Frequencies of each KIR3DL1 allele, Bw4-80I and Bw4-80T, as well as the genetic interaction between the KIR3DL1 alleles and the Bw4 epitope were analyzed. KIR3DL1 alleles were successfully genotyped in 392 PsA, 260 PsC, and 371 control subjects. Only the KIR3DL1*Null allele was associated with PsD (OR = 0.69, p = 0.008), both in the PsA (OR = 0.69, p = 0.02) and PsC patients (OR = 0.70, p = 0.04) compared to control subjects. No difference in the frequency of KIR3DL1*Null was found between the PsA and PsC patients. The presence of the HLA-Bw4 epitope was significantly associated with PsD, particularly in the PsA patients compared to controls. Bw4-80I was increased in PsD and PsA subjects, but not in PsC patients compared to controls. Bw4-80T was increased in PsA compared to both PsC patients or to controls. No interaction was detected between any of the KIR3DL1 alleles and HLA-Bw4, Bw4-80I, or Bw4-80T. The novel qPCR technique successfully identified the four variably expressed KIR3DL1 alleles. The HLA-Bw4 epitope was associated with psoriatic disease, particularly with PsA, but no genetic interactions with KIR3DL1 alleles were detected.

Clinical and Demographic Characteristics of Erosion-free and Erosion-present Status in Psoriatic Arthritis in a Cohort Study.

OBJECTIVE: Psoriatic arthritis (PsA) has been recognized as a severe erosive disease. However, some patients do not develop erosions. We aimed to determine the prevalence, characteristics, and predictors of erosion-free patients (EFP) as compared with erosion-present patients (EPP) among patients with PsA followed prospectively. METHODS: This is a retrospective analysis conducted on patients from the Toronto PsA cohort. Patients with at least 10 years of followup and radiographs were analyzed. Radiographs were scored with the modified Steinbrocker method. Baseline (first visit to clinic) characteristics were used to predict the development of erosions with logistic regression models. To examine the effect of time-varying covariates, Cox regression models were fit for the time to development of erosions from baseline. RESULTS: Among 290 patients, 12.4% were EFP and 87.6% were EPP over the study period. The mean time to development of erosion in the EPP over the course of followup was 6.8 ± 6.1 years. EFP were diagnosed with psoriasis at a younger age compared with EPP. In both models, actively inflamed joints and clinically damaged joints were predictive of the development of erosion, whereas a longer duration of psoriasis at baseline decreased the odds of developing erosion. EPP had a higher percentage of unemployment as compared with EFP at baseline and followup visits. CONCLUSION: Among patients with PsA followed for at least 10 years, 12.4% never develop erosions. The clinical and radiographic findings can ultimately assist in the stratification of a patient's prognosis regarding the development of erosions.

Further Evidence Supporting a Parent-of-Origin Effect in Psoriatic Disease.

OBJECTIVE: To further explore the "parent-of-origin" effect in a large cohort of well-phenotyped patients with cutaneous psoriasis without arthritis (PsC) and psoriatic arthritis (PsA). METHODS: Self-reported family history was obtained from PsA patients from Toronto and Newfoundland satisfying the Classification of Psoriatic Arthritis criteria, and PsC patients from Toronto, who were examined by a rheumatologist to exclude PsA. Proportions of probands with paternally and maternally transmitted psoriatic disease were compared by McNemar's and chi-square tests. Baseline clinical and genetic characteristics of probands with paternally and maternally transmitted disease were compared using logistic regression. RESULTS: A total of 849 probands reported a first-degree relative affected with psoriatic disease (PsC or PsA), of which 532 (63%) reported an affected parent. A significantly larger proportion of probands reported an affected father compared to an affected mother with psoriatic disease (289 [57%] versus 220 [43%], respectively; P = 0.003). This paternal transmission bias was evident in PsA (P = 0.006) and PsC probands, although it did not reach statistical significance in PsC probands (P = 0.20). Furthermore, the proportion of paternal PsC-proband PsA pairs (161 of 214 paternal transmissions [75%]) was significantly larger than maternal PsC-proband PsA pairs (103 of 161 maternal transmissions [64%]) (P = 0.02). Newfoundland probands with paternally transmitted disease had higher HLA-B*08 carriage (P = 0.04) and lower MICA-129Met carriage (P = 0.03). Males had higher HLA-B*38 carriage (P = 0.05) and a higher prevalence of nail lesions (P = 0.01). CONCLUSION: We have provided further epidemiologic evidence of a paternal transmission bias in psoriatic disease.

Minimal disease activity and anti-tumor necrosis factor therapy in psoriatic arthritis.

OBJECTIVE: A state of minimal disease activity (MDA) was defined and validated as target for treatment in psoriatic arthritis (PsA). We aimed to identify disease characteristics, outcome, and predictors of MDA in patients treated with tumor necrosis factor α (TNFα) blockers. METHODS: Patients fulfilling the Classification of Psoriatic Arthritis criteria treated with TNFα blockers were followed every 3-6 months. Patients were considered in MDA when they meet at least 5 of the 7 criteria. Sustained MDA was defined as an MDA state lasting ≥12 months. Patients achieving MDA were compared to non-MDA patients. A proportional odds discrete time survival analysis model was applied, adjusting for sex, age, PsA duration, abnormal erythrocyte sedimentation rate (ESR) and clinically damaged joint count at each visit to identify predictors for MDA. RESULTS: Of the 306 patients treated with TNFα blockers identified from our database, 23 patients were in an MDA state when treatment was commenced; 57 were taking TNFα blockers prior to enrollment. Therefore, 226 subjects were in a non-MDA state and constituted the study population. One hundred forty-five patients of 226 patients (64%) achieved MDA within a mean ± SD duration of 1.30 ± 1.68 years. The mean ± SD duration of MDA was 3.46 ± 2.25 years. At total of 17 patients withdrew from therapy and remained in an MDA state. Male sex (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.08-2.53; P = 0.02) and normal ESR (OR 2.27, 95% CI 1.22-4.17; P = 0.009) increased the odds for achieving MDA. CONCLUSION: MDA is achieved in 64% of patients treated with TNFα blockers in a clinical setting. Male sex and normal ESR are predictors for MDA. On withdrawal or reduction in treatment, 11.6% of patients maintained MDA state.

Immunoglobulin G subclass analysis in psoriatic arthritis.

OBJECTIVE: The occurrence of monoclonal gammopathy of undetermined significance (MGUS) is common in chronic immune mediated disorders. This increased monoclonal antibody production could result from chronic stimulation of lymphocytes, with the immunoglobulin G (IgG) subtype accounting for the majority of cases in psoriatic arthritis (PsA). We aimed to identify IgG subclass profiles in patients with PsA and to determine association with specific disease characteristics. METHODS: Serum samples from 221 patients with PsA from a single cohort were analyzed for their serum IgG subclass levels. All patients fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and were followed at 6-month to 12-month intervals according to a standard protocol. MGUS was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Patients with high abnormal IgG subclass levels were compared to patients with normal levels using descriptive tests. RESULTS: Elevations of IgG1-4 were common in PsA, with ∼20%-49% of patients having elevations of each subclass, IgG2 being the most common subclass abnormality. However, no clinical-serological correlation was found in the group with abnormal IgG2 levels. Of the 38 patients with MGUS, elevations in IgG1 were most common. Patients with an abnormal IgG1 subclass level were more likely to have a discrete band in the gammaglobulin region, higher prevalence of MGUS, and abnormal erythrocyte sedimentation rate or C-reactive protein levels. CONCLUSION: Determination of the IgG subclass concentration in PsA did not seem to add any significant value in identifying specific disease manifestations. However, this study provides insight into the pathological process leading to MGUS in PsA.

Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.

Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

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.

UGT2B17 copy number gain in a large ankylosing spondylitis multiplex family.

BACKGROUND: The primary objective of this study is to identify novel copy number variations (CNVs) associated with familial ankylosing spondylitis (AS). A customized genome-wide microarray was designed to detect CNVs and applied to a multiplex AS family with six (6) affected family members. CNVs were detected using the built-in DNA analytics aberration detection method-2 (ADM-2) algorithm. Gene enrichment analysis was performed to observe the segregation. Subsequent validation was performed using real time quantitative fluorescence polymerase reaction (QF-PCR). The frequency of copy number variation for the UGT2B17 gene was then performed on two well-defined AS cohorts. Fisher exact test was performed to quantify the association. RESULTS: Our family-based analysis revealed ten gene-enriched CNVs that segregate with all six family members affected with AS. Based on the proposed function and the polymorphic nature of the UGT2B17 gene, the UGT2B17 gene CNV was selected for validation using real time QF-PCR with full concordance. The frequency of two copies of the UGT2B17 gene CNV was 0.41 in the Newfoundland AS cases and 0.35 in the Newfoundland controls (OR = 1.26(0.99-1.59); p < 0.05)), whereas the frequency of two (2) copies of the UGT2B17 gene CNV was 0.40 in the Alberta AS cases and 0.39 in the Alberta controls (OR = 1.05(95% CI: 0.83-1.33); p < 0.71)). CONCLUSIONS: A genome-wide microarray interrogation of a large multiplex AS family revealed segregation of the UGT2B17 gene CNV among all affected family members. The association of the UGT2B17 CNV with AS is particularly interesting given the recent association of this CNV with osteoporosis and the proposed function as it encodes a key enzyme that inhibits androgens. However, two copies of the UGT2B17 gene CNV were only marginally significant in a uniplex AS cohort from Newfoundland but not in a uniplex AS cohort from Alberta.

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.

Serum kallikrein-8 correlates with skin activity, but not psoriatic arthritis, in patients with psoriatic disease.

BACKGROUND: About 30% of cutaneous psoriasis (PsC) patients develop psoriatic arthritis (PsA) in the joint, which is under-recognized by dermatologists. Biomarkers for PsA are needed so that early referral to a rheumatologist is made. Kallikreins (KLKs) are secreted serine proteases implicated in skin desquamation and inflammation. This study examined KLK potential as serum biomarkers of PsA in cutaneous psoriasis patients. METHODS: KLKs were measured by ELISAs in synovial fluids of three PsA patients and three control early osteoarthritis (OA) patients, as well as in a cohort of 152 serum samples collected from age- and sex-matched PsC patients, with (n=76) or without PsA (n=76). KLK expression in psoriatic plaques was examined by immunohistochemistry. Univariate and multivariate logistic regression analyses were conducted to analyze the association between serum KLK levels and disease class (PsC, PsA). Serum KLKs that associated with PsA were correlated with clinical parameters of skin and joint activity. RESULTS: Among the seven KLKs tested, KLK6 and KLK8 were elevated in both PsA synovial fluids and psoriatic plaques, but only serum KLK8 levels were associated with psoriatic disease (odds ratio=2.56, p=0.03). Although significantly elevated in PsC and PsA sera compared to healthy controls, KLK8 did not discriminate PsA from PsC patients. KLK8 correlated positively with the psoriasis area and severity index (PASI) (r=0.43, p=0.001) independent of age, sex and psoriasis duration ( ß=1.153, p=0.0003) and exhibited no correlations with tender or swollen joint counts. CONCLUSIONS: Increased KLK8 serum level in PsA patients reflects disease activity in the skin but not in the joints. Serum KLK levels are not useful for screening psoriasis patients for PsA.

Serum adipokines in patients with psoriatic arthritis and psoriasis alone and their correlation with disease activity.

OBJECTIVE: To compare the prevalence of metabolic syndrome (MetS) and the levels of related biomarkers in patients with psoriatic arthritis (PsA) and psoriasis without arthritis (PsC). METHODS: This study compared patients with PsA and patients with PsC. The presence of MetS was determined. Serum levels of insulin, adiponectin and leptin were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. HOMA-IR, adiponectin and leptin were log-transformed. Continuous variables were compared using the t test and the χ(2) test was used for discrete variables. Multivariate regression models were used to investigate the association of MetS and adiponectin with PsA compared to PsC after adjusting for potential confounding variables. RESULTS: 203 PsA and 155 PsC patients were analysed. The prevalence of MetS was higher in PsA patients compared to those with PsC. However, this did not reach statistical significance (36.5% vs 27.1%, p=0.056). The levels of adipokines were significantly higher in PsA compared to PsC: adiponectin (8.8±5.2 vs 7.4±4.5 log (µg/ml), p=0.009) and leptin in women (3.1±0.8 vs 2.8±0.8, log (ng/ml), p=0.04). HOMA-IR was also higher in PsA (0.97±0.63 vs 0.68±0.81, p<0.001). No difference was observed in leptin levels in men. In multivariate regression analysis, PsA (p=0.04) and the psoriasis area and severity index score (p=0.02) were associated with MetS. Adiponectin was significantly associated with PsA (p=0.005), the use of anti-tumour necrosis factor α therapy (p=0.03) and active joint count (p=0.001). CONCLUSIONS: MetS and related adipokines correlated with an increased burden of skin and joint inflammation.

Differential human leucocyte allele association between psoriasis and psoriatic arthritis: a family-based association study.

OBJECTIVE: A recent population-based study identified several HLA alleles as conferring a risk for psoriatic arthritis (PsA) among patients with psoriasis. The authors aimed to confirm these results using a family-based association study. METHODS: PsA probands, psoriasis probands and their first-degree family members were included. All participants were evaluated for the presence of psoriasis and inflammatory arthritis. HLA-B and -C genotyping was performed. The family-based association test was used to test for differences between PsA and psoriasis patients in transmission of candidate alleles from parents to offspring. RESULTS: A total of 178 PsA and 30 psoriasis probands and 561 first degree family members were analysed. The following HLA alleles were over-transmitted to PsA compared with psoriasis: HLA-C*12 (p=0.005), HLA-B*38 (p=0.04), HLA-B*39 (p=0.03), HLA-B*27 (p=0.002). CONCLUSIONS: HLA-B*27, HLA-B*38, HLA-B*39 and HLA-C*12 alleles are potential PsA-specific genetic markers among patients with psoriasis.

IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients.

AIM: To study the association between smoking and IL13 gene polymorphisms with psoriatic arthritis (PsA) and psoriasis. METHODS: The authors genotyped three groups of Caucasians: those with PsA, those with psoriasis without arthritis (PsC) and healthy controls for the rs20541 and rs848 IL13 single nucleotide polymorphisms (SNPs). An additional SNP, rs1800925, was genotyped only in the PsA and PsC groups. The differences in allelic distributions were compared by χ(2) test. The prevalence of smoking was compared between people with PsA and those with PsC. The combined effect of genotype and smoking was tested by comparing the frequencies of different combinations of rs1800925 genotype and smoking status in PsA and PsC. RESULTS: 555 PsA patients, 342 PsC patients and 217 healthy controls were included in the study. Smoking was less prevalent in patients with PsA compared with PsC (47.4% vs 59.4%, p<0.0006). rs20541*G and rs848*C alleles were associated with PsA compared with controls (OR 1.64, p=0.0005, OR 1.61, p=0.0007 respectively). The association between these alleles and PsC compared with controls was only of borderline significance (OR 1.33, p=0.06, OR 1.26, p=0.11 respectively). Two major alleles, rs1800925*C (OR 1.28, p=0.045) and rs848*C (OR 1.30, p=0.047) were increased in PsA compared with PsC. The combination of non-smoking and the genotype rs1800925*CC was associated with increased susceptibility to PsA compared with PsC. Among smokers, rs1800925*CC was not associated with PsA compared with PsC. CONCLUSIONS: IL13 gene polymorphism is associated with increased susceptibility to PsA in psoriasis patients.

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.

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.

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.

Mechanisms of copy number variation and hybrid gene formation in the KIR immune gene complex.

The fine-scale structure of the majority of copy number variation (CNV) regions remains unknown. The killer immunoglobulin receptor (KIR) gene complex exhibits significant CNV. The evolutionary plasticity of the KIRs and their broad biomedical relevance makes it important to understand how these immune receptors evolve. In this paper, we describe haplotype re-arrangement creating novel loci at the KIR complex. We completely sequenced, after fosmid cloning, two rare contracted haplotypes. Evidence of frequent hybrid KIR genes in samples from many populations suggested that re-arrangements may be frequent and selectively advantageous. We propose mechanisms for formation of novel hybrid KIR genes, facilitated by protrusive non-B DNA structures at transposon recombination sites. The heightened propensity to generate novel hybrid KIR receptors may provide a proactive evolutionary measure, to militate against pathogen evasion or subversion. We propose that CNV in KIR is an evolutionary strategy, which KIR typing for disease association must take into account.

HLA markers for susceptibility and expression in scleroderma.

OBJECTIVE: Reported associations between HLA alleles and both susceptibility to and features of scleroderma have been conflicting. Our objective was (1) to determine the role of HLA alleles in the susceptibility to scleroderma; and (2) to determine the role of HLA alleles in various aspects of disease expression. METHODS: Consecutive patients were followed in the scleroderma clinic between 1996 and 1998. Clinical data were obtained through chart review. Healthy volunteers as well as cadaveric donors served as controls. Molecular HLA typing was performed (polymerase chain reaction/sequence-specific oligonucleotides). Statistical analysis included Fisher's exact test and multivariate analyses, using logistic and linear regression models. RESULTS: Ninety-five Caucasian patients (75 women, 20 men, age 43.9 yrs, disease duration 11.9 yrs) with scleroderma and 416 controls were studied. HLA-DRB1*01 and HLA-DRB1*11 were associated with susceptibility to scleroderma, whereas HLA-DRB1*07 was protective. HLA-A*30 and HLA-A*32 were also associated with susceptibility to scleroderma, while HLA-B*57 and HLA-Cw*14 were protective. HLA-B*62 and HLA-DRB1*07 had a significant correlation with the presence of diffuse skin involvement in both univariate and multivariate analyses. HLA-DRB1*11 was associated with high skin score values, while lower values were related to the presence of HLA-Cw*14 and HLA-DQB1*06. Both alleles retained significance in a linear regression model. High skin score values were related to the absence of anticentromere antibodies. Pulmonary fibrosis was associated with HLA-B*62 and HLA-Cw*0602, whereas pulmonary hypertension was associated with HLA-B*13 and HLA-B*65. CONCLUSION: HLA alleles play a role in susceptibility to scleroderma and its disease expression.