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Objective.Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy.Methods.Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III–V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran–Armitage trend tests, and genotype imputation was used for defining the association locus.Results.Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r2= 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2Band FCRLAgenes (p = 3.4 × 10−8). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%).Conclusion.This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLAlocus, which may provide better insights to CYC metabolism and efficacy.

Objective.Rheumatoid arthritis (RA) is a chronic autoimmune disease that is often painful and debilitating. Patients with RA are increasingly receiving complementary and alternative medicine (CAM). We aimed to identify the patient characteristics and disease-specific factors associated with Korean patients with RA who decide to start treatment with CAM.Methods.Among the total 5371 patients with RA in the KORean Observational study Network for Arthritis (KORONA), 2175 patients who had no experience with CAM were included in our study. In our study, we assessed the frequency of new incident CAM use, its patterns, and the predictive factors of new CAM use.Results.Of the 2175 patients, 229 patients (10.5%) newly started receiving CAM within a year of enrolling in the cohort. Of those who started treatment with CAM, 17.0% received only herbal medicine, 54.6% only acupuncture treatments (7.0% used a combination of both), and 21.4% “Other” (e.g., physical therapy and placental extract injections). Women (OR 1.89, 95% CI 1.13–3.14) and patients with depression (OR 3.52, 95% CI 1.65–7.50) were significantly more likely to be treated with CAM. Regarding household types, patients who lived in an extended family (OR 1.78, 95% CI 1.08–2.95) or as part of a couple (OR 1.55, 95% CI 1.07–2.24) were more likely to be treated with CAM than patients living in a nuclear family.Conclusion.Our study found, within a year, an incidence rate of 10.5% for new CAM use among patients with no previous experience with CAM. Sex, depression, and household type were significantly associated with new CAM use.

Objective.Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA.Methods.All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression.Results.SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46–0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01.Conclusion.HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.

Objective.Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor in nitric oxide (NO) production. Polymorphisms in the GCH1gene have been implicated in protection against pain sensitivity. The aim of our study was to determine whether single-nucleotide polymorphisms (SNP) in the GCH1gene affect susceptibility and/or pain sensitivity in fibromyalgia syndrome (FM).Methods.A total of 409 patients with FM and 422 controls were enrolled. The alleles and genotypes at 4 positions [rs3783641(T>A), rs841(C>T), rs752688(C>T), and rs4411417(T>C)] in the GCH1gene were analyzed. The associations of the GCH1SNP with susceptibility and clinical measures in patients with FM were assessed.Results.The frequencies of alleles and genotypes of the 4 SNP did not differ between patients with FM and healthy controls. Among 13 constructed haplotypes, we further examined 4 (CCTT, TTCT, TTCA, and CCTA) with > 1% frequency in both FM and controls. No associations of GCH1polymorphisms with FM-related activity or severity indexes were found, although the number and total score of tender points in patients with FM differed among the 4 haplotypes (p = 0.03 and p = 0.01, respectively). The CCTA haplotype of GCH1was associated with significantly lower pain sensitivity and occurred less frequently than the CCTT haplotype in patients with FM (p = 0.04, OR 0.45, 95% CI 0.21–0.96).Conclusion.Our study provides evidence that certain GCH1haplotypes may be protective against susceptibility and pain sensitivity in FM. Our data suggest that NO is responsible for pain sensitivity in the pathogenesis of FM.

OBJECTIVE: To assess the safety of anti-tumor necrosis factor (TNF-α) therapy in patients with rheumatic diseases in terms of the reactivation of potential hepatitis B virus (HBV) occult infection. METHODS: Patients who had taken anti-TNF-α for the treatment of rheumatic diseases from January 2002 to May 2008 were included in the study. In this patient group, we retrospectively investigated a series of serum aminotransferase levels, HBV serologic status, the type of anti-TNF-α therapy, duration of the anti-TNF-α treatment, and concurrent use of hepatotoxic drugs. RESULTS: A total of 266 cases were documented using 3 serologic markers for HBV infection: HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), and HBV core IgG Ab (HBcAb). Of these, 8 cases had chronic hepatitis B (HBsAg+), 170 cases were HBcAb-negative, and 88 cases were identified as having potential HBV occult infections represented by HBsAg-negative and HBcAb-positive, irrespective of the status of the HBsAb. The frequency of clinically significant (> 2 times normal value) and persistent increase (> 2 consecutive tests) of aminotransferase levels was significantly higher in the group with a potential HBV occult infection compared to the HBcAb-negative group. In the multiple logistic regression analysis controlling for various potential confounding factors such as prophylactic anti-tuberculosis medication, methotrexate, nonsteroidal antiinflammatory drugs, and the type of anti-TNF-α therapy, only potential HBV occult infection was a significant risk factor for abnormal liver function test (LFT). CONCLUSION: All rheumatic patients who plan to take anti-TNF-α treatment should undergo a test for HBV serology, including HBcAb, and have a close followup with an LFT test during therapy. Further prospective studies for hepatitis B viral load using HBV-polymerase chain reaction in patients who are HbcAb positive are needed to identify whether the abnormal LFT comes from the reactivation of occult HBV infection.

OBJECTIVE: To examine whether the high incidence of herpes zoster in patients with systemic lupus erythematosus (SLE) is associated with the frequency of memory T cells specific to varicella zoster virus (VZV). METHODS: Whole blood samples from 47 subjects [24 patients with SLE, 11 with rheumatoid arthritis (RA) as a disease control, and 12 healthy negative controls] were stimulated with VZV antigen, stained for surface CD4 and CD8 and intracellularly stained for the cytokines interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), interleukin 4 (IL-4), and IL-10, followed by flow cytometry analyses. Correlations of VZV-specific T cell frequencies with the clinical status of patients were analyzed. RESULTS: Percentage of IFN-g-positive CD4 T cells was significantly lower in patients with SLE (0.043 ± 0.009%) than in RA (0.102 ± 0.019%) and healthy controls (0.126 ± 0.025%) upon VZV stimulation. A similar pattern was seen in TNF-a-positive CD4 T cell responses. These low frequencies of VZV-specific CD4 T cells in patients with SLE were significantly related with disease activity (r = –0.435, p = 0.043). CONCLUSION: These data suggest that the high incidence of herpes zoster in patients with SLE was related to the intrinsic defects in controlling VZV reactivation, and thus VZV-specific CD4 T cell frequency could be another practical risk factor of herpes zoster in patients with SLE.

OBJECTIVE: Substantial epidemiological and genetic evidence suggests that ankylosing spondylitis (AS) is likely due to an interplay of genetic and environmental factors. Recently, CARD15, located in chromosome 16q12, has been established as a disease susceptibility gene for Crohn's disease, Blau syndrome, and possibly psoriatic arthritis. Association studies in admixed populations from Northern European ancestry noted no such association between CARD15 mutations and AS. However, a homogenous population has yet to be studied. We investigated the prevalence of the 3 common CARD15 variants in a homogenous Korean population with AS. METHODS: All subjects were native Koreans with AS satisfying the modified New York criteria. Korean controls were examined and confirmed to be unaffected by AS. Subjects with AS were genotyped for the R702W, G908R, and Leu1007fsinsC variants of CARD15 using mass array MALDI-TOF mass spectrometry. RESULTS: A total of 205 AS subjects and 200 controls were genotyped. No subject with AS had any variants at the 702 and 1007 sites of CARD15. Only one subject was heterozygous for the 908 variant. The overall genotype frequency in AS for any CARD15 variant was 0.5%. No control had any of the 3 CARD15 variants. CONCLUSION: Our findings indicate that the CARD15 gene is not a major contributor to AS susceptibility in the Korean population.