Incidence of herpes zoster in Japanese patients with rheumatoid arthritis from 2005 to 2010.

OBJECTIVE: To clarify the incidence and the risks of herpes zoster infection in Japanese patients with rheumatoid arthritis (RA). METHODS: By using a self-report of occurrence of herpes zoster in patients with RA in a large observational cohort study from 2005 to 2010, the standardized incidence rate was calculated. A Cox model was used to analyze risk factors for occurrence of herpes zoster. RESULTS: A total of 7,986 patients (female 83.1%) accumulated 30,140 patient-years of observation, and 366 events were confirmed. The standardized incidence rate per 1,000 patient-years was 9.1 (95% confidence interval (CI) 6.2-12.9) in total, 7.8 (3.6-14.8) in men, and 10.3 (6.8-15.0) in women. The risk factors for herpes zoster were age [/10 years: Hazard ratio (HR) 1.268, 95% CI 1.153-1.393, p < 0.0001), high disease activity compared with remission (HR 1.642, 95% CI 1.067-2.528, p < 0.05), prednisolone (< 5 mg/day compared with 0 mg/day: HR 1.531, 95% CI 1.211-1.936, p < 0.001; ≥ 5 mg/day compared with 0 mg/day: HR 1.471, 95% CI 1.034-2.093, p < 0.05), and methotrexate (HR 1.382, 95% CI 1.076-1.774, p < 0.05). CONCLUSION: This study quantified the historical incidence and risk for herpes zoster in Japanese RA patients, and is a benchmark for future studies.

Effect of genetic polymorphisms on development of gout.

OBJECTIVE: To validate the association between genetic polymorphisms and gout in Japanese patients, and to investigate the cumulative effects of multiple genetic factors on the development of gout. METHODS: Subjects were 153 Japanese male patients with gout and 532 male controls. The genotypes of 11 polymorphisms in the 10 genes that have been indicated to be associated with serum uric acid levels or gout were determined. The cumulative effects of the genetic polymorphisms were investigated using a weighted genotype risk score (wGRS) based on the number of risk alleles and the OR for gout. A model to discriminate between patients with gout and controls was constructed by incorporating the wGRS and clinical factors. C statistics method was applied to evaluate the capability of the model to discriminate gout patients from controls. RESULTS: Seven polymorphisms were shown to be associated with gout. The mean wGRS was significantly higher in patients with gout (15.2 ± 2.01) compared to controls (13.4 ± 2.10; p < 0.0001). The C statistic for the model using genetic information alone was 0.72, while the C statistic was 0.81 for the full model that incorporated all genetic and clinical factors. CONCLUSION: Accumulation of multiple genetic factors is associated with the development of gout. A prediction model for gout that incorporates genetic and clinical factors may be useful for identifying individuals who are at risk of gout.

Two young-adult female cases of dermatomyositis with antibodies for transcriptional intermediary factor 1-γ.

A variety of myositis-specific autoantibodies (MSAs) have been detected in patients with dermatomyositis (DM). We analyzed MSAs in 20 cases with DM. Eleven of the 20 cases were positive. Out of those 11 cases, 3 were positive for antibodies against aminoacyl-tRNA synthetase and 3 had antibodies to anti-melanoma differentiation-associated gene 5 detected using an immunoprecipitation assay and/or a specific enzyme-linked immunosorbent assay. One case had anti-NXP-2 antibodies and 4 cases had anti-transcriptional intermediary factor 1 (TIF1)-α/γ antibodies detected by immunoprecipitation and Western blotting. Two of those 4 cases had antibodies for both TIF1-α and TIF1-γ, and the 2 other cases had antibodies for TIF1-γ alone. We report the 2 cases with antibodies for TIF1-γ only, who were young-adult females without an internal malignancy or interstitial pneumonia. Those 2 cases had clinically amyopathic DM. Among DM patients with antibodies against TIF1 family proteins, there seems to be a subgroup of young-adult cases who have clinically amyopathic DM and show good prognosis without malignancy.

Incidence of serious respiratory infections in patients with rheumatoid arthritis treated with tocilizumab.

We aimed to demonstrate the incidence of serious respiratory infections in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) monotherapy. We analyzed the incidence of serious respiratory infections in 601 RA patients enrolled in TCZ clinical trials and their extension studies (TCZ cohort) and in 601 age- and sex-standardized RA patients treated in daily clinical practice at Tokyo Women's Medical University (IORRA subsample cohort). The rates of serious respiratory infections were 1.77 per 100 patient-years from 1999 to 2008 in the TCZ cohort and 0.53 per 100 patient-years from 2000 to 2009 in the IORRA subsample cohort. With the IORRA subsample cohort regarded as a standard population, the standardized incidence ratio (SIR) of serious respiratory infection in the TCZ cohort was 3.64 [95% confidence interval (CI) 2.56-5.01], standardized for age and sex; 2.35 (95% CI 1.66-3.24), standardized for age sex, and corticosteroid use; 1.85 (95% CI 1.30-2.55), standardized for age sex, and pre-existing pulmonary involvement; and 2.41 (95% CI 1.68-3.34) standardized for age sex, and disease activity. The risk of serious respiratory infection in the TCZ cohort was approximately double that in the IORRA subsample cohort after standardizing for corticosteroid use, pre-existing pulmonary involvement, or disease activity. This is comparable to the risk reported when tumor necrosis factor (TNF) inhibitors are used.

Comorbidities in patients with gout.

Gout is one of the most important diseases associated with hyperuricemia. Gout is characterized by acute monoarthritis with frequent flares. Some patients with gout have gouty tophi that are composed of monosodium urate crystals and inflammatory cells. In addition to tophi, gout is associated with various comorbidities such as obesity, hypertension, abnormal lipid metabolism, renal dysfunction, and urolithiasis. We examined the associations of the presence of tophi and comorbidities with demographic and disease characteristic data of gout patients. Subjects were 422 male patients with gout who visited our outpatient clinic. The patients' background data and laboratory data at the first visit were collected from patient records. We investigated the relationship between comorbidities and characteristics of patients using multiple regression models. The age of gout onset was 44 ± 13 years. The duration of gout at the first visit was 6 ± 8 years. Five percent of subjects had tophi. The presence of tophi was significantly associated with the duration of gout and maximum serum uric acid (SUA), indicating a close association of tophi with urate deposition. Reduced estimated glomerular filtration rate was associated with older age of onset, longer duration of gout, and higher levels of maximum SUA, indicating that sustained hyperuricemia relates with renal impairment of gout. Urolithiasis did not associate with gout duration and maximum SUA. The increased frequency of hypertension was associated with the duration of gout, suggesting that poor control of gout is one of the causes of hypertension. This study provides useful information for gout management and patient education.

Functional analysis of human sodium-phosphate transporter 4 (NPT4/SLC17A3) polymorphisms.

We analyzed the functional properties of five nonsynonymous single nucleotide polymorphisms (SNPs) in the sodium-phosphate transporter NPT4 gene (SLC17A3) using the Xenopus oocyte expression system. NPT4 variants carrying SNP V257F, G279R, or P378L exhibited reduced transport of [(14)C]para-aminohippurate, [(3)H]bumetanide, [(3)H]estrone sulfate, and [(14)C]urate, when each variant clone was expressed in the plasma membrane of oocytes. This study suggests the possibility that the genetic variation of NPT4 contributes to inter-individual differences in disposition of anionic drugs such as diuretics as well as certain endogenous organic anions such as urate.

Functional Analysis of Human Sodium-Phosphate Transporter 4 (NPT4/SLC17A3) Polymorphisms.

We analyzed the functional properties of five nonsynonymous single nucleotide polymorphisms (SNPs) in the sodium-phosphate transporter NPT4 gene (SLC17A3) using the Xenopus oocyte expression system. NPT4 variants carrying SNP V257F, G279R, or P378L exhibited reduced transport of [14C]para-aminohippurate, [3H]bumetanide, [3H]estrone sulfate, and [14C]urate, when each variant clone was expressed in the plasma membrane of oocytes. This study suggests the possibility that the genetic variation of NPT4 contributes to inter-individual differences in disposition of anionic drugs such as diuretics as well as certain endogenous organic anions such as urate.

Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate.

The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4.

Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout.

OBJECTIVES: Molecular biological approaches have recently identified urate transporters in renal proximal tubular cells. Human sodium-dependent phosphate cotransporter type 1 encoded by SLC17A1 is a urate transporter localised to the renal proximal tubular cells and candidate molecule to secret urate from renal tubular cells to urine. This study investigated the roles of SLC17A1 in the development of gout. PATIENTS AND METHODS: Single nucleotide polymorphisms in the human SLC17A1 gene (rs1165176, rs1165151, rs1165153, rs1165196, rs1165209, rs1165215, rs1179086, rs3799344 and rs3757131) were selected, and an association study was conducted using male patients with gout (n=175) and male controls (n=595). RESULTS: There were significant differences between gout and control groups in the distribution of genotypes at rs1165196 (T806C; Ile269Thr, odds ratio (OR) 0.55, p=0.0035), rs1179086 (OR 0.57, p=0.0018) and rs3757131 (OR 0.54, p=0.0026). In controls, T806C alone had no effect on serum uric acid (sUA) levels. However, T806C showed significant interaction with a reduction of sUA in obese individuals (body mass index > or = 25) using multiple regression analysis. CONCLUSIONS: Our data suggest that SLC17A1 polymorphisms are associated with the development of gout.

Associations between methotrexate treatment and methylenetetrahydrofolate reductase gene polymorphisms with incident fractures in Japanese female rheumatoid arthritis patients.

Several case reports have described associations between pathological nonvertebral fractures and low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. Furthermore, a significant association between the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene and incident fractures has been reported in postmenopausal women. We attempted to determine whether MTX use and MTHFR polymorphisms are associated with incident fracture risk in Japanese female RA patients. DNA samples, laboratory data, and clinical data were obtained from 731 female RA patients more than 50 years old as part of the Institute of Rheumatology Rheumatoid Arthritis (IORRA) observational cohort study. Genotyping of the MTHFR polymorphisms C677T and A1298C was performed using TaqMan SNP Genotyping Assays. MTX use, MTHFR polymorphisms, and other potential risk factors predictive of fracture were analyzed by Cox proportional hazards regression models, including time-dependent covariates. During 78 months from October 2000 to March 2007, 25 and 90 patients developed vertebral and nonvertebral fractures, respectively. Patients with nonvertebral fractures were more likely to take MTX (P = 0.011; odds ratio, 1.77; 95% confidence interval, 1.13-2.76) compared to patients without fractures. Although the C677T and A1298C polymorphisms were not significantly associated with incident fracture risk, MTX use, age, disease duration, and Japanese health assessment questionnaire score were significantly (P < 0.05) and independently associated with nonvertebral fracture incidence. Our results suggest that MTX use is associated with a nonvertebral fracture risk, whereas MTHFR polymorphism status does not appear to be a clinically useful marker for predicting fracture risk in Japanese female RA patients.

Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice.

BACKGROUND: For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized adverse events. METHODS: We conducted retrospective studies to validate our previous three different results about the association between adverse events or efficacy of two different disease-modifying antirheumatic drugs and genomic variations. Association between single nucleotide polymorphisms in N-acetyltransferase 2 gene (NAT2) and adverse events by sulfasalazine and association between C677T or A1298C in 5,10-methylenetetrahydrofolate reductase gene (MTHFR) and responses to methotrexate were examined. RESULTS: Patients without the wild-type haplotype at NAT2 were more likely to suffer from overall adverse events [n=186, P=0.001, relative risk (RR) 3.31, 95% confidence interval (CI) 1.76-6.22] and severe adverse events (P=0.015, RR 24.6, 95% CI 2.37-254.53) by sulfasalazine. Patients with the T allele at C677T in MTHFR were more susceptible to overall adverse events (n=156, P=0.003; RR 2.4, 95% CI 1.29-4.55) while patients with the C allele at A1298C were less likely to be treated with a higher dose (>6 mg/week) of methotrexate in one year of treatment (n=159, P=0.008, RR 1.84, 95% CI 1.12-3.01). In all three association studies, the results were essentially the same as previously reported. CONCLUSION: As three studies on the associations between genomic variations and adverse events or efficacy of two different disease-modifying antirheumatic drugs were replicated, the usefulness of the tests is worth being tested in clinical practice.

[Pharmacogenomics of antirheumatic drugs and personalized medicine for rheumatoid arthritis].

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints. The inflammatory process causes a significant disability and may involve internal organs. The efficacy of disease modifying anti rheumatic drugs is widely accepted. However, the outcome of the treatment with these agents is known to vary among patients. Recently, the pharmacogenomic studies on methotrexate, sulfasalazine and tumor necrosis factor-alpha inhibitors have been reported, suggesting that the pharmacogenomic approach may be useful for the treatment of RA. Although there are points to be considered before the translation of the pharmacogenomic date into clinical practice, pharmacogenomics is considered to be an important tool for development of individualized medicine in the treatment of RA.

Prevalence of Helicobacter pylori infection and risk of upper gastrointestinal ulcer in patients with rheumatoid arthritis in Japan.

We evaluated the prevalence of Helicobacter pylori infection and the association of H. pylori infection and/or nonsteroidal anti-inflammatory drug (NSAID) use with upper gastrointestinal (UGI) ulcers in a cohort of Japanese patients with rheumatoid arthritis (RA). Using the clinical database of the cohort of RA patients and the serum titers of H. pylori antibody, 1815 patients were analyzed. Clinical data were successfully collected for 1529 patients over 2 years, and the history of NSAID use and the occurrence of newly diagnosed UGI ulcer were ascertained by patient self-reports and confirmed by their medical records. A total of 871 patients (49.3%) were H. pylori antibody-positive. Rates of positivity for H. pylori in patients with and without NSAID use were 47.5% and 54.7%, respectively (odds ratio = 0.75, 95% confidence intervals [CI]: 0.58-0.96). The incidence of newly diagnosed UGI ulcer was 0% in the H. pylori-/NSAID- group, 1.24% in the H. pylori-/NSAID+ group, 1.06% in the H. pylori+/NSAID- group, and 3.46% in the H. pylori+/NSAID+ group. The odds ratios of H. pylori infection and NSAID for the occurrence of new UGI ulcers after adjusting for age and sex were 2.97 (95% CI: 1.19-7.38) and 4.31 (95% CI: 0.57-32.4), respectively. Although the prevalence of H. pylori antibody was low in patients with RA compared with that in healthy Japanese individuals, H. pylori infection was a significant risk factor for UGI ulcer in patients with RA.

Validation of a Japanese version of the Stanford Health Assessment Questionnaire in 3,763 patients with rheumatoid arthritis.

OBJECTIVE: To develop and validate a self-administered instrument for measuring functional status in Japanese-speaking rheumatoid arthritis patients. METHODS: We translated the Stanford Health Assessment Questionnaire (HAQ) into Japanese (original HAQ), and then made a tentative Japanese version of the HAQ (J-HAQ) with culturally appropriate modifications of the arising, eating, and reach category questions. The questionnaire was then administered to 3,763 RA patients (82.6% female; mean age 58.0 years; mean onset age 47.4 years; mean disease duration 10.5 years). RESULTS: This instrument showed excellent internal reliability (Cronbach's alpha = 0.927), with a mean interitem correlation of 0.60. For the arising category question, the J-HAQ asks about arising from a futon in addition to a bed because futons are still common in Japanese culture. Arising from a futon is generally more difficult for disabled individuals than is arising from a bed, so the arising score was higher in the J-HAQ (mean score 0.82) than in the original HAQ (0.48). The average scores for the eating and reach categories were virtually identical for the original HAQ and the J-HAQ, with correlation coefficients of 0.979 and 0.926, respectively. Thus, the overall disability index (average of the scores for all functional areas) was higher in the J-HAQ (0.81) than in the original HAQ (0.76), although the correlation coefficient was high (0.993). The test-retest reliability value (0.92), studied at a 1-week interval, revealed identical disability index scores measured on the 2 occasions. CONCLUSION: The final version of the J-HAQ is a valid and reliable instrument for measuring functional status in Japanese-speaking RA patients.

Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene.

OBJECTIVE: N-acetyltransferase 2 (NAT2) is a key enzyme for the acetylation of sulfasalazine (SSZ). We examine whether there was a correlation between diplotype configurations (combinations of 2 haplotypes for a subject) at the NAT2 gene and the adverse effects of SSZ used for the treatment of rheumatoid arthritis (RA). METHODS: The findings from 144 patients with RA who had been treated with SSZ were collected from our outpatient department and used for a retrospective study. Haplotype analysis was performed by the maximum-likelihood estimation based on the EM algorithm using the obtained polymorphism data. RESULTS: Sixteen patients (11.1%) had experienced adverse effects from SSZ, the most common being allergic reactions including rash and fever. The slow acetylators who had no NAT2*4 haplotype had experienced adverse effects more frequently (62.5%) than the fast acetylators who had at least one NAT2*4 haplotype (8.1%) (p < 0.001, OR 7.73, 95% CI 3.54-16.86). In 25% of the slow acetylators, the adverse effects were so severe that they were hospitalized. CONCLUSION: Genotyping the NAT2 gene followed by estimation of diplotype configuration before administration of SSZ is likely to reduce the frequency of adverse effects in Japanese patients with RA.

The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis.

OBJECTIVE: To clarify the mechanism of decreased serum uric acid (SUA) concentrations during acute gouty arthritis. METHODS: Data from patients with acute gouty arthritis during and after an attack were investigated retrospectively. Other investigations, including changes in urinary excretion and biochemical markers, were performed prospectively. RESULTS: SUA was significantly lower in the acute phase (7.5 +/- 1.4 mg/dl) than in the intercritical phase (8.5 +/- 0.9 mg/dl) (p < 0.0001). During the acute gout phase, a normal SUA level was found in 20 of 41 patients (49%). C-reactive protein (CRP) during acute attacks was significantly correlated with plasma interleukin 6 (IL-6) and cortisol (r = 0.645, p < 0.005; r = 0.460, p < 0.05). Percentage change in SUA at onset of attack correlated with CRP and IL-6 (r = 0.762, p < 0.0001; r = 0.630, p < 0.005), as well as with increased urinary excretion of uric acid, estimated by percentage change in fractional excretion of uric acid (FEua) during attack (r = 0.447, p < 0.05). Further, change in FEua was correlated with plasma cortisol levels during the acute attack (r = 0.534, p < 0.05). CONCLUSION: Decrease in SUA during acute gouty arthritis is associated with increased urinary excretion of uric acid; an inflammatory process may play a role in the mechanism.

Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses.

5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.