Eisuke Inoue

Application of moisturizer to neonates prevents development of atopic dermatitis

BACKGROUND Recent studies have suggested that epidermal barrier dysfunction contributes to the development of atopic dermatitis (AD) and other allergic diseases. OBJECTIVE We performed a prospective, randomized controlled trial to investigate whether protecting the skin barrier with a moisturizer during the neonatal period prevents development of AD and allergic sensitization. METHODS An emulsion-type moisturizer was applied daily during the first 32 weeks of life to 59 of 118 neonates at high risk for AD (based on having a parent or sibling with AD) who were enrolled in this study. The onset of AD (eczematous symptoms lasting >4 weeks) and eczema (lasting >2 weeks) was assessed by a dermatology specialist on the basis of the modified Hanifin and Rajka criteria. The primary outcome was the cumulative incidence of AD plus eczema (AD/eczema) at week 32 of life. A secondary outcome, allergic sensitization, was evaluated based on serum levels of allergen-specific IgE determined by using a high-sensitivity allergen microarray of diamond-like carbon-coated chips. RESULTS Approximately 32% fewer neonates who received the moisturizer had AD/eczema by week 32 than control subjects (P = .012, log-rank test). We did not show a statistically significant effect of emollient on allergic sensitization based on the level of IgE antibody against egg white at 0.34 kUA/L CAP-FEIA equivalents. However, the sensitization rate was significantly higher in infants who had AD/eczema than in those who did not (odds ratio, 2.86; 95% CI, 1.22-6.73). CONCLUSION Daily application of moisturizer during the first 32 weeks of life reduces the risk of AD/eczema in infants. Allergic sensitization during this time period is associated with the presence of eczematous skin but not with moisturizer use.

Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA

Objectives: To investigate mortality, cause of death, and risk factors related to mortality in Japanese patients with rheumatoid arthritis (RA). Methods: The IORRA cohort is a large observational cohort established in 2000 at the Institute of Rheumatology, Tokyo Womens Medical University. Essentially, all RA patients were registered and clinical parameters were assessed biannually. For patients who failed to participate in subsequent surveys, simple queries were mailed to confirm survival. Standardized mortality ratios (SMRs) were calculated and mortality risk factors were analysed using a Cox proportional hazard model. Results: We analysed 7926 patients (81.9% females; mean age 56.3 ± 13.1 years; mean disease duration 8.5 ± 8.3 years) with RA who enrolled in IORRA from October 2000 to April 2007. During the observational period (35 443.0 person-years), 289 deaths were reported. Major causes of death included malignancies (24.2%), respiratory involvement (24.2%) including pneumonia (12.1%) and interstitial lung disease (ILD) (11.1%), cerebrovascular disease (8.0%), and myocardial infarction (7.6%). As death was not confirmed in all patients, the SMR was deduced to be between 1.46 [95% confidence interval (CI) 1.32–1.60] and 1.90 (95% CI 1.75–2.07) for all patients, between 1.45 (95% CI 1.22–1.70) and 1.70 (95% CI 1.45–1.97) for men, and between 1.46 (95% CI, 1.29–1.65) and 2.02 (95% CI 1.82–2.24) for women. Factors associated with increased mortality included male gender, older age, worse physical disability, positive rheumatoid factor (RF), corticosteroid use, and presence of ILD. Conclusion: The mortality of Japanese RA patients is comparable to that in previous reports from western countries, even though the causes of death were significantly different.

Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan

Objective: To determine the risk for tuberculosis infection in patients with rheumatoid arthritis before the anti-cytokine era in Japan. Patients and methods: A database of a single-institute-based large observational cohort study for rheumatoid arthritis at the Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, was analysed. Information on the history of tuberculosis infection was collected by patient self-reporting during April and October 2003. The age-adjusted incidence rate and relative risk for tuberculosis infection were investigated. Results: Among 5044 patients with rheumatoid arthritis, 483 (9.6%) patients claimed to have a history of tuberculosis infection before October 2002. The frequency of history of tuberculosis increased according to the age of the patient. Four cases of new-onset tuberculosis were identified among 5544 patients with rheumatoid arthritis during 1 year. The age-adjusted incidence of tuberculosis was 42.4/100 000 patients. The relative risk for tuberculosis was 3.21 (95% confidence interval (CI) 1.21 to 8.55), and that of men and women was 10.59 (95% CI 3.42 to 32.78) and 1.41 (95% CI 0.2 to 10), respectively. Conclusion: There was an increased risk of tuberculosis infection in Japanese patients with rheumatoid arthritis, especially in male patients before the introduction of anti-tumour necrosis factor treatment. These data should form the basis for the risk management of anti-cytokine treatment in Japan.

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.

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 ≥25) using multiple regression analysis. Conclusions Our data suggest that SLC17A1 polymorphisms are associated with the development of gout.

Decrease in orthopaedic operations, including total joint replacements, in patients with rheumatoid arthritis between 2001 and 2007: data from Japanese outpatients in a single institute-based large observational cohort (IORRA)

Several studies from different countries show that the rate of orthopaedic surgery has decreased for patients with rheumatoid arthritis (RA) in recent years. In Sweden, there was a decrease in RA-related lower limb surgical procedures between 1987 and 2001,1 and in RA-related upper limb surgery between 1998 and 2004.2 Denmark has reported a decrease in the incidence of total hip arthroplasties due to RA,3 and the number of total joint replacement (TJR) operations and synovectomies decreased in the Norwegian population from 1994 to 2004.4 Japan has also reported the declining use of synovectomy surgery for patients with RA.5 These changes may reflect trends in disease severity, management and health outcomes in each country. Meanwhile, Sokka et al reported that the rate of TJR …

Efficient management of Rheumatoid Arthritis significantly reduces long-term functional disability

Objectives: The aim of this study was to examine the effect of efficient management of rheumatoid arthritis (RA) in relation to disability levels in a large cohort of patients with RA over a period of 3 years. Methods: We studied 2775 patients with RA who had continuous enrolment for at least 3 years from 7511 patients with RA enrolled in an observational cohort study (Institute of Rheumatology, Rheumatoid Arthritis (IORRA)) from October 2000 to April 2005. The 28-joint Disease Activity Scores (DAS28) were calculated at 6 month intervals for all the patients and a value <2.6 was considered as a tight control. We have set up a new variable for each patient, “Avg-Dscore”, based on the transition of each patient’s DAS28 value, taking the threshold level of 2.6 into consideration. The “Avg-DAS28” is the average of DAS28 values over all the phases. Functional disability status was assessed by J-HAQ, the validated Japanese version of the Health Assessment Questionnaire (HAQ). The relationship of “Avg-Dscore” and “Avg-DAS28” with the functional disability level was determined using Spearman correlation coefficients and multiple linear regression models. Results: The baseline features of these 2775 patients were: female 83.7%, mean age 56.8 years, mean RA duration 9.5 years, mean initial DAS28 4.0, mean initial J-HAQ score 0.79, and mean final J-HAQ score 0.86. There was a statistically significant correlation between “Avg-DAS28” and final J-HAQ score (r = 0.57, p<0.001), indicating that tighter disease control has significant association with lower disability levels. A similar relationship was observed between “Avg-Dscore” and final J-HAQ score (r = 0.47, p<0.001). Multiple linear regression analysis, after adjusting for all the covariates, revealed that “Avg-Dscore” and “Avg-DAS28” were the most significant factors contributing to final J-HAQ score, and confirmed the strong relationship between disease activity and functional disability. Conclusions: In patients with RA efficient disease management, by maintaining the DAS28 values at a level under 2.6, has significant association with improving functional capability. The threshold DAS28 level of 2.6 may be useful in developing targeted treatment guidelines for patients with RA.

Incidence of malignancy in Japanese patients with rheumatoid arthritis

To determine the incidence of malignancy and site-specific malignancies in Japanese patients with rheumatoid arthritis (RA). In a prospective large observational cohort study named IORRA, 7,566 patients with RA were enrolled from April 2001 to April 2005 and were followed up to October 2005. Occurrence of malignancy was originally collected by patient reports of IORRA survey biannually from April 2001 to October 2005, and was confirmed by medical records. Standardized incidence rate (SIR) of the observed-to-expected cancer incidence and 95% confidence intervals (95% CI) were then calculated. Factors obtained at first enrollment in IORRA were assessed for association with risk of malignancy using the Cox proportional hazards model. A total of 177 malignancies in 173 patients (58 in men, 115 in women) were identified during the observation period of 25,567 person-years. The age- and sex-standardized incidence rate of malignancy was 437.1 (men, 706.8; women, 366.1) per 100,000 person-years. The SIR of malignancy was slightly excess (SIR 1.18, [95% CI 1.02–1.37]) in all patients, but 1.29 (95% CI 0.99–1.67) in men, and 1.13 (95% CI 0.94–1.36) in women. A significant excess of lymphoma (SIR 6.07, [95% CI 3.71–9.37]) and lung cancer (SIR 2.29, [95% CI 1.57–3.21]), whereas decreased incidence of colorectal cancer (SIR 0.49, [95% CI 0.26–0.83]), were found. Male gender and older age were identified as risk factors for malignancy. A slight excess in the incidence of overall malignancy and highly excess of lymphoma in Japanese RA patients was demonstrated.

Association between GLUT9 and gout in Japanese men

Recently, the association between single nucleotide polymorphisms (SNPs) in GLUT9 and the serum levels of uric acid (sUA) or gout has been shown in Caucasians.1,–,5 However, the associations have not been replicated in other ethnicities. Here, we report an association between GLUT9 and the development of gout in Japanese men. We isolated genomic DNA from 181 Japanese male patients with gout6 and from 595 Japanese male controls.7 The genotypes of intronic SNPs in GLUT9 (rs1014290, rs6449213, rs7442295, rs6855911, rs737267), previously reported as associated with sUA or gout,1,–,5 and non-synonymous SNPs (rs1680979, rs3733591, rs2280205) were determined using the TaqMan method (Applied Biosystems, Foster City, California, USA). Statistical analysis was made by χ2 test, …

PADI4 and HLA-DRB1 Are Genetic Risks for Radiographic Progression in RA Patients, Independent of ACPA Status: Results from the IORRA Cohort Study

Introduction Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA. Methods Sharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset. Results The number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02). Conclusions In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.