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Context: We have previously reported that a specific "AGATC" haplotype in a >34 kb tight linkage disequilibrium (LD) block within ESR1 is strongly associated with cryptorchidism and hypospadias in Japanese boys., Objective: We aimed to determine the true susceptibility factor for cryptorchidism and hypospadias linked to the "AGATC" haplotype., Methods: We performed various molecular studies in hitherto unreported 230 Italian boys (80 with cryptorchidism and 150 with normal genitalia) and previously reported and newly recruited 415 Japanese boys (149 with cryptorchidism, 141 with hypospadias, and 125 with normal genitalia). We also performed ESR1 expression analyses using breast cancer-derived MCF-7 cells., Results: Haplotype analysis revealed the LD block and positive association of the "AGATC" haplotype with cryptorchidism in Italian boys. Whole genome sequencing identified an identical 2249-bp microdeletion (ΔESR1) generated by a microhomology-mediated replication error in both Japanese and Italian boys with the specific haplotype. ΔESR1 was found to be strongly associated with cryptorchidism and hypospadias by Cochran-Armitage trend test and was revealed to show nearly absolute LD with the "AGATC" haplotype. ESR1 expression was upregulated in MCF-7 cells with a homozygous deletion encompassing ΔESR1 and those with a homozygous deletion involving a CTCF-binding site within ΔESR1., Conclusion: The results reveal that ΔESR1, which has been registered as "DEL_6_75504" in gnomAD SVs v2.1, is the true susceptibility factor for cryptorchidism and hypospadias. It appears that ΔESR1 was produced in a single ancestral founder of modern humans and has been maintained within the genome of multiple ethnic groups by selection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach., Methods: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations., Results: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day., Conclusion: Tacrolimus is effective with acceptable safety in the management of RA.

Objective: Patients' values and preferences are among the key factors that determine the strength of recommendations presented in clinical practice guidelines (CPG). The aim of this study was to summarize the integration process for patients' perceptions into the development of CPG for rheumatoid arthritis (RA) management in Japan., Methods: We used a mixed-methods approach. Questionnaires that could be self-administered were mailed to 2222 RA patients randomly selected from the Japan Rheumatism Friendship Association (JRFA) membership list that was age- and prefecture-stratified. A focus group with five JRFA executive members was formed to verify the results of the questionnaire., Results: A total of 1470 patients aged 20-79 years old returned the questionnaire. Analysis of the questionnaire data revealed that the topics selected by the CPG task force met the patients' needs. The focus group participants showed reluctance to use the term 'preference' because patients would not want to take any medications but would have to take them out of necessity., Conclusions: We confirmed that the new CPG successfully addressed clinical issues that were important to both rheumatologists and patients. Clinicians should understand patients' reluctance to take medications and explain the role of each medication well to increase adherence.

Objectives: To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan., Methods: The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients., Results: Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined., Conclusions: Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.

Objectives: To evaluate, through a systematic review of the literature, the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and surgical site infection (SSI) or wound healing delay after orthopedic surgery in patients with rheumatoid arthritis (RA)., Methods: A systematic review of articles indexed in the Cochrane Library, PubMed, and Web of Science from 1992 to 2012 was performed. The search aimed to identify studies describing SSI or wound healing delay in patients with RA treated with or without bDMARDs. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality was appraised., Results: There was no Cochrane review on this subject. We found 75 articles through specific searches of PubMed and Web of Science, and hand searching. After inclusion and exclusion by full-text review, 10 articles were found for SSI, and 5 articles for delayed wound healing. The use of bDMARDs appeared to increase the rate of SSI slightly, especially in large joint-replacement surgery. Delayed wound healing was not increased by the use of bDMARDs. However, the definitions of SSI and delayed wound healing varied between the reviewed articles. Most of the articles focused on tumor necrosis factor-α inhibitors., Conclusion: bDMARDs slightly increase the relative risk of SSI but not that of delayed wound healing after orthopedic surgery and should be used with appropriate caution.

Objective. To re-evaluate the roles of HLA-DRB1 alleles in susceptibility to SLE and RA and their effects on autoantibody status in large-scale Japanese cohorts. Methods. A total of 656 SLE, 2410 RA and 911 control subjects, who were all Japanese, were genotyped for HLA-DRB1 alleles using sequence-specific oligonucleotide probes. The association of alleles with disease susceptibility was tested by logistic regression analysis and by the relative predispositional effect method. The association with autoantibody status was examined by the standard χ(2) test. Results. HLA-DRB1*15:01, *09:01, *08:02 and *04:01 were significantly associated with SLE susceptibility, while shared epitope (SE) alleles and DRB1*09:01 were associated with RA susceptibility. The compound heterozygote of DRB1*09:01/*15:01 conferred an increased risk for SLE compared with the homozygotes for DRB1*09:01 and *15:01 and was associated with earlier onset of disease, whereas the compound effect of DRB1-SE/*09:01 was not clear in RA. DRB1*09:01 was significantly associated with the appearance of anti-Sm antibody in SLE as well as ACPA in RA, while protectively associated with anti-dsDNA antibody in SLE. No significant interaction was observed between DRB1*09:01 and smoking status for the appearance of ACPA, unlike that observed in SE alleles in RA. Conclusion. We identified HLA-DRB1 alleles associated with SLE and RA in a Japanese population and demonstrated a shared susceptibility of DRB1*09:01 between the diseases as well as its effect on autoantibody production.

Background: A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohn's disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations., Methods: We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran-Armitage trend test. In addition, genotype-phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification., Results: Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype-phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes., Conclusions: Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.

Background: Although several direct-acting antivirals (DAAs) are now available, the therapy regimen for chronic hepatitis C will continue to include pegylated interferon and ribavirin for the foreseeable future. Despite their improved rate of sustained virological response (SVR), DAAs pose increased risks of side effects and selection for antiviral resistance. Not all patients require DAA to achieve SVR, whereas others are unlikely to respond even to triple therapy. Therefore, a personalized approach to candidate selection is necessary., Methods: In this retrospective study, data from 640 Japanese patients who were treated for chronic hepatitis C genotype 1, 2, or 3 with pegylated interferon plus ribavirin combination therapy was compiled to identify robust pretreatment predictive factors for SVR., Results: A logistic regression model for personalized therapy was developed based on age, viral genotype, initial viral load, aspartate aminotransferase/alanine aminotransferase ratio, α-fetoprotein levels, and IL28B single-nucleotide polymorphism genotype. The area under the receiver-operating characteristic curve (AUC) was 0.85. The mean AUC following 10 rounds of 10-fold cross validation was 0.82, with a true positive rate of 78.2%., Conclusions: A personalized approach to therapy may better inform treatment decisions and reduce incidence of side effects and antiviral resistance.

Background: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies., Methods: We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects., Results: We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R., Conclusions: These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: We aimed to identify disease-predisposing variations with nevirapine-induced rash using genome-wide single-nucleotide polymorphisms (SNPs) as genetic markers., Methods: A genome-wide association study (GWAS) was performed using ∼550000 markers in 72 human immunodeficiency virus (HIV)-infected Thai patients with nevirapine-induced rash and 77 nevirapine-tolerant patients, and then candidate SNPs were further evaluated in a replication set (88 patients with nevirapine-induced rash and 145 nevirapine-tolerant patients)., Results: The genome-wide association analysis and replication studies of candidate SNPs identified significant associations of nevirapine-induced rash with 2 SNPs (rs1265112 and rs746647) within CCHCR1 on chromosome 6p21.3 (P(GWAS) = 1.6 × 10(-4); P(replication) = 2.6 × 10(-5); P(combined) = 1.2 × 10(-8)). The odds ratio (OR) of the risk genotypes under a dominant model was 4.36 (95% confidence interval [CI], 2.58-7.36). The noncoding SNPs rs1265112 and rs746647 were in complete linkage disequilibrium with the nonsynonymous SNP rs1576 (r(2) = 1.00), which has been associated with psoriasis. The logistic regression analysis also indicated genetic variations in CCHCR1 to be significantly associated with rash, with an OR of 2.59 (95% CI, 1.82-3.68; P = .007). The receiver operating characteristic curve showed that the algorithm had an area under the curve of 76.4%, which was developed with 5 factors: rs1576*G status, HLA-B*3505 status, not receiving prescribed lead-in of nevirapine, history of drug allergy, and CD4 cell count prior to the nevirapine treatment., Conclusions: We demonstrated that genetic variations in CCHCR1 are strongly associated with nevirapine-induced rash. A predictive model that includes genetic and clinical risk factors for nevirapine-associated rash might be useful in lowering the incidence of rash associated with nevirapine initiation among HIV-infected patients.

Background: Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent., Methods: We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins., Results: Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes., Conclusions: Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.

Interstitial lung disease (ILD) is a frequently encountered and sometimes life-threatening complication among patients with rheumatoid arthritis (RA). In this study, we aim to clarify the incidence of and risk factors for ILD using a large observational cohort of RA patients. We analyzed the database from a large observational cohort of Japanese RA patients, the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. We defined as interstitial pneumonia (IP) computed tomography (CT) pattern of nonspecific interstitial pneumonia or diffuse alveolar damage. Newly developed IP was identified from patient reports over 2.5 years (April 2004 to October 2006) and was confirmed by extensive medical record, chest X-ray radiograph, and CT. The raw and age/gender-adjusted incidence of IP were reported. IP risk factors were analyzed using a nested case-control design was employed using conditional logistic regression analysis with a stepwise method. Thirty-seven patients among 5,699 RA patients were diagnosed with newly developed IP, including 18 cases with methotrexate-induced pneumonitis (MTX-IP) and 15 cases with IP associated with RA (RA-IP). The age-adjusted incidence of MTX-IP among total patients, males, and females was 3.775, 6.667, and 1.013 per 1,000 cases, respectively, and of RA-IP among total patients, males, and females was 1.056, 1.452, and 0.677 per 1,000 cases, respectively. Conditional logistic regression analysis after stepwise variable selection identified male gender, increased Japanese version of the Health Assessment Questionnaire (J-HAQ) score, decreased pain visual analog scale (VAS), and elevated erythrocyte sedimentation rate as significant risk factors for MTX-IP, while the only risk factor for RA-IP was male gender. The incidence of and risk factors for IP in RA patients were determined in a large observational cohort of RA patients in Japan.

We examined whether polymorphisms upstream of the TNF-α gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen's score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5'-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen's score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

Lupus profundus is a rare lupus-specific skin lesion with skin biopsies exhibiting lobular lymphocytic infiltration and destruction of subcutaneous fat tissue. In this report, a CT scan was effective in demonstrating both the presence and the extent of inflammation of lupus profundus in two patients with systemic lupus erythematosus (SLE). Case 1 was a 30-year-old woman developing erythema with subcutaneous induration on the upper arms during the quiescent phase of SLE. A skin biopsy confirmed a diagnosis of lupus profundus. A CT scan of the right upper arm demonstrated a high density area (HDA) of the subcutis under the erythema: a finding consistent with lupus profundus. Case 2 was a 28-year-old woman recently diagnosed with SLE. She also developed a skin ulcer on the right hip. A CT scan of the hip revealed an HDA and lipoatrophy of the subcutis around the ulcer: these findings were compatible with lupus profundus. Treatment with high-dose prednisolone improved the illness in the both cases. A CT scan is a useful and convenient imaging modality for confirming the diagnosis of lupus profundus.

We attempted to determine whether the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 (LRP5) gene is associated with a risk of self-reported incident fractures and hypercholesterolemia in Japanese patients with rheumatoid arthritis (RA). DNA samples, laboratory data, and clinical data were obtained from 563 female RA patients who participated in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) observational cohort study. A1330V genotyping was performed using a custom TaqMan assay. Multiple logistic regression analyses showed that any incident fracture was significantly associated with older age (P = 0.000000036), high Japanese Health Assessment Questionnaire (J-HAQ) score (P = 0.016), and high daily prednisolone dose (P = 0.031), but not with the A1330V polymorphism, while serum total cholesterol levels >or=220 mg/100 mL were independently correlated with baseline older age (P = 0.00011), low J-HAQ score (P = 0.0098), high body mass index (P = 0.024), 1330VV genotype (P = 0.027), and high daily prednisolone dose (P = 0.031). Our results suggest that this LPR5 polymorphism does not appear to be a clinically useful marker for the prediction of fracture risk in Japanese female RA patients, although it is associated with increased serum total cholesterol levels.

We examined whether polymorphisms upstream of the TNF-alpha gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen's score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5'-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen's score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

Kohamaic acid A is a potent DNA polymerase inhibitor isolated from the Okinawan marine sponge Ircinia sp. A series of structurally simplified analogs of kohamaic acid A were synthesized with the aim of evaluating structure-activity relationships.

Objective: Corticosteroids constitute one of the most common treatments of RA. The purpose of this study is to investigate whether long-term corticosteroid use suppresses the progression of disability in RA patients with low disease activity state., Methods: Data collected from a large observational cohort of RA patients at our institution were analysed for 214 RA patients whose disease activity score (DAS) 28 and HAQ were available consecutively from October 2000 to October 2004. All 214 patients had average DAS 28 <3.2, meaning only those who had well-controlled RA disease activity were chosen as subjects. The subjects were divided into steroid users who received continuous corticosteroids every month and non-steroid users who did not receive consecutive corticosteroids continuously every month., Results: Fifty-five patients (25.7%) were corticosteroid users and 159 (74.3%) were non-users. Average prednisolone for the former group was 4.2 mg/day. No significant differences were observed among baseline variables and RA disease activity variables. However, for steroid users, HAQ progressively worsened with time and for non-steroid users, HAQ progressively improved., Conclusions: Although DAS 28 and other variables may suggest well-controlled RA disease activity, functional capacity of patients on low-dose corticosteroids deteriorated. Thus, low disease activity state with corticosteroid may not represent the 'true' low disease activity state. Along with the achievement of a low disease activity state, long-term efficacy, prognosis, and the quality of remission need to be also considered in the tight control of RA activity.

Objectives: To investigate the association between single-nucleotide polymorphisms (SNPs) in the pulmonary surfactant protein (SP) genes and the presence or absence of interstitial lung disease (ILD) in SSc patients., Methods: We studied 127 Japanese patients with SSc and 206 normal subjects. Investigated SNPs were C/T within amino acid (aa) 219, Arg219Trp in the SP-A1 gene (rs4253527), C/T within aa 131 (at nucleotide 1580) and Thr131Ile of the SP-B gene (rs1130866). Genotypes were determined by the TaqMan method., Results: Genotype frequencies were not different between the SSc patients and normal controls for both loci. The patients were subsequently divided into two groups based on presence or absence of ILD. In the SNP in the SP-B gene, the frequency of the T/T genotype was significantly lower in the patients with ILD than in those without ILD. Limited in the patients who were positive for anti-Scl-70 antibody, the difference in the frequency of the T/T genotype between the ILD-positive and ILD-negative groups became more apparent. On the other hand, in the SNP in the SP-A1 gene, there was no significant skewing for a certain genotype., Conclusion: In SSc, where massive fibrosis occurs, possession of the T/T genotype in the SP-B gene would reduce the risk of ILD in Japanese.

The current study investigates the role of regulatory T (Treg) cells in the pathogenesis of ocular attack in patients with Behcet's disease (BD). Nineteen BD patients with ocular complications (BDo), including 11 BD patients with ocular attack (BDa) and eight BD patients with inactive ocular complications (BDi), were studied. Four BD patients without ocular complications (BDwo) were also evaluated as controls. All patients were prospectively followed by our outpatient clinic between autumn 2004 and spring 2005. CD4+ CD25+bright T cells (Treg cells) from peripheral blood were measured by flow cytometry. The percentages of Treg cells in CD4+ T cells from BDo were significantly decreased before ocular attack compared with those after ocular attack. Moreover, surprisingly, these levels before attack were significantly lower than normal level, whereas the percentages of Treg cells in both BDi and BDwo patients were normal. Treg cells were significantly decreased in BDa before active ocular attack. These findings suggest that Treg cells play an important role in ocular attack in BD patients. In addition, decreased percentages of Treg cells may be a predictive marker of ocular attack in BD patients allowing treatment of BD patients before an ocular attack.

Fasciitis panniculitis syndrome (FPS) has been proposed as a new category of 'fasciitis' and includes the well-established eosinophilic fasciitis (EF). Unlike EF, FPS exhibits inconsistent eosinophilia and/or eosinophilic infiltration of the lesions. Principal histological FPS findings include dermal thickening, inflammation and thickening of the subcutaneous fat tissue, fibrous thickening of the fascia and inflammation of the adjacent muscle. FPS is commonly resistant to corticosteroids, and cimetidine is effective in approximately 80% of FPS patients. A new therapy for FPS is required for cases refractory to treatment or intolerant to cimetidine because of adverse drug reaction. In this report, two FPS patients were resistant to corticosteroids. Both received intravenous cyclophosphamide (IVCY) concomitant with moderate- to high-dose prednisolone (PSL), and this effectively treated the induration of the FPS lesions. Patient 1 was a 50-year-old woman who had been diagnosed with fasciitis following en bloc muscle biopsy of the thigh. She had been treated with high-dose PSL for 6 years, but the fasciitis was refractory. Induration of the neck, thorax and thighs resulted in impaired neck rotation, restrictive respiratory failure and impaired walking. A diagnosis of FPS was made by re-assessing the en bloc muscle biopsy. Although PSL (40 mg/day) for 18 days was ineffective, the addition of IVCY (400 mg) dramatically improved the disease manifestations. Patient 2 was a 68-year-old man who was diagnosed with fasciitis based on en bloc muscle biopsy of the left foot. He had been treated with PSL for 16 years, but the fasciitis was refractory. He exhibited lower limb induration and a refractory skin ulcer of the left foot. A diagnosis of FPS was made by re-assessing the en bloc muscle biopsy. Although PSL (40 mg/day) for 2 weeks was ineffective, the addition of IVCY (450 mg) improved both the lower limb induration and the skin ulcer. FPS may cause both entrapment vasculopathy of subcutis and perivasculitis of the subcutaneous fat tissue such that the skin ulcer might be closely related with the ischemic mechanism triggered by FPS. According to the clinical courses of our cases, IVCY combined with moderate- to high-dose PSL may be a new therapeutic choice for corticosteroid-resistant FPS patients.

We report on three Japanese patients (two families) with familial Mediterranean fever (FMF), a rare disease in the Far East. Two of the patients (siblings with definite FMF) were heterozygous for both E148Q and M694I, and the remaining patient (with probable FMF and no family history of the disease) was heterozygous for both P369S and R408Q. Although the M694I mutation is less common among Mediterranean populations, it was present in 22 (76%) of 29 Japanese patients with FMF (previously reported cases). We therefore investigated the allele frequency of M694I in the healthy Japanese population, as well as other FMF-causing mutations in exon 10 (M680I, M694V, and V726A) and polymorphisms (E148Q, P369S, and R408Q) of the Mediterranean fever gene (MEFV). The allele frequencies of disease-causing mutations, even M694I, were <0.001. While those of E148Q, P369S, and R408Q were 0.23, 0.057, and 0.054, respectively. Because of the low allele frequencies of disease-causing mutations, FMF is an extremely rare disease among Japanese individuals. However, FMF is an important component of hereditary autoinflammatory syndrome, and a diagnosis of FMF is crucial for the choice of treatment, because of the benefit of colchicine therapy.

Objective: A bi-allelic polymorphism on the promoter region, -1612 ins/del A, was found to influence the production of MMP-3. Since MMP-3 plays a particularly pivotal role in joint destruction, the MMP-3 gene is thought to be an interesting target gene of disease severity in RA. We attempt to determine whether the MMP-3 promoter polymorphism is associated with serum titre of MMP-3, disease activity and severity in Japanese RA patients., Methods: DNA samples were obtained from 1504 RA patients as part of the Institute of Rheumatology Rheumatoid Arthritis observational cohort study. From the 2006 spring data, serum MMP-3 levels of 820 patients were available by enzyme immunoassay. Joint damage score at 5-yr disease duration could be measured using the Sharp/van der Heijde method in 162 patients. Genotyping of -1612 ins/del A was performed using fluorescent-labelled fragment analysis. Differences in serum MMP-3 level and joint damage score among genotypes of -1612 ins/del A polymorphism were analysed by linear regression analysis., Results: No significant differences were found among MMP-3 genotypes on patient characteristics including disease activity score (P = 0.51) or health assessment questionnaire (P = 0.99). A significant effect of risk allele on serum MMP-3 level was observed (P = 0.038), while no significant effect was observed on radiographic joint damage (P = 0.47)., Conclusion: We conclude that MMP-3 functional polymorphism is associated with serum MMP-3 titre, but is not a direct predictor for outcome measures in Japanese RA patients.

Objectives: To examine whether a seasonal fluctuation exists with rheumatoid arthritis (RA) activity and to analyse seasonal effects of varying components that express disease activity in RA patients., Methods: A group of 1665 RA patients (mean age 57.2 yrs, mean disease duration 9.9 yrs) whose data were available for 10 consecutive phases from a large observational cohort study conducted at our institution from October 2000 to April 2005, bi-annually, were evaluated. Ten criteria were analysed to assess RA disease activity., Results: All criteria revealed decrease in disease activity during fall and increase in disease activity during spring, except for the physician's global assessment of disease activity in which significant differences were not observed between the two seasons., Conclusions: We found definite seasonal differences in RA patients, both subjectively and objectively. RA disease activity was higher in spring and lower during fall. Seasonal changes may play an important role in evaluating disease activity of RA patients and should be taken into account when examining these patients.

Background: We have recently suggested that homozygosity for a specific 'AGATA' haplotype within a approximately 50 kb linkage disequilibrium (LD) block of the gene for estrogen receptor alpha (ESR1) may raise the susceptibility to cryptorchidism by enhancing estrogenic effects of environmental endocrine disruptors (EEDs)., Methods: Haplotype analysis of ESR1 was performed in 328 Japanese subjects, i.e. 70 patients with micropenis (MP), 43 patients with hypospadias (HS), 80 patients with spermatogenic failure (SF) and 135 control males. Genotyping was performed by the 5' nuclease assay., Results: The LD block was identified in each of the patient groups and in the control males. The frequency of homozygotes for the specific 'AGATA' haplotype was markedly higher in the HS patients [P = 0.0000033, odds ratio [OR] = 11.26] and slightly higher in the MP patients (P = 0.034, OR = 3.64) than in the control males, and the 'AGATA' haplotype was strongly associated with HS (P = 0.0000022, OR = 11.26) and weakly associated with MP (P = 0.040, OR = 3.64) in a recessive mode. There was no significant difference between the SF patients and the control males., Conclusions: Our results support the hypothesis that homozygosity for the specific ESR1 'AGATA' haplotype may increase the susceptibility to the development of male genital abnormalities in response to estrogenic EEDs.

Context: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear., Objective: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs)., Design and Setting: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P < or = 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied., Patients: Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); n = 711) were recruited for this study., Results: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77-30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides., Conclusions: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

Motivation: The Invader assay is a fluorescence-based high-throughput genotyping technology. If the output data from the Invader assay were classified automatically, then genotypes for individuals would be determined efficiently. However, existing classification methods do not necessarily yield results with the same accuracy as can be achieved by technicians. Our clustering algorithm, Genocluster, is intended to increase the proportion of data points that need not be manually corrected by technicians., Results: Genocluster worked well even when the number of clusters was unknown in advance and when there were only a few points in a cluster. The use of Genocluster enabled us to achieve an acceptance rate (proportion of assay results that did not need to be corrected by expert technicians) of 84.4% and a proportion of uncorrected points of 95.8%, as determined using the data from over 31 million points., Availability: Information for obtaining the executable code, example data and example analysis are available at http://www.genstat.net/genocluster.

We evaluated the effects of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on endoscopic and histological findings in patients with rheumatoid arthritis (RA) before and after the eradication of Helicobacter pylori infection. Helicobacter pylori (H. pylori) eradication using lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week was conducted in 44 patients (mean age: 56.5 years) with RA. Using the updated Sydney system, endoscopic and histological findings of the greater curvature of the antrum, the greater curvature of the upper corpus, and the lesser curvature of the lower corpus were compared before and after eradication, for a mean follow-up period of 3.5 months. Overall, H. pylori eradication was successful in 32 patients (72.7%). Of these 32 patients, 23 were NSAID users. In the successful eradication group, (1) there was no significant change on endoscopic findings, including gastric erythema and erosion in all three regions irrespective of NSAIDs use; (2) of 17 active ulcers before eradication in NSAIDs users, all healed except for one duodenal ulcer that persisted, where one patient newly developed a gastric ulcer, one developed erosive duodenitis, and two developed reflux esophagitis, all in NSAID users; (3) neutrophil infiltration and chronic inflammation were significantly improved in all three regions after H. pylori eradication irrespective of use of NSAIDs, while atrophic change and intestinal metaplasia did not change. In the eradication failure group; (1) there was no significant change on endoscopic and histological findings in the three regions; (2) two of three ulcers present before eradication on NSAID users persisted even after eradication, and no new cases of gastric ulcer or erosive duodenitis occurred. In conclusion, over a mean follow-up period of 3.5 months, use of NSAIDs in Japanese patients with RA did not impair the healing process of gastric and duodenal ulcers nor did it affect the endoscopic and histological improvements associated with H. pylori eradication.

A 33-year-old woman suffered from epistaxis and perforation of the nasal septum. Based on a biopsy of nasal mucosa, Wegener's granulomatosis was suspected initially. Her nasal symptoms improved spontaneously, but tinnitus, hearing loss, and dizziness appeared within 3 months. Laboratory analyses revealed no inflammation, and antineutrophil cytoplasmic antibodies were negative. Audiometry revealed bilateral sensorineural hearing loss. A second biopsy of the nasal septum showed an inflammatory change in the cartilage. Thus we diagnosed early-stage relapsing polychondritis.

We conducted a study to assess the predictive factors for total knee arthroplasty (TKA) in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 5 years. A linked registry study using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA) was done. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate piecewise-linear Cox (PL-Cox) regression model; the model initially included variables such as gender, age, duration of the disease, visual analog scale (VAS) generated by physicians (VAS-physician), patient-reported VAS for pain (VAS-pain), VAS for general health (VAS-GH), disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), and hemoglobin. Of the 3945 patients registered at baseline, 955 (24.2%) had pain or tenderness in their knee joints, and 114 (11.9%) had TKA surgery in one or both knee joints. On PL-Cox regression, the variables with positive coefficients were J-HAQ, VAS-pain, VAS-physician, and RF positive; advanced age was associated with a reduced risk of TKA. The hazard ratios were: 0.920 for age >60 years; 2.64 for J-HAQ <1.5; 1.01 for J-HAQ >1.5; 1.47 for VAS-pain >6 (cm); 1.20 for VAS-physician >4 (cm); and 2.08 for RF positive. The consistently predictive factors for TKA in RA were age, J-HAQ, VAS-pain, VAS-physician, and RF positive. Age greater than 60 years was associated with a decreased risk of TKA, while J-HAQ from 0 to 1.5, VAS-pain >6 (cm), and VAS-physician >4 (cm) were associated with an increased risk for TKA surgery. These results suggest that, when treating RA patients, physicians should pay particular attention to pain complaints, the patient's daily activity level, and the RF factor status.

The optimal methotrexate dose differs between rheumatoid arthritis (RA) patients, and dose-escalation strategies also differ among rheumatologists. By taking advantage of the heterogeneous methotrexate dosing that occurs among Japanese rheumatologists, we analyzed the efficacy and safety of different methotrexate doses. A large observational cohort of RA patients, IORRA, was established in 2000. A dataset from April 2003 that included 4578 RA patients was used for a cross-sectional analysis, while a dataset of 1649 patients who received methotrexate from October 2000 to October 2005 was used for a longitudinal analysis. The cross-sectional analysis included 12 rheumatologists who prescribed methotrexate to more than 60 patients. Mean methotrexate dose ranged widely (4.8-9.0 mg/week) among rheumatologists with a significant positive relationship between average methotrexate dose and the percentage of patients with Disease Activity in 28 Joints (DAS28) scores below 3.2. During the longitudinal analysis, both methotrexate prescription frequency and the average dose prescribed by 16 rheumatologists increased. Overall disease activity as assessed by DAS28-area under the curve (AUC) and disability progression as assessed by Japanese version of the Health Assessment Questionnaire (JHAQ)-slope inversely correlated with the extent of methotrexate use. This study demonstrated that extensive methotrexate use effectively suppressed RA disease activity and inhibits disability progression. In addition, we have found that it is critical to pay attention to patient-reported adverse reactions.

Matrix metalloproteinases (MMPs) are the proteases responsible for the destruction of cartilage in rheumatoid arthritis (RA) patients; especially the role of MMP-3 in RA has been highlighted from both pathophysiological studies and clinical studies. However, the role of serum MMP-3 in a large observational cohort of RA patients has not been well demonstrated. In a large observational cohort of RA patients in our Institute (IORRA, October 2000-October 2005, n=3834-5049/phase), disease activity and functional status were routinely assessed biannually. In October 2001, serum MMP-3 was measured in 1265 patients in this cohort, and the data of these patients in the subsequent 4 years were analyzed. The functional status of disability was assessed by JHAQ, the verified Japanese version of HAQ. A cut-off point of 121.0 ng/ml (men) and 59.7 ng/ml (women) was used for MMP-3 positive/negative categorization. The baseline data of these 1265 patients include 81.5% women, mean age 57.9, mean duration 11.1 years, and 71.7% of patients were rheumatoid factor (RF)-positive. Serum MMP-3 levels at the baseline (195.1+227.9 ng/ml) were weakly correlated with C-reactive protein (CRP), but qualitative elevation of serum MMP-3 using cut-off points correlated significantly with corticosteroids use, DAS28, CRP, erythrocyte sedimentation rate, JHAQ, or other markers for the disease activity, but not with age or the disease duration. Thus, elevation of serum MMP-3 level represents the disease activity of RA patients regardless of age or the disease duration. In the longitudinal analysis, the slope of JHAQ progression in patients with MMP-3 positive and RF positive, MMP-3 positive and RF negative, MMP-3 negative and RF positive and MMP-3 negative and RF negative were 0.0179, 0.0162, 0.0156, and 0.0119, respectively, indicating that JHAQ increased most progressively in RA patients with MMP-3 positive and RF positive patients, although statistically apparent differences were not identified. In 502 female patients without talking corticosteroid, patients with MMP-3 positive and RF positive were statistically more progressive in the disability than patients with MMP-3 negative and RF negative. In conclusion, elevation of serum MMP-3 in RA patients is an indicator of inflammation, and together with RF, elevation of serum MMP-3 is a predictive marker for the progression in disability especially in female patients without corticosteroid.

The objective of this study was to show whether the disease activity of rheumatoid arthritis (RA) patients had improved in Japan, and whether the improvement of disease activity had resulted in a better outcome of patients. In a single-institute-based prospective observational cohort of RA patients (Institute of Rheumatology, Rheumatoid Arthritis, IORRA), a total of 7512 patients were enrolled, and their information was collected biannually. A cross-sectional data set A that included all patients in each phase was analyzed. From October 2000 to April 2006, disease activity score DAS28 significantly improved from 4.15 to 3.63, and the frequency of patients in remission (DAS28 < 2.6) increased from 8.5% to 21.5%. During this period, the frequency of methotrexate users increased from 33.9% to 58.7% and the average dosage of methotrexate also increased from 5.59 mg/week to 6.94 mg/week; on the other hand, there was no increase in any adverse reaction among the methotrexate users. To investigate the relationship between longitudinal disease control and progression of disability, a longitudinal data set B that included 712 patients who completed all phases of the study from 2000 to 2006 was selected and was analyzed. The disability index JHAQ of a poorly controlled group (average DAS > 5.1) increased (+34.8%), that of a moderately controlled group (average DAS 3.2-5.1) also increased (+14.0%), but that of a well-controlled group (average DAS < 3.2) decreased (-13.0%). In conclusion, by using a prospective observational cohort IORRA in Japan, we demonstrate that RA disease activity improved from 2000 to 2006, which correlates with an increased use of methotrexate. The suppression of disease activity resulted in a better outcome for patients.

Objective: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is a member of the PTPs that negatively regulate T-cell activation. A missense single nucleotide polymorphism (SNP) in the PTPN22 gene known as R620W was recently reported to be associated with several autoimmune diseases including rheumatoid arthritis (RA). The association was confirmed repeatedly in the populations of North European ancestry. However, the SNP was reported to be non-polymorphic in the Asian populations. Because the gene confers an impact on autoimmune diseases, we attempt to explore an association between PTPN22 gene and RA in a Japanese population without restricting to the SNP, R620W., Methods: We studied 1128 RA patients and 455 controls. In addition to the SNP, R620W, we selected eight testing SNPs spanning 45 kb over the PTPN22 gene using the International HapMap Project. Genotyping was performed using the TaqMan fluorogenic 5' nuclease assay. Associations between RA and each of the SNPs were estimated by the Fisher's exact test. Haplotype was constructed using the expectation-maximization algorithm., Results: R620W was not polymorphic enough in both the patients and the controls, and was therefore excluded from further analysis. Each allele frequency for the eight other SNPs in both groups was compared and no association was detected. Haplotype analysis also revealed that PTPN22 gene was not associated with RA in a Japanese population., Conclusion: We found no association between PTPN22 and RA in a Japanese population. The result suggests that the PTPN22 gene is associated with RA only in a specific ethnic group.

The use of haplotype information in case-control studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. We examined the validity of the application of the likelihood-based algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from case-control studies. This algorithm was implemented in a computer program called PENHAPLO. In this program, haplotype frequencies and penetrances are estimated using the expectation-maximization algorithm, and the haplotype-phenotype association is tested using the generalized likelihood ratio. We show that this algorithm was useful not only for cohort studies but also for case-control studies. Simulations under the null hypothesis (no association between haplotypes and phenotypes) have shown that the type I error rates were accurately estimated. The simulations under alternative hypotheses showed that PENHAPLO is a robust method for the analysis of the data from case-control studies even when the haplotypes were not in HWE, although real penetrances cannot be estimated. The power of PENHAPLO was higher than that of other methods using the likelihood-ratio test for the comparison of haplotype frequencies. Results of the analysis of real data indicated that a significant association between haplotypes in the SAA1 gene and AA-amyloidosis phenotype was observed in patients with rheumatoid arthritis, thereby suggesting the validity of the application of PENHAPLO for case-control data.

Objective: Polymorphisms and haplotypes of the peptidylarginine deiminase type 4 gene (PADI4) have been reported to be associated with rheumatoid arthritis (RA) in a Japanese population. However, subsequent replication studies showed conflicting results. The aim of this study was to determine whether meta-analysis would prove the existence of the association., Methods: PubMed was searched using the term 'PADI4' for articles from the publication of the first study to December 2005. Replication studies that tested the association between PADI4 and RA were reviewed for meta-analysis. The Breslow-Day test for homogeneity across the studies was calculated. The Mantel-Haenszel procedure was used to pool odds ratios (OR) with 95% confidence intervals (CI) to evaluate the association., Results: Six replication studies, one from Japan and five from Europe and North America, fulfilled the selection criteria for inclusion in the meta-analysis. Homogeneity was confirmed across the replication studies. The common OR was 1.14 (95% CI = 1.07-1.21) for allelic distribution. The association was confirmed when only five replication studies in the European descent populations were combined (P = 0.0096, common OR = 1.10)., Conclusions: Our meta-analysis showed a positive association between PADI4 and RA not only in the Japanese population but also in populations of European descent.

Objectives: To study the role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 in the pathogenesis of rheumatoid arthritis (RA), we analysed the expression of MCP-4/CCL13 in chondrocytes, synovial fluid and serum from patients with RA and investigated the effect of MCP-4/CCL13 on the proliferation of synovial cells., Methods: Human articular cartilage specimens were obtained from joints from RA and osteoarthritis (OA) patients and normal joints (controls). Transcript levels of MCP-4 in cartilage were determined by real-time polymerase chain reaction. Protein levels were measured by enzyme-linked immunoassay. Cultured fibroblast-like synoviocytes (FLS) were treated with various concentrations of recombinant MCP-4/CCL13 protein, and cell proliferation was evaluated with a viability assay., Results: The gene expression of MCP-4 was significantly higher in cartilage from RA patients than in that from OA patients (P = 0.00902) and in normal cartilage (P = 0.00902). The concentration of MCP-4/CCL13 protein in serum from RA patients (mean 94.7 +/- 37.6 pg/ml) was significantly higher than in serum from OA patients (mean 49.2 +/- 31.2 pg/ml, P = 0.0051) and controls (mean 32.6 +/- 23.9 pg/ml, P = 0.0001). The concentration of MCP-4/CCL13 protein in synovial fluid from RA patients (mean 247.2 +/- 161.2 pg/ml) was also significantly higher than in that from OA patients (mean 29.6 +/- 50.5 pg/ml, P = 0.000019). Moreover, MCP-4/CCL13 enhanced the proliferation of FLS in a dose-dependent manner., Conclusions: MCP-4/CCL13 is highly expressed in RA joints at the mRNA and protein levels. Our results suggest that MCP-4/CCL13 is secreted from chondrocytes and activates the proliferation of rheumatoid synovial cells, thereby leading to joint destruction in RA.

Here, we describe a case of severe pancreatitis in overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in an adult female patient. Treatment with plasmapheresis and high-dose prednisone successfully saved her life and led to remission of the pancreatitis. This is the first case report of severe acute pancreatitis in the setting of overlap syndrome of SLE and SSc. The advantages and disadvantages of the use of corticosteroids are discussed.

A 58-year-old Japanese woman with rheumatoid arthritis (RA) suffered from high fever triggered by administration of an influenza vaccine after a 4-month-long effective treatment course with the TNF-alpha inhibitor etanercept. Influenza vaccine had been previously administrated safely to the patient before initiation of etanercept therapy. The fever occurred without other symptoms soon after vaccine administration, progressed to high fever 1 day later, and spontaneously resolved the second day. The clinical course appears to be compatible with drug fever closely associated with immediate hypersensitivity (in particular, late-phase type I allergic reaction), in which T helper (Th) 2 cells play a crucial role. Etanercept can strongly suppress Th1-mediated reactions; therefore, Th2 activity may be augmented by etanercept treatment in aspect of antagonism between Th1 and Th2 mechanisms. In RA patients who receive treatment with TNF-alpha inhibitor such as etanercept, activation of Th2-mediated immune responses such as immediate hypersensitivity may be a necessary side effect for those who receive vaccinations.

We conducted a retrospective, clinical evaluation of connective tissue disease (CTD) patients who were tested for either sputum or bronchoalveolar lavage fluid Pneumocystis polymerase chain reaction (PC-PCR) and analyzed the risk factors that cause Pneumocystis pneumonia (PCP) susceptibility and fatality. PC-PCR was performed on 66 CTD patients who presented with symptoms, data, or radiological findings strongly suggesting respiratory infection. Patients with higher oral corticosteroid doses, use of oral methotrexate (MTX), bilateral lung findings, positive beta-D-glucan, and no prophylaxis use were more susceptible to PCP. They had significantly low immunoglobulin G and significantly high beta-D-glucan and lactate dehydrogenase. Survivors and nonsurvivors of PCP were also evaluated. Poor prognoses were observed with older age, elevated beta-D-glucan, rheumatoid arthritis (RA) patients using MTX, hypoxemia, bilateral lung findings, and mechanical ventilation use. Nonsurvivors had significantly lower lymphocytes, oxygen saturation, and significantly higher beta-D-glucan. In RA, poor prognoses were seen with those taking MTX. Disease duration, underlying pulmonary complications, and oral corticosteroid doses did not lead to poor prognoses in RA. Because PCP in CTD leads to abrupt onset of symptoms with poor survival rates, early diagnosis and initiation of treatment are critical, and it is essential for clinicians to recognize risk factors that predispose patients to PCP and its mortality.

The aim of this study was to evaluate the factors responsible for depressed mood in rheumatoid arthritis (RA). Clinical and laboratory measures were collected from 4558 RA patients enrolled in a large clinical cohort study for RA conducted at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA study). A two-question depressed screening included in the U.S. Preventive Services Task Force recommendation were utilized to identify "depressed patients." A total of 1875 (41.1%) were identified as "depressed patients" who presented with symptoms suggestive of depression. Patient's Visual Analog Scale (VAS) for general health (43.3 mm vs 24.6 mm, P < 0.0001) and pain (40.9 mm vs 23.8 mm, P < 0.0001) and the disability index scores measured by the Health Association Questionnaire (HAQ) (0.986 vs 0.574, P < 0.0001) were significantly higher in depressed patients than in nondepressed patients. The presence of three or more comorbidities (odds ratio [OR] 2.157, P < 0.0001), infection (OR 1.754, P < 0.0001), and joint surgery (OR 1.878, P < 0.0001) were significantly correlated with depressed mood in RA. The results of the Generalized Linear Model analysis showed that HAQ disability index (P < 0.0001) and patient's VAS for general health (P < 0.0001) were also strongly and significantly associated to the response variable "probability of depressed patients." Patient appraisal of poor general health and greater disability were associated with depressed mood in RA.

Bucillamine (Buc) is a disease-modifying antirheumatic drug (DMARD) developed in Japan, which has been used as one of the first-line DMARDs for the treatment of rheumatoid arthritis (RA) in Japan. However, direct comparison of this drug with standard DMARDs including sulfasalazine (SASP) and methotrexate (MTX) has been scarcely reported. We therefore tried to evaluate the clinical efficacy of Buc by analyzing the database from the long-term observational cohort study IORRA (previously known as J-ARAMIS). The cross-sectional analysis revealed that responses to Buc treatment were better in males, patients with shorter duration of illness, and those who were rheumatoid factor-negative. In the longitudinal analysis, although there was no marked difference among the baseline variables of patients with Buc, SASP, and MTX, the percentage of patients exhibiting moderate or good response to treatment, as rated using the European League Against Rheumatism improvement criteria, was higher in the Buc group (41.0%) than in the MTX (32.6%) and SASP groups (25.6%). These data support Buc as a candidate for being a first-line drug for the treatment of patients with RA.

This report documents the results of a study performed to examine clinical use of mizoribine (MZR), using data from a large-scale prospective cohort study, IORRA (Institute of Rheumatology Rheumatoid Arthritis). The number of patients with RA entered in this study from October 2000 through October 2003 was 6238. Three hundred and six patients (4.9%) received MZR therapy. Mizoribine users who were taking methotrexate (MTX) (MTX-MZR group, n = 94) and over 70 years of age (elderly group, n = 45) were collected. Cumulative retention rates of MZR were calculated by Kaplan-Meier analysis. Median drug survival of MZR was 28 months for the poor responders to MTX and 43 months for the poor responders to MZR, with no significant difference between these groups. Cumulative retention rate of MZR in the elderly group did not show a significant difference compared to that in patients aged under 70 years. Ten patients (10.6%) in the MTX-MZR group and 10 patients (22.2%) in the elderly group experienced adverse effects of MZR. None of these adverse effects was serious. This study indicated that, although MZR has not been frequently prescribed for RA patients, it may be useful and relatively safe for patients who are poor responders to MTX as an additional regimen to MTX therapy as well as for elderly patients.

We investigated the prevalence and predictors of complementary and alternative medicine (CAM) use by patients with rheumatoid arthritis (RA) in Japan. A cross-sectional descriptive study was performed using the database from a large observational cohort of RA patients in the Institute of Rheumatology, Tokyo Women's Medical University. Logistic regression analysis was carried out to reveal predictive factors for CAM use. Among 3815 RA patients, 1321 (34.6%; 174 males, 1147 females) used at least one type of CAM. Health foods, including dietary supplements, were the most commonly used. CAM was more frequently used by female patients (odds ratio: 0.578; 95% confidence interval [CI] = 0.451-0.740). A multiple logistic regression analysis revealed that sex (odds ratio: 0.489; 95% CI = 0.333-0.718) and degree of satisfaction with disease-modifying antirheumatic drugs (DMARDs) (odds ratio: 0.899; 95% CI = 0.852-0.948) were significant independent predictive factors for CAM use. The serum C-reactive protein level and erythrocyte sedimentation rate showed no significant associations with CAM use. Approximately 35% of RA patients used CAM in Japan. Female patients and patients dissatisfied with DMARDs used CAM more frequently, regardless of their disease activity.

Context: The prevalence of cryptorchidism (CO) has increased during the past few decades in several countries, and this event has primarily been ascribed to the estrogenic effects of environmental endocrine disruptors (EEDs). Little is known, however, about the role of genetic susceptibility to EEDs in this phenomenon., Objective: The objective of this study was to determine whether CO is associated with a specific haplotype of the gene for estrogen receptor alpha (ESR1) that mediates the estrogenic effects of EEDs., Design: This was a case-control study., Setting: The study was performed at the National Research Institute and University Hospitals., Subjects: Sixty-three cryptorchid males, aged 1-13 yr, and 47 control males, aged 4-12 yr, were studied., Intervention: After genotyping 15 single nucleotide polymorphisms widely distributed in the greater than 300-kb genomic sequences of ESR1, haplotype analysis was performed., Main Outcome Measure: Identification of a specific ESR1 haplotype associated with CO was the main outcome measure., Results: A haplotype block was identified for an approximately 50-kb region encompassing single nucleotide polymorphisms 10-14 in the 3' region of ESR1 in both groups. The frequency of the estimated AGATA haplotype within the block was higher in the patients than in the control males (34.0% vs. 21.3%; P = 0.037), and the association of this haplotype with CO phenotype was significant in a recessive mode (P = 0.0060). The homozygosity for this haplotype was identified only in the patients, and the frequency of the homozygotes was significantly different between the two groups (10 of 63 vs. zero of 47; P = 0.0042)., Conclusions: The association of CO with homozygosity for the specific ESR1 haplotype suggests the relevance of genetic susceptibility to EEDs in the development of CO.