Pathogenetic associations of anti-ribosomal P protein antibody titres and its subclasses in patients with systemic lupus erythematosus.

OBJECTIVES: We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese systemic lupus erythematosus (SLE) patients. METHODS: Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. Anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA. RESULTS: Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed the anti-RibP index was independently associated with initial prednisolone dose and prevalence of skin rash. Anti-RibP IgG were mainly IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher disease activity score, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity. CONCLUSION: Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE.

Mood Disorder in Systemic Lupus Erythematosus Induced by Antiribosomal P Protein Antibodies Associated with Decreased Serum and Brain Tryptophan.

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.

Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

Changes in the Quality of Life of Patients with Left Ventricular Assist Device and their Caregivers in Japan: Retrospective Observational Study.

Left ventricular assist devices (LVAD) improve quality of life (QOL) in many patients with end-stage severe heart failure, but not in some patients. In addition, the burden on caregivers is expected to increase after LVAD patients are discharged. Our study aimed to investigate the impact of LVAD on the QOL of patients and caregivers. Thirty-two LVAD patients were assessed for changes in QOL, mental status, and activity level using the Euro QOL (EQ-5D-5L), Short Form 12 (SF-12), Minnesota Living with Heart Failure Questionnaire, Hospital Anxiety and Depression Scale (HADS), and Frenchay Activities Index. Twenty-four caregivers were assessed for changes in QOL, mental status, and burden of care using the EQ-5D-5L, SF-12, HADS, and Burden Index of Caregiver (BIC-11). The LVAD patients and caregivers responded contemporaneously regarding two points: pre-and post-LVAD. Patients' physical and mental QOL was significantly improved, but not social QOL and activity level. Caregivers' QOL and burden of care did not change, and anxiety was reduced (p = 0.028). The patients were divided into two groups based on whether EQ-5D-5L was improved: twelve patients in the unimproved group (UG) and twenty patients in the improved group (IG). In the UG, 50% had LVAD-related strokes (p = 0.001, IG: 0%), and their social QOL decreased (p = 0.023). The activity levels improved in the IG. Multi-dimensional analyses on the QOL in LVAD patients yielded mixed results. Anticipated benefits derived from LVAD therapy may be limited by LVAD-related complications such as stroke that negatively impacts on the QOL.

Association of coexisting anti-ribosomal P and anti-dsDNA antibodies with histology and renal prognosis in lupus nephritis patients.

OBJECTIVES: Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients. METHODS: Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for > 3 months. RESULTS: Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P. CONCLUSION: Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.

Lower trabecular bone score is associated with an increased incidence of localized femoral periosteal thickening.

INTRODUCTION: Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes an atypical femoral fracture (AFF). Bisphosphonate (BP) use, glucocorticoid use, and Asian race are major risk factors for developing such fractures. The aim of this study was to determine whether the trabecular bone score (TBS) reflecting the lumbar trabecular microarchitecture was related to LPT in glucocorticoid-treated Japanese patients with autoimmune diseases. MATERIALS AND METHODS: We retrospectively investigated 111 women with autoimmune diseases treated with prednisolone (PSL) who had undergone both femoral X-ray and dual-energy X-ray absorptiometry of the L1 - L4 lumbar vertebrae and for whom TBS could be evaluated for two or more of these. RESULTS: Femoral LPT was evident in the X-rays of 18 of 111 patients (16.2%). Higher body mass index (BMI), longer duration of PSL use and longer duration of BP use were significant in patients with LPT compared to those without. The TBS was significantly lower in patients with LPT than in those without (1.314 ± 0.092 vs. 1.365 ± 0.100, p = 0.044); however, the lumbar bone mineral density did not differ significantly (0.892 ± 0.141 vs. 0.897 ± 0.154 g/cm2, p = 0.897). TBS was significantly associated with LPT (odds ratio, 0.004; 95% CI, 0 - 0.96; p = 0.048), but not in the multivariate analysis including BMI, duration of PSL use and duration of BP use. CONCLUSIONS: The TBS was lower in glucocorticoid-treated Japanese women with autoimmune diseases with LPT than in those without LPT, and deteriorated trabecular microarchitecture influenced by longer use of BP and glucocorticoid might be associated with the development of LPT.

High bisphosphonate treatment rates and the prevalence of atypical femoral fractures in patients with systematic lupus erythematosus: a single-center retrospective study performed in Japan.

Treatment of systemic lupus erythematosus (SLE) often continues with moderate-to-low doses of glucocorticoids for the long term. Bisphosphonates aid in the prevention and management of glucocorticoid-induced osteoporosis (GIOP). However, long-term use of bisphosphonates increases the relative risk of atypical femoral fracture (AFF) and the incidence is typically 16 or 113 per 100,000 person-years in patients treated with bisphosphonates for 5 or 10 years, respectively. Here, we explored bisphosphonate prescription rate and prevalence of AFF in patients with SLE. In total, 270 patients with SLE were enrolled. The Japanese Society for Bone and Mineral Research Guideline 2014 for GIOP management and treatment was used. We also explored AFF history through medical records. Most (n = 251) patients were recommended to treat by the GIOP guideline (scores ≥ 3); bisphosphonates, denosumab, teriparatide, or active vitamin D was prescribed for 85.7%. Bisphosphonates were currently used by 66.1% of the patients, and 65% had used them for ≥ 5 years. Of all patients, 76.7% had a history of bisphosphonate use, 5 of 270 (1.9%) had histories of AFF. Four of five patients with AFF had taken bisphosphonates for ≥ 3.5 years, in addition to moderate doses (≥ 10 mg/day) of glucocorticoids. For the SLE patients with a history of bisphosphonate use, the incidence of AFF was calculated to be 278 per 100,000 person-years. Our single-center study found that bisphosphonates were commonly used long term by Japanese patients with SLE. As AFF is not rare, AFF should be cared in patients with SLE.

Bone Formation Parameters of the Biopsied Ilium Differ between Subtrochanteric and Diaphyseal Atypical Femoral Fractures in Bisphosphonate-Treated Patients.

Atypical femoral fractures (AFFs) are defined as atraumatic or low-trauma fractures located in the subtrochanteric or diaphyseal sites. Long-term bisphosphonates (BPs) are administered to prevent fragility fractures in patients with primary osteoporosis or collagen diseases who are already taking glucocorticoids (GCs). Long-term BP use is one of the most important risk factors for AFFs. Its pathogenesis is characterized by severely suppressed bone turnover (SSBT), but whether the characteristics of patients are different regarding to location of fracture site remains unknown. In this study, we compared the characteristics and bone histomorphometric findings between subtrochanteric and diaphyseal sites in patients with BP-associated AFFs. Nine women with BP-associated AFFs were recruited, including 3 with systemic lupus erythematosus, 2 with rheumatoid arthritis, 2 with primary osteoporosis, 1 with polymyalgia rheumatica, and 1 with sarcoidosis. Patients were divided into the subtrochanteric group (n = 5; average age, 52 years; BP treatment, 5.9 years) and the diaphyseal group (n = 4; average age, 77 years; BP treatment, 2.6 years). Compared with the diaphyseal group, the subtrochanteric group had significantly higher daily GC doses (average, 10.9 vs. 2.3 mg/day) and significantly lower serum 25-hydroxyvitamin-D levels (17.8 vs. 25.6 ng/mL). Bone histomorphometry of the biopsied iliac bone showed SSBT in 3 cases (subtrochanteric, n = 1; diaphyseal, n = 2). Osteoid volume and trabecular thickness were significantly lower in the subtrochanteric group than in the diaphyseal group. Bone formation was inhibited more severely in subtrochanteric than in the diaphyseal group due to the higher GC doses used.

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review.

On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol-O-methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish.

Gender, variation in opioid receptor genes and sensitivity to experimental pain.

BACKGROUND: Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included. RESULTS: Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain. CONCLUSION: This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis.

BACKGROUND: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. METHODS: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. RESULTS: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04 × 10(-17); OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. CONCLUSIONS: We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.

Analgesia and central side-effects: two separate dimensions of morphine response.

AIMS: To present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study. METHODS: Two hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored. RESULTS: Two principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects. CONCLUSIONS: Although replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively.

A case of MPO- and PR3-ANCA-positive hypertrophic cranial pachymeningitis with elevated serum IgG4.

We report a case of orbital tumor and hypertrophic cranial pachymeningitis in a 64-year-old woman, who was initially suspected to have IgG4-related disease because of an elevated level of serum IgG4 at onset. However, her condition was resistant to glucocorticoid therapy, and additional cyclophosphamide was necessary to control the disease activity. Additional features included elevated levels of serum myeloperoxidase (MPO) and proteinase-3-anti-neutrophil cytoplasmic antibody (PR3-ANCA), and biopsy specimens from the orbital mass revealed very few infiltrating IgG4-positive cells. Instead, rupture of the elastic layer of the arterial walls with neovascularization and a small number of giant cells were observed. Considering these findings and the clinical course, the disease was considered more likely to be ANCA-associated pachymeningitis with elevation of the serum IgG4 level.

Atypical severe central serous chorioretinopathy in a patient with systemic lupus erythematosus improved with a rapid reduction in glucocorticoid.

A 36-year-old woman was diagnosed with systemic lupus erythematosus (SLE). Seven days after beginning glucocorticoid treatment, she developed reduced visual acuity, and atypical severe central serous chorioretinopathy (CSC) was confirmed. Since glucocorticoid use is an important risk factor for CSC, the PSL was reduced, tacrolimus was added, and the visual acuity improved rapidly. Reduction in glucocorticoid combined with the use of immunosuppressive agents is one option for preventing a deterioration in atypical severe CSC while still controlling SLE.

Interferon regulatory factor 5 polymorphisms in sarcoidosis.

OBJECTIVE: Interferon regulatory factor 5 (IRF5) gene polymorphisms are associated with susceptibility to autoimmune diseases. The aim of this study is to determine the roles of IRF5 single-nucleotide polymorphisms (SNPs) in sarcoidosis. METHODS: A total of 175 Japanese patients with biopsy-proven sarcoidosis and 150 sex-matched controls were genotyped for four IRF5 SNPs: rs729302A/C, rs2004640G/T, rs10954213A/G, and rs2280714G/A. The associations of these SNPs with susceptibility to sarcoidosis were examined. RESULTS: Carriage of rs10954213A and rs2280714A conferred significant risks for sarcoidosis [carriage of rs10954213A: odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.15-3.33, P = 0.01, corrected P = 0.04; carriage of rs2280714A: OR = 1.97, 95% CI = 1.22-3.16, P = 0.005, corrected P = 0.02]. The haplotype carrying rs10954213A and rs2280714A (haplotype 2) was significantly associated with susceptibility to sarcoidosis (OR = 2.00, 95% CI = 1.24-3.24, P = 0.004, corrected P = 0.01). rs729302 and rs2004640 were not associated with susceptibility to sarcoidosis, whereas carriage of rs2004640G was protective against pulmonary hypertension (OR = 0.017, 95% CI = 0.002-0.15, P < 0.001, corrected P < 0.001). CONCLUSION: A haplotype carrying two functional SNPs of IRF5, rs10954213A and rs2280714A, was associated with the risk of sarcoidosis in the Japanese population.

Giant Cell Arteritis That Presented with Buccal Skin Ulceration along the Facial Artery.

A 68-year-old man presented with right buccal ulceration along the facial artery, temporal pain, lagophthalmos, diplopia, and tongue deviation to the right. Contrast-enhanced computed tomography showed bilateral temporal artery and right maxillary artery wall thickening, and a diagnosis of giant cell arteritis (GCA) was made according to the American College of Rheumatology 1990 criteria. Treatment with corticosteroids ameliorated his symptoms. This is the first report of GCA with buccal skin ulceration along a facial artery. Because a delayed diagnosis can lead to irreversible damage, it is essential to notice rare symptoms, such as skin ulceration and multiple cranial neuropathy-like symptoms.

Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups.

The HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We therefore typed HLA-DRB1 and DQB1 in 340 UK, 139 Dutch and 163 Japanese sarcoidosis patients and, respectively, 354, 218 and 168 healthy controls from these populations. We applied consistent phenotyping and genotyping and investigated associations between HLA class II alleles and distinct disease phenotypes within and between ethnic groups. DRB1*01 and DQB1*0501 are protective against all manifestations of sarcoidosis. Lung-predominant sarcoidosis is associated with DRB1*12 and *14. Löfgren's syndrome is a common sarcoidosis phenotype in the Dutch and is strongly associated with the DRB1*0301 allele. This phenotype is not seen among the Japanese in whom DRB1*0301 is absent. The same allele is protective for UK uveitis. Sarcoid uveitis is common in Japan. The DRB1*04-DQB1*0301 haplotype is a risk factor for this disease manifestation in Japanese and UK subjects but protective for sarcoidosis overall. We show that distinct sarcoidosis phenotypes have similar genetic associations across ethnic groups. The disease case mix differs between centres and may be explained by different ethnic allelic frequencies.

Risk of chronic beryllium disease by HLA-DPB1 E69 genotype and beryllium exposure in nuclear workers.

RATIONALE: Beryllium sensitization (BeS) and chronic beryllium disease (CBD) are determined by at least one genetic factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, and by exposure to beryllium. The relationship between exposure and the E69 genotype has not been well characterized. OBJECTIVES: The study goal was to define the relationship between beryllium exposure and E69 for CBD and BeS. METHODS: Workers (n = 386) from a U.S. nuclear weapons facility were enrolled into a case-control study (70 BeS, 61 CBD, and 255 control subjects). HLA-DPB1 genotypes were determined by sequence-specific primer-polymerase chain reaction. Beryllium exposures were reconstructed on the basis of worker interviews and historical exposure measurements. MEASUREMENTS AND MAIN RESULTS: Any E69 carriage increased odds for CBD (odds ratio [OR], 7.61; 95% confidence interval [CI], 3.66-15.84) and each unit increase in lifetime weighted average exposure increased the odds for CBD (OR, 2.27; 95% CI, 1.26-4.09). Compared with E69-negative genotypes, a single E69-positive *02 allele increased the odds for BeS (OR, 12.01; 95% CI, 4.28-33.71) and CBD (OR, 3.46; 95% CI, 1.42-8.43). A single non-*02 E69 allele further increased the odds for BeS (OR, 29.54; 95% CI, 10.33-84.53) and CBD (OR, 11.97; 95% CI, 5.12-28.00) and two E69 allele copies conferred the highest odds for BeS (OR, 55.68; 95% CI, 14.80-209.40) and CBD (OR, 22.54; 95% CI, 7.00-72.62). CONCLUSIONS: E69 and beryllium exposure both contribute to the odds of CBD. The increased odds for CBD and BeS due to E69 appear to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes.

Effect of etanercept and entecavil in a patient with rheumatoid arthritis who is a hepatitis B carrier: a review of the literature.

In this report, we describe a case of a 48-year-old Japanese woman who is a hepatitis B (HB) carrier with rheumatoid arthritis (RA). She had the following antibody profile: HBs Ag(+), HBs Ab(-), HBe Ag(-), HBe Ab (+), HBc Ab(-) and undetectable HBV-DNA level. She was treated with auranofin, salazosulfapyridine, and bucillamine. Finally, she was treated with D: -penicillamine, but her disease activity remained elevated. Prophylactic treatment of entecavir 0.5 mg daily was started in March 2008 and all disease-modifying anti-rheumatic drugs were stopped. After 2 weeks, etanercept monotherapy was started at 25 mg subcutaneously once a week. Significant improvement in clinical parameters of disease activity and well being was observed. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and HB virus viral load did not change significantly. Serum ALT, AST, and HB virus viral load were followed-up at every 3-month intervals, from initiation of therapy up to 24 months after the start of treatment with etanercept. We have also summarized the course of nine RA patients who received etanercept and were HB carriers or had chronic HB according to our literature search. Based on the results of our study, treatment of these patients with etanercept co-administered with lamivudine or entecavir appears to be safe.

Association between clinical parameters and amyloid-positive area in gastroduodenal biopsy in reactive amyloidosis associated with rheumatoid arthritis.

Our study was aimed to clarify an association between gastrointestinal (GI) amyloid-positive area and various kinds of factors including renal function in reactive amyloidosis associated with rheumatoid arthritis (RA). Twenty-five patients with an established diagnosis of reactive AA amyloidosis participated in the study between January 1989 and December 2009. Each patient satisfied the 1987 American Rheumatism Association criteria for RA. All patients showed amyloid deposits in both of GI and renal tissues. The average amyloid-deposited area was 2.2% in renal tissues and 3.7% in GI tissues although the difference was not statistically significant. Twenty-two patients out of 25 patients showed less than 5% of amyloidosis in renal tissues and nineteen patients showed 5% of amyloidosis in GI tissues. In 5 out of a total of 25 cases, the amyloid-deposited area in GI tissues was lesser than that in renal tissues. Mesangial proliferative glomerulonephritis, thin basement membrane disease (TBMD) and membranous nephropathy were frequently combined with renal amyloidosis. For statistical analyses, renal and GI tissues of % amyloid-positive areas were transformed to common logarithmic values (Log(10)%amyloid), since the histograms showed log-normal distribution. Clinical data were assessed by patient record at the time of GI biopsy. The correlation between Log(10)%GI-amyloid and age, creatinine (Cr), creatinine clearance (Ccr), blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR) were not significantly associated with Log(10)%GI-amyloid in crude correlation analyses and also in sex- and age-adjusted linear regression analyses. Although GI biopsy was not correlated with clinical factors, GI amyloid-positive areas were larger than renal amyloid-positive areas. Endoscopic screening of the upper GI tract is common in Japan, and amyloid-deposited area in GI tissues was sufficient to use for the diagnosis of amyloidosis compared with renal tissues in terms of convenience and sensitivity.