Baseline MRI bone erosion predicts the subsequent radiographic progression in early rheumatoid arthritis patients who achieved sustained good clinical response.

OBJECTIVE: To examine whether magnetic resonance imaging (MRI) findings at baseline predict radiographic progression in early-stage rheumatoid arthritis (RA) patients who have achieved sustained good clinical response. METHODS: This is a sub-analysis from the one-year observational study of Nagasaki University Early Arthritis Cohort. Definition of 'good clinical response' was a decrement of disease activity score (DAS) 28 ≧ 1.2 at three months with achievement of DAS28 remission through 6-12 months. Gd-enhanced MRI of both wrists and finger joints were examined at baseline and scored using rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Annual increment of Genant-modified Sharp score (GSS) > 0 was defined as 'radiographic progression'. Predictors of radiographic progression were determined by logistic regression analysis. RESULTS: Twenty-four subjects were selected in the present study. Each median RAMRIS synovitis, bone edema, bone erosion, and GSS at baseline were 6.5, 0.5, 0, and 0, respectively. Five patients developed radiographic progression at one year. Multivariate logistic regression analysis has shown that RAMRIS bone erosion at baseline is the only independent predictor of radiographic progression at one year (p = .032). CONCLUSIONS: Our data suggest that MRI bone erosion predicts poor radiographic outcome of early-stage RA even if it has been successfully treated.

Magnetic Resonance Imaging Bone Edema at Enrollment Predicts Rapid Radiographic Progression in Patients with Early RA: Results from the Nagasaki University Early Arthritis Cohort.

OBJECTIVE: To clarify whether magnetic resonance imaging (MRI) bone edema predicts the development of rapid radiographic progression (RRP) in the Nagasaki University Early Arthritis Cohort of patients with early-stage rheumatoid arthritis (RA). METHODS: Patients with early-stage RA (n = 76) were enrolled and underwent 1.5-T MRI of both wrists and finger joints. Synovitis, bone edema, and bone erosion were evaluated using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS). RRP was defined as an annual increment > 3 at 1 year by the Genant-modified Sharp score of plain radiographs. A multivariate logistic regression analysis was performed to establish the risk factors for RRP. RESULTS: Median disease duration at enrollment was 3 months. RRP was found in 12 of the 76 patients at 1 year. A univariate analysis revealed that matrix metalloprotease-3, RAMRIS bone edema score, and RAMRIS bone erosion score were associated with RRP. Multivariate logistic regression analyses demonstrated that the RAMRIS bone edema score at enrollment (5-point increase, OR 2.18, 95% CI 1.32-3.59, p = 0.002) was the only independent predictor of the development of RRP at 1 year. A receiver-operating characteristic analysis identified the best cutoff value for RAMRIS bone edema score as 5. RRP was significantly rare among the patients with a RAMRIS bone edema score < 5 at enrollment (2 from 50 patients). CONCLUSION: Our findings suggest that MRI bone edema is closely associated with the development of RRP in patients with early-stage RA. Physicians should carefully control the disease activity when MRI bone edema is observed in patients with early RA.

Characteristics of microbial communities in crustal fluids in a deep-sea hydrothermal field of the suiyo seamount.

To directly access the sub-seafloor microbial communities, seafloor drilling has been done in a deep-sea hydrothermal field of the Suiyo Seamount, Izu-Bonin Arc, Western Pacific. In the present study, crustal fluids were collected from the boreholes, and the bacterial and archaeal communities in the fluids were investigated by culture-independent molecular analysis based on 16S rRNA gene sequences. Bottom seawater, sands, rocks, sulfide mound, and chimneys were also collected around the boreholes and analyzed for comparisons. Comprehensive analysis revealed the characteristics of the microbial community composition in the crustal fluids. Phylotypes closely related to cultured species, e.g., Alteromonas, Halomonas, Marinobacter, were relatively abundant in some crustal fluid samples, whereas the phylotypes related to Pelagibacter and the SUP05-group were relatively abundant in the seawater samples. Phylotypes related to other uncultured environmental clones in Alphaproteobacteria and Gammaproteobacteria were relatively abundant in the sand, rock, sulfide mound, and chimney samples. Furthermore, comparative analysis with previous studies of the Suiyo Seamount crustal fluids indicates the change in the microbial community composition for 3 years. Our results provide novel insights into the characteristics of the microbial communities in crustal fluids beneath a deep-sea hydrothermal field.

Oral administration of Lactobacillus delbrueckii subspecies bulgaricus OLL1073R-1 suppresses inflammation by decreasing interleukin-6 responses in a murine model of atopic dermatitis.

The oral intake of Lactobacillus spp. can provide beneficial effects to the host by modulating the immune response. Atopic dermatitis (AD) is an allergic inflammatory disease mediated by various immune responses. In this study, we examined the effect of a Lactobacillus strain, Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (OLL1073R-1), on AD development in a murine model of AD that was developed by the topical application of mite antigen in NC/Nga mice. The oral intake of heat-killed OLL1073R-1 cells inhibited both the development of dermatitis and the elevation of an acute inflammation marker, serum amyloid A. Another bacterial strain, Lactobacillus rhamnosus OLL2984, exerted no inhibitory effects on dermatitis. The oral intake of heat-killed OLL1073R-1 cells also attenuated secretion of IL-6 from lymph node cells in response to mite antigen and reduced IL-6 levels in inflamed tissues, such as auricles. Production of IFN-γ or IL-4 was not influenced by OLL1073R-1 intake. We also found that inhibition of IL-6 signaling by gp130-Fc (a fusion protein consisting of the extracellular portion of glycoprotein 130 fused to the Fc region of human IgG1) markedly decreased the severity of dermatitis in NC/Nga mice. Moreover, secretion of IL-6 by lymph node cells was augmented in NC/Nga mice compared with that in BALB/c mice. These results indicate that IL-6 plays an essential role in the development of dermatitis in the NC/Nga mouse model of AD, and that OLL1073R-1 inhibits dermatitis, at least in part, by suppressing the IL-6 response.

Significant improvement in MRI-proven bone edema is associated with protection from structural damage in very early RA patients managed using the tight control approach.

OBJECTIVE: To identify the value of magnetic resonance imaging (MRI)-proven bone edema in patients with very early rheumatoid arthritis (RA). METHODS: All of the 13 patients included in the study were positive at entry for MRI-proven bone edema of the wrist and finger joints and anti-cyclic citrullinated peptide antibodies or IgM-rheumatoid factor. A tight control approach was applied for 12 months. Plain MRI and radiographs of both wrist and finger joints were examined every 6 months. MRI was scored by the RA MRI scoring (RAMRIS) technique and plain radiographs were scored using the Genant-modified Sharp score. Variables that were correlated with plain radiographic changes at 12 months were examined. RESULTS: Simplified disease activity index (SDAI) remission was achieved in 7 patients, and a significant reduction in the RAMRIS bone edema score, which declined to <33 % as compared with the baseline, was achieved in 8 out of 13 patients. Four patients showed plain radiographic progression while 9 patients did not. Significant reductions in the RAMRIS bone edema score (p = 0.007) and the time-integrated SDAI (p = 0.031) were the variables involved in plain radiographic progression. CONCLUSIONS: Improvement in bone edema may be associated with protection against structural damage in very early RA patients managed using the tight control approach.

Treatment discontinuation in patients with very early rheumatoid arthritis in sustained simplified disease activity index remission after synthetic disease-modifying anti-rheumatic drug administration.

We aimed to identify whether drug-free remission could be achieved in patients with very early rheumatoid arthritis (RA) with poor prognosis factors by treatment with synthetic disease-modifying antirheumatic drugs (DMARDs). Thirteen patients with very early RA, whose disease was considered to have highly erosive potential, were included. Magnetic resonance imaging (MRI)-proven bone edema and autoantibodies were determined in these patients. A treat-to-target strategy initiated with synthetic DMARDs was employed for 12 months. If the patients achieved simplified disease activity index (SDAI) remission along with a reduction of the RA MRI scoring bone edema score to <33% as compared with baseline at 12 months, DMARD treatment was stopped and the clinical status was further observed for the following 12 months. Synthetic DMARDs were stopped at 12 months in 5 patients. One of the 5 was lost to follow-up because of sustaining an injury that required orthopedic surgery. Three of the remaining 4 patients showed continued SDAI remission that was DMARD-free without any evidence of radiographic progression for the following 12 months. Although this was a small clinical trial, we have shown-for the first time-that true remission of very early RA with poor prognosis factors can be achieved by treatment with synthetic DMARDs.

Delayed treatment with tumor necrosis factor inhibitors in incomplete responders to synthetic disease-modifying anti-rheumatic drugs shows an excellent effect in patients with very early rheumatoid arthritis with poor prognosis factors.

We aimed to investigate whether delayed treatment with tumor necrosis factor (TNF) inhibitors in incomplete responders to synthetic disease-modifying anti-rheumatic drugs (DMARDs) was effective among patients with very early rheumatoid arthritis (RA) with poor prognosis factors. We examined 22 patients with very early RA who were positive for anti-cyclic citrullinated peptide antibodies or IgM-rheumatoid factor. The mean disease duration at entry was 14.1 weeks. A treat-to-target strategy, aiming at simplified disease activity index (SDAI) remission, was initiated with synthetic DMARDs. SDAI remission was not achieved in 9 of the 22 patients with synthetic DMARDs alone, and TNF inhibitors were added in these patients. SDAI values in these 9 patients were further examined for the following 6 months. The TNF inhibitors (infliximab 8, etanercept 1) were added at a mean interval of 34.1 weeks after the initiation of synthetic DMARDs. SDAI remission was achieved in 4 of the 9 patients (44.4%) at 3 months and in 8 of the 9 patients (88.9%) at 6 months after the introduction of the TNF inhibitors. Radiographic damage had not progressed in these patients. Delayed treatment with TNF inhibitors is effective and tolerable for patients with very early RA with poor prognosis factors.

Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells.

OBJECTIVES: Zc3h12a is an RNA binding protein with a CCCH-type finger motif and is known to regulate mRNA metabolism. Previous reports suggest that Zc3h12a acts as a negative regulator of inflammatory processes because it is involved in the degradation of IL-6 mRNA. We investigate the effect of Zc3h12a on IL-6 production in fibroblast-like synovial cells (FLS) from rheumatoid arthritis (RA) patients. METHODS: The expression of Zc3h12a in FLS was determined by polymerase chain reaction. To knock down Zc3h12a expression in FLS, siRNA for Zc3h12a was transfected by the lipofection method. The supernatants were collected after siRNA transfection for the quantification of IL-6 production. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was examined by Western blotting. Cell proliferation was analysed by the Cell Counting Kit-8 assay after Zc3h12a knockdown. RESULTS: mRNA for Zc3h12a were demonstrated in FLS from RA patients. Zc3h12a transcripts were induced by LPS or IL-1ß in FLS. The production of IL-6 as well as its mRNA expression was significantly increased by the Zc3h12a knockdown. The Zc3h12a knockdown also induced the activation of STAT3, which the anti IL-6 receptor antibody inhibited. Proliferation of Zc3h12a-knockdown FLS increased significantly in the presence of recombinant soluble IL-6 receptor (sIL-6R). CONCLUSIONS: Our data suggest that Zc3h12a is a novel IL-6 regulator in FLS, which may be involved in the progression of RA.

Soluble urokinase plasminogen activator receptor as a useful biomarker to predict the response to adalimumab in patients with rheumatoid arthritis in a Japanese population.

OBJECTIVES: To determine whether soluble urokinase plasminogen activator receptor is a useful biomarker to predict the response to adalimumab (ADA) in Japanese patients with rheumatoid arthritis. METHODS: Rheumatoid arthritis (RA) patients administrated ADA (n=51) were classified as good responders (n=18) or nonresponders (n=9) according to the EULAR response criteria after 8 weeks of bi-weekly ADA administration. We examined the expression of cytokines and chemokines in these groups by antibody array methods. Positive results obtained by antibody array methods were further confirmed by ELISA. RESULTS: Antibody array has identified that the macrophage migration inhibitory factor (MIF), vascular endothelial growth factor (VEGF) and soluble urokinase plasminogen activator receptor (uPAR) decreased in the good responders to ADA whereas these changes were not observed in the non-responders. The decrement of serum uPAR was confirmed by ELISA in the good responders to ADA. Furthermore, serum uPAR at baseline was significantly high in non-responders compared with good responders. CONCLUSIONS: An antibody array is convenient for screening the expression of proteins of interest. Examination of serum uPAR at baseline and thereafter may be useful as a predictive biomarker for primary failure toward ADA in patients with RA.

Contribution of an adenine to guanine single nucleotide polymorphism of the matrix metalloproteinase-13 (MMP-13) -77 promoter region to the production of anticyclic citrullinated peptide antibodies in patients with HLA-DRB1*shared epitope-negative rheumatoid arthritis.

We examined whether matrix metalloproteinase-13 (MMP-13) contributes to disease susceptibility or severity of rheumatoid arthritis (RA). Eighty-seven patients with RA whose disease duration was <2 years and 71 healthy controls were enrolled in the study. Adenine (A) to guanine (G) single nucleotide polymorphism (SNP) of the -77 MMP-13 promoter region in RA and healthy controls was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Human leukocyte antigen (HLA)-DRB1 genotyping was also performed using the same populations. Anticyclic citrullinated peptide (anti-CCP) antibodies from RA patients at entry were studied, and their relationships were examined. The genotype and allele frequency of SNP of MMP-13 at -77 did not differ between RA patients and healthy controls. We focused on the RA patients who were negative for HLA-DRB1*shared epitope (SE) alleles and found that the seropositivity of anti-CCP antibodies with a titer >25 U/ml was high in the A/A genotype compared with the G/G genotype. The same characteristic was also found in HLA-DRB1*0405 allele-negative patients. Our data suggest that SNP of the -77 MMP-13 promoter region acts as a surrogate marker of anti-CCP antibody production in HLA-DRB1*SE allele-negative RA patients, which may reflect RA severity.

Comparative study of the detection of joint injury in early-stage rheumatoid arthritis by magnetic resonance imaging of the wrist and finger joints and physical examination.

OBJECTIVE: To verify whether magnetic resonance imaging (MRI)-proven joint injury is sensitive as compared with joint injury determined by physical examination. METHODS: MRI of the wrist and finger joints of both hands was examined in 51 early-stage rheumatoid arthritis (RA) patients by both plain and gadolinium diethylenetriaminepentaacetic acid-enhanced MRI. Synovitis, bone edema, and bone erosion (the latter two included as bone lesions at the wrist joints); metacarpophalangeal joints; and proximal interphalangeal joints were considered as MRI-proven joint injury. Japan College of Rheumatology-certified rheumatologists had given a physical examination just before the MRI study. The presence of tender and/or swollen joints in the same fields as MRI was considered as joint injury on physical examination. The association of MRI-proven joint injury with physical examination-proven joint injury was examined. RESULTS: A total of 1,110 sites were available to be examined. MRI-proven joint injury was found in 521 sites, whereas the other 589 sites were normal. Physical examination-proven joint injury was found in 305 sites, which was significantly low as compared with MRI-proven joint injury (P = 1.1 × 10(-12) versus MRI). Joint injury on physical examination was not found in 81.5% of the sites where MRI findings were normal. Furthermore, an association of the severity of MRI-proven joint injury with that of joint injury on physical examination was clearly demonstrated (P = 1.6 × 10(-15), r(s) = 0.469). CONCLUSION: Our present data suggest that MRI is not only sensitive but accurately reflects the joint injury in patients with early-stage RA.

Regulation of disease susceptibility and mononuclear cell infiltration into the labial salivary glands of Sjögren's syndrome by monocyte chemotactic protein-1.

OBJECTIVE: To investigate how monocyte chemotactic protein-1 (MCP-1) is involved in the pathological process of primary SS (pSS). METHODS: Guanine (G) to adenine (A) single nucleotide polymorphism (SNP) of the -2518 MCP-1 promoter region in pSS and healthy controls was determined by the PCR-restriction fragment length polymorphism technique. Immunohistochemical staining towards MCP-1 and C-C motif chemokine receptor-2 (CCR2), a receptor of MCP-1, of the labial salivary glands of pSS was investigated. Furthermore, the expression of MCP-1 and CCR2 from the cultured primary salivary epithelial cells was studied by RT-PCR, ELISA and western blotting. RESULTS: The genotype and allele frequency of SNP of MCP-1 at -2518 showed that the G/G genotype is low but the presence of allele A as well as the A-allele frequency are high in pSS (n = 52) as compared with healthy controls (n = 164). Immunohistochemistry showed in situ expression of MCP-1 and CCR2 in the ductal structure and infiltrating mononuclear cells (MNCs) of patients with pSS. Primary salivary epithelial cells in vitro from pSS produced MCP-1, which was significantly stimulated by IFN-gamma, as identified by both ELISA and RT-PCR. In contrast to MCP-1, CCR2 expression of primary salivary epithelial cells in vitro was not so changed by IFN-gamma. CONCLUSIONS: MCP-1 is involved in the disease susceptibility of pSS in the Japanese population. MCP-1 interactions with CCR2, which may be facilitated by IFN-gamma, are thought to perpetuate MNC infiltration into the salivary glands of SS.

Multiple bone fracture due to Fanconi's syndrome in primary Sjögren's syndrome complicated with organizing pneumonia.

Abstract A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren's syndrome (SS). Fanconi's syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi's syndrome with OP in SS is described.

Intake of phytochemicals among Japanese, calculated by the new FFF database.

Effects of phytochemicals on human health are suggested from various animal experiments, but human studies remain insufficient. We have constructed a database of various phytochemicals (polyphenols, carotenoids, and sulphur compounds) (http://www.life-science.jp/fff/) and estimated the amount of intake among Japanese population. The subjects were volunteers (16 males and 63 females, averagely aged 71 and 61, respectively) in Iwate city. Average BMI was 23 in both sexes. Intake of 36 phytochemicals was calculated from one-day dietary records of all intake, by multiplying concentrations of each phytochemical in foods. Phytochemicals with average intake of at least 10 micromole per day were catechin, isoflavones, isothiocyanate, ferulic acid, quercetin, cinnamic acid and chlorogenic acid. Chief component analysis yielded 12 factors (80%).