Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

OBJECTIVE: The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS). METHODS: We conducted MWAS of the RA gut microbiome in the Japanese population (ncase=82, ncontrol=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis). RESULTS: Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls. CONCLUSION: Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome's role in RA aetiology.

Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis.

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

Diffusion Weighted Whole Body Imaging with Background Body Signal Suppression (DWIBS) Was Useful for the Diagnosis and Follow-up of Giant Cell Arteritis.

A 66-year-old woman with symptoms of fatigue and headache was diagnosed with giant cell arteritis (GCA). Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed the strong accumulation of FDG in the descending aorta, abdominal aorta, bilateral subclavian artery, and total iliac artery. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement at the descending aorta and abdominal aorta. We repeated FDG-PET and DWIBS 2 months after the initiation of therapy with prednisolone. In line with the FDG-PET findings, the signal enhancement of the aortic wall completely vanished on DWIBS. DWIBS may be a novel useful tool for the diagnosis and follow-up of GCA treatment.

Diffusion-weighted Whole-body Imaging with Background Body Signal Suppression (DWIBS) as a Novel Imaging Modality for Disease Activity Assessment in Takayasu's Arteritis.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Sporotrichal Tenosynovitis Diagnosed Helpfully by Musculoskeletal Ultrasonography.

A 72-year-old man presented with persistent oligoarthritis and positive results for rheumatoid factor and was suspected of having rheumatoid arthritis (RA). However, the musculoskeletal ultrasonography (MSUS) findings were not consistent with those of typical RA. He had undergone surgery for carpal tunnel syndrome, which allowed both histopathological and microbiological examinations to be performed. A synovial tissue culture was positive for Sporothrix schenckii, and he was diagnosed with sporotrichal tenosynovitis. He received anti-fungal therapy, and the sporotrichal tenosynovitis resolved. This case suggests that MSUS is a useful modality, and sporotrichal tenosynovitis, though rare, should be considered in the differential diagnosis of RA.

Hemophagocytic lymphohistiocytosis with leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still's disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma. CASE PRESENTATION: A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system. CONCLUSIONS: Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation.

Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study.

OBJECTIVES: To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti-citrullinated peptide antibody (ACPA) titers. METHODS: The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti-rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year. RESULTS: The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups. CONCLUSIONS: This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers.