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Intestinal bacterial compositions of rheumatoid arthritis (RA) patients have been reported to be different from those of healthy people. Dysbiosis, imbalance of the microbiota, is widely known to cause gut barrier damage, resulting in an influx of bacteria and their substances into host bloodstreams in animal studies. However, few studies have investigated the effect of bacterial substances on the pathophysiology of RA. In this study, eighty-seven active RA patients who had inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or severe comorbidities were analyzed for correlations between many factors such as disease activities, disease biomarkers, intestinal bacterial counts, fecal and serum lipopolysaccharide (LPS), LPS-binding protein (LBP), endotoxin neutralizing capacity (ENC), and serum antibacterial substance IgG and IgA antibody levels by multiple regression analysis with consideration for demographic factors such as age, sex, smoking, and methotrexate treatment. Serum LBP levels, fecal LPS levels, total bacteria counts, serum anti-LPS from Porphyromonas gingivalis (Pg-LPS) IgG antibody levels, and serum anti-Pg-LPS IgA antibody levels were selected for multiple regression analysis using Spearman’s correlation analysis. Serum LBP levels were correlated with disease biomarker levels, such as erythrocyte sedimentation rate ( p < 0.001 ), C-reactive protein ( p < 0.001 ), matrix metalloproteinase-3 ( p < 0.001 ), and IL-6 ( p = 0.001 ), and were inversely correlated with hemoglobin ( p = 0.005 ). Anti-Pg-LPS IgG antibody levels were inversely correlated with activity indices such as patient global assessments using visual analogue scale (VAS) ( p = 0.002 ) and painVAS ( p < 0.001 ). Total bacteria counts were correlated with ENC ( p < 0.001 ), and inversely correlated with serum LPS ( p < 0.001 ) and anti-Pg-LPS IgA antibody levels ( p < 0.001 ). These results suggest that substances from oral and gut microbiota may influence disease activity in RA patients.

Objectives: To preliminarily evaluate the feasibility of maintenance therapy with reduced dose of intravenous abatacept (ABT) to 250 mg/body/month after achieving remission or low disease activity (LDA). Patients and methods: RA patients treated with ABT at 13 sites were enrolled in this prospective interventional pilot study during the period between March 2013 and March 2015. Inclusion criteria were (1) age at 20 years or older, (2) under treatment with monthly intravenous ABT at approved doses, (3) DAS28-CRP lower than 2.7 at least for 6 months, (4) agreed to join this trial with written informed consent and (5) body weight under 125 kg. Enrolled patients were maintained with intravenous monthly ABT at a reduced dose of 250 mg/body (MATADOR protocol). The primary end point was the proportion of the patients continued with MATADOR protocol at week 48. MATADOR protocol was discontinued upon disease flare or other reasons such as patients’ request or severe adverse event (AE). Disease activities and structural changes were also evaluated. Results: Fifty-three patients fulfilled the entry criteria and were followed for 1-year. MATADOR protocol was continued for 1-year in 43 (81%) of the evaluated patients. Three patients experienced severe AEs. Mean DAS28-CRP and remission rate were 1.56 and 88% when ABT reduced and 1.80 and 81% at 1-year, respectively. Structural remission was achieved in 34 out of 42 evaluated patients. Conclusions: Reduced dose of intravenous ABT was proposed as a feasible choice for maintenance therapy for RA after achievement of remission/LDA, although further randomized trials would be awaited.

To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA).In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients.When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes.TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

The recent paper from Kishikawa et al 1 provides an extremely important new insight on the concept of oral-gut microbiome axis and rheumatoid arthritis (RA) pathogenesis. Alterations in the gut microbiome at mucosal sites have been implicated in the pathogenesis of RA.2–4 Increasing evidence suggests a link between RA and periodontal infections caused by Porphyromonas gingivalis (Pg) .5 Oral infection by Pg in an animal model revealed increased serum levels of lipopolysaccharide (LPS), dysbiosis and aggravation of arthritis.6 7 Therefore, the pathogenesis of RA is considered to be associated with the immunomodulatory activity of oral and gut microbiome.8 However, few studies have explored the relationship between the oral-gut microbiome axis and RA pathogenesis. We previously investigated the relationship between RA disease activity using activity indices and biomarkers; the total bacterial counts and the counts of five well-known gut bacteria species; LPS-related biomarkers and IgG and IgA anti- Pg -LPS antibodies in 87 patients with established RA showing inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or exhibiting severe complications.9 (online supplementary table 1)### Supplementary data [annrheumdis-2020-217808supp001.pdf] Little significant relationship was observed between the counts of the total bacteria, five species of bacteria and activity indices and biomarkers.(table 1) The levels of LPS-related biomarkers, particularly serum LPS-binding protein (LBP), were positively correlated with activity indices and biomarkers, suggesting …

Hepatitis B virus (HBV) reactivation has been increasingly recognized in patients receiving chemotherapy and immunosuppressive therapy; however, the prevalence of HBV infection and rate of HBV screening in patients with rheumatic diseases remains unclear. In this study, we aimed to assess the prevalence of HBV infection and fulminant HBV hepatitis in patients with rheumatic diseases. We also investigated the rate of HBV screening before immunosuppressive therapy in patients with rheumatic diseases. A retrospective questionnaire survey was conducted in the North-east area (Tohoku) of Japan. Questionnaires, comprising 6 questions, were sent to 318 rheumatologists in May 2010, and responses were gathered until June 2011. In total, 71 rheumatologists (22.3%) responded to the survey. We enrolled 7,650 patients with rheumatoid arthritis (RA) and 1,031 patients with systemic lupus erythematosus (SLE). When limited to institutes at which almost all (≥ 90%) patients were tested for HBV serology, 1.1% (40/3,580) patients with RA and 0.3% (3/1,128) patients with SLE were positive for hepatitis B surface antigen (HBsAg), and 25.2% (177/703) patients with RA and 13.7% (34/248) patients with SLE were positive for hepatitis B core antibody (HBcAb). About one-third of rheumatologists did not check HBsAg and more than half did not check hepatitis B surface antibody (HBsAb) or HBcAb at all before therapy. Fulminant HBV hepatitis was observed in 1 RA patient who was current HBV carrier. In conclusion, the prevalence of HBV infection is high in patients with RA and SLE. HBV screening before immunosuppressive therapy should be strictly performed.

KUROE, K., YOSHIHARA, A., AKIYAMA, M., TAKEMORI, H., and YOSHIDA, Y. The Growth of Mouse Hybridoma Cells between Peyer's Patch Lymphocyte and Myeloma Cell in the Gastrointestinal Tract. A model for Human Multiple Lymphomatous Polyposis of the Gastrointestinal Tract. Tohoku J. Exp. Med., 1993, 170 (3), 197-205 - To elucidate the mechanism of multiple lesions in human primary lymphoma or multiple lymphomatous polyposis of the gastrointestinal tract, we developed a experimental model utilizing mouse hybridoma cells. Syngeneic mice were immunized with human hemoglobin via gastric incubation and a hybridoma clone (13c) between the Peyer's patch cell and mouse myeloma cell was obtained. The 13c cells were infused into normal syngeneic mice through a lateral tail vein. About 2 months after injection mice were sacrificed and their viscera were scrutinized histologically. All 11 mice receiving 13c showed multiple tumors at the colon, microscopic massive invasions at the small intestine, and scattered invasions at Peyer's patch, mesenteric lymph nodes and the spleen, exhibiting the similar distribution patterns as in human multiple lymphomatous polyposis of the gastrointestinal tract. ME-1 or MU-1 cells (hybridomas between P3 and mouse spleen cell) were distributed at the liver, spleen and paraaortic lymph nodes. Such migration patterns of 13c cells and their adherence to vessel walls suggest that multiple invasions may be lymphocyte homing receptor- mediated phenomena. - multiple lymphomatous polyposis of the gastrointestinal tract; gastrointestinal lymphoma; Peyer's patch; mouse hybridoma; lymphocyte homing

We have previously reported that the combination of murine recombinant interferon beta (Mu-rIFN beta) with murine recombinant interferon gamma (Mu-rIFN gamma) provided greater inhibition of tumor growth than did each one alone in MethA-bearing mice. In the present study the effect of addition of human recombinant interleukin-2 (Hu-rIL-2) to the combination of Mu-rIFN beta with Mu-rIFN gamma on tumor growth in BALB/c mice bearing syngeneic MethA fibrosarcoma was examined. Low doses of Hu-rIL-2 (5 x 10(3) U or 5 x 10(4) U at 3-day intervals) showed no antitumor activity, while a high dose of Hu-rIL-2 (5 x 10(5) U) showed profound growth inhibition. The administration of IL-2 (ranging between 5 x 10(3) U and 5 x 10(5) U) in addition to the combination of IFN beta and IFN gamma showed more augmented antitumor effects in a dose-dependent manner. Furthermore, the simultaneous administration of IL-2, IFN beta and IFN gamma had more effective therapeutic activity, compared with the sequential administration of interferons and IL-2. These findings indicated that IL-2 in combination with IFN beta and gamma was effective for cancer treatment.

A 66 year-old male patient with rheumatoid arthritis, was admitted due to bronchial pneumonia. Anti-nuclear antibody and anti-DNA antibody were both detected in the patient's serum and many LE-like cells were found in the pleural effusion. In addition, M-proteins(IgG-kappa type, IgM-kappa type) were detected in both serum and pleural effusion by immunofixation electrophoresis. Purified IgG fraction by gel filtration(Superdex 200HR) showed high titer of anti-nuclear antibody(x160) and anti-DNA(39.2 AU/ml) antibody. Furthermore, anti-DNA antibody was detected in the fraction III(fraction of M-protein) by ion-exchange chromatography. In conclusion, these results indicate that M-protein(IgG3-kappa type) contains anti-DNA antibody and it is suggests that M-protein induces the production of LE like cell in this case.

Neuropathological examination in a 48-year-women of SLE with chorea was performed. Histological examination of the putamen showed a widespread neuronal loss associated with reactive astrocyte proliferation and neuropil rarefaction at both sides. Disappearance of large neurons was more prominent than that of small ones. Although a few old and fresh microinfarcts were scattered in the same area, there was no significant pathological abnormality in small vessels. The caudate nuclei also showed a few irregular microinfarcts and spotty loss of neurons associated with reactive astrocytosis. These neuropathological changes might be related to the appearance of choreatic movement in patients with SLE.

A 66-year-old woman with malignant histiocytosis was treated with a combination of recombinant gamma interferon (GI-3) and etoposide. Following partial response to intravenous gamma interferon (9 x 10(6) units (U)/day) alone, the patient received an eight-months course of subcutaneous gamma interferon (0.5 x 10(6) U/day) and intravenous etoposide (100 mg/week). After two years, the patient remains in complete remission. The present case report discusses the successful use of combination gamma interferon and etoposide for the treatment of malignant histiocytosis.