CpG ODN (K3)-toll-like receptor 9 agonist-induces Th1-type immune response and enhances cytotoxic activity in advanced lung cancer patients: a phase I study.

BACKGROUND: Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients' immune responses. METHODS: The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29. RESULTS: Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46-181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8+ T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p = 0.0039) CD8+ T cells significantly increased. The median PFS was 398 days. CONCLUSIONS: This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined. TRIAL REGISTRATION: UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649.

Continuous Use of Etanercept During Pregnancy Does Not Affect TNF-Alpha Levels in Umbilical Cord Blood.

TNF-alpha-targeted therapies during pregnancy is a topic of interest in rheumatology. Etanercept (ETN) is expected to have lower transplacental transfer, however, clinical evidence is lacking on the usefulness and safeness of continuing etanercept throughout pregnancy. We here described the first reported case of relapsing polychondritis where continuous use of ETN throughout pregnancy was required. The patient was a pregnant Japanese woman who presented with bilateral ear cartilage redness, swelling, saddle nose and severe subglottic oedema. Due to severe systemic and life-threatened disease, we decided to continue using ETN throughout pregnancy and resulted in successful vaginal delivery. The treatment with ETN was successful and TNF-alpha levels in umbilical cord blood were not affected. The infant did not have any signs of chondritis although levels of anti-type 2 collagen antibodies in maternal and umbilical cord blood were similar, suggesting that anti-type 2 collagen antibodies crossed the placenta. This case is an important clinical experience that strengthens the safety to continue ETN during the entire pregnancy if necessary.

Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease.

OBJECTIVE: The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases. METHODS: Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects. RESULTS: Our case-control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, Podoviridae significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus-bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus-bacterium interaction analysis. We identified a symbiosis between Podoviridae and Faecalibacterium. In addition, multiple bacterial targets of crAss-like phages were identified (eg, Ruminococcus spp). CONCLUSION: Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.

Prokaryotic and viral genomes recovered from 787 Japanese gut metagenomes revealed microbial features linked to diets, populations, and diseases.

We reconstructed 19,084 prokaryotic and 31,395 viral genomes from 787 Japanese gut metagenomes as Japanese metagenome-assembled genomes (JMAG) and Japanese Virus Database (JVD), which are large microbial genome datasets for a single population. Population-specific enrichment of the Bacillus subtilis and ß-porphyranase among the JMAG could derive from the Japanese traditional food natto (fermented soybeans) and nori (laver), respectively. Dairy-related Enterococcus_B lactis and Streptococcus thermophilus were nominally associated with the East Asian-specific missense variant rs671:G>A in ALDH2, which was associated with dairy consumption. Of the species-level viral genome clusters in the JVD, 62.9% were novel. The ß crAss-like phage composition was low among the Japanese but relatively high among African and Oceanian peoples. Evaluations of the association between crAss-like phages and diseases showed significant disease-specific associations. Our large catalog of virus-host pairs identified the positive correlation between the abundance of the viruses and their hosts.

Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese.

OBJECTIVE: Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis. METHODS: We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals (Ncase=47, Ncontrol=203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data. RESULTS: Via species level phylogenetic analysis, we identified and validated increases of Streptococcus intermedius and Streptococcus anginosus in the patients with SLE. Microbial gene analysis revealed increases of Streptococcus-derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and ß-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with Streptococcus intermedius, an SLE-associated taxon. CONCLUSION: Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.

Therapeutic efficacy of denosumab for rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: Denosumab is used for osteoporosis because it inhibits osteoclast maturation and suppresses bone resorption. Although denosumab is expected to inhibit the bone erosion in RA, its therapeutic efficacy is not well established. The aim of this study was to estimate the effects of denosumab on RA through a meta-analysis. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Web of Science and Scopus were searched for original studies providing information on BMD, joint destruction and disease activity in denosumab-treated RA. A random-effects model was used in the meta-analysis. RESULTS: Of the 367 studies identified, 18 met the selection criteria. The BMDs of the lumbar spine, total hip and femoral neck at 12 months after denosumab treatment increased by 5.27% (95% CI: 4.37, 6.18), 2.82% (2.46, 3.18) and 3.07% (2.66, 3.48), respectively. In the sensitivity analysis, age and sex tended to influence the effect of denosumab therapy on the rate of variation of BMD, but not glucocorticoid use. The changes in the modified total sharp, erosion and joint space narrowing scores at 12 months after denosumab treatment were significantly smaller with denosumab than with placebo, although the DAS did not change after denosumab treatment. CONCLUSION: Although denosumab has an inhibitory effect on the bone resorption in RA, its effects might be influenced by the age and sex of RA patients, but not by glucocorticoid use.

Recovery from prolonged thrombocytopenia in patients with TAFRO syndrome: case series and literature review.

TAFRO syndrome is a newly proposed disease that is characterised by thrombocytopenia, anasarca, fever, reticulin fibrosis (or renal dysfunction), and organomegaly. Generally, high doses of corticosteroids are recommended for the initial treatment of TAFRO syndrome; however, some patients experience prolonged refractory thrombocytopenia after initiating such therapies. If corticosteroid treatment alone is ineffective, additional immunosuppressive therapies such as cyclosporine A are recommended. Since long-term use of immunosuppressive therapies with TAFRO syndrome sometimes causes serious infection, it is important to recognise the time to recovery from thrombocytopenia. In this study, we investigated how long it took to recover from thrombocytopenia, to aid clinicians in decision-making regarding the need to strengthen treatment for prolonged thrombocytopenia. Here, we describe three of our patients with TAFRO syndrome exhibiting prolonged thrombocytopenia. We also investigated the median period to recovery from this complication (defined as the time to increase the platelet count above 50,000/µL) after the initiation of high-dose corticosteroid treatment in our 3 cases and 38 peer-reviewed cases. We found that it took our patients 61 days to recover from thrombocytopenia; in comparison, our investigation of the 38 peer-reviewed case reports revealed a median recovery time of 47.5 days among previously reported patients. We showed the time to recovery from thrombocytopenia in patients with TAFRO syndrome for the first time. Our findings ought to be useful for decision-making among clinicians regarding the administration of other immunosuppressive treatments in addition to corticosteroid.

Systemic Lupus Erythematosus Associated with Ovarian Cancer.

Systemic lupus erythematosus (SLE) may be associated with various types of malignancy. However, SLE occurring with ovarian cancer seems rare, and reliable therapeutic approaches for such cases have yet to be identified. We herein report a case of SLE with ovarian cancer that was successfully treated with corticosteroid, plasmapheresis and chemotherapy. This case may provide new insights into treatment approaches for SLE with ovarian cancer.

Atypical Presenting Symptoms of Acute Onset Systemic Lupus Erythematosus with Enteritis and Cystitis.

Lupus enteritis and lupus cystitis are relatively rare manifestations of systemic lupus erythematosus. Some patients develop severe complications such as bowel perforation, infarction, obstruction, or irreversible bladder dysfunction. Early diagnosis is critical for management of lupus enteritis and cystitis. We report a 48-year-old Japanese man who presented with initial manifestations of abdominal pain, severe diarrhea, and bloody feces. The diagnosis was delayed due to atypical initial symptoms, resulting in clinical worsening. Physicians should be aware of typical computed tomography findings of lupus enteritis and lupus cystitis.