Concentrically expanded reversed halo sign caused by nivolumab-related pneumonia.

Among immune-related adverse events, pneumonitis is relatively uncommon, and nivolumab-related pneumonitis may present with a reversed halo sign.

Comparison of pathological findings and accumulation of fluorin-18 fluorodeoxyglucose on positron emission tomography/computed tomography: A case of relapsing polychondritis.

A 70-year-old woman with a hoarse voice and dry cough was referred to our hospital. Positron emission tomography/computed tomography showed abnormal accumulation of fluorine-18 fluorodeoxyglucose (FDG) at the nasal septum, larynx, trachea, bronchus, and costal cartilages. The maximum standard uptake values of FDG accumulation in the nasal septum and costal cartilage were similar. Biopsies of the nasal septum and costal cartilage were performed. The patient was diagnosed with relapsing polychondritis (RP) based on the clinical features and pathological findings. Histopathological examination revealed progressive initial RP findings. The disease progression was different, even with the same FDG accumulation.

The Clinical Characteristics of Allergic Bronchopulmonary Mycosis Differ Among Pathogenic Fungi.

Background: Allergic bronchopulmonary mycosis (ABPM) occurs with fungi, other than Aspergillus fumigatus. However, the clinical characteristics of ABPM caused by non-Aspergillus species are unspecified. Methods: We retrospectively reviewed all patients with ABPM who visited to our hospital between April 2005 and December 2020. The causative fungi and clinical characteristics were analyzed. Patients were divided into the Aspergillus group and the non-Aspergillus group. Results: Fourteen patients and five patients were included in the Aspergillus group and the non-Aspergillus group, respectively. Compared to the Aspergillus group, the non-Aspergillus group had a significantly low serum immunoglobulin E level and low forced vital capacity. In addition, the non-Aspergillus group had a lower rate of the requirement for oral corticosteroid treatment and a low frequency of recurrence. Conclusion: Patients with non-Aspergillus ABPM had lower type 2 inflammation than did patients with allergic bronchopulmonary aspergillosis.

Granulomatosis with polyangiitis diagnosed during the treatment of otitis media with prednisolone in a patient with anti-neutrophil cytoplasmic antibody-associated vasculitis: A case report.

A 78-year-old woman with severe auditory disturbance was referred to our hospital and was diagnosed with otitis media with anti-neutrophil cytoplasmic antibody -associated vasculitis (OMAAV). The auditory disturbance improved moderately with prednisolone 40 mg/day, but multiple pulmonary masses were detected on chest computed tomography six months later. Transbronchial lung biopsy revealed granulomatosis with polyangiitis (GPA). Administration of prednisolone 50 mg/day and cyclophosphamide 500 mg once every two weeks for 12 weeks improved the lung lesions, but no further improvement in the hearing ability was observed. Prednisolone monotherapy was not able to prevent progression of OMAAV to GPA.

Pembrolizumab-induced aseptic meningitis in a patient with non-small cell lung cancer: A case report and literature review of aseptic meningitis as an immune-related adverse event.

Aseptic meningitis is a rare immune-related adverse event (irAE), which occurs during treatment with immune checkpoint inhibitors (ICIs). This condition has non-specific symptoms and exhibits no clear signs on magnetic resonance imaging (MRI). There are only a few reports of aseptic meningitis caused by pembrolizumab treatment for non-small cell lung cancer (NSCLC). The present study includes a report of such a case and a review of the related literature. A 67-year-old Japanese man received first-line pembrolizumab treatment for NSCLC and subsequently developed severe nausea and vomiting. No significant findings were observed following a computed tomography (CT) scan, MRI of the brain and upper gastrointestinal tract, or upper gastrointestinal endoscopy. Cerebrospinal fluid analysis revealed lymphocyte infiltration and elevation of the IgG index, without indications of metastasis or infection, which suggested the presence of aseptic meningitis. The symptoms immediately improved following prednisolone treatment, and aseptic meningitis was diagnosed as an irAE related to pembrolizumab treatment. Given that aseptic meningitis can cause non-specific symptoms, including headache and nausea, the possibility of an irAE should be considered in patients with non-specific symptoms who are receiving ICIs, and a cerebrospinal fluid examination should be performed.

Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts.

Background: Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, is involved in the pathogenesis of rheumatoid arthritis (RA). The omega-3 unsaturated fatty acid-derived metabolites resolvin (Rv) D1, RvE1, and maresin-1 (MaR1) have been reported as anti-inflammatory lipid mediators and are known as specialized pro-resolving mediators (SPMs). In this study, we aimed to investigate the anti-inflammatory effects of SPMs on TNF-α-induced responses in synovial fibroblasts. Methods: We investigated the effects of SPMs on gene expression and/or production of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), interleukin (IL)-6, and matrix metalloproteinase (MMP)-3, which are involved in TNF-α-induced synovitis in RA or OA synovial fibroblasts, by quantitative real-time PCR. We also investigated the effects of SPMs on the mitogen-activated protein kinase (MAPK) signaling pathway by western blotting. Anti-inflammatory effects of SPMs were evaluated by applying SPMs to cultured synovial fibroblasts, followed by TNF-α stimulation. Results: The induction of COX-2, mPGES-1, IL-6, and MMP-3 by TNF-α in synovial fibroblasts was not suppressed by omega 3-derived SPMs regardless of their origin such as RA or OA. SPMs had no effect on lipid mediator receptor gene expression induce by TNF-α and did not inhibit the TNF-α-activated MAPK signaling pathway. The production of COX-2 and IL-6 protein was significantly decreased by p38 inhibitor. Conclusion: Despite reports on the anti-inflammatory effect of omega 3-derived SPMs, its anti-inflammatory effect on TNF-α-induced responses was not observed in synovial fibroblasts. The reason may be that SPMs have no suppressive effect on p38 activation, which plays an important role in the production of inflammatory cytokines in synovial fibroblasts.

The efficacy and safety of reduced-dose sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with rheumatic diseases.

OBJECTIVES: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection. Sulfamethoxazole-trimethoprim (SMX/TMP) is the first-line drug for PCP prophylaxis. However, adverse events (AEs) force clinicians to alter or reduce the drug dosage. METHODS: We retrospectively reviewed all patients with rheumatic diseases who received SMX/TMP for prophylaxis and glucocorticoid therapy between April 2004 and March 2018. The rates of AEs, SMX/TMP discontinuation, and incidence of PCP were analyzed. Patients were divided into the conventional group and the dose-reduction group. RESULTS: One hundred forty-five patients and 75 patients were included in the conventional group and the dose-reduction group, respectively. Compared to the dose-reduction group, the conventional group had a significantly high frequency of AEs (10.7% vs. 24.1%; p = .017); however, the rate of discontinuing SMX/TMP was not significantly different (8.0% vs. 14.5%; p = .165). Thirteen conventional group patients required a reduced SMX/TMP dose because of AEs; no patient developed PCP. The conventional SMX/TMP dose and renal dysfunction were associated with AEs in multivariate analysis. CONCLUSION: Patients who received a reduced SMX/TMP dose did not have PCP and had a lower frequency of AEs. A reduction in SMX/TMP for PCP prophylaxis is effective and safe in patients with rheumatic disease.

Nivolumab-induced cholangitis in patients with non-small cell lung cancer: Case series and a review of literature.

Immune checkpoint inhibitors (ICIs), including nivolumab, have exhibited substantial benefits in the treatment of several types of cancers. However, treatment with ICIs is often accompanied by immune-related adverse events (irAEs), and a clear understanding of the precise indications and management of irAEs is important for harnessing the full potential of these agents. While skin- or gastrointestinal-associated irAEs have been relatively well studied, there are few reports regarding nivolumab-induced cholangitis. We retrospectively reviewed data from patients with advanced or recurrent non-small cell lung cancer who were treated with nivolumab between December 2015 and December 2018 at Tottori University in Japan. Among the 59 patients, we identified four patients who experienced nivolumab-induced cholangitis. Of these four patients, stable disease (SD) was observed in two patients (50%), while partial response (PR) was achieved in two patients (50%) under nivolumab treatment. Patients were treated with corticosteroid alone (n=2) or in combination with mycophenolate mofetil (MMF) (n=2); these treatments resulted in improvements in nivolumab-induced cholangitis in three patients. In conclusion, the present retrospective study identified four cases of nivolumab-induced cholangitis. The combination of corticosteroid and MMF was effective in two cases with grade 4 nivolumab-induced cholangitis. Further reports are needed to establish the optimal management of patients with this irAE.

Resolvin E1 Inhibits Osteoclastogenesis and Bone Resorption by Suppressing IL-17-induced RANKL Expression in Osteoblasts and RANKL-induced Osteoclast Differentiation.

BACKGROUND: Resolvin E1 (RvE1) derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid is known to be a potent pro-resolving lipid mediator that prevents chronic inflammation and osteoclastogenesis. We investigated the inhibitory effects of RvE1 on osteoclastogenesis and bone resorption to clarify its therapeutic potential for rheumatoid arthritis (RA). METHODS: Receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation was assessed with tartrate-resistant acid phosphatase staining. RANKL-induced bone resorption was assessed by the measurement of pit formation using calcium phosphate-labeled fluorescent polyanionic molecules in RAW264.7 cells as osteoclast precursors. The effects of RvE1 on the RANKL-induced mRNA expression of osteoclast-specific genes and transcriptional factors such as c-fos and nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells were measured by quantitative real-time PCR. The distribution of NFATc1 induced by RANKL was evaluated by immunofluorescence staining in RAW264.7 cells. To analyze the mechanism of the inhibitory effect of RvE1 on osteoclastogenesis, we measured IL-17-induced RANKL mRNA expression in MC3T3-E1 osteoblast cells treated with RvE1 using quantitative real-time PCR and determined the level of prostaglandin E2 (PGE2) production by enzyme-linked immunosorbent assay. RESULTS: RvE1 significantly suppressed RANKL-induced osteoclast differentiation and bone resorption. RvE1 inhibited the RANKL-induced mRNA expression of osteoclast-specific genes along with the transcription factors NFATc1 and c-fos. Moreover, NFATc1 translocation from the cytoplasm to the nucleus of RAW264.7 cells was suppressed following RvE1 treatment. RvE1 also inhibited IL-17-induced RANKL mRNA expression and PGE2 production in MC3T3-E1 cells. CONCLUSION: RvE1 inhibited osteoclastogenesis and bone resorption by suppressing RANKL-induced NFATc1 and c-fos expression in osteoclasts and IL-17-induced RANKL expression through the autocrine action of PGE2 in osteoblasts. Our data suggest RvE1 as a new therapeutic target of RA.

Splenic Infarction in Acute Cytomegalovirus and Human Parvovirus Concomitant Infection.

We present a case report of a 35-year-old woman who had splenic infarction. She had persistent high fever, systemic joint pain, and abnormal liver function. She was diagnosed with cytomegalovirus and human parvovirus B19 concomitant infection. Her coagulopathy test revealed no abnormal results. She was treated with intravenous ganciclovir for 13 days; consequently, her splenic infarction improved after 7 weeks. As per our knowledge, this is the first case of cytomegalovirus and parvovirus B19 coinfection complicated by splenic infarction. Cytomegalovirus and parvovirus B19 may induce a hypercoagulation state during the acute phase.

An onion farmer with a case of hypersensitivity pneumonitis caused by Aspergillus niger.

A 62-year old man was admitted to our hospital with a 2-week complaint of a dry cough, general fatigue, and dyspnea on effort. He has been an onion farmer for several years and developed these symptoms after cleaning up onion peels with air compressors. A chest roentgenogram and computed tomography showed a ground glass shadow in the bilateral upper lung field. Cellular analysis of the bronchoalveolar lavage fluid showed elevated total cell numbers and lymphocytes. Transbronchial lung biopsies revealed a non-caseating granuloma with both epithelioid cells and Langhans giant cells. After the admission, these symptoms and radiological findings gradually improved without any treatment. Then, a returning-home provocation test was positive only when he worked cleaning up onion peels with air compressors. A. niger was cultured from his workplace and black mold from the onion peels. The precipitation antibody and the antigen were both positive for Aspergillus. Therefore, we diagnosed this case as hypersensitivity pneumonitis caused by inhalation of A. niger. Although hypersensitivity pneumonia caused by A. niger is rare, physicians should aware the possibility of this condition in farmers because A niger is ubiquitously present in several vegetables and fruits.

Relationship between Oxidative Stress, Physical Activity, and Vitamin Intake in Patients with Asthma.

BACKGROUND: Oxidative stress plays an important role in the pathogenesis of bronchial asthma. Antioxidant nutrition and supplementation have been used to reduce oxidative stress. However, a clinical trial with antioxidant supplementation showed no beneficial effects in patients with asthma. On the other hand, physical activity is related to the prognosis of chronic obstructive pulmonary disease (COPD) and is also related to oxidant status. We investigated the relationships between oxidative stress, serum levels of vitamins, dietary vitamin intake, daily activities, and pulmonary functions in patients with asthma. METHODS: Eighteen patients with bronchial asthma were enrolled in this study. Reactive oxidative stress was assessed by measuring organic hydroperoxides (diacron reactive oxygen metabolites: dROM) in sera and by measuring H2O2 levels in exhaled breath condensates. The biological antioxidant capacity in serum was evaluated by measuring antioxidant potential capacity against ferric ion. We also assessed pulmonary functions, fraction of exhaled nitric oxide, serum levels of vitamins, dietary vitamin intake, and physical activities. RESULTS: There were no relationships between the index of oxidative stress (dROM and H2O2 in exhaled breathe condensates) and pulmonary functions, serum levels of vitamins, daily vitamin intakes, and activity levels in patients with asthma. CONCLUSION: The status of transient oxidative stress may not be related to daily activities, vitamin levels, and pulmonary functions in patients with asthma in a real-life setting. However, our results were obtained in the short-term period from a small number of subjects, so a large longitudinal study is required to ascertain the relationships between oxidative stress, physical activity and vitamin intake in patients with asthma.

γ-Tocotrienol Inhibits TGF-ß1-Induced Contractile Phenotype Expression of Human Airway Smooth Muscle Cells.

BACKGROUND: Tocotrienols, members of the vitamin E family, exist in four different isoforms (α, ß, γ and δ tocotrienol) that have can be protective against brain damage, as well as having anticancer effects in vivo and in vitro. We have shown that γ-tocotrienol inhibits human airway smooth muscle cell proliferation and migration induced by platelet-derived growth factor (PDGF)-BB by suppressing RhoA activation. In this study, we tested whether γ-tocotrienol modulates transforming growth factor (TGF) -ß-induced induction of human airway smooth muscle (ASM) into a contractile phenotype and concomitant synthesis of extracellular matrix proteins. METHODS: ASM cells were stimulated with TGF-ß1 (2 ng/mL) for 48 hours and the effect of γ-tocotrienol (50 µM) on α-smooth muscle actin, fibronectin and collagen I expression was assessed using Western blotting. The signaling pathways involved in TGF-ß1 stimulation were also investigated. RESULTS: TGF-ß1 increased α-smooth muscle actin, fibronectin and collagen Ⅰ abundance by 3- to 5-fold. This response was inhibited significantly by γ-tocotrienol. Furthermore, γ-tocotrienol suppressed RhoA activation, but did not affect Smad2 or Smad3 phosphorylation. CONCLUSION: These results indicate that γ-tocotrienol has potential for benefit in modulating on airway remodeling in asthma, likely via a mechanism involving the suppression of TGF-ß activation of RhoA.