Takashi Ozaki

Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: a case series and literature review

OBJECTIVE Relapsing polychondritis (RPC) is relatively rare and early diagnosis is difficult. We investigated the utility of fluorodeoxyglucose (FDG)-PET/CT for the diagnosis of RPC and evaluation of disease activity. METHODS Five RPC patients undergoing FDG-PET/CT in our hospital between 2006 and 2012 were studied. Eight RPC cases examined by PET reported in the literature were also assessed. Data from a total of 13 patients were analysed. RESULTS Typical FDG accumulation was noted in the tracheobronchial trees of nine patients, the costal cartilage of five, joints of five, larynx of four, nasal cavity/paranasal sinuses of three, auricles of three, lymph nodes of three and the aorta of one. One patient showed nasal chondritis on a PET scan despite the absence of nasal changes on physical examination. Of five patients with costochondritis, four remained asymptomatic. Of nine patients with airway FDG accumulation, eight developed respiratory symptoms and all had CT abnormalities. In the other patient, airway FDG accumulation was evident despite the absence of airway symptoms and a lack of abnormalities in the respiratory function test and CT. PET also revealed bronchial chondritis in asymptomatic patients. The mean maximum standardized uptake values (SUVmax) of the upper and lower airways was 5.79 (s.d. 2.87) and 6.47 (s.d. 4.08), respectively. In five patients with a PET after treatment, FDG accumulation had diminished with symptomatic and inflammatory improvement. CONCLUSION FDG-PET/CT is a potentially powerful tool for the early diagnosis of RPC, especially in patients without easily biopsied organ involvement. This modality also facilitates evaluation of disease extent and disease activity during treatment.

Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice

ABSTRACT Zika fever, a mosquito‐borne infectious disease caused by Zika virus (ZIKV), is an epidemic disease for which no effective therapy has been established. The recent outbreaks of ZIKV in Brazil and French Polynesia have been linked to a considerable increase in the incidence of fetal microcephaly and other diseases such as Guillain‐Barre syndrome. Because there is currently no specific therapy or vaccine, the early exploitation of a method to prevent expansion of ZIKV is a high priority. To validate commonly used antiviral drugs, we evaluated the effect of ribavirin, a drug used to treat hepatitis C with interferon‐&bgr; (IFN‐&bgr;), on ZIKV replication. In mammalian cells, we observed an inhibitory effect of ribavirin on ZIKV replication and ZIKV‐induced cell death without cytotoxic effect. Furthermore, we found that STAT1‐deficient mice, which lack type I IFN signaling, were highly sensitive to ZIKV infection and exhibited lethal outcome. Ribavirin abrogated viremia in ZIKV‐infected STAT‐1‐deficient mice. These data suggest that the inhibition of viral RNA‐dependent RNA polymerases may be effective for treatment of ZIKV infection. Our data provide a new insight into the mechanisms for inhibition of ZIKV replication and prevention of Zika fever. HighlightsRibavirin inhibits ZIKV replication in mammalian cells.Ribavirin prevents ZIKV‐induced apoptosis and cell death.Ribavirin administration abrogates viremia in ZIKV‐infected STAT1‐deficient mice.Leading to a prolonged survival.

Successful tocilizumab therapy in seven patients with refractory adult-onset Still's disease

To evaluate the effects of tocilizumab (TCZ) on adult-onset Stills disease (AOSD), we reviewed medical records of seven patients with refractory AOSD treated with TCZ at our institution. TCZ therapy might allow rapid corticosteroid tapering and help maintain remission status, that is, resolution of clinical symptoms and normalization of biomarkers such as CRP and ferritin. Patients, however, should be monitored for the development of macrophage activation syndrome when TCZ is administered for active AOSD.

Characteristics of 10 patients with paraneoplastic rheumatologic musculoskeletal manifestations

Abstract Objectives. To evaluate the possible correlation of malignant neoplasms and paraneoplastic rheumatologic syndromes. Methods. We studied a series of 10 patients with paraneoplastic rheumatological syndromes collected from our Division of Rheumatic Disease between 2006 and 2012. Results. Our series consisted of four males and six females, with a mean age of 65.5 years (range, 57–78 years). Of the 10 patients recruited, six had hematological malignancies and four had solid cancers. Malignancies were diagnosed after rheumatic symptoms were reported in all patients. Compared to solid tumors, hemopathy was diagnosed at a later time point (16.2 vs. 7.3 months). Extra-articular symptoms were associated with rheumatologic musculoskeletal manifestations in 100% of the patients. Polyarthritis was the main rheumatologic musculoskeletal manifestation (50% of the patients). The other manifestations were oligopolyarthritis and polymyalgia rheumatic-like symptoms (20% of the patients). Symmetric arthritis was present in 60% of the patients, and the remaining patients developed asymmetric arthritis. Musculoskeletal manifestations completely regressed in 66.7% of the patients after cancer therapy. When tumor relapse was observed, rheumatic symptoms did not recur in any of our patients (100%). Conclusions. Rheumatic disorders with atypical clinical presentation in older patients, poor response to usual treatment and systemic features such as weight loss and clinical findings compatible with well-recognized paraneoplastic syndromes should alert clinicians to the possible coexistence of an occult malignancy. Especially in cases of paraneoplastic rheumatic/musculoskeletal manifestations associated with hemopathy, the primary disease is unlikely to have manifested yet, making the diagnosis difficult. Thus, caution is required.

Large-vessel involvement in granulomatosis with polyangiitis successfully treated with rituximab: A case report and literature review

Granulomatosis with polyangiitis (GPA) is primary necrotizing vasculitis, which predominantly affects small to medium vessels. Herein, we describe a case of a 60-year-old female with GPA who developed inflammatory wall thickening localized in the aortic arch, upper abdominal aorta, and pulmonary artery. The wall thickening in the large vessels and other GPA lesions such as lung nodules and orbital mass had failed to respond to high-dose glucocorticoids combined with cyclophosphamide; however, all were successfully treated with rituximab. Our literature review identified 24 cases of large-vessel involvement associated with GPA. Luminal stenosis, occlusion, or wall thickening were observed in 8, periaortitis in 11, and aneurysms in 5 cases. The most commonly affected vessel was the abdominal aorta (12 cases), followed by the thoracic aorta (6 cases), subclavian artery (4 cases), and internal carotid artery (4 cases). Glucocorticoids were used in 23 cases, 20 of which received combination therapy with cyclophosphamide. Surgical or endovascular therapies were performed in 10 cases with aneurysmal dilatation. This is the first case showing the potential efficacy of rituximab for refractory large-vessel involvement associated with GPA.

Rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome

Abstract We herein report two cases of myelodysplastic syndrome with rheumatic manifestations. (Case 1) A 70-year-old man presented with fever, arthritis and bone pain and developed cranial nerve palsy caused by an epipharyngeal mass. Steroid therapy led to a prolonged remission of the febrile condition and mass lesion. (Case 2) An 82-year-old male was treated for intractable polyarthritis and fever with steroid therapy, and serious side effects resulted in lethal pneumonia. We herein describe the entire course of steroid therapy in these two cases. Various rheumatic manifestations in myelodyaplastic syndrome often require empirical steroid therapy. It was effective for the soft tissue mass in Case 1, in which indolent lymphoma could not be denied, and was only partially effective for Case 2 of the febrile and putatively benign conditions, suggesting heterogeneous nature of rheumatic complications in myelodysplastic syndrome.

l-Leucine influx through Slc7a5 regulates inflammatory responses of human B cells via mammalian target of rapamycin complex 1 signaling

Abstract Objectives: Increasing evidence has revealed the close correlation between immune cell functions and their intracellular metabolism. Mammalian target of rapamycin complex 1 (mTORC1) is the important metabolism-modulating signal that regulates cellular activities. In certain types of cell, it is known that mTORC1 activation depends on influx of l-leucine through an amino acid transporter, Slc7a5. In B cells, however, the expression and the role of Slc7a5 have never been investigated. Methods: CD19+ B cells were obtained from peripheral blood of healthy adults and stimulated by a toll-like receptor 9 ligand, CpG oligodeoxynucleotides. The expression of Slc7a5 and l-leucine uptake were evaluated by RT-PCR, flow cytometry and radioisotope assay. Then the effect of Slc7a5 inhibition on mTORC1 activity, plasmablast differentiation and production of IgG and inflammatory cytokines were analyzed. Results: CpG stimulation significantly induced the expression of Slc7a5 in B cells, resulting in l-leucine influx. Furthermore, inhibition of Slc7a5 abrogated mTORC1 activation, plasmablast differentiation, and production of IgG and inflammatory cytokines in CpG-stimulated B cells. Conclusion: l-leucine influx through Slc7a5 critically regulates mTORC1 activity and the immunological responses of human B cells. Slc7a5-mTORC1 pathway may provide a novel therapeutic strategy for autoimmune diseases.

Oral administration of antibiotics results in fecal occult bleeding due to metabolic disorders and defective proliferation of the gut epithelial cell in mice

Antibiotics sometimes exert adverse effects on the pathogenesis of colitis due to the dysbiosis resulting from the disruption of gut homeostasis. However, the precise mechanisms underlying colitogenic effects of antibiotic‐induced colitis are largely unknown. Here, we show a novel murine fecal occult bleeding model induced by the combinatorial treatment of ampicillin and vancomycin, which is accompanied by an enlarged cecum, upregulation of pro‐inflammatory cytokines IL‐6 and IL‐12, a reduction in Ki‐67‐positive epithelial cell number and an increase in the apoptotic cell number in the colon. Moreover, gas chromatography–tandem mass analysis showed that various kinds of metabolites, including glutamic acid and butyric acid, were significantly decreased in the cecal contents. In addition, abundance of butyric acid producer Clostridiales was dramatically reduced in the enlarged cecum. Interestingly, supplementation of monosodium glutamate or its precursor glutamine suppressed colonic IL‐6 and IL‐12, protected from cell apoptosis and prevented fecal occult blood indicating that the reduced level of glutamic acid is a possible mechanism of antibiotic‐induced fecal occult bleeding. Our data showed a novel mechanism of antibiotic‐induced fecal occult bleeding providing a new insight into the clinical application of glutamic acid for the treatment of antibiotic‐induced colitis.

Two patients in the same family with anti-ARS antibody-associated myositis.

during exertion and weakness of the left arm. In July 2003, her chest radiograph revealed bilateral infi ltrates, which were not seen in a radiograph obtained in September 2002. She was diagnosed with ILD and administered pulsed intravenous methylprednisolone, which was ineff ective, followed by low-dose methylprednisolone. She was referred to our hospital in October 2003. Her physical examination revealed fi ne crackles in the left lower lung fi eld and muscle weakness of the proximal upper and lower extremities. Gottron ’ s sign was present on the fi ngers and elbows. Laboratory tests indicated that the serum CK and CRP levels were in the normal range, and the KL-6 was elevated at 836 U/ml. Anti-PL-12 (alanyl-tRNA synthetase) antibody was detected by RNA immunoprecipitation, whereas other serologic test results were negative. Her chest HRCT showed ground-glass attenuation, traction bronchiectasis and interlobular septal thickening in the bilateral lobes (Figure 1). There were no abnormal electromyogram fi ndings. She was diagnosed with dermatomyositis (DM) and prescribed 50 mg/ day of oral prednisolone. Although no signifi cant improvement was found in her HRCT, only a slight progression of ILD had occurred in the following nine years. Among 122 patients with PM or DM in the 2004 – 2012 database of our institution, no other familial cases were identifi ed. Although several cases of familial myositis have been reviewed [1], to our knowledge, this is the fi rst report of familial cases of myositis with ILD and anti-ARS antibodies, suggesting a relationship between myositis with anti-ARS antibodies and genetic or environmental factors. O ’ Hanlon et al. [2] demonstrated that the primary human leukocyte antigen susceptibility factors in African-American patients with idiopathic infl ammatory myopathy (IIM) with anti-ARS antibodies were DRB1 * 03 and * 04, whereas those in Euro-American patients with IIM with anti-ARS antibodies were B * 0801 and DRB1 * 0301. Although genetic examination could not be performed in our patients, some genetic factors may have aff ected their disease susceptibilities. None of the other members in their family were screened for anti-ARS antibodies. Our two cases lived separately at the time of onset, which was almost four years apart. Therefore, it is not known whether potential environmental factors contributed to the development of myositis and anti-ARS antibodies in these patients. The mother presented with typical PM with anti-EJ antibody, whereas her daughter had DM with anti-PL-12 antibody. In Mod Rheumatol, 2013; Early Online: 1–2