Hiroyuki Hagiyama

Signaling through the antigen receptor of B lymphocytes activates a p53-independent pathway of c-Myc-induced apoptosis

Deregulated expression of c-Myc has been shown to induce or enhance apoptosis in various different cell types. c-Myc requires p53 for apoptosis in some but not all the cell types, indicating heterogeneous mechanisms for c-Myc-induced apoptosis. In B lymphoma line WEHI-231, stable expression of c-Myc has been demonstrated to protect cells from BCR-mediated apoptosis. However, stable expression of c-Myc carrying pro-apoptotic functions may generate variant cells resistant to apoptosis. By utilizing an inducible system for c-Myc, we demonstrated here that deregulated expression of c-Myc induced apoptosis of WEHI-231 by itself, indicating that c-Myc induces apoptosis in WEHI-231 as is the case for other cell types. When transactivation of p53 was inactivated, WEHI-231 cells overexpressing c-Myc no longer underwent apoptosis in the absence of other stimuli, but showed markedly enhanced apoptosis in the presence of BCR ligation. These results indicate that deregulated c-Myc expression enhances apoptosis by a p53-independent pathway in the presence of BCR signaling but requires p53 for apoptosis in the absence of BCR crosslinking in WEHI-231. BCR ligation may thus activate a p53-independent pathway of c-Myc-induced apoptosis.

Two cases of acute respiratory distress syndrome resulting from adult-onset Still's disease

Abstract Adult-onset Stills disease (AOSD) is a systemic inflammatory disorder of unknown origin. Acute respiratory distress syndrome (ARDS) is a rare complication of AOSD, with only nine cases having been reported in the literature. Here, we describe two cases of AOSD complicated with ARDS that were successfully treated with immunosuppressive therapy, including corticosteroids. Although ARDS is a life-threatening complication in AOSD, early commencement of high-dose corticosteroids and mechanical ventilation improve the prognosis.

全身性エリテマトーデスに肥厚性硬膜炎を合併し，低髄圧症候群様の頭痛・難聴を呈した1例

We report a case of systemic lupus erythematosus (SLE) complicated with hypertrophic pachymeningitis. A 34-year old woman who was diagnosed as SLE in 1985 was admitted to our hospital for a high grade fever and a headache. Laboratory findings showed increased titer of anti-double strand DNA antibody and decreased number of platelets. She complained a severe headache and hearing loss which were worsened by head-up position, resembling the symptoms of intracranial hypotension. MRI findings revealed thickened dura and she was diagnosed as hypertrophic pachymeningitis. Both clinical symptoms and laboratory findings were resolved after methyl-prednisolone pulse therapy followed by a high dose of prednisolone. Although hypertrophic pachymeningitis is a rare complication with SLE, it should be considered in SLE patients with severe headache.

Assessment of Risks of Pulmonary Infection During 12 Months Following Immunosuppressive Treatment for Active Connective Tissue Diseases: A Large-scale Prospective Cohort Study

Objective. Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. Methods. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. Results. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22–6.74), ≥ 20 pack-years of smoking (2.63, 1.37–5.04), higher serum creatinine level (1.21, 1.05–1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35–5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36–17.01 per 1.0 mg/dl increase; 2.57, 1.28–5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Conclusion. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan

Abstract Objective: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA). Methods: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI). Results: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI <3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI <0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (ΔmTSS ≤0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328–10.489) and structural remissions (OR, 4.301; 95% CI, 1.298–14.243) at month 12 after adjusting for covariates. Conclusions: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.