Hirotoshi Kawashima

Correlation of Radiographic Progression with the Cumulative Activity of Synovitis Estimated by Power Doppler Ultrasound in Rheumatoid Arthritis: Difference Between Patients Treated with Methotrexate and Those Treated with Biological Agents

Objective. Our prospective study aimed to demonstrate that the cumulative synovial power Doppler (PD) ultrasound scores correlate with radiographic progression better than conventional measures in patients with rheumatoid arthritis (RA). We also investigated the difference between antirheumatic agents. Methods. Sixty-nine patients with RA who had recently received either methotrexate (MTX; n = 23), tumor necrosis factor (TNF) antagonists (n = 28), or tocilizumab (TCZ; n = 18) were enrolled. Patients underwent clinical, laboratory, and ultrasonographic assessment at baseline, 12 weeks, and 24 weeks. Radiographic damage was evaluated using van der Heijde modified total Sharp score (TSS) at baseline and 24 weeks. Results. Fifty-seven patients continued the same treatment regimen for 24 weeks and completed the study, and 21 patients (36.8%) showed radiographic progression during the study period. In all patients, ΔTSS significantly correlated both with cumulative 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP; ρ = 0.342, p = 0.009) and cumulative total PD scores (ρ = 0.357, p = 0.006). In MTX-treated patients, cumulative total PD scores significantly correlated with ΔTSS (ρ = 0.679, p = 0.004), whereas cumulative DAS28-CRP did not (ρ = 0.487, p = 0.056). However, cumulative total PD scores did not correlate with ΔTSS in TNF antagonist–treated or TCZ-treated patients. Conclusion. Our data confirm the evidence that synovial PD activity more accurately reflects active synovial inflammation (which actually causes joint destruction) than do conventional measures in patients treated with MTX. Our data also indicate that TNF antagonists can inhibit short-term radiographic progression in the presence of active synovitis.

Tumor Suppressor p53 Inhibits Systemic Autoimmune Diseases by Inducing Regulatory T Cells

The tumor suppressor p53 plays a central role in tumor suppression by inducing apoptosis, cell cycle arrest, senescence, and DNA repair. In addition to the antitumor functions of p53, accumulating evidence using systemic p53-deficient mice suggests that p53 suppresses autoimmunity. However, it remains unknown how p53 suppresses autoimmunity. In this study, we generated T cell–specific p53-deficient mice (CD4-Cre p53fl/fl mice, or p53 conditional knockout [cKO] mice) and found that aged p53-cKO mice spontaneously developed inflammatory lesions in various organs, including lung, liver, stomach, thyroid gland, submandibular gland, and kidney. Additionally, anti-nuclear Abs and autoantibodies against gastric parietal cells were detected in p53-cKO mice but not in control p53fl/fl mice (p53 wild-type mice). Importantly, the number of Foxp3+CD4+ regulatory T cells (Tregs) in the spleen and lung as well as in vitro differentiation of induced Tregs was significantly reduced in p53-cKO mice as compared with that in p53 wild-type mice. Regarding the mechanisms underlying p53-mediated Treg induction, p53 enhanced the transcription of Foxp3 by binding to the promoter and the conserved noncoding DNA sequence-2 of the Foxp3 gene. Taken together, these results suggest that p53 expressed in T cells functions as a suppressor for autoimmunity by inducing Treg differentiation.

Helios Enhances Treg Cell Function in Cooperation With FoxP3.

Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor β (TGFβ)–induced Treg cell function.

Erratum to: Bucillamine-induced yellow nail in Japanese patients with rheumatoid arthritis: two case reports and a review of 36 reported cases

Yellow nail syndrome is an idiopathic condition characterized by a triad consisting of yellow nail, lymphedema, and pulmonary manifestations. Thiol compounds such as D-penicillamine have been reported to be the major cause of drug-induced yellow nail syndrome in patients with rheumatoid arthritis (RA). We recently experienced two Japanese cases with RA who developed yellow nail under treatment with bucillamine, a thiol-containing anti-rheumatic drug developed and approved in Japan. We reviewed the literature for similar cases and identified 36 RA cases with bucillamine-induced yellow nail, mostly in Japanese medical journals. Most of these cases (90.3%) showed improvement of yellow nail after discontinuation of bucillamine, whereas lymphedema and pulmonary manifestations improved only in 30.8 and 35.0% of the patients, respectively.

Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity

Dendritic cells (DCs) play critical roles in determining the fate of CD4⁺ T cells. Among DC sub-populations, monocyte-derived inflammatory DCs (iDCs) have been shown to play an important role in the induction of adaptive immune responses under inflammatory conditions. Although previous studies have shown that DCs have an indispensable role in the induction of allergic airway inflammation and airway hyperreactivity (AHR) in murine asthma models, the precise roles of iDCs in the asthmatic responses remain largely unknown. We show here that T(h)2 cell-mediated inflammation in murine asthma models induces the expression of some markers of alternatively activated macrophage such as arginase 1 and resistin-like molecule-α in iDCs by a mechanism depending on the intrinsic expression of STAT6. In contrast, T(h)1 cell-mediated inflammation induces iDCs to express TNF-α and inducible nitric oxide synthase (iNOS), markers of TNF-α- and iNOS-producing DCs. Moreover, we show that iDCs under a T(h)2 environment play an important role in the induction of AHR, independently of allergic airway inflammation. Our results thus indicate the importance of iDCs in the induction of AHR as downstream effector cells in T(h)2 cell-mediated asthmatic responses.

STAT4 Is Required for IFN-β-Induced MCP-1 mRNA Expression in Murine Mast Cells

Background: Mast cells are immunocompetent cells that are found in almost all tissues and function as sentinels of immune responses. Recently, it has been shown that mast cells play significant roles in innate immune responses. However, it is still largely unknown whether signal transducers and activators of transcription 4 (STAT4), one of the STAT proteins under type I IFN signaling, is involved in type I IFN-mediated gene expression in mast cells. Methods: We investigated the role of STAT4 in IFN-β-induced gene expression in mast cells by using STAT4-deficient (STAT4–/–) bone marrow-derived mast cells (BMMCs). Results: STAT4 was expressed in BMMCs and activated in response to IFN-β but not to IL-12 or IL-23. The development of BMMCs as well as IgE-induced degranulation of BMMCs was normal in STAT4–/– mice. On the other hand, while IFN-β-induced mRNA expression of interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), protein kinase interferon-inducible double stranded RNA dependent (PKR), and myxovirus resistance 1 (Mx1) was similar between STAT4–/– BMMCs and wild-type (WT) BMMCs, IFN-β-induced MCP-1 mRNA expression was severely diminished in STAT4–/– BMMCs as compared with WT BMMCs. Conclusions: STAT4 plays an essential role in IFN-β-induced MCP-1 mRNA expression in mast cells.

Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics

ABSTRACT Objective: Periostin, a matricellular protein, is produced from airway epithelial cells and lung fibroblasts by IL-13. It has been suggested that periostin is involved in allergic inflammation and fibrosis. However, the usefulness of serum periostin measurement in the assessment of airway inflammation and remodeling and management of asthmatic patients is still debated. We aimed to determine whether serum periostin levels reflect eosinophilic airway inflammation and airway remodeling in asthma. Methods: We examined the relationship of serum periostin levels with clinical features, biomarkers for eosinophilic airway inflammation, fraction of exhaled nitric oxide (FeNO) levels and blood eosinophil counts, and pulmonary functions in 235 well-controlled asthmatic patients on inhaled corticosteroids (ICS) treatment. Results: Serum periostin levels were positively correlated with blood eosinophil counts (%) and age (r = 0.36 and 0.23, respectively), and were negatively correlated with body weight and FEV1/FVC (%) (r = −0.24 and − 0.23, respectively) in well-controlled asthmatic patients on ICS treatment (daily dose of 453 µg equivalent to fluticasone propionate). Blood eosinophil counts and serum periostin levels were similarly associated with increased FeNO levels (≥40 ppb) in the asthmatics. Serum periostin levels were better associated with fixed airflow limitation (FEV1/FVC ratio <70%) than FeNO levels, blood eosinophil counts or total IgE levels in the asthmatics. Multivariate analysis showed that fixed airflow limitation was significantly associated with high serum periostin levels (≥97 ng/ml) (Odds ratio 3.2). Conclusions: Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics on ICS treatment.

Sarcoidosis Presenting Addison's Disease.

We herein describe a second Japanese case of sarcoidosis presenting Addisons disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory findings, including bilateral hilar lymphadenopathy and elevated levels of serum angiotensin-converting enzyme and lysozyme, as well as the presence of noncaseating epithelioid granulomas. The patient also exhibited general fatigue, pigmentation, weight loss, hypotension and hyponatremia, suggestive of chronic adrenocortical insufficiency. An endocrine examination confirmed primary adrenocortical insufficiency. This case suggests the direct involvement of sarcoid granuloma in the adrenal glands.

Diffuse Cerebral Vasoconstriction in a Intravascular Lymphoma Patient with a High Serum MPO-ANCA Level

An 87-year-old woman presented with a 3-month history of fever, edema of the lower legs, and gait disturbance. A laboratory examination revealed high serum levels of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). Although microscopic polyangiitis was initially suspected and treated, the patient subsequently developed transient hemiparesis and disturbed consciousness. Brain magnetic resonance imaging/angiography revealed infarct-like lesions, pachymeningeal involvement, and diffuse cerebral vasoconstriction. A random skin biopsy confirmed the histological diagnosis of intravascular lymphoma. Diffuse cerebral vasoconstriction and a high serum MPO-ANCA level have rarely been reported in patients with intravascular lymphoma. Endothelial damage due to immune-mediated mechanisms, tumor derived factors, or the direct interaction of lymphoma cells with endothelial cells may commonly predispose patients to both cerebral vasoconstriction and the development of ANCAs.