Yun-Hong Cheon

Myeloid Deletion of SIRT1 Aggravates Serum Transfer Arthritis in Mice via Nuclear Factor-κB Activation

Objective SIRT1 modulates the acetylation of the p65 subunit of nuclear factor-κB (NF-κB) and plays a pivotal role in the inflammatory response. This study sought to assess the role of SIRT1 in rheumatoid arthritis (RA) using a myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mouse. Methods mSIRT1 KO mice were generated using the loxP/Cre recombinase system. K/BxN serum transfer arthritis was induced in mSIRT1 KO mice and age-matched littermate loxP control mice. Arthritis severity was assessed by clinical and pathological scoring. The levels of inflammatory cytokines in the serum and joints were measured by ELISA. Migration, M1 polarization, cytokine production, osteoclastogenesis, and p65 acetylation were assessed in bone marrow-derived monocytes/macrophages (BMMs). Results mSIRT1 KO mice showed more severe inflammatory arthritis and aggravated pathological findings than control mice. These effects were paralleled by increases in IL-1, TNF-α, TRAP-positive osteoclasts, and F4/80+ macrophages in the ankles of mSIRT1 KO mice. In addition, BMMs from mSIRT1 KO mice displayed hyperacetylated p65 and increased NF-κB binding activity when compared to control mice, which resulted in increased M1 polarization, migration, pro-inflammatory cytokine production, and osteoclastogenesis. Conclusion Our study provides in vivo evidence that myeloid cell-specific deletion of SIRT1 exacerbates inflammatory arthritis via the hyperactivation of NF-κB signaling, which suggests that SIRT1 activation may be beneficial in the treatment of inflammatory arthritis.

Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis

IntroductionAngiogenesis plays a critical role in synovial inflammation and joint destruction in rheumatoid arthritis (RA). Vascular endothelial growth factor A (VEGF-A) and angiopoietins are two important mediators of synovial angiogenesis. We have previously developed a novel chimeric decoy receptor, namely, double-antiangiogenic protein (DAAP), which can both bind VEGF-A and angiopoietins and block their actions. This study was performed to evaluate the antiarthritic effect of DAAP and the combination effect with the tumor necrosis factor α (TNF-α) inhibitor in collagen-induced arthritis (CIA).MethodsRecombinant DAAP, VEGF-Trap, Tie2-Fc and dimeric Fc proteins were produced and purified from CHO cells in large-scale bioreactors. CIA was induced in DBA/1 mice with type II collagen. The preventive effect of DAAP was determined and compared with other decoy receptors such as VEGF-Trap or Tie2-Fc, which block VEGF-A or angiopoietins, respectively. The clinical, radiographic, pathologic and immunohistochemical analyses were performed in CIA mice. The levels of matrix metalloprotease 3 (MMP-3) and interleukin 1β (IL-1β) were quantified by enzyme-linked immunosorbent assay, and receptor activator of nuclear factor κB ligand (RANKL) mRNA levels were measured by polymerase chain reaction. Finally, we investigated the combination effects of DAAP with a low dose of TNF-α decoy receptor (etanercept 10 mg/kg).ResultsOn the basis of clinical and radiographic evaluation, DAAP had a much greater inhibitory effect than VEGF-Trap or Tie2-Fc on arthritis severity and bone destruction. These inhibitory effects were accompanied by significantly diminishing pathologic abnormalities, CD31-positive vasculature and synovial infiltration by F4/80-positive macrophages. The levels of MMP-3, IL-1β and RANKL were much lower in the DAAP-injected group than those of the control. Furthermore, DAAP showed a therapeutic effect and a combination effect with etanercept when injected after arthritis onset in established CIA.ConclusionsDAAP has not only potent prophylactic effects on both inflammation and bone destruction but also therapeutic effects, alone and in combination with a TNF-α inhibitor in CIA mice. These results suggest that DAAP could be used as an effective new therapeutic agent for RA.

Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation

The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.

Bowel Perforation after Erlotinib Treatment in a Patient with Non-Small Cell Lung Cancer

Erlotinib is accepted as a standard second-line chemotherapeutic agent in patients with non-small cell lung cancer who are refractory or resistant to first-line platinum-based chemotherapy. There has been no previous report of bowel perforation with or without gastrointestinal metastases related to erlotinib in patients with non-small cell lung cancer. The exact mechanism of bowel perforation in patients who received erlotinib remains unclear. In this report, we report the first case of enterocutaneous fistula in a female patient with metastatic non-small cell lung cancer 9 months, following medication with erlotinib as second-line chemotherapy.

Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of beliefabout medication and illness perception

Background/Aims To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors. Methods A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence. Results The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease-modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (p = 0.872). In univariate analysis, beliefs in necessity and concerns of medication differed significantly in adherent and nonadherent patients (intentional or unintentional). When controlling for other factors that may impact medication nonadherence, less belief in necessity of medication (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.68 to 0.95) and greater emotional response to disease (OR, 1.19; 95% CI, 1.01 to 1.40) were important predictors of intentional nonadherence. Conclusions Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes.

Usefulness of plain radiography for assessing hypouricemic treatment response in patients with tophaceous gout.

To investigate whether plain radiography is useful for assessing the changes in gouty tophi size following hypouricemic therapy.

The association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression in patients with rheumatoid arthritis

Inflammation and trophic factors (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor-1) are associated with depression in the general population. Rheumatoid arthritis (RA) is a chronic representative inflammatory autoimmune disease; however, the association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression has not been sufficiently investigated. Therefore, we determined the prevalence of depression and risk factors for depression and deterioration of depressive symptoms in RA patients. In addition, we analyzed the association between disease activity, pro-inflammatory cytokines, trophic factors, and depression in RA (N = 474). Demographic and laboratory data were examined, and routine assessment of patient index data 3 (RAPID 3) and disease activity score 28-joint count C-reactive protein (DAS 28-CRP) was performed to assess disease activity of RA. Depression was measured using the Korean version of the Beck Depression Inventory-second edition (K-BDI II). A K-BDI score ≥18 was considered the cut-off for depression in accordance with a previous validation study. The serum level of pro-inflammatory cytokines and neurotrophic factors was assessed by enzyme-linked immune sorbent assay. The prevalence of depression was 32.4% in patients with RA. The severity of disease activity of RA (RAPID 3 score [OR 2.34; 95% confidence interval, CI 1.22-4.51], DAS 28-CRP [≥3.2] [OR 1.60, 95% CI 1.01-2.53]) and severity of fatigue (OR 1.26 95% CI 1.15-1.38) were associated with depression and deterioration of depressive symptoms in the multivariate analysis. Among the components of RAPID 3 and DAS 28-CRP, patient assessment for global health and abilities for daily performance were more related to depression. The level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-alpha) was not related to depression. The level of BDNF was significantly lower in RA patients with depression and was negatively correlated with K-BDI II score. Depression was related with the level of fatigue, low expression of BDNF, and high RA disease activity, which was associated with impaired ability to perform activities of daily life. Strict control of fatigue and disease activity to improve ones capacity to perform daily life activities would be important to regulate depression. The level of BDNF might be one of the possible biomarkers to predict or monitor depression in patients with RA.

Ankylosing spondylitis associated with primary aldosteronism in a middle-aged woman.

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Relationship between decreased lower extremity muscle mass and knee pain severity in both the general population and patients with knee osteoarthritis: Findings from the KNHANES V 1-2

Objective To identify the prevalence of and risk factors for knee pain and radiographic knee osteoarthritis (RKOA) and to investigate the relationship between decreased lower extremity muscle mass (DLEM) and knee pain severity. Methods Using data from the Korea National Health and Nutrition Examination Survey, 3,278 participants who were ≥50 years old and who underwent dual x-ray absorptiometry, plain knee radiographs and completed a knee pain questionnaire were enrolled. Lower extremity muscle mass (LEM) was defined as the sum of the fat-free soft tissue mass of the legs, and lower extremity muscle mass index (LMI) was calculated as LEM/body weight (%). DLEM was defined as an LMI more than two standard deviations below the mean of a gender-matched young reference group. Categorical variables were presented as numbers (weighted %). Results The prevalence of knee pain and RKOA were 22% (n = 721) and 34.7% (n = 1,234), respectively. Multivariate logistic regression analysis showed being female (OR 2.15, 95% CI 1.67–2.79), older (OR 1.03, 95% CI 1.01–1.04), less educated (OR 1.72, 95% CI 1.09–2.71), stiffness (OR 16.15, 95% CI 12.04–21.66), bed rest (OR 2.49, 95% CI 1.81–3.43), RKOA (OR 2.20, 95% CI 1.78–2.74) and DLEM (OR 1.54, 95% CI 1.09–2.17) were associated with knee pain. Participants with simultaneous RKOA and DLEM complained of more severe pain (pain score 7.18 ± 2.48) than those with knee pain without RKOA or DLEM (5.02 ± 2.44), those with only RKOA (6.29 ± 2.50), or those with only DLEM (6.78 ± 2.18) (P<0.001). These results remained after multivariate analyses of variance (MANOVAs). Conclusion The prevalence of knee pain and RKOA were 22% and 34.7%, respectively, in the general Korean population. DLEM was an independent risk factor for knee pain and it was associated with increased pain severity, regardless of RKOA.

Development of autoimmune hepatitis in a psoriasis patient without immunosuppressive therapy

We present a case of a 65-year-old man with psoriasis who developed autoimmune hepatitis (AIH) without receiving immunosuppressive therapy with either anti-tumor necrosis factor-α or methotrexate. The AIH had completely resolved at 2 months after prednisolone and azathioprine therapy. This case confirms the need to consider AIH in psoriasis patients who experience new elevations in liver enzymes. To our knowledge, this is first description of the development of AIH in an immunosuppressant-naïve patient with psoriasis.