Bin Yoo

Advanced glycation end products increases matrix metalloproteinase-1, -3, and -13, and TNF-α in human osteoarthritic chondrocytes

We investigated the effects of advanced glycation end products (AGE) which accumulate in articular cartilage with age in human osteoarthritic chondrocytes. We found AGE‐BSA significantly increased MMP‐1, ‐3, and ‐13, and TNF‐α in a dose‐dependent manner. AGE‐BSA‐stimulated JNK, p38, and ERK and NF‐κB activity. The stimulatory effect of AGE‐BSA on MMP‐1, ‐3, and ‐13 were reversed by treatment with specific JNK, p38 inhibitors, suggesting JNK and p38 are involved in AGE‐BSA‐induced MMPs and TNF‐α. We also observed that NF‐κB is involved in AGE‐BSA‐induced TNF‐α. Pretreatment with soluble receptor for AGE (sRAGE) also reduced AGE‐stimulated MMPs and TNF‐α, implicating the involvement of receptor for AGE (RAGE). In conclusion, accumulation of AGE may have a role in the development of osteoarthritis by increasing MMP‐1, ‐3, and ‐13, and TNF‐α.

Effect of interleukin‐32γ on differentiation of osteoclasts from CD14+ monocytes

OBJECTIVE Interleukin-32 (IL-32) induces various inflammatory molecules in human monocytes and differentiation of monocytes into macrophage-like cells. This study was undertaken to evaluate the effects of IL-32gamma, the most biologically active isoform, on the differentiation and activation of osteoclasts. METHODS CD14+ monocytes were obtained from healthy volunteers, and samples of synovial tissue and synovial fluid were obtained from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). The concentration and expression levels of IL-32gamma in RA and OA samples were evaluated by enzyme-linked immunosorbent assay and immunoblotting, respectively. To examine the osteoclastogenic effects and functional activities, isolated monocytes were treated with either IL-32gamma or IL-17 in the presence or absence of soluble RANKL (sRANKL) on a culture system and on Osteologic disks. The expression of RANKL and osteoprotegerin (OPG) messenger RNA (mRNA) in RA fibroblast-like synoviocytes (FLS) was measured using reverse transcription-polymerase chain reaction (PCR) and real-time PCR. RESULTS The concentration and expression levels of IL-32gamma were higher in the RA samples than in the OA samples. Upon costimulation with sRANKL, the osteoclast count and resorbed area increased more significantly in the IL-32gamma-stimulated cultures than in those stimulated with IL-17. In the IL-32gamma-treated group without sRANKL stimulation, osteoclasts were differentiated, but the cells displayed low resorption activity. In RA FLS, RANKL mRNA expression increased in the presence of both IL-32gamma and IL-17. However, transcription of OPG decreased following IL-32gamma stimulation, resulting in a significant increase in the RANKL:OPG ratio. CONCLUSION Our results suggest that IL-32gamma is a potent mediator of active osteoclast generation in the presence of sRANKL. Moreover, this novel cytokine creates more favorable conditions for osteoclastogenesis in the RA joint by increasing the RANKL:OPG ratio in FLS.

Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients treated with anti-TNFα agents: A retrospective analysis of 49 cases

Clinical guidelines regarding anti-viral prophylaxis for HBV surface antigen (HBsAg) carriers starting anti-TNFα agents are not yet fully established, even in endemic regions of HBV infection. We retrospectively collected the clinical data of 52 HBsAg carriers with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) that had been administered anti-TNFα treatment at seven medical centers in South Korea. Periodic data of liver function tests and serum HBV DNA were both utilized to assess HBV reactivation. The YMDD motif mutation of HBV DNA polymerase was tested in lamivudine-treated patients with elevated HBV DNA. Three of the 52 patients were excluded from the analysis. Of the 49 analyzed patients, 20 patients received anti-viral prophylaxis (15 lamivudine, five entecavir) with anti-TNFα treatment. The remaining 29 patients were treated with anti-viral agents if needed at the discretion of the clinician and did not receive prophylaxis. Of the 29 patients who did not receive primary prophylaxis, two (6.9%) developed viral reactivation within a year of anti-TNFα treatment. In the prophylaxis group, one patient developed viral reactivation at week 64 of anti-TNFα therapy attributed to YMDD mutation caused by lamivudine. Patients with HBV reactivation all responded well to anti-viral therapy. In summary, anti-viral prophylaxis helped preventing HBV reactivation in HBsAg carriers with RA or AS starting anti-TNFα, yet mutation in the YMDD motif of HBV DNA polymerase could be detrimental to some patients under long-term lamivudine prophylaxis.

Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis : A 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial

BACKGROUND SKI306X, which consists of biologically active ingredients from Clematis mandsburica, Tricbosantbes kirilowii, and Prunella vulgaris, was developed and tested in preclinical trials in Korea. Those studies found that SKI306X was associated with an anti-inflammatory and analgesic effect, and that it can delay the destruction of cartilage in rheumatoid arthritis (RA). OBJECTIVE The aim of this study was to compare the pain relief and tolerability of SKI306X and celecoxib in patients with RA. METHODS This study was a 6-week, multicenter, randomized, double-blind, double-dummy, Phase III, noninferiority clinical trial. Eligible patients were aged 18 to 80 years, had a history of RA with a disease duration of > or =3 months, and were functional American College of Rheumatology (ACR) class I, II, or III before entry. After a washout period of 2 weeks, patients were randomized to SKI306X 200 mg TID or celecoxib 200 mg BID for 6 weeks. The primary end point was a change in patient assessment of pain intensity using a visual analog scale (VAS). The secondary end points were a 20% improvement in response rate as defined by the ACR (ACR20) and the frequency of rescue medication use. Results after 3 and 6 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. AEs were identified based on spontaneous reports by patients during interviews conducted by the investigators and the study coordinator. RESULTS Two hundred twenty-two Korean patients from 7 medical centers were assessed and 183 were enrolled and randomized to 1 of 2 treatment groups. Ninety-one patients (10 male, 81 female; mean [SD] age, 52.13 [12.64] years; mean [SD] duration of RA, 9.08 [10.23] years; no. [%] of ACR class I, II, and III, 13 [14.29], 44 [48.35] and 34 [37.36] patients, respectively) received SKI306X 200 mg TID and 92 patients (10 male, 82 female; mean [SD] age, 51.78 [10.94] years; mean [SD] duration of RA, 8.78 [7.78] years; no. [%] of ACR class I, II, and III, 14 [15.22], 44 [47.83], and 34 [36.96] patients, respectively) received celecoxib 200 mg BID. An analysis of the change in reported pain intensity as determined by VAS (mm) score between baseline and week 3 (mean [SD], 13.64 [16.62] vs 14.45 [15.89]), and between baseline and week 6 (18.4 [20.8] vs 17.9 [19.1], respectively) suggested that SKI306X was not inferior to celecoxib. The number of patients who achieved ACR20 response rate was not significantly different between the SKI306X group and the celecoxib group at week 3 (16/87 [18.4%] vs 24/87 [27.6%], respectively) and at week 6 (29/87 [33.3%] vs 29/87 [33.3%]). The frequency of rescue medication use was not significantly different between the SKI306X group and celecoxib group at week 3 (54/87 [62.1%] vs 47/87 [54.0%], respectively) or week 6 (57/87 [65.5%] vs 49/87 [56.3%]). Drug-related AEs were reported by 27 (29.7%) patients in the SKI306X group and 22 (23.9%) patients in the celecoxib group. The most frequent drug-related AEs were epigastric pain (9/91 [9.9%]) in the SKI306X group and glutamyltranferase elevation (4/92 [4.3%]) in the celecoxib group. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. CONCLUSION The results of this study suggest that SKI306X was generally well tolerated and not inferior to celecoxib in regard to pain relief in these Korean patients with RA.

Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: An 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients

BACKGROUND S-adenosylmethionine (SAMe) has antiinflammatory and analgesic effects and has been reported to ameliorate the pain and dysfunction of osteoarthritis (OA). The metabolism of SAMe can be affected by geographic or ethnic factors. However, its efficacy and tolerability versus NSAIDs have not been reported in an Asian population. OBJECTIVE This study compared the efficacy and tolerability of SAMe 1200 mg/d and nabumetone 1000 mg/d in Korean patients with knee OA. METHODS This study was an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV clinical trial. Eligible patients were aged >18 years and had knee OA according to the clinical and radiologic criteria of the American College of Rheumatology, with a symptom duration of > or =3 months and with a baseline pain rating of >40 mm on a visual analog scale (VAS) or a pain rating on the VAS that was increased by >10 mm or 20% during the washout period compared with the screening visit. After a washout period of 2 weeks, patients with OA were randomly assigned to receive SAMe 1200 mg/d (400 mg TID) or nabumetone 1000 mg once a day in the evening for 8 weeks. The primary end point was the patients assessment of pain intensity using a VAS at week 8, and the secondary end points were functional class, patients global assessment of disease status, physicians global assessment of response to therapy, and the Western Ontario and McMaster Universities (WOMAC) index. Adverse events were assessed based on spontaneous reports by patients during interviews and by laboratory tests. RESULTS One hundred thirty-four patients, all Asians, were randomly allocated to 1 of 2 treatment groups: 67 patients (56 women, 11 men; mean [SD] age, 63.9 [8.2] years) received SAMe 400 mg TID, and 67 patients (60 women, 7 men; mean age, 62.1 [8.4] years) received nabumetone 1000 mg once daily for 8 weeks. An analysis of changes in pain intensity between weeks 0 and 8 found that both SAMe and nabumetone effectively reduced pain intensity from baseline in each group (mean [SD] change: SAMe, -13.0 [20.8] mm, P < 0.001; nabumetone, -15.7 [20.9] mm, P < 0.001), and the degree of decrease in pain intensity was not significantly different between groups. Secondary end points showed significant improvements from baseline to 8 weeks in both groups. The patients global assessment of disease status, physicians global assessment of response to therapy, and WOMAC index scores were not significantly different between the groups. Use of acetaminophen as rescue medication did not differ significantly between the groups during weeks 0 to 4 (SAMe, 88.5% [54/61]; nabumetone, 81.3% [52/64]) or weeks 4 to 8 (SAMe, 79.5% [35/44]; nabumetone, 68.5% [37/54]). No significant differences were observed between the treatments in the proportions of patients with all adverse events (SAMe, 35.8% [24/67]; nabumetone, 31.3% [21/67]), drugrelated clinical or laboratory-determined adverse events (SAMe, 22.4% [15/67]; nabumetone, 25.4% [17/67]), or discontinuations due to any adverse events (SAMe, 13.4% [9/67]; nabumetone, 10.4% [7/67]). CONCLUSION This study found no significant differences in pain relief or tolerability between treatment with SAMe or nabumetone over 8 weeks in Korean patients with knee OA.

Protective effects of ginsenoside Rg3 on human osteoarthritic chondrocytes

ObjectivesTo explore whether Rg3, a major and especially potent ginsenoside, modulates human osteoarthritic (OA) chondrocyte senescence.MethodsIsolated chondrocytes were cultured in medium containing interleukin-1 beta (IL-1β) with or without Rg3. The expression levels of mRNAs encoding aggrecan (ACAN), a major structural proteoglycan, type II collagen (COL2A1), and metalloproteinases (MMP) -1, -3, and -13, respectively, were determined using real-time PCR. Cellular senescence was detected by measuring senescence-associated β-galactosidase (SA-β-Gal) activity. Chondrocyte telomerase activity also served as a senescence marker.ResultsChondrocytes stimulated by IL-1β showed increased MMP-1, MMP-3, and MMP-13 levels, whereas the expression of COL2A1 and ACAN decreased. However, in cells co-treated with IL-1β and Rg3, the levels of MMP-1 and MMP-13 were lower than in cells treated with IL-1β alone, and COL2A1 and ACAN expression levels recovered from the low values seen when cultured only in the presence of IL-1β. Also, compared to vehicle-treated controls, IL-1β stimulation alone resulted in an increased number of SA-β-Gal-positive cells, while co-incubation with IL-1β and Rg3 significantly suppressed the expression of this senescence marker. Chondrocytes cultured with Rg3 showed significantly higher proliferative and telomerase activities than did control cells.ConclusionsThese findings indicate that Rg3 protects the cell against the development of chondrocyte senescence in osteoarthritis.

Enhanced cough response to hyperpnea with cold air challenge in chronic cough patients showing increased cough sensitivity to inhaled capsaicin

Background: Although many chronic cough patients have complained of an induced cough by cold air contact, the clinical relevance of cold air to inducing a cough and the diagnostic value of a hyperpnea with cold air (HCA) challenge to detect a hyperreactive cough reflex have not yet been investigated.

Febuxostat in Hyperuricemic Patients With Advanced CKD

Age, y 58.7 6 13.9 59.6 6 14.0 54.4 6 12.5 Male sex, n (%) 227 (77.2) 186 (75.9) 41 (83.7) Follow-up, mo 14.5 6 11.1 14.8 6 11.3 12.7 6 10.2 Kidney disease cause Diabetic nephropathy 74 (25.1) 66 (26.9) 8 (16) IgA nephropathy 50 (16.9) 42 (17.1) 8 (16) Primary glomerulonephritis 30 (10.2) 24 (9.8) 6 (12) Polycystic kidney 14 (4.7) 9 (3.7) 5 (10) Urate nephropathy 4 (1.4) 4 (1.6) 0 (0) Lupus nephritis 2 (0.7) 1 (0.4) 1 (2) Others 120 (41.0) 99 (40.5) 21 (43)

The usefulness of pancreatoscopic examination in patients with mucinous ductal ectasia

Mucinous ductal ectas ia는 다량의 점액이 쉐관내에 존재하여 춰l관이 확장되고 점액이 유두 개 구부로 유출되는 특징적인 십이지장경 소견 및 례관 조영 소견을 보이는 비교적 드문 질환이다 저자등은 최근 경구 혜관경 검사를 시행하여 특징적인 춰l관경 검사 소견을 관찰할 수 있었던 mucinous ductal ectasia 3예를 쉐관경 검사의 유용성에 대한 고찰과 함께 보고하는 바이다 십이 지장경 소견상 3예 모두 개대된 유두 개구부와 점액 유출이 보였고 쉐관경 검사상 백색조의 점 액 배경내에 유두상 또는 융모상의 점막 증식이 관찰되었다 Mucinous ductal ectasia 환자에서 춰l 관경 검사는 방사선학적 검사상 진단이 확실치 않은 쉐장 낭성 종양의 감별 진단, 춰l관 조영상 에서 음영결손의 감별 진단에 유용할 뿐만 아니라 특히 수숨을 시행하는 환자에서 병변 부위의 범위 판정과 절제 범위 결정에 도움이 될 수 있다고 사료된다.

IL-17A+GM-CSF+ Neutrophils Are the Major Infiltrating Cells in Interstitial Lung Disease in an Autoimmune Arthritis Model

Objective To gain a better understanding of the pathogenesis of autoimmune arthritis-associated interstitial lung disease (ILD), we sought to identify the characteristics of lung-infiltrating cells in SKG mice with ILD. Methods We injected curdlan in SKG mice at 8 weeks of age, and identified the presence of ILD by PET-MRI at 20 weeks post-injection and histological analysis at 22 weeks post-injection. Lung-infiltrating cells were examined by flow cytometry. Analysis of serum cytokines by the Luminex multiplex cytokine assay was performed at 14 and 22 weeks post-injection, and cytokine profiles before and after the development of ILD were compared. Opal multiplexed immunofluorescent staining of lung tissue was also performed. Results At 20 weeks post-injection, curdlan-treated SKG mice developed not only arthritis but also lung inflammation combined with fibrosis, which was identified by PET-MRI and histological analysis. The majority of inflammatory cells that accumulated in the lungs of curdlan-treated SKG mice were CD11b+Gr1+ neutrophils, which co-express IL-17A and GM-CSF, rather than TNF-α. Compared with 14 weeks post-injection, serum levels of GM-CSF, MCP1, IL-17A, IL-23, TSLP, and soluble IL-7Rα had increased at 22 weeks post-injection, whereas those of IFN-γ, IL-22, IL-6, and TNF-α remained unchanged. Furthermore, IL-23, CXCL5, IL-17A, and GM-CSF, but not TNF-α, were observed in immunofluorescent-stained lung tissue. Conclusion We found that IL-17A+GM-CSF+ neutrophils represented the major inflammatory cells in the lungs of curdlan-treated SKG mice. In addition, GM-CSF and IL-17A appear to play a more important role than TNF-α in ILD development.