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Objective The aim of this study was to assess the role of thioredoxin-interacting protein (TXNIP) in nuclear factor-κB (NF-κB) signaling and the interaction between TXNIP and NOD-like receptor protein 3 (NLRP3) in activation of the NLRP3 inflammasome in monosodium urate (MSU)-induced inflammation. Methods Interleukin-1β (IL-1β), IL-18, caspase-1, phospho-IκBα (pIκBα), phospho-NF-κB, (pNF-κB), and TXNIP in U937 macrophage-like cells treated with MSU crystals were analyzed using western blotting and real-time polymerase chain reaction (RT-PCR). Expression of these molecules was also assessed in U937 macrophages transfected with TXNIP siRNA and treated with antioxidants. Results U937 macrophages treated with MSU crystals showed increased expression of IL-1β, IL-18, caspase-1, and TXNIP and activation of NF-κB signaling, which were strongly inhibited by addition of antioxidants or transfection with TXNIP siRNA. Intracellular translocation of TXNIP from the nucleus to mitochondria was observed in cells treated with MSU crystals. And quercetin and ascorbic acid suppressed translocation of TXNIP. Binding between TXNIP and NLRP3 under oxidative stress caused by MSU crystals was observed and was blocked by quercetin or ascorbic acid. Conclusion This study showed that activation of MSU-induced NLRP3 inflammasome requires TXNIP-mediated NF-κB signaling pathway and intracellular TXNIP shifting.

Objective There is some evidence that an enhanced Th17 response is attributable to interleukin-1β (IL-1β) matured by activation of the NLRP3 inflammasome. In this study, we assessed the expression of NLRP3 inflammasome components and their associated proinflammatory cytokines in patients with ankylosing spondylitis (AS). Methods A total of 23 male patients with AS and 29 male controls were recruited and peripheral blood mononuclear cells (PBMCs) were collected. Transcript and protein expression of NLRP3, caspase-1, ASC, IL-1β, IL-17A, and IL-23 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay, respectively. Data were analyzed using Spearman's correlation coefficient, Mann-Whitney U test, and receiver operating characteristic curves. Results Higher mRNA expression of NLRP3, ASC, IL-1β, IL-17A, and IL-23 was noted in the PBMCs of AS patients than those of controls (p = 0.013, p = 0.001, p = 0.002, p = 0.011, and p = 0.037, respectively). Similarly, protein expression of NLRP3, caspase-1, ASC, IL-1β, IL-17A, and IL-23 was higher in the AS group than the control group. There were significant correlations among NLRP3, caspase-1, ASC, IL-1β, IL-17A, and IL-23 expression in patients with AS, except for a weak association between NLRP3 and IL-17A. Treatment of cultured PBMCs with 10 ng of lipopolysaccharide induced NLRP3, caspase-1, ASC, IL-1β, IL-17A, and IL-23 expression, which was marked suppressed by treatment with ascorbic acid. Conclusion This study suggests that the NLRP3 inflammasome may be involved in the pathogenesis of AS and therefore a potential therapeutic target in AS.

High-mobility group box 1 (HMGB1) was originally identified as a highly conserved non-histone DNA-binding factor and demonstrated to be a potent mediator in inflammatory diseases. We performed this study to investigate the role of HMGB1 in the pathogenesis of uric acid-induced inflammation in human U937 macrophages. To simulate uric acid-induced inflammation, human U937 macrophages were treated with monosodium urate (MSU) crystals. In addition to determining the effects of MSU crystal treatment on expression of various genes and proteins, cells were transfected with interfering RNA (siRNA) for HMGB1, or caspase-1 and then treated with MSU. Expression of interleukin-1β (IL-1β), IL-18, HMGB1, and caspase-1 was detected in human U937 cells and peripheral blood mononuclear cells (PBMCs) in gout patients and healthy controls by western blot analysis or quantitative real-time polymerase chain reaction. Transcript expression of IL-1β, IL-18, caspase-1, HMGB1 in PBMCs was significantly higher in active gout patients than inactive gout patients and healthy controls. The protein levels of these molecules were significantly increased by stimulation of U937 cells with 0.2 mg/ml MSU crystals. Stimulation of U937 cells with MSU crystals induced translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular release. U937 cells transfected with caspase-1 siRNA had significantly lower HMGB1 expression in the cytoplasm and supernatant than non-transfected cells. Antioxidants, such as N-acetyl- l -cysteine and quercetin, markedly inhibited the nuclear-to-cytoplasmic translocation of HMGB1 and its release into the extracellular milieu. In conclusion, HMGB1, regulated by the enzymatic activity of caspase-1, is a crucial mediator in uric acid-induced inflammation.

The aim of this study was to identify the association of NLRP3 inflammasome-induced inflammation with disease activity and damage in Sjögren's syndrome.A total of 33 female patients with Sjögren's syndrome and 34 sex- and age-matched, healthy controls were consecutively enrolled. The mRNA expression levels of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in peripheral blood mononuclear cells (PBMCs) were measured, as well as serum IL-1β and IL-18 protein expression levels. Protein levels for mature IL-1β (p17) and caspase-1 (p20) were analyzed by western blotting. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Sjögren's Syndrome Disease Damage Index (SSDDI) were also evaluated.Patients with Sjögren's syndrome group showed higher expression of mRNA IL-1β and IL-1β at the protein level than controls (p0.001 of both). Enhanced expression of mature IL-1β (p17) and caspase-1 (p20) proteins in Sjögren's syndrome were noted, compared to controls. The mRNA levels of caspase-1 and ASC were significantly increased in patients with Sjögren's syndrome compared to controls (p=0.001 and p=0.002, respectively). Based on the SSDDI scores, patients with damage (SSDDI≥1) had higher IL-1β mRNA expression compared to patients without damage (SSDDI=0) (p=0.034). SSDDI scores were closely related with IL-18 protein levels (r=0.357, p=0.041). The levels of IL-1β mRNA and IL-1β protein were correlated with the mRNA level of NLRP3 (r=0.597, p0.001 and r=0.502, p=0.003, respectively). IL-1β mRNA expression was responsible for the presence of damage for Sjögren's syndrome (p=0.034).This study confirmed that NLRP3 inflammasome-mediated inflammation might be implicated in the pathogenesis of Sjögren's syndrome.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 20 mars 2017

Matrix metalloproteinases-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis and migration of vascular smooth muscle cells (VSMCs) after an arterial injury. In this study, we investigated the potential molecular mechanisms underlying the anti-atheroscleroic effects of melittin, a major component of bee venom, in human aortic smooth muscle cells (HASMCs). Melttin significantly suppressed MMP-9 and MMP-2 secretion, as well as TNF-α-induced MMP-9 expression in the HASMCs. In addition, we found that the inhibitory effects of melittin on TNF-α-induced MMP-9 protein expression are associated with the inhibition of MMP-9 transcription levels. Mechanistically, Melittin suppressed TNF-α-induced MMP-9 activity by inhibiting the phosphorylation of p38 and ERK1/2, but did not affect the phosphorylation of JNK and Akt. Reporter gene and western blotting assays showed that melittin inhibits MMP-9 transcriptional activity by blocking the activation of NF-κB via IκBα signaling pathway. Moreover, the matrigel migration assay showed that melittin reduced TNF-α-induced HASMC migration. These results suggest that melittin suppresses TNF-α-induced HASMC migration through the selective inhibition of MMP-9 expression and provide a novel role of melittin in the anti-atherosclerotic action.

To identify the clinical features of elderly-onset rheumatoid arthritis (EORA) and their impact on disease outcome.A total of 3169 rheumatoid arthritis (RA) patients were recruited as part of the Korean Observational Study Network for Arthritis, the nationwide cohort of South Korea. Patients were stratified according to age at disease onset:40 years (younger age-onset RA, n = 1167), between the ages of 40 and 59 (middle-aged-onset RA, n = 1516), and ≥60 years (EORA, n = 486). To evaluate the significance of differences in clinical features among these 3 groups, we performed analysis of variance (anova) and the χ(2) test. We used multivariable logistic regression analysis to examine the association of onset age with functional disability measured with Health Assessment Questionnaire-Disability Index (HAQDI).EORA patients were associated with high HAQDI (≥1) in bivariable analysis [odds ratio (OR) 1.36, confidence interval (CI) 1.04-1.77]. However, in multivariable analysis, not elderly onset but patients' age, female gender, high disease activity, disease duration over 10 years, and comorbidity with cardiovascular disease were associated with high HAQDI. Only in a predefined subgroup with disease duration10 years, elderly onset was an independent influencing factor for the functional disability of RA patients (OR 3.04, CI 1.85-5.67: disease duration of5 years, OR 3.07, CI 1.64-5.74: disease duration of 5 to 10 years).Disease onset in older age was associated independently with functional disability of RA patients who have relatively short disease duration.

Object This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway. Methods IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time–polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining. Results IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK. Conclusion This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA.

Objective Numerous epidemiologic data have shown that smoking may play a role in the disease manifestations or severity of chronic musculoskeletal pain. The authors of the present study investigated the effect of smoking on clinical features such as pain, fatigue, functional impairment, and psychiatric features in the Korean population with fibromyalgia syndrome (FMS). Methods A total of 336 patients with FMS were consecutively enrolled from 10 medical centers which participated in the Korean national fibromyalgia survey. Smoking was divided into current smokers and non-smokers. Instruments of FMS assessment included tender points, Fibromyalgia Impact questionnaire (FIQ), 36-item Medical Outcomes Study Short-Form Health Survey (SF-36), Brief Fatigue Inventory (BFI), Brief Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI)-1 and STAI-2, and social family support and social friend support. Statistical analyses included Chi-square test, Fisher's exact test, Mann-Whitney U test, and multivariate logistic regression analysis. Results Thirty-three patients (9.8%) out of 336 participants were current smokers. The number of tender points ( P = 0.037), BFI ( P = 0.026), general health of SF-36 ( P = 0.028), BDI ( P = 0.014), syncope ( P = 0.024), and reflex sympathetic dystrophy ( P = 0.003) showing significance between current smokers and non-smokers were not associated with smoking habits after adjustment. The significance of the number of tender points ( P = 0.009), scores of total tender points ( P = 0.032), BDI ( P = 0.038), general weakness ( P = 0.047), and reflex sympathetic dystrophy ( P = 0.011) was observed between randomized non-smokers ( n = 55) and smokers ( n = 33). In addition, the number of tender points ( P = 0.027, OR = 1.379) was associated with smoking status after adjustment. The analysis between randomized non-smokers ( n = 45) and smokers ( n = 22) in female FMS patients showed that BDI in FMS was associated with smoking status ( P = 0.023, OR = 1.077) after logistic regression analysis. Conclusions This study revealed that smoking habits may, in part, influence pain or functional and psychiatric features in FMS patients. The impact of smoking on clinical features in FMS should be assessed in a larger study population.

Resume Objectif De nombreuses donnees epidemiologiques ont montre que le tabac peut jouer un role dans les manifestations de la maladie ou la severite des douleurs de l’appareil locomoteur. Les auteurs de la presente etude se sont interesses a l’effet du tabac sur les composantes cliniques comme la douleur, la fatigue, les perturbations fonctionnelles et les caracteristiques psychiatriques dans une population coreenne atteinte du syndrome fibromyalgique (SFM). Methodes Trois cent trente-six patients atteints du SFM ont ete consecutivement inclus dans l’etude. Ils ont ete recueillis a partir de dix centres medicaux participant a l’etude nationale coreenne sur la fibromyalgie. Le statut tabagique etait divise en fumeurs actuels et non-fumeurs. Les moyens de mesure d’evaluation du SFM etaient les sites douloureux, le questionnaire d’impact de la fibromyalgie (QIF), les 36 items du questionnaire generaliste qualite de vie SF-36, le questionnaire brief fatigue inventory (BFI), le questionnaire brief depression inventory (BDI), les questionnaires state-trait anxiety inventory (STAI)-1 et STAI-2, et l’etude des supports sociaux et familiaux. Les analyses statistiques comprenaient le test du Chi 2 , le test exact de Fisher, le test U de Mann-Whitney ainsi qu’une analyse de regression logistique multivariee. Resultats Trente-trois (9,8 %) des 336 patients participant a l’etude etaient fumeurs. Le nombre de sites douloureux ( p = 0,03), le BFI ( p = 0,02), l’etat general a partir du SF-36 ( p = 0,02), le BDI ( p = 0,01), la syncope ( p = 0,02), et la dystrophie sympathique reflexe ( p = 0,003) montraient une difference significative entre les fumeurs actuels et les non-fumeurs, mais n’etaient pas associes aux habitudes tabagiques apres ajustement. Une significativite entre le nombre de sites douloureux ( p = 0,009), le score total de nombre de sites douloureux ( p = 0,03), le BDI ( p = 0,03), la faiblesse generale ( p = 0,04), et la dystrophie sympathique reflexe ( p = 0,01) etait observee entre les sujets randomises non-fumeurs ( n = 55) et les fumeurs ( n = 33). De plus, le nombre de points douloureux ( p = 0,02, OR = 1,37) etait associe au statut tabagique apres ajustement. Une analyse entre les sujets randomises non-fumeurs ( n = 45) et fumeurs ( n = 22) chez la femme SFM a montre que le BDI dans le SFM etait associe au statut tabagique ( p = 0,02, OR = 1,07), apres analyse de regression logistique. Conclusions Cette etude montre que les habitudes tabagiques sont susceptibles d’influencer en partie les composantes douloureuses ou fonctionnelles et psychiatriques des patients atteints du SFM. L’impact du tabac sur les composantes cliniques du SFM devrait etre etudie sur une plus large population.

Resume Objectifs Evaluer le degre de fibrose hepatique a l’aide des techniques non invasives de l’elastometrie ultrasonore et des marqueurs biochimiques chez des patients atteints de polyarthrite rhumatoide (PR) traites par methotrexate (MTX). Methodes Nous avons revu les dossiers medicaux de 177 patients consecutifs atteints de PR ayant recu du MTX pendant plus de trois ans. L’elastometrie ultrasonore et l’evaluation des marqueurs biologiques seriques de la fibrose hepatique ont ete evalues de maniere prospective. Les resultats ont ete compares avec ceux d’une population de sujets temoins sains. Nous avons evalue la correlation entre la dose totale cumulee de MTX et, d’une part, les valeurs de l’elastometrie (kilo pascal [kPa]), d’autre part, les marqueurs biochimiques seriques. Deux groupes de patients ont ete compares selon que la dose totale cumulee de MTX etait inferieure ou egale a 4 g (groupe 1) ou superieure a 4 g (groupe 2). Resultats La dose totale cumulee moyenne de MTX etait de 3,988 ± 1,566 mg, avec des extremes allant de 652,5 mg et 10,415 mg. La valeur moyenne de la durete du foie etait de 4,01 ± 0,77 kPa. Ni les valeurs de la durete du foie (en kPa), ni les marqueurs seriques n’etaient correles avec la dose totale cumulee de MTX. En revanche, ils etaient correles avec le rapport ASAT/ALAT, le ratio ASAT/plaquettes, le taux d’haptoglobine. Les valeurs moyennes de la durete hepatique (kPa) n’etaient pas statistiquement differentes entre les patients des groupes 1 et 2. Une fibrose hepatique significative est rare chez les patients atteints de PR traites par des doses cumulees importantes de MTX et n’est pas detectee de maniere precise par les anomalies des transaminases. Conclusion En tenant compte du rapport benefice-risque de la ponction-biopsie hepatique, l’elastometrie pourrait etre proposee comme une methode diagnostique supplementaire.

Objective This study was designed to assess the degree of liver fibrosis with transient elastography and noninvasive biochemical methods in rheumatoid arthritis patients treated with methotrexate. Methods We reviewed the medical records of rheumatoid arthritis patients who were administered methotrexate for more than 3 years. Transient elastography was performed and serological markers of liver fibrosis were evaluated by prospectively and was compared with the result of healthy control group. A correlation of the cumulative dose of methotrexate with the elastography value (kPa) or the level of serological markers was assessed. Two subgroups of patients were compared; patients who received a cumulative dose of methotrexate of less than 4000 mg (group 1) and more than 4000 mg (group 2). A total of 177 consecutive rheumatoid arthritis patients were evaluated. Results The mean cumulative dose of methotrexate was 3988 ± 1566 mg with doses ranging from 652.5 to 10,415 mg. The mean elastography value of all patients was 4.01 ± 0.77 kPa. The kilopascal values and levels of biochemical markers did not correlate with the cumulative dose of methotrexate, but did correlate with the AST to ALT ratio, AST to platelet ratio index, haptoglobin level. Mean kilopascal values were not statistically different for group 1 and group 2 patients. For rheumatoid arthritis patients treated with a high cumulative dose of methotrexate, significant liver fibrosis is rare and is not accurately detected in patients with liver enzyme abnormalities. Conclusion Taking into account the risk and benefit of a liver biopsy, transient elastography can be recommended as an additional diagnostic option.

Resume Objectif L’angiogenese peut etre impliquee dans la pathogenie de la maladie de Behcet (MB). Quelques facteurs angiogeniques comme le facteur endothelial de croissance, la proteine-1 chimioattractive et l’endotheline-1 sont significativement associes a la MB. Nous etudions le role eventuel de l’angiopoietine dans l’activite et aux manifestations cliniques de la MB. Methodes Nous avons recrute 59 patients atteints de MB et 65 sujets sains temoins, apparies pour l’âge et le sexe. Nous avons revu les donnees concernant les caracteristiques cliniques, la vitesse de sedimentation (VS) et la proteine-C reactive (PCR) au moment de l’inclusion. Les taux seriques d’angiopoietine-1 et d’angiopoietine-2 etaient determines au moyen de la technique enzyme-linked immunosorbent assay (Elisa). Les analyses statistiques ont ete realisees en utilisant le test t de Student et l’analyse du coefficient de correlation de Pearson. Resultats Les taux seriques d’angiopoietine-1 et d’angiopoietine-2 sont significativement augmentes chez les patients atteints de MB, par comparaison aux patients temoins (284,5 ± 101,2 ng/ml dans le groupe MB vs 237,1 ± 76,4 ng/ml dans le groupe temoin, p = 0,012). Cependant, les taux d’angiopoietine-2 sont comparables dans les deux groupes (974,2 ± 679,3 pg/ml dans le groupe MB vs 858,3 ± 535,3 pg/ml dans le groupe temoin, p = 0,562). L’expression serique de l’angiopoietine serique est significativement augmentee chez les patients presentant des lesions cutanees (p = 0,025) et positivement correlee a la duree de la maladie (r = 0,320, p = 0,015). Les valeurs de la VS sont etroitement associees aux taux seriques d’angiopoietine-2 (r = 0,306, p = 0,018). Conclusion L’expression de l’angiopoietine-1 est augmentee chez les patients atteints de MB en comparaison aux patients temoins. Cette etude preliminaire etablit le fait que l’angiopoietine-1 peut jouer un role important dans la pathogenie de la MB.

This study was designed to identify susceptibility to insulin resistance and the association of serum resistin and adiponectin with insulin resistance in patients with Behçet's disease (BD). Also, we identify risk determinants for insulin resistance in BD patients.The study population consisted of 82 BD patients (n = 26 males) and 89 healthy controls (n = 40 males). Clinical data were collected at the time of enrollment, and serum resistin and adiponectin levels were measured using enzyme-linked immunosorbent assays. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by measuring fasting plasma glucose and insulin levels.BD patients and healthy controls differed significantly in insulin resistance (HOMA-IR) (1.3 +/- 1.1 vs. 0.7 +/- 0.5, p0.001) and serum resistin level (7901.7 +/- 1314.9 vs. 7444.2 +/- 1841.6, p = 0.001) but not in serum adiponectin level (p = 0.223). No differences in HOMA-IR, serum adiponectin, and serum resistin were found between patients with active and inactive BD. It is determined that plasma glucose, plasma insulin, and serum resistin may be determinant for the HOMA-IR. The number of metabolic syndrome components is closely correlated with HOMA-IR in BD patients (r = 0.245, p = 0.029).This study demonstrates that there is an increased susceptibility to insulin resistance in patients with BD as compared to healthy controls. Serum resistin level may be an independent determinant for insulin resistance in BD patients.

Background and object It has been suggested that the SLC22A12 gene polymorphism may be involved in the mechanism of renal urate handling. The purpose of the current study was to identify the effect of the T6092C polymorphism of the SLC22A12 gene on serum uric acid concentrations in the Korean population. Methods We examined 196 healthy subjects (141 males and 55 females) in this study. Among the SLC22A12 gene polymorphism, the T6092C polymorphism in intron 4 at rs1529909 of the SLC22A12 gene was evaluated using denaturing high performance liquid chromatography analysis. Diverse clinical parameters of renal urate handling derived from fasting blood and urine samples, such as the serum uric acid concentration and the fractional excretion of uric acid (FEUA), were also assessed for identification of the relationship between genotypic variations. Statistical analysis was performed using the chi-square test, ANOVA test, and the Pearson correlation coefficient analysis to determine which indicators involved serum uric acid. And the significance of these indicators was then confirmed by multivariate regression analysis. Results The prevalence of the T6092C polymorphism (TT, TC, and CC) was 58.2%, 37.2%, and 4.6%, respectively. Only the concentration of serum uric acid and the FEUA in male subjects differed significantly among each genotype ( p = 0.038 and p = 0.013, respectively). Serum uric acid concentrations in male subjects with the TT genotype were increased compared with those with the TC as well as the TC or CC genotypes (6.2 ± 1.2 vs. 5.7 ± 1.3, p = 0.039 and 6.2 ± 1.2 vs. 5.6 ± 1.3, p = 0.019, respectively), whereas there was no significant difference between CC genotype and TT genotype in serum uric acid ( p = 0.066). No significant difference between clinical indicators and genotypes existed in females. The T6092C polymorphism of the SLC22A12 gene, serum creatinine, and the FEUA were significantly associated with the concentration of serum uric acid. Conclusion This study showed that the T6092C polymorphism of the SLC22A12 gene may be involved in renal urate handling and the concentration of serum uric acid, in male subjects.

Background: Combined tramadol/acetaminophen is used to treat pain related to osteoarthritis. However, adverse events (AEs) leading to discontinuation can occur. Dose titration may decrease the risk for AEs. Objective: The aim of this study was to assess the effect of tramadol/acetaminophen titration on the development of AEs leading to treatment discontinuation in patients with knee osteoarthritis. Methods: This 2-week, multicenter, randomized, double-blind, double-dummy, add-on study was conducted at 12 tertiary referral university hospitals in the Republic of Korea. Patients aged 35 to 75 years with knee osteoarthritis receiving a stable dose of NSAIDs and with a daily mean pain-intensity score of ≥4 on a numeric rating scale (NRS) (0 = no pain to 10 = worst pain) during the 48 hours prior to enrollment were eligible. Patients were randomly assigned to receive 1 tablet of tramadol/acetaminophen 37.5/325 mg QD and 1 placebo BID for 3 days, followed by 1 active tablet BID and 1 placebo QD for 4 days, followed by 1 active tablet TID for 7 days (titration group) or 1 tablet of combined tramadol 37.5 mg/acetaminophen 325 mg TID for 14 days (nontitration group). The primary outcome measure was the rate of treatment discontinuation due to AEs. Secondary outcome measures were time to discontinuation due to AEs, prevalences and characteristics of AEs, decrease from baseline in pain intensity as measured on the NRS, and change in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score (scale: 0 = best to 100 = worst). Results: A total of 250 patients were enrolled (92.0% female; mean [SD] age, 60.2 [7.8] years; mean [SD] weight, 60.0 [9.2] kg [range, 37.5-90.7 kg]; all Korean). The discontinuation rate was significantly lower in the titration group than in the nontitration group (10.5% vs 26.2%; P < 0.001). The Kaplan-Meier survival curve showed that the rates of discontinuation due to AEs were similar in the 2 groups up to day 2, but thereafter the discontinuation rate was significantly lower in the titration group. The most common AEs were nausea (12.1% and 24.6% in the titration and nontitration groups, respectively; P = 0.008), vomiting (4.0% and 17.2%; P < 0.001), and dizziness (9.7% and 22.1%; P = 0.005). No serious AEs were reported in either group. Tramadol/acetaminophen use was associated with a similar decrease from baseline in pain in both the titration and nontitration groups (mean [SD] Δ: NRS, -1.60 [1.62] vs -1.68 [1.58]; total K-WOMAC, -12.86 [13.73] vs -12.52 [16.58]). Conclusions: In this population of Korean patients with knee osteoarthritis pain managed with a stable dose of NSAIDs, titration of tramadol/acetaminophen over 12 days was associated with improved tolerability and a significantly lower discontinuation rate compared with nontitration. Both regimens significantly reduced from baseline associated with osteoarthritis.