Serum biomarker panel for the diagnosis of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of inflammatory joint damage, wherein C-reactive protein and autoantibodies including rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) are rapidly elevated. These serological factors are diagnostic markers of RA; however, their sensitivity and specificity for prediction warrant improvement for an early and accurate diagnosis. METHODS: We aimed to identify alternative biomarkers by serum protein profiling using LC-MS/MS. We performed statistical and functional analysis of differentially expressed proteins to identify biomarker candidates complementing conventional serological tests. RESULTS: Seven biomarker candidates were verified through multiple reaction monitoring-based quantitative analysis, of which angiotensinogen (AGT), serum amyloid A-4 protein (SAA4), vitamin D-binding protein (VDBP), and retinol-binding protein-4 (RBP4) had an area under the curve over 0.8, thus distinguishing RA patients, including seronegative (RF- and anti-CCP-negative) RA patients, from healthy controls. CONCLUSIONS: Therefore, among seronegative RA patients, a four-biomarker panel (AGT, SAA4, VDBP, and RBP4) can prevent false negatives and help diagnose RA accurately.

Analysis of hair and plasma samples for methotrexate (MTX) and metabolite using high-performance liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) detection.

Methotrexate (MTX), a folate antagonist, is the anchor drug used to treat several diseases. Therapeutic effects are attributed to intracellular levels of various methotrexate conjugates that are present in the cell as polyglutamates (MTX-Glu). The present study was conducted to develop a new liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS)-based assay to separately quantitate the MTX-Glu in hair cells, red blood cells, and serum using internal standards. Sample preparation consisted of extraction with an organic solution followed by solid-phase extraction. The presented methodology was applied for the analysis of methotrexate and its polyglutamates in hair cells, red blood cells, and serum obtained from clinical patients. The developed LC-ESI-MS/MS method for the quantitative measurement of MTX-Glu was both sensitive and precise within the clinically relevant range. This method is possibly be superior with respect to sensitivity, selectivity, and speed than all previously described approaches and can be easily applied in routine clinical tests owing to the combination of a simple pretreatment process with robust LC-MS/MS.

Health-related Quality of Life Outcomes of Adalimumab for Patients With Rheumatoid Arthritis in Korea.

Objective: Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disorder that impairs patients' overall health-related quality of life (HRQOL) In this study, we evaluated the effect of adalimumab in Korean patients with active RA on HRQOL. Methods: Patients included in the study had moderate to severe active RA that did not respond to conventional drugs with a Disease Activity Score of 28 joints >32 and were biologics-naïve All patients received adalimumab 40 mg subcutaneously every other week and were followed for 24 weeks The primary endpoint was the change in baseline Health Assessment Questionnaire Disability Index (HAQ-DI) score at week 24 Secondary endpoints were changes in the EuroQol 5-dimension 3-Level (EQ-5D-3L) baseline score and Short Form 36-Item Health Survey (SF-36) domain scores at weeks 12 and 24 and change in baseline HAQ-DI score at week 12. Results: In total, 91 Korean patients were included Ninety-three percent of patients were in high disease activity with a baseline mean DAS28 value of 61 within all patients The mean change from baseline in HAQ-DI scores were -046 at week 12 and∼067 at week 24 (p<00001) Additionally, EQ-5D-3L score at weeks 12 and 24 had significantly improved (p<00001) compared to baseline SF-36 at weeks 12 and 24 had significantly improved (p<00001, p=00001) compared to baseline. Conclusion: Treatment with adalimumab resulted in significant improvement in HAQ-DI, EQ-5D-3L, and SF-36 scores at 12 and 24 weeks in Korean RA patient.

Serum Exosomal miRNA-1915-3p Is Correlated With Disease Activity of Korean Rheumatoid Arthritis.

BACKGROUND/AIM: It has been found that microRNAs (miRNA) affect rheumatoid arthritis (RA) pathophysiology. This study aimed to identify novel serum exosomal miRNAs related to RA disease activity in patients with an inadequate treatment response. PATIENTS AND METHODS: The sample population comprised clinical remission (CR) and non-clinical remission (non-CR) groups of RA patients. To identify potent miRNA markers for RA disease activity, miRNA array and qPCR were performed after patient serum exosomes preparation. RESULTS: Has-miR-1915-3p and has-miR-6511b-5p were significantly higher in the serum exosomes of the CR group. The level of serum C-reactive protein (CRP) was negatively correlated with has-miR-1915-3p level in serum exosomes. CONCLUSION: Has-miR-1915-3p may be a potential marker for Korean RA disease activity.

A discovery of screening markers for rheumatoid arthritis by liquid chromatography mass spectrometry: A metabolomic approach.

AIM: This study aimed to discover serum metabolite biomarkers for potential use in screening for rheumatoid arthritis (RA). METHODS: The sera from 43 healthy controls (HCs) and 49 RA patients were globally analyzed using high-performance liquid chromatography- tandem mass spectrometry. Molecular features (MFs) from samples were analyzed using volcano plots, partial least squares discriminant analysis, and variable importance in projection scores to select candidates. The spectra of candidate MFs were matched with the METLIN database. We confirmed the association between candidates and RA and analyzed the receiver-operating characteristic (ROC) curves. RESULTS: We selected a total of 57 candidate MFs that had a fold change ≥1.5, P value ≤.05, and over 80% of frequency. Among them, 18 MFs were identified as metabolites with the METLIN database. Six metabolites (dehydroepiandrosterone sulfate, androsterone sulfate, γ-linolenic acid, 9[E],11[E]-conjugated linoleic acid, docosahexaenoic acid, and docosapentaenoic acid [22n-3]) out of the 18 were associated with mechanisms of RA and were selected as final candidates. ROC curve analysis revealed their area under the curve (AUC) values were all above 0.75 and the combined AUC of the six candidates was 0.89. CONCLUSION: Using six candidates as a marker set showed potential in distinguishing RA patients from HCs, based on high AUC values. Therefore, we propose that a marker set of these six candidates has potential clinical application in RA screening.

Associations of Mitochondrial Deoxyribonucleic Acid Polymorphisms With Behçet's Disease in the Korean Population.

OBJECTIVES: This study aims to examine the possible associations of mitochondrial single nucleotide polymorphisms (SNPs) and Behçet's disease (BD) in a larger patient group. PATIENTS AND METHODS: Whole blood or buffy coat was collected from 98 BD patients (31 males, 67 females; mean age 48±2.8 years; range 20 to 60 years) from four university hospitals located in the Chung-Cheong district of the Republic of Korea, and 196 age- and sex-matched healthy controls (HCs) (62 males, 134 females; mean age 46.91±12.90 years; range 20 to 68 years) from Konyang University Hospital. Twenty targeted mitochondrial deoxyribonucleic acids (DNAs) were genotyped and compared using the revised Cambridge Reference Sequence. Chi square and Fisher's exact tests were used to analyze association of mitochondrial DNA SNPs with BD susceptibility and its clinical characteristics. RESULTS: There were no differences for m.248A>G, m.304C>A, m.709G>A, m.3010G>A, m.3970C>T, m.4883C>T, m.5178C>A, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.14668C>T, m.16129G>A, and m16304T> between patient and HC groups. However, m.16182A>C and m.16183A>C were more frequently observed in the patient group than the HC group (22 [22.4%] vs. 24 [12.2%], p=0.061 and 32 [32.7%] vs. 42 [21.4%], p=0.092) but without statistical significance. m.4883C>T and m.5178C>A were associated with posterior location of oral ulcers (p=0.025 for each) and m.16183A>C was associated with deep oral ulcers (p=0.001), while m.16189T>C was associated with deep oral ulcers and thrombosis (p=0.042, 0.048, respectively). CONCLUSION: m.16182A>C and m.16183A>C may be associated with BD in the Korean population.

Proteomics Approach for the Discovery of Rheumatoid Arthritis Biomarkers Using Mass Spectrometry.

Rheumatoid arthritis is an autoimmune disease that causes serious functional loss in patients. Early and accurate diagnosis of rheumatoid arthritis may attenuate its severity. Despite a diagnosis guideline in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis, the practical difficulties in its diagnosis highlight the need of developing new methods for diagnosing rheumatoid arthritis. The current study aimed to identify rheumatoid arthritis diagnostic biomarkers by using a proteomics approach. Serum protein profiling was conducted using mass spectrometry, and five distinguishable biomarkers were identified therefrom. In the validation study, the five biomarkers were quantitatively verified by multiple reaction monitoring (MRM) analysis. Two proteins, namely serum amyloid A4 and vitamin D binding protein, showed high performance in distinguishing patients with rheumatoid arthritis from healthy controls. Logistic analysis was conducted to evaluate how accurately the two biomarkers distinguish patients with rheumatoid arthritis from healthy controls. The classification accuracy was 86.0% and 81.4% in patients with rheumatoid arthritis and in healthy controls, respectively. Serum amyloid A4 and vitamin D binding protein could be potential biomarkers related to the inflammatory response and joint destruction that accompany rheumatoid arthritis.

Development of a Novel Diagnostic Biomarker Set for Rheumatoid Arthritis Using a Proteomics Approach.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that starts with inflammation of the synovial membrane. Studies have been conducted to develop methods for efficient diagnosis of RA and to identify the mechanisms underlying RA development. Blood samples can be useful for detecting disturbance of homeostasis in patients with RA. Nanoliquid chromatography-tandem mass spectrometry (LC-MS/MS) is an efficient proteomics approach to analyze blood sample and quantify serum proteins. METHODS: Serum samples of 18 healthy controls and 18 patients with RA were analyzed by LC-MS/MS. Selected candidate biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) using sera from 43 healthy controls and 44 patients with RA. RESULTS: Thirty-eight proteins were significantly differentially expressed by more than 2-fold in healthy controls and patients with RA. Based on a literature survey, we selected six candidate RA biomarkers. ELISA was used to evaluate whether these proteins effectively allow distinguishing patients with RA from healthy controls and monitoring drug efficacy. SAA4, gelsolin, and vitamin D-binding protein were validated as potential biomarkers of RA for screening and drug efficacy monitoring of RA. CONCLUSIONS: We identified a panel of three biomarkers for RA which has potential for application in RA diagnosis and drug efficacy monitoring. Further, our findings will aid in understanding the pathogenesis of RA.

Long-term Treatment with Anti-platelet Agents for Collagen-induced Arthritis Improves Radiological Findings.

OBJECTIVES: The objectives of this study were to evaluate the long-term effect of anti-platelet treatment on the radiological progression of collagen-induced arthritis in rats. METHODS: Female Lewis rats with collagen-induced arthritis were divided into three experimental groups: saline, aspirin monotherapy (n = 12), and aspirin-clopidogrel dual therapy (n = 12). Drugs were administered daily and continued up to 70 days after the induction of arthritis. The clinical arthritis index (weight, morphology score, and paw thickness) and radiological scores were evaluated. RESULTS: The clinical arthritis index peaked on day 20, while the radiological scores peaked on day 35. No intergroup difference was observed in the clinical arthritis index throughout the experiment. The aspirin-clopidogrel dual therapy group had a significantly higher mean radiological score than the other groups (p = 0.045) on day 35. Further treatments resulted in significantly improved radiological findings in the aspirin monotherapy and aspirin-clopidogrel dual therapy groups on day 70 but no significant improvement in the saline group. CONCLUSION: Anti-platelet agent treatment improved radiological findings on day 70. These observations emphasize the importance of a future long-term study of the effects of anti-platelet agent treatment on arthritis.

Heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to tuberculosis in Koreans.

The aim of this study was to determine whether peptidyl arginine deiminase (PADI) genes could affect susceptibility to tuberculosis (TB), which can be a presumptive base to explain the increased incidence of TB in patients with rheumatoid arthritis (RA) in Korean. The study population consisted of 47 patients with active TB, 35 patients with nontuberculous mycobacterial disease, 50 RA patients, and 83 healthy controls who had received comprehensive medical testing. Genomic DNA was isolated from peripheral blood mononuclear cells using a standard protocol. All of the patients and healthy controls were genotyped for two nonsynonymous SNPs in PADI4, namely PADI4_89, PADI4_90, and one synonymous SNP in PADI4_104. There was the complete linkage between PADI4_89 and PADI4_90 SNPs. In the allele and haplotype analyses of PADI4_89 and PADI4_104, no significant associations are observed between disease groups and control groups. The frequencies of heterozygote (A/G) for PADI4_89 were significantly lower in patients with active TB than in controls [adjusted odd ratios (OR) = 0.35, p values = 0.020]. When the analysis was conducted by overdominant model, more significant associations are observed (adjusted OR = 0.34, p values = 0.005). We found that heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to TB.

Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis.

OBJECTIVE: To identify ankylosing spondylitis (AS)-associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS. METHODS: A genome-wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS-associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion-typing PCR. RESULTS: In the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA-DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion-type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in ≥4 risk-increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P = 2.3 × 10(-7) ). Among patients with CNV regions in ≥2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P = 4.0 × 10(-10) ). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion-typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology-based nonhomologous end joining. CONCLUSION: The results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.

Role of citrullinated fibrinogen peptides in the activation of CD4 T cells from patients with rheumatoid arthritis.

This study was conducted to determine whether CD4 T cell responses to citrullinated fibrinogen occur in patients with rheumatoid arthritis (RA), especially in HLA-DR4-positive subjects. Whole peripheral blood mononuclear cells (PBMCs) of RA patients and control subjects were stimulated with citrullinated fibrinogen peptides, and T-cell production of proliferation and proinflammatory cytokines, such as interferon-γ(IFN-γ) and interleukin-17A (IL-17A), were measured. In addition, CD4 T cells from RA patients were stimulated with the citrullinated fibrinogen peptide, Fib-α R84Cit, identified as a DRB1(*)0401-restricted T cell epitope in HLA-DR4 transgenic mice, and the degree of T cell activation was examined similarly. No proliferative responses to the citrullinated fibrinogen peptides were observed in whole PBMCs or CD4 T cells from RA patients. Furthermore, no increased production of IFN-γ or IL-17A was found in whole PBMCs or CD4 T cells stimulated with the citrullinated fibrinogen peptides, although these cells responded to recall antigen, a mixture of tetanus toxoid, purified protein derivative (PPD) from Mycobacterium tuberculosis, and Candida albicans. The results of this study indicate that anti-citrulline immunity in RA patients may be mediated by fibrinogen because there is no evidence of CD4 T cell-mediated immune responses to citrullinated fibrinogen peptides.

Gene Expression Profile of T-cell Receptors in the Synovium, Peripheral Blood, and Thymus during the Initial Phase of Collagen-induced Arthritis.

BACKGROUND: Current management strategies attempt to diagnose rheumatoid arthritis (RA) at an early stage. Transcription profiling is applied in the search for biomarkers for detecting early-stage disease. Even though gene profiling has been reported using several animal models of RA, most studies were performed after the development of active arthritis, and conducted only on the peripheral blood and joint. Therefore, we investigated gene expression during the initial phase of collagen-induced arthritis (CIA) before the arthritic features developed in the thymus in addition to the peripheral blood and synovium. METHODS: For gene expression analysis using cDNA microarray technology, samples of thymus, blood, and synovium were collected from CIA, rats immunized only with type II collagen (Cll), rats immunized only with adjuvant, and unimmunized rats on days 4 and 9 after the first immunization. Arrays were scanned with an Illumina bead array. RESULTS: Of the 21,910 genes in the array, 1,243 genes were differentially expressed at least 2-fold change in various organs of CIA compared to controls. Among the 1,243 genes, 8 encode T-cell receptors (TCRs), including CD3ζ, CD3δ, CD3ε, CD8α, and CD8ß genes, which were down-regulated in CIA. The synovium was the organ in which the genes were differentially expressed between CIA and control group, and no difference were found in the thymus and blood. Further, we determined that the differential expression was affected by adjuvant more than Cll. The differential expression of genes as revealed by real-time RT-PCR, was in agreement with the microarray data. CONCLUSION: This study provides evidence that the genes encoding TCRs including CD3ζ, CD3δ, CD3ε, CD8α, and CD8ß genes were down-regulated during the initial phase of CIA in the synovium of CIA. In addition, adjuvant played a greater role in the down-regulation of the CD3 complex compared to CII. Therefore, the down-regulation of TCR gene expression occurred dominantly by adjuvant could be involved in the pathogenesis of the early stage at CIA.

Associations of vitamin d binding protein gene polymorphisms with the development of peripheral arthritis and uveitis in ankylosing spondylitis.

OBJECTIVE: Genetic factors account for more than 90% of overall susceptibility to ankylosing spondylitis (AS), and recent studies have focused on non-major histocompatibility complex genes. Vitamin D binding protein (DBP) is a highly polymorphic protein that transports vitamin D and its metabolites. In addition to its sterol binding capacity, DBP has many other roles in the inflammatory and immune systems, and has been reported to be associated with autoimmune diseases. We investigated the association between DBP polymorphisms and susceptibility to AS. METHODS: This case-control study was conducted in 223 patients with AS and 239 ethnically matched controls who were genotyped for 8 single-nucleotide polymorphisms (SNP) in the DBP and its promoter. Genomic DNA was isolated from peripheral blood leukocytes using the standard phenolchloroform method, and the GoldenGate assay was used for genotyping. RESULTS: No significant association was found between the susceptibility to AS and DBP polymorphisms. In a subgroup analysis of patients with AS, G alleles at rs222016 and rs222020 (OR 0.63, 95% CI 0.42-0.95, p = 0.03; OR 0.63, 95% CI 0.42-0.95, p = 0.03, respectively) and A allele at rs3733359 (OR 0.59, 95% CI 0.39-0.90, p = 0.01) showed the decreased risk of peripheral arthritis. G allele at rs4752 showed increased risk of uveitis (OR 2.04, 95% CI 1.12-3.72, p = 0.02). On the haplotype analyses, haplotype 2 (AGGA) protected against the development of peripheral arthritis (p = 0.01) and haplotype 3 (GAAG) was associated with an increased likelihood of uveitis (p = 0.02). CONCLUSION: DBP gene polymorphisms are associated with the development of peripheral arthritis and uveitis in Korean patients with AS. Given the influence of different DBP variants on the immune system, larger-scale studies are warranted to elucidate the role of DBP in the pathogenesis of AS.

Anti-cyclic citrullinated peptide antibodies distinguish hepatitis B virus (HBV)-associated arthropathy from concomitant rheumatoid arthritis in patients with chronic HBV infection.

OBJECTIVE: To determine whether anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are a highly specific test for rheumatoid arthritis (RA), could differentiate between hepatitis B virus (HBV)-associated arthropathy and concomitant RA in Korean patients with chronic HBV infection. METHODS: We investigated 240 patients with HBV infection. Anti-CCP antibodies were measured by ELISA and rheumatoid factor (RF) by the latex fixation test. Patient records were reviewed, and a standard form was used to record all demographic, clinical, and laboratory characteristics. Patients were divided into 4 groups according to joint symptoms: asymptomatic, arthralgia, oligoarthritis, and RA. We categorized liver disease into 3 groups: carrier, chronic hepatitis, and cirrhosis. RESULTS: Anti-CCP antibodies and RF were detected in 11 and 28 of 240 patients, respectively. Anti-CCP antibodies were detected in 9 of 10 RA (90%) and 2 of 230 non-RA patients (0.86%). The positive rate for RF was 90% in RA and 8.3% in non-RA. Eight of 10 RA patients were positive for both RF and anti-CCP antibodies. RF was detected in 11 patients without joint symptoms, 4 with arthralgia, and 4 with oligoarthritis, whereas anti-CCP antibodies were found in 1 patient without joint symptoms and 1 with oligoarthritis. Specificity of anti-CCP antibody for RA was 99.1%, whereas RF showed 91.7% specificity (p<0.0002). We compared the titers and positive detection rates of anti-CCP antibodies and RF among liver disease subgroups. There was no significant between-subgroup difference. CONCLUSION: Measurement of anti-CCP antibodies is better than RF detection to discriminate HBV-associated arthropathy from concomitant RA in patients with chronic HBV infection.

Association of FOXJ1 polymorphisms with systemic lupus erythematosus and rheumatoid arthritis in Korean population.

The forkhead-box J1 (FOXJ1) transcription factor could suppress a spontaneous activation of T cells and B cells through an induction of IkappaBbeta that results in repression of NF-kappaB activity. In Foxj1 deficiency mice, systemic autoimmune inflammation is quite common symptom. Therefore, deregulated Foxj1 is supposed to be associated with autoimmune diseases and/or other inflammatory diseases. Previously, we identified that polymorphisms of human FOXJ1 gene (g.??460C>T, g.1805G>T and g.3375G>C) are associated with allergic rhinitis in a Korean population. In present study, we compared the genotype and allele frequencies of these SNPs between healthy controls and systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) patients. We also investigated the relationships between each genotype and the expression levels of anti- nuclear antibodies in SLE patients, and rheumatoid factor and anti-cyclic citrullinated peptide in RA patients. The frequencies of haplotypes constructed by these FOXJ1 SNPs were compared between controls and SLE (or RA) patients. The results of genotype and allele analysis showed that the prevalence of polymorphism g.3375G>C was associated with the susceptibility of SLE (P = 0.0072 and 0.0042, respectively). But no significant association was found with RA. In the haplotype analysis, however, the main CGG showed a weak association between controls and RA patients (P = 0.048).

A 2-week, multicenter, randomized, double-blind, double-dummy, add-on study of the effects of titration on tolerability of tramadol/acetaminophen combination tablet in Korean adults with knee osteoarthritis pain.

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 > or = 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] Delta: 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.

Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. METHODS: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). RESULTS: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group (P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse event--chest discomfort, nausea, and vomiting after taking study medication-occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP. CONCLUSIONS: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.