IL-12p40 Homodimer Ameliorates Experimental Autoimmune Arthritis.

IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)2 subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist-knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)2 on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)2 model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)2 inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4(+)CD25(+)Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor-related organ receptor γt and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.

Impact of interstitial lung disease on mortality of patients with rheumatoid arthritis.

To identify the prevalence of interstitial lung disease (ILD) in Korean patients with rheumatoid arthritis (RA) and assess its effect on mortality. A total of 3555 patients with RA, with chest X-ray or chest computed tomography (CT) data at enrollment were extracted from the KORean Observational study Network for Arthritis cohort, a nationwide prospective cohort for patients with RA in Korea. The patients were classified into two groups: (1) an ILD group by chest X-ray or chest CT scan, and (2) a non-ILD group by these modalities. After comparing the characteristics of the groups at enrollment, mortalities were compared using the log-rank test. To explore the impact of ILD on mortality, Cox proportional hazard models were used. Sixty-four patients (1.8%) were identified with ILD. Male and older patients were more common in the ILD group. During a mean follow-up of 24 months, 6 patients (9.4%) in the ILD group and 25 patients (0.7%) in the non-ILD group died; the survival rate was significantly worse in the ILD group (p < 0.01). On adjusted analysis, ILD was significantly associated with increased mortality (HR 7.89, CI 3.16-19.69, p < 0.01); the risk of death in patients with ILD was even higher than in patients with cardiovascular disease (CVD, HR 4.10, CI 1.79-9.37, p < 0.01). The prevalence of ILD was 1.8% in Korean patients with RA. ILD is a major risk factor for mortality in patients with RA.

Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance.

BACKGROUND: Foxp3 is a key regulator of the development and function of regulatory T cells (Tregs), and its expression is thought to be T cell-restricted. We found that B cells in mice can express Foxp3 and B cells expressing Foxp3 may play a role in preventing the development of collagen-induced arthritis (CIA) in DBA/1J mice. METHODS: Foxp3 expression was modulated in CD19(+) B cells by transfection with shRNA or using an over-expression construct. In addition, Foxp3-transfected B cells were adoptively transferred to CIA mice. We found that LPS or anti-IgM stimulation induced Foxp3 expression in B cells. Foxp3-expressing B cells were found in the spleens of mice. RESULTS: Over-expression of Foxp3 conferred a contact-dependent suppressive ability on proliferation of responder T cells. Down-regulation of Foxp3 by shRNA caused a profound induction in proliferation of responder T cells. Adoptive transfer of Foxp3(+)CD19(+) B cells attenuated the clinical symptoms of CIA significantly with concomitant suppression of IL-17 production and enhancement of Foxp3 expression in CD4(+) T cells from splenocytes. CONCLUSION: Our data indicate that Foxp3 expression is not restricted to T cells. The expression of Foxp3 in B cells is critical for the immunoregulation of T cells and limits autoimmunity in a mouse model.

Detection of Anti-Type II Collagen Antibodies in Patients With Chronic Gouty Arthritis: Findings From a Pilot Study.

OBJECTIVE: We hypothesized that chronic gouty arthritis patients would develop an immune response to type II collagen that would be revealed by the presence of anti-type II collagen (CII) antibodies in serum, which may in turn be involved in progression to non-remitting arthritis. METHODS: Chronic gouty arthritis was defined as crystal-confirmed gout in patients with no pain-free intercritical period, with or without the presence of tophi, who did not have clinical features of other forms of chronic arthritis. Age-matched gout patients suffering acute gouty attacks who had definite intercritical periods were selected as a control group. Four RA patients who had active disease were enrolled as a positive control group. Anti-CII antibodies were quantified in patient sera via ELISA using a human IgG anti-CII antibody assay kit. Correlations between anti-CII levels and clinical parameters were sought. RESULTS: Fifteen chronic gouty arthritis patients were identified. The anti-CII level was significantly higher among subjects with chronic gout compared to controls, but did not significantly differ in control gout patients during acute attacks and in the intercritical periods. Five patients with chronic gouty arthritis had anti-CII antibody levels higher than 200 AU/mL, whereas only one control gout patient exhibited this feature. Two of four patients with active RA had anti-CII antibody levels higher than 200 U/mL.Patients with tophi had significantly higher anti-CII levels than those without, whereas patients showing radiographic erosion tended to have higher anti-CII levels than those without. CONCLUSION: Patients with chronic gouty arthritis had significantly higher levels of anti-CII antibodies than control gout patients. Such antibody production would be triggered by initiation of cartilage damage but may also play a role in perpetuation of inflammation.

Interleukin-27 suppresses osteoclastogenesis via induction of interferon-γ.

Interleukin (IL)-27 is a heterodimeric cytokine that is known to have both stimulatory and inhibitory functions during immune responses. We investigated the effects of IL-27 on arthritis and bone erosion in the murine collagen-induced arthritis (CIA) model. We demonstrate that the inhibitory effect of IL-27 on osteoclastogenesis is associated with interferon-γ (IFN-γ) production by using an IFN-γ knockout mouse model. The IL-27-Fc was injected into both CIA and IFN-γ-deficient mice. The effects of IL-27-Fc on osteoclast differentiation were evaluated both in vitro and in vivo. The IL-27-Fc-injected mice showed significantly lower arthritis indices and fewer tartrate-resistant acid-phosphatase-positive osteoclasts in their joint tissues than untreated mice. Interleukin-27 inhibited osteoclastogenesis from bone marrow-derived mononuclear cells in vitro, which was counteracted by the addition of anti-IFN-γ antibody. The IL-27-Fc did not affect arthritis in IFN-γ knockout mice. Interleukin-27 also suppressed osteoclast differentiation in human and intriguingly, it could promote the expression of IFN-γ on priming osteoclasts. These results imply that IL-27 suppressed the generation of CIA and osteoclastogenesis, which were mediated by the induction of IFN-γ.

Familial Mediterranean fever: the first adult case in Korea.

Familial Mediterranean fever (FMF) is known to be a genetic disorder that prevalent among populations surrounding the Mediterranean Sea. Since Mediterranean fever gene (MEFV) was discovered at 1997, some cases have been reported in countries not related or close to this area like Japan. In addition it has been generally accepted that the clinical onset of FMF begins before 20 yr of age in most patients. Onset of the disease at an older age may occur but is rare. Adult-onset FMF may be a form of disease with distinct clinical, demographic and molecular characteristics. We describe a case of adult-onset FMF confirmed by DNA analysis of the MEFV gene in a Korean patient. A 32-yr-old man, who has no family history of FMF, presented with periodic fever, abdominal pain and vomiting. Though several various tests were thoroughly performed to evaluate the cause of his symptoms, there was no evidence of infectious, autoimmune or neoplastic diseases. Several gene analysis of periodic fever syndrome was finally performed and two point mutations (p.Leu110Pro, p.Glu148Gln) were identified. We confirmed the first adult case of FMF through detection of MEFV gene mutations in Korea and describe his clinical characteristics.

Prevalence of knee pain and its influence on quality of life and physical function in the Korean elderly population: a community based cross-sectional study.

To investigate the prevalence of knee pain and its influence on physical function and quality of life (QOL), we examined 504 community residents of Chuncheon, aged ≥ 50 yr. Demographic information was obtained by questionnaire, and radiographic evaluations consisted of weight-bearing semi-flexed knee anteroposterior radiographs. Self-reported QOL and function were assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Short Form 12 (SF-12). Performance-based lower extremity function was assessed using the tests consisting of standing balance, usual walk and chair stands. The prevalence of knee pain was 46.2% (32.2% in men and 58.0% in women) and increased with age in women. After adjustment of confounders including the presence of knee OA, the subjects with knee pain had significantly worse WOMAC function and SF-12 scores compared to subjects without knee pain. Among the subjects with knee pain, women had worse WOMAC and SF-12 scores than men. Subjects with knee pain had worse physical performance score compared to those without knee pain, especially among females. In conclusion, the prevalence of knee pain is high (32.2% in men and 58.0% in women) in this elderly community population in Korea. Independent of knee OA and other confounding factors, subjects with knee pain have more than 5-fold increase in the risk of belonging to the worst lower extremity function compared to subjects without knee pain.

Clinical and radiographic features of adult-onset ankylosing spondylitis in Korean patients: comparisons between males and females.

The objective of this study was to investigate clinical and radiographic features and gender differences in Korean patients with adult-onset ankylosing spondylitis. Multicenter cross-sectional studies were conducted in the rheumatology clinics of 13 Korean tertiary referral hospitals. All patients had a confirmed diagnosis of ankylosing spondylitis according to the modified New York criteria. Clinical, laboratory, and radiographic features were evaluated and disease activities were assessed using the Bath ankylosing spondylitis disease activity index. Five hundred and five patients were recruited. The male to female ratio was 6.1:1. Average age at symptom onset was 25.4+/-8.9 yr and average disease duration was 9.6+/-6.8 yr. Males manifested symptoms at a significantly earlier age. HLA-B27 was more frequently positive in males. Hips were more commonly affected in males, and knees in females. When spinal mobility was measured using tragus-to-wall distance and the modified Schober's test, females had significantly better results. Radiographic spinal changes, including bamboo spine and syndesmophytes, were more common in males after adjustment of confounding factors. In conclusion, we observed significant gender differences in radiographic spinal involvement as well as other clinical manifestations among Korea patients with adult-onset ankylosing spondylitis. These findings may influence the timing of the diagnosis and the choice of treatment.

Standardized, musculoskeletal ultrasonographic reference values for healthy Korean adults.

BACKGROUND/AIMS: To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. METHODS: A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. RESULTS: The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. CONCLUSION: We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

IL-17 induces the production of IL-16 in rheumatoid arthritis.

The purpose of this study was to investigate the expression of IL-16 in the rheumatoid synovium and the role of inflammatory cytokines and Toll-like receptor (TLR) ligands in IL-16 production by fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients. Immunohistochemical staining was performed with a monoclonal antibody to IL-16 in synovial tissues from patients with RA and likewise in patients with osteoarthritis (OA). FLS were isolated from RA synovial tissues and stimulated with IL-15, IL-1beta, IFN-gamma, and IL-17. The IL-16 mRNA level was assessed by semiquantitative RT-PCR and real time (RT) PCR and a comparison was made between IL-16 mRNA levels produced by RA-FLS and OA-FLS. Production of IL-16 was identified by a western blot assay, and IL-16 production after stimulation by specific ligands of TLR2 and TLR4 was assessed by RT-PCR. While immunohistochemical staining demonstrated strong expression of IL-16 mRNA in synovial tissues from patients with RA, similar findings were not present in the OA group. Moreover, mRNA expression of IL-16 by RA-FLS increased after treatment with IL-17 but not with IL-15, IL-1beta, and IFN-gamma. Specifically, IL-17 increased IL-16 mRNA level by RA-FLS and peripheral blood mononuclear cells in a dose-dependent manner. However, IL-17 did not stimulate IL-16 production in OA-FLS. Peptidoglycan, a selective TLR2 ligand, also increased production of IL-16 by RA-FLS dose- dependently, whereas LPS, a selective TLR4 ligand, had no such stimulatory effect. The results from our data demonstrate that IL-17 and TLR2 ligands stimulate the production of IL-16 by RA-FLS.

Novel Genetic Variants Associated with Lumbar Spondylosis in Koreans : A Genome-Wide Association Study.

OBJECTIVE: The aim of this study was to identify the susceptibility genes responsible for lumbar spondylosis (LS) in Korean patients. METHODS: Data from 1427 subjects were made available for radiographic grading and genome wide association studies (GWAS) analysis. Lateral lumbar spine radiographs were obtained and the various degrees of degenerative change were semi-quantitatively scored. A pilot GWAS was performed using the AffymetrixGenome-Wide Human single-nucleotide polymorphisms (SNPs), 500K array. A total of 352228 SNPs were analyzed and the association between the SNPs and case-control status was analyzed by stepwise logistic regression analyses. RESULTS: The top 100 SNPs with a cutoff p-value of less than 3.7×10-4 were selected for joint space narrowing, while a cutoff p-value of 6.0×10-4 was applied to osteophytes and the Kellgren-Lawrence (K-L) osteoarthritis grade. The SNPs with the strongest effect on disc space narrowing, osteophytes, and K-L grade were serine incorporator 1 (rs155467, odds ratio [OR]=17.58, p=1.6×10-4), stromal interaction molecule 2 (STIM1, rs210781, OR=5.53, p=5×10-4), and transient receptor potential cation channel, subfamily C (rs11224760, OR=3.99, p=4.8×10-4), respectively. Leucine-rich repeat-containing G protein-coupled receptor 4 was significantly associated with both disc space narrowing and osteophytes (rs1979400, OR=2.01, p=1.1×10-4 for disc space narrowing, OR=1.79, p=3×10-4 for osteophytes), while zinc finger and BTB domain containing 7C was significantly and negatively associated with both osteophytes and a K-L grade >2 (rs12457004,OR=0.25, p=5.8×10-4 and OR=0.27, p=5.3×10-4, respectively). CONCLUSION: We identified SNPs that potentially contribute to the pathogenesis of LS. This is the first report of a GWAS in an Asian population.

Factors associated with quality of life and functional disability among rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs for at least 6 months.

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes. METHOD: A total of 2000 RA patients aged > 20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs). RESULTS: Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR < 3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR > 5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P < 0.001), and worse in females compared to males (P < 0.001). Compared to patients having lower DAS (< 3.2), those with moderate and highest DAS (3.2-5.1 and > 5.1) had worse outcome measures (P < 0.001). CONCLUSION: In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.

Toll-like receptor 2 and 4 combination engagement upregulate IL-15 synergistically in human rheumatoid synovial fibroblasts.

Toll-like receptors (TLRs) are pattern-recognition receptors that connect innate and adaptive immunity. Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector functions in inflammatory synovitis of rheumatoid arthritis (RA). The aim of this study was to clarify whether stimulation of TLR2 and TLR4 by their specific ligands induces the production of IL-15 in fibroblast-like synoviocytes (FLS) from RA patients. FLS were isolated from RA synovial tissues and stimulated with the TLR2 ligand bacterial peptidoglycan (PGN) and the TLR4 ligand lipopolysaccharide (LPS). IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real time PCR. The expression of TLR2, TLR4, and IL-15 in the RA synovium was quantified by immunohistochemistry and compared with values obtained in osteoarthritis synovium. IL-15 production increased in culture supernatants of RA FLS stimulated with PGN or PGN plus LPS, and this was upregulated at the transcriptional level. In contrast, LPS did not increase the level of IL-15 although it augmented the stimulatory effect of PGN on IL-15 production. Inhibition of nuclear factor (NF)-kappaB with a specific inhibitor abrogated the stimulatory effect of PGN or PGN plus LPS on IL-15. Neutralization of TLR2 with a blocking monoclonal antibody significantly reduced IL-15 production (P<0.05), reflecting the functional relevance of TLR2 activation in the induction of IL-15 production. These data suggest that TLR2 activation in RA FLS by microbial constituents is involved in the induction of IL-15 and that TLR2 promotes inflammation through NF-kappaB. TLR4 augmented the stimulatory effect of TLR2 on IL-15, possibly contributing to the maintenance of synovitis in patients with RA.

CD8alpha+ dendritic cells enhance the antigen-specific CD4+ T-cell response and accelerate development of collagen-induced arthritis.

To investigate the role of CD8alpha(+) DCs in the development of collagen-induced arthritis (CIA). The immunogenic properties of CD8alpha(+) and CD8alpha(-) DC subsets were investigated by mixed-lymphocyte reaction and cytokine enzyme-linked immunoassay. CII-pulsed CD8alpha(+) DCs or CD8alpha(-) DCs with CD4(+) T cells from CIA mice were adoptively transferred onto the hind footpad of DBA mice. The onset of arthritis and the arthritis index were examined for 14 weeks after adoptive transfer. Expression of MHC-II and CD80 but not CD86 and CD40 was higher in CD8alpha(+) DCs than in CD8alpha(-) DCs from the spleens of CIA mice. Culturing CD8alpha(+) DCs with CD4(+) T cells significantly increased the proliferative response of CD4(+) T cells in the presence of CII. The production of interleukin (IL)-12p70, IL-17, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha was slightly increased in CD8alpha(+) DCs than in CD8alpha(-) DCs. DBA/1 mice that were adoptively transferred with CII-pulsed CD8alpha(+) DCs and CD4(+) T cells into the footpads showed accelerated onset of CIA compared to control group. By contrast, CD8alpha(-) DCs showed a partial inhibitory effect on CIA. These findings show that CD8alpha(+) DCs accelerated the onset of CIA when aoptively transferred with CD4(+) T cells and that CD8alpha(+) DCs provoke the development of CIA probably by stimulating the immune responses of CII-reactive CD4(+) T cells and by increasing the production of inflammatory cytokines.

Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-beta in fibroblast like synoviocytes of patients with RA.

Cytokine and chemokine receptors play a key role in inflammation caused by rheumatoid arthritis (RA). Two isoforms of human CC chemokine receptor R2 (CCR2), the receptor of monocyte chemoattractant protein 1 (MCP-1), have been identified but their relative expression in fibroblast-like synoviocytes (FLS) and their contribution to inflammatory responses mediated by MCP-1 or inflammatory cytokines in patients with RA remain uncertain. We examined the pattern of expression of two CCR2 isoforms upon stimulation by proinflammatory cytokines and CD40 ligation. FLS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1beta, IL-18, IL-15, and LPS. CCR2A and CCR2B expression was examined by immunohistochemistry, RT-PCR and western blot analysis. IL-15, TNF-alpha and MCP-1 production was determined by ELISA. Immunohistochemistry showed that CCR2A is highly expressed in RA synovium compared with OA synovium. Transcripts of both CCR2A and CCR2B were detected in FLS. Exogenous MCP-1, CD40L, TGF-beta, and IL-15 significantly increased the expression of CCR2A but not CCR2B. Exposure of FLS to sCD40L caused strong upregulation of CCR2A but not of CCR2B protein expression. MCP-1 increased the proliferation of FLS and the production of IL-15, TNF-alpha, and IL-18. Because CCR2A is the main target of regulation by cytokines and CD40 ligation, the relatively higher expression of CCR2A on the cell surface suggests that this isoform of MCP-1 receptor functions as the principal mediator of inflammatory signals in RA FLS.

Prevalence and Risk Factors for Lumbar Spondylosis and Its Association with Low Back Pain among Rural Korean Residents.

OBJECTIVE: The purpose of this study was to investigate the prevalence of and the relevant risk factors for lumbar spondylosis (LS) among middle-aged and elderly rural Korean residents and to explore the association between radiographic LS and lower back pain (LBP) in relation to age and gender. METHODS: This community-based, cross-sectional study evaluated 1512 subjects with available radiograph. The prevalence of LBP was obtained using a questionnaire and disability resulting from LBP was measured using a validated Korean version of the Oswestry disability index (ODI). In lumbar spine radiographs, vertebral levels from L1/2 to L4/5 were evaluated for the presence of osteophytes and joint-space narrowing (JSN), and Kellgren-Lawrence (KL) grading was applied. RESULTS: Of 4261 subjects aged 40-79 years, data from 1512 subjects were included. The prevalence of radiographic LS indicated by grade ≥2 osteophytes and JSN were 53.9 and 15.8%, respectively. Seventy-three percent of subjects had KL grade ≥2 spondylosis and LBP was present in 36.5% of subjects. Although LS was more common among males, the prevalence of LBP was higher among females. Age, male gender and history of hand or knee arthritis were risk factors for LS. LS was significantly associated with LBP mostly among females over 60 years old and correlated with the ODI after adjusting for age and gender. CONCLUSION: Our study among rural Korean residents revealed a high prevalence of LS and LBP. The association between LS and LBP was observed mostly among females and LS was significantly correlated with the severity of back pain.

Comparative efficacy of biological agents in methotrexate-refractory rheumatoid arthritis patients: a Bayesian mixed treatment comparison.

BACKGROUND/AIMS: Biological agents (biologics) targeting proinflammatory signaling have emerged as an important treatment option in rheumatoid arthritis (RA). Despite the clinical effectiveness of biologics for patients with RA who do not respond to 'traditional' disease-modifying anti-rheumatic drugs (DMARDs), there are concerns regarding their cost and long-term safety. In this study, we aimed to compare the efficacy of various biologics and traditional DMARDs in RA patients refractory to methotrexate (MTX). METHODS: Four DMARDs (hydroxychloroquine, sulfasalazine, MTX, lef lunomide) and five anti-tumor necrosis factor drugs (adalimumab, etanercept, golimumab, inf liximab, and certolizumab) were selected. A systematic search of published studies was performed from inception through July 2013. Randomized trials of adults with MTX-refractory RA comparing two or more of the selected medications were included. Among 7,938 titles identified, in total, 16 head-to-head trials were selected. Two reviewers independently abstracted the study data and assessed methodological quality using the Cochrane Risk of Bias. Comparative efficacy was analyzed using a Bayesian mixed treatment comparison (MTC). RESULTS: In total, 9, 4, and 11 studies were included for the outcome measures of the Health Assessment Questionnaire (HAQ), Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) < 2.6 (remission), and American College of Rheumatology (ACR) 70 response, respectively. The treatments with the highest efficacy for each outcome measure were certolizumab combined with MTX, golimumab combined with MTX, and certolizumab combined with MTX, respectively. CONCLUSIONS: Based on MTC analysis, using data from published randomized controlled trials, certolizumab and golimumab combined with MTX showed the highest efficacy in the three outcome measures (HAQ, DAS28-ESR < 2.6, and ACR 70 response) in MTX-refractory RA patients.

Impact of early diagnosis on functional disability in rheumatoid arthritis.

BACKGROUND/AIMS: To determine whether early diagnosis is beneficial for functional status of various disease durations in rheumatoid arthritis (RA) patients. METHODS: A total of 4,540 RA patients were enrolled as part of the Korean Observational Study Network for Arthritis (KORONA). We defined early diagnosis as a lag time between symptom onset and RA diagnosis of ≤ 12 months, whereas patients with a longer lag time comprised the delayed diagnosis group. Demographic characteristics and outcomes were compared between early and delayed diagnosis groups. Logistic regression analyses were performed to identify the impact of early diagnosis on the development of functional disability in RA patients. RESULTS: A total of 2,597 patients (57.2%) were included in the early diagnosis group. The average Health Assessment Questionnaire-Disability Index (HAQ-DI) score was higher in the delayed diagnosis group (0.64 ± 0.63 vs. 0.70 ± 0.66, p < 0.01), and the proportion of patients with no functional disability (HAQ = 0) was higher in the early diagnosis group (22.9% vs. 20.0%, p = 0.02). In multivariable analyses, early diagnosis was independently associated with no functional disability (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40). In a subgroup analysis according to disease duration, early diagnosis was associated with no functional disability in patients with disease duration < 5 years (OR, 1.37; 95% CI, 1.09 to 1.72) but not in patients with longer disease duration (for 5 to 10 years: OR, 1.07; 95% CI, 0.75 to 1.52; for ≥ 10 years: OR, 0.92; 95% CI, 0.65 to 1.28). CONCLUSIONS: Early diagnosis is associated with no functional disability, especially in patients with shorter disease duration.