Association of a Single Nucleotide Variant in TERT with Airway Disease in Japanese Rheumatoid Arthritis Patients.

Interstitial lung disease and airway disease (AD) are often complicated with rheumatoid arthritis (RA) and have a poor prognosis. Several studies reported genetic associations with interstitial lung disease in RA. However, few genetic studies have examined the susceptibility to AD in RA patients. Here, we investigated whether single nucleotide variants susceptible to idiopathic pulmonary fibrosis might be associated with interstitial lung disease or AD in Japanese RA patients. Genotyping of rs2736100 [C/A] in TERT and rs1278769 [G/A] in ATP11A was conducted in 98 RA patients with usual interstitial pneumonia, 120 with nonspecific interstitial pneumonia (NSIP), 227 with AD, and 422 without chronic lung disease using TaqMan assays. An association with AD in RA was found for rs2736100 (p = 0.0043, Pc = 0.0129, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77). ATP11A rs1278769 was significantly associated with NSIP in older RA patients (>65 years, p = 0.0010, OR 2.15, 95% CI 1.35-3.40). This study first reported an association of rs2736100 with AD in RA patients and ATP11A rs1278769 with NSIP in older RA patients.

Antibodies against Serum Anti-Melanoma Differentiation-Associated Gene 5 in Rheumatoid Arthritis Patients with Chronic Lung Diseases.

Chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway diseases (ADs), are common complications of rheumatoid arthritis (RA). Rheumatoid factor (RF) and anti-citrullinated peptide antibodies are reported to be associated with CLD in RA patients. The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (Abs) is associated with clinically amyopathic dermatomyositis developing into rapidly progressive ILD. However, few studies on anti-MDA5 Abs in RA have been published. Here, we analyzed the association of anti-MDA5 Abs with CLD complications in RA. Anti-MDA5 Abs were quantified in sera from RA patients with or without CLD. Anti-MDA5 Ab levels were higher in RA patients with ADs than without (mean ± SDM, 4.4 ± 2.4 vs. 4.0 ± 4.2, p = 0.0001). AUC values of anti-MDA5 Ab and RF ROC curves were similar in RA patients with or without CLD (0.578, 95%CI 0.530-0.627 and 0.579, 95%CI 0.530-0.627, respectively, p = 0.9411). Multiple logistic regression analysis of anti-MDA5 Abs and clinical characteristics yielded an MDA5-index with a higher AUC value than anti-MDA5 Ab alone (0.694, 95%CI 0.648-0.740, p = 5.08 × 10-5). Anti-MDA5 Abs were associated with ADs in RA patients and could represent a biomarker for CLD, similar to RF. The involvement of anti-MDA5 Abs in the pathogenesis of ADs in RA is proposed.

Association of a FAM13A variant with interstitial lung disease in Japanese rheumatoid arthritis.

BACKGROUND: Interstitial lung disease (ILD) occasionally occurs in rheumatoid arthritis (RA) and confers a dismal prognosis. We previously reported that a single-nucleotide variant (SNV) of MUC5B was associated with ILD in RA. However, the pathogenesis of ILD in Japanese patients with RA could not be explained solely by this SNV because its frequency is extremely low in the Japanese population. Here, we examined whether a different idiopathic pulmonary fibrosis susceptibility SNV might be associated with ILD in Japanese patients with RA. METHODS: Genotyping of rs2609255 (G/T) in FAM13A was conducted in 208 patients with RA with ILD and 420 without chronic lung disease using TaqMan assays. RESULTS: A significant association with usual interstitial pneumonia (UIP) in RA was detected for rs2609255 under the allele model (p=0.0092, Pc=0.0276, OR 1.53, 95% CI 1.12 to 2.11) and recessive model for the G allele (p=0.0003, Pc=0.0009, OR 2.63, 95% CI 1.59 to 4.32). FAM13A rs2609255 was significantly associated with UIP in male patients with RA (p=0.0043, OR 3.65, 95% CI 1.52 to 8.73) under the recessive model. CONCLUSIONS: This study is the first to document an association of rs2609255 with ILD in Japanese patients with RA, implicating it in the pathogenesis of UIP, though studies on the function of rs2609255 are warranted.

Serum rheumatoid factor IgA, anti-citrullinated peptide antibodies with secretory components, and anti-carbamylated protein antibodies associate with interstitial lung disease in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is often complicated with chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway disease, which occur as extra-articular manifestations. CLD in RA have been associated with the production of rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), or anti-carbamylated protein (CarP) antibody. However, few validation studies have been performed thus far. In the present study, we investigated the association of RF, ACPA, and anti-CarP antibodies with RA complicated with CLD. METHODS: Sera from RA patients with or without CLD were collected. The levels of serum RF, RF immunoglobulin A (IgA), ACPA IgG, ACPA IgA, and ACPA secretory component (SC) were measured using enzyme-linked immunosorbent assay. RESULTS: The comparison of RA patients with and without CLD showed that RF IgA was associated with ILD (mean ± standard deviation: 206.6 ± 400.5 vs. 95.0 ± 523.1 U/ml, respectively, P = 1.13 × 10- 8), particularly usual interstitial pneumonia (UIP) (263.5 ± 502.0 U/ml, P = 1.00 × 10- 7). ACPA SC was associated with RA complicated with ILD (mean ± standard deviation: 8.6 ± 25.1 vs. 2.3 ± 3.4 U/ml, respectively, P = 0.0003), particularly nonspecific interstitial pneumonia (NSIP) (10.7 ± 31.5 U/ml, P = 0.0017). Anti-CarP antibodies were associated with RA complicated with ILD (0.042 ± 0.285 vs. 0.003 ± 0.011 U/ml, respectively, P = 1.04X10- 11). CONCLUSION: RF IgA and ACPA SC in RA were associated with UIP and NSIP, respectively, suggesting different specificities in patients with RA. Anti-CarP antibodies were associated with ILD in RA. These results may help elucidate the different pathogeneses of UIP and NSIP in RA.

Serum Metabolomic Profiling in Rheumatoid Arthritis Patients With Interstitial Lung Disease: A Case-Control Study.

Objectives: Interstitial lung disease (ILD) is an extra-articular manifestation in rheumatoid arthritis (RA), detected in 10.7% of patients, and causing a poor prognosis. Hence, biomarkers for ILD are urgently required in RA. Low molecular weight metabolites can be assessed by metabolomic analyses, and although these have been conducted in RA and in idiopathic pulmonary fibrosis, few have been carried out for ILD in the context of RA. Therefore, we analyzed serum metabolomic profiles of ILD in RA to identify novel biomarkers. Methods: Serum samples from 100 RA patients with ILD and 100 matched RA patients without chronic lung disease (CLD) were collected. These samples were subjected to metabolomic analyses using capillary electrophoresis time-of-flight mass spectrometry. Results: A total of 299 metabolites were detected in the metabolomic analysis. By univariate analysis, serum levels of decanoic acid and morpholine were lower in RA with ILD (false discovery rate Q = 1.87 × 10-11 and 7.09 × 10-6, respectively), and glycerol was higher (Q = 1.20 × 10-6), relative to RA without CLD. Serum levels of these metabolites in RA with usual interstitial pneumonia or RA with non-specific interstitial pneumonia were also altered. The partial least squares-discriminant analysis model generated from these three metabolites could successfully discriminate ILD in RA (area under the curve: 0.919, 95% confidence interval: 0.867-0.968, sensitivity 0.880, specificity 0.780). Conclusions: Serum levels of some metabolites were significantly different in RA with ILD compared with RA without CLD. It is concluded that metabolomic profiling will be useful for discovering candidate screening biomarkers for ILD in RA.

Association of HLA-DRB1 genotype with younger age onset and elder age onset rheumatoid arthritis in Japanese populations.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint destructions and human leukocyte antigen (HLA)-DRB1 is an important genetic risk factor for RA and influences the phenotype of RA. The clinical features of elder age onset RA (EORA) were known to be different from those of younger age onset RA (YORA). Previous studies reported the different association pattern of DRB1 alleles with YORA or EORA. The associations of DRB1 genotype with these RA subsets remained almost unknown. We investigated the genotype association of DRB1 with YORA or EORA in Japanese populations.HLA genotyping was performed in Japanese RA patients and the association of allele or genotype carrier frequencies were analyzed.The genotype frequency of DRB104:05/DRB104:06 (P = .0204, OR 7.69, 95%CI 1.39-42.72), DRB104:05/DRB112:01 (P = .0050, OR 5.53, 95%CI 1.71-17.88), and DRB104:05/DRB115:01 (P = .0124, OR 3.34, 95%CI 1.39-8.02) in YORA was higher than EORA. However, the frequencies of DRB101:01/DRB104:05 in YORA was tended to be lower than EORA (P = .0784, OR 0.14, 95%CI 0.01-2.42). The gene dosage effect of the shared epitope alleles was detected in EORA, but not in YORA. Trans-complementing DQ heterodimer molecules, formed by DQA1 and DQB1 of the haplotypes with and without shared epitope alleles, might explain the higher genotype frequencies of "shared epitope /not shared epitope". Linear regression analyses showed the primary role of DQB104:01 allele for the age at onset of RA.This is the first report for the associations of DRB1 genotype with YORA or EORA in the Japanese population and the differential distribution of the genotypes was noted between these RA subsets. The involvement of DQ molecules for the age at onset of RA was suggested.

Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized with joint destructions; environmental and genetic factors were thought to be involved in the etiology of RA. The production of anti-citrullinated peptide antibodies (ACPA) is specifically associated with RA. DRB1 is associated with the susceptibility of RA, especially ACPA-positive RA [ACPA(+)RA]. However, a few studies reported on the independent associations of DPB1 alleles with RA susceptibility. Thus, we investigated the independent association of DPB1 alleles with RA in Japanese populations. METHODS: Association analyses of DPB1 were conducted by logistic regression analysis in 1667 RA patients and 413 controls. RESULTS: In unconditioned analysis, DPB1*04:02 was nominally associated with the susceptibility of ACPA(+)RA (P = 0.0021, corrected P (Pc) = 0.0275, odds ratio [OR] 1.52, 95% confidence interval [CI] 1.16-1.99). A significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on DRB1 (Padjusted = 0.0003, Pcadjusted = 0.0040, ORadjusted 1.47, 95%CI 1.19-1.81). DPB1*05:01 was tended to be associated with the protection against ACPA(+)RA, when conditioned on DRB1 (Padjusted = 0.0091, Pcadjusted = 0.1184, ORadjusted 0.78, 95%CI 0.65-0.94). When conditioned on DRB1, the association of DPB1*04:02 with ACPA(+)RA was disappeared. No association of DPB1 alleles with ACPA-negative RA was detected. CONCLUSION: The independent association of DPB1*02:01 with Japanese ACPA(+)RA was identified.

Trends in Treatment, Outcomes, and Incidence of Orthopedic Surgery in Patients with Rheumatoid Arthritis: An Observational Cohort Study Using the Japanese National Database of Rheumatic Diseases.

OBJECTIVE: In this study, we investigated the changes in clinical outcome, treatment, and incidence of orthopedic surgery in patients with rheumatoid arthritis (RA) from 2004 to 2014. METHODS: Data were studied from the Japanese nationwide cohort database, NinJa (National Database of Rheumatic Diseases by iR-net in Japan), from 2004 to 2014. The time trends in the incidence of orthopedic procedures were analyzed using linear regression analysis. The cross-sectional annual data were compared between 2004 and 2014 to analyze the changes in clinical outcome and treatment. RESULTS: The incidence of orthopedic surgeries in patients with RA consistently decreased from 72.2 procedures per 1000 patients in 2004 to 51.5 procedures per 1000 patients in 2014 (regression coefficient = -0.0028, 95% CI -0.0038 to -0.0019, p < 0.001). The greatest reduction was found in total knee arthroplasty and total hip arthroplasty. Disease activity and functional disability improved significantly over this decade. The proportions of patients receiving methotrexate and biologic disease-modifying antirheumatic drugs significantly increased from 39.6% and 1.7% in 2004 to 63.8% and 27.4% in 2014, respectively. CONCLUSION: The overall incidence of orthopedic surgeries in patients with RA significantly decreased, accompanied by improved clinical outcomes because of the expanded use of effective drugs; however, the declining trend differed between procedures or locations. The results from the present study suggest that there might be a change in supply and demand for orthopedic surgeries.

Association of human leukocyte antigen alleles with chronic lung diseases in rheumatoid arthritis.

OBJECTIVES: Chronic lung diseases including interstitial lung disease and airway disease (AD) occur in RA patients. Interstitial lung disease and AD in RA are extra-articular manifestations that influence the prognosis quoad vitam of RA. Studies on associations of HLA alleles with RA have been carried out, and shared epitopes of several alleles are reported to be associated with RA susceptibility. Few association studies in RA subpopulations with chronic lung diseases have been conducted. The aim of the study was to identify HLA alleles predisposing to RA phenotypes including the presence of AD. METHODS: Associations of HLA-DRB1 and DQB1 alleles with chronic lung diseases in RA were analysed. RESULTS: A positive association was found between the DR4 serological group and resistance to usual interstitial pneumonia [P = 0.0250, odds ratio (OR) 0.62, 95% CI: 0.41, 0.93]. The DR2 serological group was associated with susceptibility to usual interstitial pneumonia (P = 0.0036, OR = 1.86, 95% CI: 1.23, 2.81). An association was found for shared epitopes alleles with bronchiolitic AD (P = 0.0040, OR = 2.06, 95% CI: 1.24, 3.41). DQB1*03:01 was associated with bronchiectatic AD (P = 0.0021, corrected P-value (Pc) = 0.0315, OR = 1.99, 95% CI: 1.30, 3.06), as well as with emphysema (P = 0.0007, Pc = 0.0104, OR = 2.43, 95% CI: 1.49, 3.95). In combined analysis, a predisposing association of DQB1*03:01 (P = 1.94 ×10(-5), Pc = 0.0003, OR = 2.16, 95% CI: 1.53, 3.06) and a negative association of DQB1*03:02 (P = 0.0008, Pc = 0.0117, OR = 0.33, 95% CI: 0.17, 0.67) with bronchiectatic AD or emphysema were observed in RA. CONCLUSION: The present study identified an association of HLA-DQB1*03:01 with predisposition to, and DQB1*03:02 with resistance to, bronchiectatic AD or emphysema in RA.

Prevalence of chronic kidney disease and administration of RA-related drugs in patients with RA: The NinJa 2012 study in Japan.

OBJECTIVES: To estimate the prevalence of chronic kidney disease in patients with rheumatoid arthritis (RA) and the administration of disease-modifying anti-rheumatic-drugs (DMARDs), using data from the National Database of Rheumatic Disease by iR-net in Japan (NinJa) 2012 study. METHODS: From a total of 11,940 RA patients, 7135 who underwent an estimated glomerular filtration rate (eGFR) test were studied. Renal dysfunction staging was assessed using Japanese eGFR equations and classified according to the Kidney Disease Improving Global Outcomes 2012 clinical practice guideline. RESULTS: The prevalence of GFR stages was as follows: stage G1, 25.4%; stage G2, 55.9%; stage G3, 17.5%; stage G4, 0.8%; and stage G5, 0.2%. Overall, 92.7% of patients received at least one DMARD. Sulfasalazine, tacrolimus, and biologics (except inflixmab) were administered in all GFR stages. Methotrexate was not prescribed in patients with stage G5, but methotrexate 3.5 mg/week (mean) was prescribed in four patients (6.8%) with stage G4. Non-steroidal anti-inflammatory drugs and glucocorticoids were prescribed in 40.5% and 43.7% of patients, respectively. CONCLUSION: The prevalence of kidney disease in this large sample of RA patients was higher than that in the general population, and the results suggest that RA patients with renal dysfunction require careful drug selection.

Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study.

OBJECTIVES: To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti-citrullinated peptide antibody (ACPA) titers. METHODS: The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti-rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year. RESULTS: The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups. CONCLUSIONS: This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers.

Venous thromboembolism after total joint arthroplasty: results from a Japanese multicenter cohort study.

INTRODUCTION: Real-world evidence of the effectiveness of pharmacological thromboprophylaxis for venous thromboembolism (VTE) is limited. Our objective was to assess the effectiveness and safety of thromboprophylactic regimens in Japanese patients undergoing joint replacement in a real-world setting. METHOD: Overall, 1,294 patients (1,073 females and 221 males) who underwent total knee arthroplasty (TKA) and 868 patients (740 females and 128 males) who underwent total hip arthroplasty (THA) in 34 Japanese national hospital organization (NHO) hospitals were enrolled. The primary efficacy outcome was the incidence of deep vein thrombosis (DVT) detected by mandatory bilateral ultrasonography up to post-operative day (POD) 10 and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding (major or minor) and death from any cause up to POD28. RESULTS: Patients undergoing TKA (n = 1,294) received fondaparinux (n = 360), enoxaparin (n = 223), unfractionated heparin (n = 72), anti-platelet agents (n = 45), or no medication (n = 594). Patients undergoing THA (n = 868) received fondaparinux (n = 261), enoxaparin (n = 148), unfractionated heparin (n = 32), anti-platelet agents (n = 44), or no medication (n = 383). The incidence rates of sonographically diagnosed DVTs up to POD10 were 24.3% in patients undergoing TKA and 12.6% in patients undergoing THA, and the incidence rates of major bleeding up to POD28 were 1.2% and 2.3%, respectively. Neither fatal bleeding nor fatal pulmonary embolism occurred. Significant risk factors for postoperative VTE identified by multivariate analysis included gender (female) in both TKA and THA groups and use of a foot pump in the TKA group. Only prophylaxis with fondaparinux reduced the occurrence of VTE significantly in both groups. Propensity score matching analysis (fondaparinux versus enoxaparin) showed that the incidence of DVT was lower (relative risk 0.70, 95% confidence interval (CI) 0.58 to 0.85, P = 0.002 in TKA and relative risk 0.73, 95% CI 0.53 to 0.99, P = 0.134 in THA) but that the incidence of major bleeding was higher in the fondaparinux than in the enoxaparin group (3.4% versus 0.5%, P = 0.062 in TKA and 4.9% versus 0%, P = 0.022 in THA). CONCLUSIONS: These findings indicate that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of DVT but increases bleeding tendency in patients undergoing TKA and THA. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000001366. Registered 11 September 2008.

Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. Certain HLA-DRB1 "shared-epitope" alleles are reported to be positively associated with increased RA susceptibility, whereas some of the other alleles may be negatively associated. However, studies on the latter are rare. Here, we focus on the protective effects of DRB1 alleles in Japanese RA patients in an association study. Relative predispositional effects (RPE) were analyzed by sequential elimination of carriers of each allele with the strongest association. The protective effects of DRB1 alleles were investigated in patients stratified according to whether they possessed anti-citrullinated peptide antibodies (ACPA). The DRB1*13:02 allele was found to be negatively associated with RA (P = 4.59×10(-10), corrected P (Pc) = 1.42×10(-8), odds ratio [OR] 0.42, 95% CI 0.32-0.55, P [RPE] = 1.27×10(-6)); the genotypes DRB1*04:05/*13:02 and *09:01/*13:02 were also negatively associated with RA. The protective effect of *13:02 was also present in ACPA-positive patients (P = 3.95×10(-8), Pc = 1.22×10(-6), OR 0.42, 95%CI 0.31-0.58) whereas *15:02 was negatively associated only with ACPA-negative RA (P = 8.87×10(-5), Pc = 0.0026, OR 0.26, 95%CI 0.12-0.56). Thus, this study identified a negative association of DRB1*13:02 with Japanese RA; our findings support the protective role of DRB1*13:02 in the pathogenesis of ACPA-positive RA.

Current treatments of rheumatoid arthritis: from the 'NinJa' registry.

In this review, recent changes in both treatments and outcomes of rheumatoid arthritis (RA) in Japan were analyzed by viewing the National Database of Rheumatic Diseases by iR-net, one of the largest clinical databases for RA patients in Japan. Regarding drug therapy, the use of methotrexate has been continuously increasing and has established a place as an anchor drug in the treatment of RA among other nonbiologic disease-modifying antirheumatic drugs; however, the dosage used is still significantly less compared with that of western countries. In addition to methotrexate, the use of tacrolimus has increased gradually. The most prominent observed change is a rapid increase in the use of biologics, which rose to stardom in the treatment of RA in Japan and western countries. These changes in drug therapy could allow us to control RA disease activity more tightly. In line with this, the outcomes of patients with RA in Japan have been improving continuously, both clinically and functionally. Subsequently, the use of both NSAIDs and corticosteroids has decreased. In addition, overall rates of joint operations related to RA have also decreased; in particular, a significant decrease was noticed in the incidence of joint replacement and synovectomy. Overall, the trends in treatments and subsequent outcomes for RA in Japan have exactly followed those seen in western countries.

Prevalence of joint replacement surgery in rheumatoid arthritis patients: cross-sectional analysis in a large observational cohort in Japan.

The purpose of this study was to describe the prevalence of total joint arthroplasty (TJA) in Japanese rheumatoid arthritis (RA) patients undergoing conventional drug treatment in a large observational cohort in Japan. A total of 5,177 RA patients were studied for the prevalence of TJA, who were enrolled in the NinJa database during the fiscal year of 2006. The cases of 2,695 RA patients with more than ten years of disease duration were extracted and subjected to further analysis. The prevalence of TJA increased in accordance with the disease duration, and the prevalence was markedly increased after ten years. Among the 2,695 patients with more than ten years of disease duration, 1,431 TJAs were performed in 645 (24.6%) patients. The patients with TJA had higher disease activity than those without TJA. In this cross-sectional study, TJAs were performed in approximately a quarter of the Japanese RA patients with more than ten years of disease duration. The result showed that patients with higher disease activity required TJA.

Disease Activity Score 28 (DAS28) using C-reactive protein underestimates disease activity and overestimates EULAR response criteria compared with DAS28 using erythrocyte sedimentation rate in a large observational cohort of rheumatoid arthritis patients in Japan.

OBJECTIVES: To compare disease activity and the improvement of disease activity evaluated between by Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR) and by DAS28 using C-reactive protein (DAS28-CRP) in Japanese patients with rheumatoid arthritis (RA). METHODS: Data from 3073 RA patients registered in the large cohort database (NinJa: National Database of Rheumatic Diseases by iR-net in Japan) of 2003 was used to calculate DAS28-ESR and DAS28-CRP and disease activities were evaluated. Improvements in disease activities were also evaluated according to the European League Against Rheumatism (EULAR) response criteria in 1482 RA patients whose DAS28-ESR and DAS28-CRP could be calculated from data for both 2002 and 2003. RESULTS: The mean value of DAS28-CRP (3.59, SD 1.25) was significantly smaller than that of mean DAS28-ESR (4.31, SD 1.32) (p < 0.0001). The number of patients who satisfied the criteria of remission was 297 (9.7%) in DAS28-ESR versus 705 (22.9%) in DAS28-CRP and the number of patients with high disease activity was 842 (27.4%) versus 357 (11.6%) for DAS28-ESR and DAS28-CRP, respectively; there was a significant difference between the two (p < 0.0001). Change of respective DAS28 was significantly correlated (DeltaDAS28-ESR -0.05, SD 1.14 versus DeltaDAS28-CRP -0.10, SD 1.10) (p < 0.0001); however, the number of "good response" patients was significantly different (p < 0.03) between DAS28-ESR (97 patients, 6.5%) and DAS28-CRP (136 patients, 9.2%). CONCLUSIONS: DAS28-CRP significantly underestimated disease activity and overestimated the improvement in disease activity compared with DAS28-ESR. DAS28-CRP should be evaluated using different criteria from that for DAS28-ESR.