Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort.

OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.

Incidence of comprehensive hospitalization due to infection, cardiovascular disease, fractures, and malignancies in patients with rheumatoid arthritis.

To comprehensively analyze the overall incidence of hospitalization for comorbidities in patients with rheumatoid arthritis (RA). We prospectively analyzed overall hospitalizations for comorbidities using the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. The incidence of hospitalized comorbidity was calculated. Risk factors for the most frequent hospitalized comorbidities were determined by multivariate logistic regression analysis. Among 5519 RA patients contributing 5336.5 person-years of observation, 435 incidences of hospitalized comorbidity [8.15/100 person-years; 95% confidence interval (CI) 7.40-8.95] were confirmed. The most frequent cause of hospitalized comorbidity was infection (1.52/100 person-years), primarily respiratory system infection (0.77/100 person-years), followed by malignancy (1.03/100 person-years), extra-articular manifestations (0.78/100 person-years), bone fracture (0.77/100 person-years), and acute coronary syndrome (0.22/100 person-years). Death occurred in 0.34/100 person-years (95% CI 0.20-0.53), and in 94.4% of cases the cause of death was the same as that of admission. The risk factors for the most frequent cause of hospitalization, hospitalized infection, were age [odds ratio (OR) 1.03; 95% CI 1.00-1.05], serum albumin level (OR 0.30; 95% CI 0.13-0.69), and corticosteroid use (prednisone > 5 mg/day; OR 3.66; 95% CI 1.81-7.35), but not methotrexate or biological agent use. The present study determined the overall burden of hospitalized comorbidities in patients with RA. These comprehensive data on hospitalized comorbidities may provide a basis for future improvements in the treatment of RA.

The minimally important difference for the Japanese version of the health assessment questionnaire in patients with rheumatoid arthritis in daily practice.

OBJECTIVE: To validate the minimally important difference (MID) of physical function using the Japanese version of the Health Assessment Questionnaire (J-HAQ) in a cohort of rheumatoid arthritis (RA). METHODS: Patients who participated in a cohort study in both October 2008 and April 2009 were analyzed. Patients self-rated their change in overall status over 6 months using a 5-point Likert scale ("much better", "somewhat better", "same", "somewhat worse", or "much worse"). The MID for J-HAQ score was defined as the mean J-HAQ score change in patients who rated themselves "somewhat better". An effect size (ES) of 0.2-0.5 was considered to be suitable for MID. RESULTS: A total of 4560 patients were analyzed. The mean (standard deviation [SD]) MID for J-HAQ score was -0.06 (0.29), corresponding to an ES of 0.08. As exploratory analysis, 1999 patients with a J-HAQ score ≥0.5 and 28-joint disease activity score (DAS28) ≥ 2.6 at baseline were assessed. The mean (SD) MID for J-HAQ score of these patients was 0.13 (0.01), corresponding to an ES of 0.21. CONCLUSIONS: The MID for J-HAQ score was 0.13 in patients with baseline J-HAQ score ≥0.5 and DAS28 ≥ 2.6. The MID for J-HAQ score was influenced by disease status and functional disability.

Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients with rheumatoid arthritis based on real-world data from the IORRA observational cohort study in Japan.

OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan.

Profiles of EQ-5D utility scores in the daily practice of Japanese patients with rheumatoid arthritis; Analysis of the IORRA database.

OBJECTIVE: Along with the advances of newly developed medical therapies in rheumatoid arthritis (RA), the number of pharmacoeconomical issues has been paid attention rapidly. For cost-utility analysis and determination of quality-adjusted life years, measurement of the EuroQol 5-dimensional descriptive system (EQ-5D) is essential, and has been used in several clinical studies. However, EQ-5D utility measure in Japanese patients with RA, especially in daily practice has not been fully documented. We analyzed the distribution of EQ5D utility scores and investigated the relationship between other clinical measures based on our Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. METHOD: Among 5,284 outpatients who participated in the IORRA cohort study on October 2007, data from 5,043 patients who completed the EQ-5D questionnaire were cross-sectionally analyzed. EQ-5D scores in each subgroup for baseline feature such as gender, age, disease activity score 28 (DAS28), and Japanese version of health assessment questionnaire (J-HAQ) were evaluated. For the evaluation of variables that influenced EQ-5D score, the contribution of each variable was evaluated by ANOVA. RESULTS: Average EQ-5D score was 0.76 in 5,284 patients (84% females, average age: 59.0 years, average disease duration: 12.4 years) whose average DAS28 was 3.3 and average J-HAQ was 0.74. EQ-5D scores were highly correlated with J-HAQ and DAS28, and were significantly lower in females and rheumatoid factor-positive patients. Older age, longer disease duration, higher DAS28, and higher J-HAQ were also significantly associated with lower EQ-5D scores. In multivariate analysis, the factor that most strongly influenced EQ-5D was J-HAQ (57.6%), followed by pain visual analog score (VAS; 12.5%). CONCLUSION: This study clearly demonstrated the distribution of EQ-5D score in the daily practice of RA patients, and provides important information for the pharmacoeconomical studies in rheumatology.

Cost-effectiveness of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, versus methotrexate in patients with rheumatoid arthritis using real-world data from the IORRA observational cohort study.

OBJECTIVES: To evaluate the cost-effectiveness of tocilizumab in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: The cost-effectiveness was determined using a Markov model-based probabilistic simulation. Data from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study between April 2007 and April 2011 were extracted using a pair-matching method: tocilizumab group (n = 104), patients who used at least 1 disease-modifying anti- rheumatic drug and in whom tocilizumab treatment was initiated; methotrexate group (n = 104), patients in whom methotrexate treatment was initiated for the first time or after an interruption of 6 or more months. Assuming a 6-month cycle length, health benefits and costs were measured over a lifetime and discounted at an annual rate of 3%. RESULTS: Compared with methotrexate treatment, lifetime costs and quality-adjusted life years (QALYs) for tocilizumab treatment were approximately 1.5- and 1.3-times higher, respectively. Incremental cost per QALY gained with tocilizumab was $49,359, which was below the assumed cost-effectiveness threshold of $50,000 per QALY. The probability of tocilizumab being cost- effective was 62.2%. CONCLUSION: The simulation model using real-world data from Japan showed that tocilizumab (at a certain price) may improve treatment cost-effectiveness in patients with moderate-to-severe RA by enhancing quality-adjusted life expectancy.

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice.

OBJECTIVES: To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. METHODS: We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. RESULTS: We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. CONCLUSIONS: Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.

Chronological changes in baseline disease activity of patients with rheumatoid arthritis who received biologic DMARDs between 2003 and 2012.

BACKGROUND/PURPOSE: The use of biologic disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) has been increasing since 2003. In this study, we evaluated changes in the characteristics of patients receiving biologic DMARDs daily, in Japan. METHODS: The characteristics of all RA patients who received any biologic DMARD at the Institute of Rheumatology, Tokyo Women's Medical University, within 1 year after its approval in Japan, were retrospectively evaluated. The periods of patient enrollment for each biologic agent were: infliximab (IFX), 2003-2004; etanercept (ETN), 2005-2006; tocilizumab (TCZ), 2008-2009; adalimumab (ADA), 2008-2009; abatacept (ABT), 2010-2011; and golimumab (GLM), 2011-2012. We retrospectively collected individual patient characteristics, concomitant medication usage, and disease activity assessed by disease activity score 28 (DAS28) at the time of administration, from the medical records. The retention rate for each agent at 6 months after treatment initiation was also assessed. RESULTS: The numbers of patients who received each biologic DMARD at our institute within 1 year after its approval were: IFX, 49; ETN, 50; TCZ, 62; ADA, 52; ABT, 40; and GLM, 77. From 2003 to 2012, the proportion of patients with prior use of any biologic DMARD increased, as did concomitant use and dose of methotrexate (MTX); however, corticosteroid use and doses decreased. DAS28, at the time of treatment initiation, gradually decreased. At the time of IFX administration, 75% and 25% of patients had high and moderate disease activity respectively, compared to 25% and 58% respectively, of patients who received GLM. No significant difference was observed in the retention rate of biologic DMARDs at 6 months (range, 75.0% to 89.6%). CONCLUSION: Baseline disease activity of RA patients who received biologic DMARDs between 2003 and 2012 has changed from high to moderate in daily practice in Japan.

Disability is the major negative predictor for achievement of Boolean-based remission in patients with rheumatoid arthritis treated with tocilizumab.

OBJECTIVE: To analyze the efficacy of tocilizumab (TCZ) and the factors that influence achievement of Boolean-based remission in patients with rheumatoid arthritis (RA) treated with TCZ in daily clinical practice. METHODS: The efficacy of TCZ at 24 weeks after initiation of TCZ in 80 patients with RA was analyzed by comparing achievement of "DAS28 remission" with that of "Boolean-based remission". The predictive factors that influence achievement of Boolean-based remission were determined using multiple logistic regression analysis using a step-wise method. RESULTS: DAS28 remission and Boolean-based remission were achieved in 50.0 and 12.5% of patients, respectively. Significant differences in achieving Boolean-based remission were observed when patients were stratified by disease duration in tertiles (p < 0.05) and by physical function in tertiles (p < 0.05); no such differences were observed for achieving DAS28 remission. The least achievable component among the Boolean-based remission criteria was patient's global assessment. The predictive factor for not achieving Boolean-based remission at 24 weeks was having a worse baseline physical function (odds ratio, 3.66; 95 % confidence interval, 1.17-14.48). CONCLUSIONS: This study suggests that baseline disability predicts a lack of achievement of Boolean-based remission. Thus, better responses to TCZ may be obtained when TCZ is initiated in RA patients before disability develops.

Functional disability can deteriorate despite suppression of disease activity in patients with rheumatoid arthritis: a large observational cohort study.

OBJECTIVE: To analyze the relationship between the progression of disability and disease activity in patients with rheumatoid arthritis (RA) in daily practice. METHODS: Patients from an observational cohort, IORRA, who completed surveys during 2009-2011 were eligible. Linear regression of disease activity score 28 (DAS28), Japanese version of Health Assessment Questionnaire (J-HAQ), and EQ-5D from baseline were calculated, and the angles of the regression lines were designated DAS28 slope, J-HAQ slope, and EQ-5D slope, respectively, in each patient; averages were compared between treatment groups. RESULTS: A total of 5,038 patients [84.0% female, mean age 59.4 (SD 13.1) years, disease duration 13.2 (9.6) years, DAS28 3.29 (1.14), and J-HAQ 0.715 (0.760)] were analyzed. The average DAS28 slope indicated improvement in all groups, whereas J-HAQ slopes were negative in patients on methotrexate (MTX), biologics, combination biologics/disease-modifying antirheumatic drugs (DMARDs), and combination biologics/MTX at baseline, but positive in patients on prednisolone >5 mg/day [0.010 (0.153)] and not on MTX at baseline [0.007 (0.122)], representing a worsening of disability. CONCLUSION: There is some disparity between improvement of disease activity and progression of disability, suggesting that quality of remission must be considered.

Analysis of direct medical and nonmedical costs for care of rheumatoid arthritis patients using the large cohort database, IORRA.

OBJECTIVES: Our goal was to determine the annual direct medical and nonmedical costs for the care of patients with rheumatoid arthritis (RA) using data from a large cohort database in Japan. METHODS: Direct medical costs [out of pocket to hospitals and pharmacies and for complementary and alternative medicine (CAM)] and nonmedical costs (caregiving, transportation, self-help devices, house modifications) were determined for RA patients who were participants in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) studies conducted in October 2007 and April 2008. Correlations between these costs and RA disease activity, disability level, and quality of life (QOL) were assessed. RESULTS: Data were analyzed from 5,204 and 5,265 RA patients in October 2007 and April 2008, respectively. The annual direct medical costs were JPY132,000 [out of pocket to hospital (US$1 = JPY90 in 2007)], JPY84,000 (out of pocket to pharmacy), and JPY146,000 (CAM). Annual direct nonmedical costs were JPY105,000 (caregiving), JPY22,000 (transportation), JPY30,000 (self-help devices), and JPY188,000 (house modifications). Based on the utilization rate for each cost component, the annual medical and nonmedical costs for each RA patient were JPY262,136 and JPY61,441, respectively. Costs increased with increasing RA disease activity and disability level or worsening quality of life (QOL). CONCLUSIONS: Based on the IORRA database, patients with RA bear heavy economic burdens that increase as the disease is exacerbated. The results also suggest that the increase in medical and nonmedical costs may be ameliorated by the proactive control of disease activity.

Anti-cyclic citrullinated peptide antibody predicts functional disability in patients with rheumatoid arthritis in a large prospective observational cohort in Japan.

To clarify the clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP) in the long-term outcome of RA, we established a large observational cohort of RA patients (IORRA) in our institute beginning in 2000. Essentially all RA patients who consulted our institute were registered, and clinical parameters, including disease activity and drug use, were assessed biannually based on patient reports, physician examinations, and laboratory data. In the third phase (October 2001) of the IORRA survey, anti-CCP levels were measured in 1,226 RA patients. In a cross-sectional analysis, clinical variables were compared in anti-CCP-positive versus -negative patients and in RF-positive versus -negative patients. In a longitudinal analysis, subsequent progression of disability was analyzed in anti-CCP-positive versus -negative and in RF-positive versus -negative patients. A verified Japanese version of the Health Assessment Questionnaire (J-HAQ) was used to measure functional disability. In the cross-sectional analysis, anti-CCP-positive patients (84.2%) had a significantly longer disease duration and higher disease activity score and more frequently used corticosteroids and methotrexate compared to anti-CCP-negative patients statistically. Similar phenomena were noted between RF-positive and -negative patients. In contrast, the longitudinal analysis revealed that J-HAQ slopes-a measure of progression of functional disability-were strongly associated with anti-CCP positivity but not with RF positivity. In a linear regression model, J-HAQ scores significantly worsened in anti-CCP-positive patients compared to anti-CCP-negative patients at the third year (annual progression 0.0317, P = 0.001) and the fifth year (annual progression 0.0199, P = 0.0012); however, J-HAQ progression was not influenced by RF status. Anti-CCP is a better predictive and discriminative marker for progression of disability in the long-term outcome of RA patients compared to RF.

Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study).

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.

Incidence of serious respiratory infections in patients with rheumatoid arthritis treated with tocilizumab.

We aimed to demonstrate the incidence of serious respiratory infections in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) monotherapy. We analyzed the incidence of serious respiratory infections in 601 RA patients enrolled in TCZ clinical trials and their extension studies (TCZ cohort) and in 601 age- and sex-standardized RA patients treated in daily clinical practice at Tokyo Women's Medical University (IORRA subsample cohort). The rates of serious respiratory infections were 1.77 per 100 patient-years from 1999 to 2008 in the TCZ cohort and 0.53 per 100 patient-years from 2000 to 2009 in the IORRA subsample cohort. With the IORRA subsample cohort regarded as a standard population, the standardized incidence ratio (SIR) of serious respiratory infection in the TCZ cohort was 3.64 [95% confidence interval (CI) 2.56-5.01], standardized for age and sex; 2.35 (95% CI 1.66-3.24), standardized for age sex, and corticosteroid use; 1.85 (95% CI 1.30-2.55), standardized for age sex, and pre-existing pulmonary involvement; and 2.41 (95% CI 1.68-3.34) standardized for age sex, and disease activity. The risk of serious respiratory infection in the TCZ cohort was approximately double that in the IORRA subsample cohort after standardizing for corticosteroid use, pre-existing pulmonary involvement, or disease activity. This is comparable to the risk reported when tumor necrosis factor (TNF) inhibitors are used.

Comparison of the second and third generation anti-cyclic citrullinated peptide antibody assays in the diagnosis of Japanese patients with rheumatoid arthritis.

The anti-cyclic citrullinated peptide (CCP) antibody has become increasingly important in the diagnosis of rheumatoid arthritis (RA), especially for early diagnosis. The purpose of this study is to compare the diagnostic usefulness of the second and third generation anti-CCP antibody kits among Japanese patients with RA. Anti-CCP antibody titers were measured with the second generation (MESACUP CCP test, Medical and biological laboratories) and third generation (QUANTA Lite CCP3 IgG ELISA, Inova Diagnostics) kits using serum samples from 106 rheumatoid arthritis (RA) patients and 57 non-RA patients. Sensitivities and specificities were compared. The sensitivity and specificity of the second generation anti-CCP (anti-CCP2) kit were 88.7 and 89.5%, and those of the third generation anti-CCP (anti-CCP3) kit were 91.5 and 87.7%. Area under the receiver operating curve showed that anti-CCP2 and anti-CCP3 had similar diagnostic performances. Diagnostic performance of the anti-CCP3 assay was comparable with the anti-CCP2 assay in Japanese patients with RA.

Standard treatment in daily clinical practice for early rheumatoid arthritis improved disease activity from 2001 to 2006.

We aimed to clarify the degree of improvement in disease control following early treatment of rheumatoid arthritis (RA) in daily clinical practice in 2006 compared to that in 2001. Using a large observational Japanese RA cohort (IORRA), we analyzed changes in clinical parameters, including disease activity assessed by the disease activity score 28 (DAS28) and physical disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), which occurred within 2 years of cohort inception. All patients had enrolled in the IORRA cohort within 1 year of RA onset, in either 2001 (2001-cohort) or 2006 (2006-cohort). For both cohorts, changes in clinical features over 2 years were compared by Fisher's exact test or the Wilcoxon test. The 2001-cohort included 71 patients and the 2006-cohort included 56 patients. Over the 2-year period for each cohort, DAS28 significantly decreased from 3.9 to 3.5 in the 2001-cohort (p < 0.001) and from 4.1 to 3.1 in the 2006-cohort (p < 0.0001), and J-HAQ significantly decreased from 0.62 to 0.49 (p < 0.02) in the 2001-cohort and from 0.71 to 0.41 (p < 0.001) in the 2006-cohort. Greater improvement in disease activity over 2 years occurred in the 2006-cohort than in the 2001-cohort (p < 0.05). Better disease control was obtained following changes in RA treatment strategy that occurred in Japan between 2001 and 2006.

Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA.

Interstitial lung disease (ILD) is a frequently encountered and sometimes life-threatening complication among patients with rheumatoid arthritis (RA). In this study, we aim to clarify the incidence of and risk factors for ILD using a large observational cohort of RA patients. We analyzed the database from a large observational cohort of Japanese RA patients, the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. We defined as interstitial pneumonia (IP) computed tomography (CT) pattern of nonspecific interstitial pneumonia or diffuse alveolar damage. Newly developed IP was identified from patient reports over 2.5 years (April 2004 to October 2006) and was confirmed by extensive medical record, chest X-ray radiograph, and CT. The raw and age/gender-adjusted incidence of IP were reported. IP risk factors were analyzed using a nested case-control design was employed using conditional logistic regression analysis with a stepwise method. Thirty-seven patients among 5,699 RA patients were diagnosed with newly developed IP, including 18 cases with methotrexate-induced pneumonitis (MTX-IP) and 15 cases with IP associated with RA (RA-IP). The age-adjusted incidence of MTX-IP among total patients, males, and females was 3.775, 6.667, and 1.013 per 1,000 cases, respectively, and of RA-IP among total patients, males, and females was 1.056, 1.452, and 0.677 per 1,000 cases, respectively. Conditional logistic regression analysis after stepwise variable selection identified male gender, increased Japanese version of the Health Assessment Questionnaire (J-HAQ) score, decreased pain visual analog scale (VAS), and elevated erythrocyte sedimentation rate as significant risk factors for MTX-IP, while the only risk factor for RA-IP was male gender. The incidence of and risk factors for IP in RA patients were determined in a large observational cohort of RA patients in Japan.

Anti-arthritis effects of vitamin K(2) (menaquinone-4)--a new potential therapeutic strategy for rheumatoid arthritis.

Vitamin K(2) (menaquinone-4, MK-4) has been reported to induce apoptosis in hepatocellular carcinoma, leukemia and myelodysplastic syndrome cell lines. The effects of MK-4 on the development of arthritis have never been addressed thus far. In the present study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis. We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The pro-apoptotic effect of MK-4 upon fibroblast-like synoviocytes was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of collagen-induced arthritis in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of fibroblast-like synoviocytes and the development of collagen-induced arthritis in a dose-dependent manner. We conclude that MK-4 may represent a new agent for the treatment of rheumatoid arthritis in the setting of combination therapy with other disease-modifying antirheumatic drugs.

Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort.

The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient's report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12-1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00-1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.

Continual Maintenance of Remission Defined by the ACR/EULAR Criteria in Daily Practice Leads to Better Functional Outcomes in Patients with Rheumatoid Arthritis.

OBJECTIVE: To evaluate longterm functional outcomes in rheumatoid arthritis (RA) based on the number of times that the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) or the 28-joint Disease Activity Score (DAS28) remission criteria were fulfilled. METHODS: Patients with RA who participated in all 6 data collections in an observational cohort from 2008 to 2010 and who fulfilled the DAS28 remission criteria at baseline were studied. Patients were classified by the number of times they fulfilled the ACR/EULAR [Boolean trial, Boolean practice, Simplified Disease Activity Index (SDAI), or Clinical Disease Activity Index (CDAI)] or DAS28 remission criteria at each collection. The OR for the Japanese version of the Health Assessment Questionnaire (J-HAQ) progression, based on the number of times each set of remission criteria was fulfilled, were calculated by logistic regression. RESULTS: A total of 915 patients were studied. The OR (95% CI) for J-HAQ progression were 0.54 (0.33-0.87), 0.55 (0.33-0.92), 0.48 (0.28-0.82), 0.29 (0.16-0.51), 0.24 (0.13-0.47), and 0.07 (0.03-0.15) for those fulfilling the Boolean trial remission from 1 to 6 times. This tendency was also observed for the other 4 criteria. The OR (95% CI) for J-HAQ progression in patients who achieved remission at all 6 data collections were 0.07 (0.03-0.14) for the Boolean practice, 0.10 (0.05-0.20) for the SDAI, and 0.07 (0.04-0.15) for the CDAI, whereas 0.15 (0.08-0.29) for the DAS28. CONCLUSION: Continual fulfillment of any remission criteria was strongly effective in preventing patients from progression of functional disability; however, the ACR/EULAR criteria appear to be preferable.