Yohei Seto

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.

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

ObjectivesOur 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.MethodsDirect 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.ResultsData 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

Comparison of characteristics and therapeutic efficacy in rheumatoid arthritis patients treated by rheumatologists and those treated by orthopedic surgeons under a team medicine approach at the same institute

1xa0=xa0JPY90 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).ConclusionsBased 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.

Studies of the efficacy and safety of methotrexate at dosages over 8 mg/week using the IORRA cohort database.

The treatment of rheumatoid arthritis (RA) has improved dramatically with the advent of the latest generation of disease-modifying antirheumatic drugs. Despite these advances, in some patients inflammation is not diminished sufficiently to prevent irreversible musculoskeletal damage, thereby necessitating surgical intervention to reduce pain and improve function. For RA treatment, Japanese orthopedic surgeons also prescribe medication. In this study, we examined whether this Japanese system is effective for RA treatment. We analyzed the clinical condition of RA patients treated by rheumatologists and those treated by orthopedists in a linked registry study using information from a large observational cohort of RA patients followed every half year from 2000 to 2010 (the IORRA cohort). Two groups of patients were compared: patients treated by rheumatologists (rheumatologic group) and patients treated by orthopedists (orthopedic group). The results revealed that patients in the orthopedic group were older, more likely to be female, and had a longer disease duration than patients in the rheumatologic group. The proportion of patients with a history of joint surgery was also much higher in the orthopedic group than in the rheumatologic group. The average scores on the Japanese version of the Health Assessment Questionnaire, and the remission ratio determined using a Boolean-based definition gradually increased from 2000 until 2010, and these findings were consistently better in the rheumatologic group than in the orthopedic group. These data suggest that patients treated primarily by orthopedists are more likely to have long-standing RA compared to patients treated by rheumatologists. Therefore, it is critical for rheumatologists and orthopedists to complement each other medically in the treatment of RA patients.

Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs

The maximum dosage of methotrexate (MTX) for treatment of rheumatoid arthritis (RA) formally approved in Japan is 8xa0mg/week. We intended to examine the efficacy and safety of MTX at dosages over 8xa0mg/week in Japanese rheumatoid arthritis patients using the large Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort database. Among 9,122 patients registered in the IORRA database from the October 2000 survey to the October 2007 survey, 5,201 patients who had been treated with MTX were selected. We attempted to overcome the drawbacks innate to nonrandomized studies by using longitudinal analyses and multifactorial logistic regression analyses. Cross-sectional analysis of data obtained from the October 2007 survey indicated that dosages of MTX higher than 8xa0mg/week were used in 27.5% of patients treated with MTX. Longitudinal analyses based on data from three consecutive phases showed that final Disease Activity Score-28 (DAS28) values were significantly lower [nxa0=xa0260, mean difference 0.563, 95% confidence interval (CI) 0.438–0.688, Pxa0<xa02.2xa0×xa010−22, two-sided paired t test] than initial values when MTX was increased from 8xa0mg/week or lower to over 8xa0mg/week. In addition, longitudinal analyses based on data from two consecutive phases indicated decreases in DAS28 values of 0.26xa0±xa01.04 (nxa0=xa0690, Pxa0=xa06.78xa0×xa010−11, two-sided paired t test) when MTX dosages were increased from 8xa0mg/week or lower to over 8xa0mg/week, compared with decreases of 0.07xa0±xa00.89 (nxa0=xa02,125, Pxa0=xa00.000307) when the dosage was maintained at 8xa0mg/week. The decreases in DAS28 values were significantly larger in the former than the latter (Pxa0=xa02.27xa0×xa010−6, two-sided unpaired t test). Concerning safety of MTX at dosages over 8xa0mg/week, we performed logistic regression analysis in which the objective variable was the existence or nonexistence of self-reported side-effects and the explanatory variable was the MTX dosage in the former phase, with adjustments made for age, sex, body mass index (BMI), steroid administration, folic acid administration, concomitant pulmonary diseases, and renal dysfunction. The results indicated that MTX dosages over 8xa0mg/week did not have any association with either severe or severexa0+xa0moderate side-effects. These data regarding both efficacy and safety of MTX at dosages over 8xa0mg/week in Japanese RA patients would provide the basis for use of the drug at dosages currently not formally approved by the Japanese government.

A retrospective study of serum KL-6 levels during treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology

ObjectiveThe associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials.MethodsPercentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated.ResultsIn RISING, a clinical trial for infliximab, 15.6xa0% of the enrolled patients met criterion B (KL-6 ≥500xa0U/ml and >1.5-fold increase over the baseline value) by weekxa054. In HIKARI, 7.8xa0% of the certolizumab pegol (CZP) group and 0xa0% of the placebo group met criterion B during the double-blind (DB) period (pxa0=xa00.003). In J-RAPID, 8.4xa0% of the methotrexate (MTX)xa0+xa0CZP and 3.9xa0% of the MTXxa0+xa0placebo groups met criterion B during the DB period. In GO-MONO, 1.8xa0% of the golimumab (GLM) and 1.3xa0% of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1xa0% of the MTXxa0+xa0GLM and 0xa0% of the MTXxa0+xa0placebo groups met criteron B during the DB period (pxa0=xa00.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7xa0% of these patients.ConclusionSerum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.

Structural damages disturb functional improvement in patients with rheumatoid arthritis treated with etanercept

ObjectiveWe investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA).MethodsUsing a standardized form, data were collected retrospectively from medical records and analyzed descriptively.ResultsOf a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (monthxa00) and two or more times by monthxa012, 27 (17.9xa0%) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6xa0%) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterionxa0B (max. KL-6 ≥500xa0U/ml and >1.5-fold from baseline) by 12xa0months. The majority of patients (nxa0=xa028) meeting criterionxa0B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9xa0%) of the 21 then met criterionxa0R [decrease to less than 500xa0U/ml or to less than (baselinexa0+xa00.5xa0×xa0(maximumxa0−xa0baseline))] by monthxa012.ConclusionSerum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.

C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: Defining subtypes of nonresponse and subsequent response to etanercept

Tumor necrosis factor (TNF) inhibitors have produced improvements in clinical, radiographic, and functional outcomes in rheumatoid arthritis (RA) patients. However, it remains unclear whether factors affecting physical functions remain following TNF therapy. The objective of our study was to assess factors affecting improvement of physical functions and to shed light on relations to disease activity and structural changes in patients with RA treated with etanercept. The study enrolled 208 patients, all of whose composite measures regarding clinical, radiographic, and functional estimation both at 0 and 52xa0weeks after etanercept therapy were completed. Mean disease duration of 208 patients was 9.6xa0years, mean Disease Activity Score for 28 joints (DAS28) was 5.4, and mean van der Heijde modified total Sharp score (mTSS) was 94.6. Mean Health Assessment Questionnaire Disability Index (HAQ-DI) improved from 1.4 at 0xa0weeks to 1.0 at 52xa0weeks after etanercept therapy, a 31% reduction, which was much less than changes in DAS28 and mTSS. By multivariate analysis, HAQ-DI and mTSS at baseline were significantly correlated HAQ remission. Median HAQ-DI improved in 100 versus 20% of the HAQ-DIxa0≤0.6 versus ≥2.0 groups, respectively. The mTSS cutoff point at baseline to obtain HAQ remission was 55.5. During etanercept treatment in the mTSS <55.5 versus >55.5 groups, median HAQ-DI improved in 70 versus 39%; remission was achieved in 59 versus 33%; and there was no improvement in14 versus 30%, respectively. HAQ-DI improvement was significantly correlated with that of DAS28 but not of mTSS. In conclusion, higher HAQ and mTSS at baseline inhibits HAQ-DI improvement within 1xa0year of etanercept treatment, and the cutoff point necessary for mTSS to improve physical functions in patients with RA was 55.5.