IL-6 is an independent predictive factor of drug survival after dose escalation of infliximab in patients with rheumatoid arthritis.

OBJECTIVE: We aimed to investigate factors predictive of increased serum infliximab (IFX) concentration with improvement of disease activity, as well as better 1-year continuation rate after dose escalation, in patients with rheumatoid arthritis (RA) who showed inadequate response to 3 mg/kg IFX. METHODS: Among 42 patients allotted to receive 3 mg/kg IFX, 13 patients showed adequate response (DAS28 < 3.2) and 29 patients required dose escalation to 4.5 or 6 mg/kg after inadequate response (DAS28 ≥ 3.2) to 3 mg/kg IFX. DAS28, mHAQ, serum level of CRP, interleukin (IL)-6, IL-17, anti-infliximab antibody (AIA) titers and IFX concentration before and on average 2.7 months after dose escalation were examined to explore the baseline factors predictive of a clinically beneficial increase of serum IFX concentration and drug survival. RESULTS: One year after IFX dose escalation, 25 patients completed the study protocol, and 16 patients (64%) continued to show a good response for one year, while 9 patients (36%) required switching of biologics because of inadequate response. Multivariate analyses revealed that a serum IL-6 level of less than 4.0 pg/mL at baseline was the only factor predictive of a clinically beneficial increase of serum IFX concentration in patients who required dose escalation. Receiver operating characteristic analysis revealed that 5.16 pg/mL of IL-6 was the cut-off value with sensitivity 0.833 and specificity of 0.769 (95%CI for AUC: 0.712-1.006). In patients with IL-6 levels of less than 5.16 pg/mL at baseline, the serum IFX concentration significantly increased after dose escalation with adequate response. The 1-year drug survival rates of patients with IL-6 levels less than 5.16 pg/mL and in those with levels greater than or equal to 5.16 pg/mL at baseline were 83.3% and 30.8%, respectively (log-rank test, p = .011). CONCLUSIONS: The results of our study indicated that a baseline serum level of IL-6 below 5.16 pg/mL might be a predictive factor for a clinically beneficial increase of serum IFX concentration with improvement of disease activity and better 1-year continuation rate after IFX dose escalation.

A comparison of incidence and risk factors for serious adverse events in rheumatoid arthritis patients with etanercept or adalimumab in Korea and Japan.

OBJECTIVE: To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries. METHODS: We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared. RESULTS: Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs. CONCLUSIONS: The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.

The association of change in medication regimen and use of inappropriate medication based on beers criteria with adverse outcomes in Japanese long-term care facilities.

AIM: To describe medication use including potentially inappropriate medication (PIM) and examine the association between adverse outcomes and patient factors including PIM use in Japanese elderly patients in long-term care facilities. METHODS: This was a retrospective cohort study of 470 patients in 53 Geriatric Health Service Facilities and 44 Sanatorium Type Medical Care Facilities for the Elderly Requiring Long Term Care. Standardized forms were used to collect information including oral and parenteral medication use on admission, and 1 month and 3 months after admission. PIMs were determined by the 2003 or 2012 Beers criteria. Adverse outcomes were any medical events leading to emergency department transfer, hospitalization to acute care hospitals or death. RESULTS: A total of 2,227 oral medications and 197 parenteral medications were prescribed for 470 patients on admission. PIM exposure based on the 2003 and 2012 Beers criteria was observed in 11.9% and 37.5%, respectively. Adverse outcomes within 3 months after admission were observed in 8.9% of the entire cohort, and were associated with age, sex, facility type and number of parenteral medications on admission. Adverse outcomes between one and three months after admission were associated with age, sex, number of parenteral medications at one month, and a change in the number of oral and parenteral medications within one month after admission. PIM exposure was not associated with adverse outcomes in any models. CONCLUSIONS: Use of PIM was prevalent in long-term care facilities. Our findings support the importance of comprehensive assessment of medication regimens including parenteral medication. Geriatr Gerontol Int 2017; 17: 591-597.

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population.

INTRODUCTION: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. METHOD: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. RESULTS: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 × 10(-6)) and rs17727339 in FCRL3 (p = 1.4 × 10(-5)). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. CONCLUSION: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.

INTRODUCTION: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. RESULTS: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). CONCLUSIONS: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Priorities of health care outcomes for the elderly.

OBJECTIVES: Physicians are uncertain about what medical services should be provided to older and/or disabled patients. Better understanding of health outcome prioritization among health care providers and recipients may help the process of decision- and policy-making. For this purpose, surveys were conducted on priorities of health care outcomes for the elderly. DESIGN: Survey research. SETTING: Four groups of health care providers and four groups of health care recipients. PARTICIPANTS: A total of 2512 health care providers and 4277 recipients. MEASUREMENTS: Questionnaires were sent to more than 8000 health care providers and more than 9000 health care recipients: geriatricians, physicians who commonly see older patients or work in long term care facilities, staff members and participants in adult day care, patients in outpatient geriatric clinics, family members of patients with dementia, and community-dwelling older adults. The questionnaire asked the subjects to rank 12 measures of health care outcomes. RESULTS: The mean response rate was 49%. All health care provider groups considered "improvement of quality of life" the most important. In contrast, in health care recipient groups, "effective treatment of illness," "improvement of physical function," and "reduction of carer burden" were given high priority, whereas "improvement of quality of life" was perceived as less important. All the groups, including health care providers and recipients, ranked "reduction of mortality" the least important, followed by "avoiding institutional care." Stratification analysis showed that the results did not differ by sex, nursing care level, or the existence of relatives who required nursing care, whereas age slightly influenced the order of high-ranked measures. CONCLUSION: Priorities of health care services and their differences between providers and recipients should be taken into account in the health care of older patients and the design of health care policies and research.

Radiographic measurements in the evaluation and classification of elbow joint destruction in patients with rheumatoid arthritis.

We developed two new radiographic parameters-the humeral surface height ratio and ulnar surface height ratio-to precisely detect changes in the bony structure of rheumatoid elbows. Of the 59 patients with rheumatoid arthritis, 101 elbows were classified into four types (osteoarthritis, ankylosis, erosive, and resorptive) according to the radiographic appearance. Clinically, osteoarthritis type and ankylosis type were considered to be stable form, and erosive type and resorptive type were unstable form. Patients' clinical data and yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio were compared among the four types and between the two forms. There were significant differences between the two forms and among the three types except for the ankylosis type in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio. Stable and unstable forms were distinguished by a cut-off point of 0.65 and 2.58 in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and the ulnar surface height ratio, respectively. These parameters might be useful for monitoring the structural changes of the elbow joint in rheumatoid arthritis.

Efficacy and safety of tacrolimus treatment for rheumatoid arthritis patients undergoing hemodialysis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.