Yasuhide Kanayama

Depression, inflammation, and pain in patients with rheumatoid arthritis

OBJECTIVE An association between depression and inflammation has been suggested. In patients with rheumatoid arthritis (RA), pain is a major symptom associated with depression and inflammation. We examined the independent associations between depression, the inflammation marker C-reactive protein (CRP) level, and pain in patients with RA. METHODS In total, 218 RA outpatients completed self-administered questionnaires, using the Beck Depression Inventory II to measure depressive symptoms and a visual analog scale to quantify their perceived pain. Functional disability and CRP level were also measured. RESULTS Depression scores were mildly and positively correlated with the CRP level (r = 0.46, P < 0.001). Both the depression score (standardized beta = 0.35, P < 0.001) and the CRP level (standardized beta = 0.35, P < 0.001) were significantly associated with pain, even after adjustment for clinical covariates in regression analysis. In logistic analysis, the combined effects on the risk of severe pain (pain score in the upper tertile) increased with depression scores and CRP levels linearly. CONCLUSION Depression severity and inflammation were associated with each other and appeared to have independent effects on perceived pain. Therefore, a clinical approach that takes into account both the body and the mind could have benefits and could enable optimal pain control.

Study protocol of a multicenter registry of patients with rheumatoid arthritis starting biologic therapy in Japan: Tsurumai Biologics Communication Registry (TBCR) Study

Biologic agents have proven to be effective against rheumatoid arthritis (RA) in clinical trials and post-marketing surveillance (PMS) studies. However, limited follow-up periods and strict criteria for recruitment might lead to an underestimation of adverse events. To document the long-term course of patients with RA treated with biologics in clinical settings, we established the Tsurumai Biologics Communication Registry (TBCR). First, we retrospectively collected data of patients registered for any biologic PMS study or clinical trial at participating institutes. Thus far, thirteen institutes have joined the registry and 860 patients have been identified. Comparing baseline characteristics by age and initiation year of biologics, young patients had significantly less joint damage and dysfunction and a higher dose of concomitant methotrexate (MTX) compared to older patients. Older age and functional class were significantly related to the incidence of adverse events that resulted in discontinuation of the 1st biologic treatment. The TBCR is in its initial stages, and information on all patients newly starting biologic therapy at participating institutes is being collected prospectively. Differences in baseline characteristics by age and initiation year of biologics need to be carefully evaluated in order to report on drug-related survival and long-term prognosis, using follow-up data in the near future.

Predictors of aggravation of cervical spine instability in rheumatoid arthritis patients: the large joint index

BackgroundImproved rheumatic drugs have provided significant benefits, but activities of daily living are not improved if spinal symptoms are overlooked. Furthermore, the appropriate timing for examining the cervical spine during follow-up is unclear.MethodsTo evaluate the relations of cervical spine instabilities and an index for cervical spine lesion in rheumatoid arthritis (RA) based on extremity radiographs, we examined preoperative radiographs of 100 RA patients who underwent total knee arthroplasty. Radiographic results for eight large joints (bilateral shoulders, elbows, hips, and knees) were graded as follows: Larsen grade ≥2 for each joint was scored as 1 point, which we refer to as the “large joint index” (LJI), based on 0–8 points. The associations of radiographic cervical lesions with LJI, Ranawat class, the disease duration, RA drugs, or blood analysis data were evaluated.ResultsAtlantoaxial subluxation (AAS) (≥5 mm) was found in 45 patients, vertical subluxation (VS) (≤13 mm) in 42, a posterior atlantodental interval (PADI) (<14 mm) in 21, and subaxial subluxation (SAS) (≥3 mm) in 23. Most patients with a PADI < 14 mm (19/21, 90%) were complicated with both AAS and VS. LJI had a significant association with AAS (P < 0.0001), VS (P < 0.01), and PADI (P < 0.01). The PADI was significantly lower (P < 0.0001) and the LJI was significantly higher (P < 0.01) in patients of Ranawat class II compared to patients of Ranawat class I. The disease duration, age at surgery, and age at onset were also significantly associated with cervical instabilities.ConclusionsPADI should be recognized as a predictor of paralysis with anteroposterior instability and vertical and middle-low cervical spine instability. The LJI proposed in this study has the possibility of being a predictor of cervical lesions. Patients with RA onset at a young age and a long disease duration also have a risk of progression of cervical spine instability.

Longterm Efficacy and Safety of Abatacept in Patients with Rheumatoid Arthritis Treated in Routine Clinical Practice: Effect of Concomitant Methotrexate after 24 Weeks

Objective. Our study aimed to evaluate the longterm efficacy and safety of abatacept (ABA), and to explore factors that increase its longterm efficacy in patients with rheumatoid arthritis (RA) treated in routine clinical practice. Methods. There were 231 participants with RA treated with ABA who were prospectively registered in a Japanese multicenter registry. They were followed up for at least 52 weeks. Results. Mean age of the patients was 64.3 years, mean disease duration was 12.1 years, mean 28-joint Disease Activity Score (DAS28)-C-reactive protein was 4.49, and 48.5% of patients were concomitantly treated with methotrexate (MTX). Overall retention rate of ABA was 77.1% at 52 weeks; 14.8% of patients discontinued because of inadequate response and 3.5% because of adverse events. The proportion of patients achieving DAS28-defined low disease activity (LDA) significantly increased from baseline to 52 weeks (7.3% to 43.8%, p < 0.01); 40.9% of patients who did not achieve LDA at 24 weeks had more than 1 categorical improvement in DAS28-defined disease activity at 52 weeks. Multivariate logistic regression revealed concomitant MTX use to be an independent predictor of the categorical improvement in DAS28-defined disease activity from 24 to 52 weeks (adjusted OR 3.124, p = 0.010). Conclusion. In routine clinical practice, ABA demonstrated satisfactory clinical efficacy and safety in patients with established RA for 52 weeks. The clinical efficacy of ABA increased with time even after 24 weeks, and this was strongly influenced by concomitant MTX use. Our study provides valuable real-world findings on the longterm management of RA with ABA.

Drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors for rheumatoid arthritis in Japanese patients on low-dose methotrexate or without methotrexate

Abstract Objectives. The purpose of this study was to explore drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors (TNFi) in clinical practice in patients with rheumatoid arthritis (RA) on low-dose methotrexate (MTX) or without MTX. Methods. A total of 169 RA patients who had been withdrawn from first-course TNFi therapy and received a different TNFi or tocilizumab (TCZ) as a second biologic agent were selected from the Tsurumai Biologics Communication Registry, an observational cohort database. Retention rates of second biologic treatment were compared by the type of first TNFi and second biologic agents. Results. Eighty-six patients received first-course infliximab (IFX) or adalimumab (ADA) therapy, and 83 patients received first-course etanercept (ETN) therapy. The former group had a significantly higher retention rate (IFX, 81.1%; ADA, 83.3%) of the second biologic therapy compared to the latter (56.6%, p < 0.001, log-rank test). Drug retention rates of the second biologic agent after switching from IFX/ADA were significantly higher with ETN (90.0%) and TCZ (94.7%) than with ADA/IFX (59.3%). Drug retention rates of the second biologic agent after switching from ETN were significantly higher with TCZ (75.9%) than with ADA/IFX (46.3%). The differences were significant even after adjusting for baseline clinical variables using the Cox proportional hazards model. Conclusions. Drug retention rates of IFX and ADA after switching from the first TNFi were significantly lower compared to those of ETN and TCZ in patients on low-dose MTX or without MTX.

Effects of Concomitant Methotrexate on Large Joint Replacement in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: A Multicenter Retrospective Cohort Study in Japan

To determine the effects of concomitant methotrexate (MTX) on the incidence of large joint replacement resulting from the progression of large joint destruction in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors.

Longterm Retention Rate and Risk Factor for Discontinuation Due to Insufficient Efficacy and Adverse Events in Japanese Patients with Rheumatoid Arthritis Receiving Etanercept Therapy

Objective. Assessing retention rate and risk factor for drug discontinuation is important for drug evaluation. We examined a 3-year retention rate and the risk factor for discontinuation due to insufficient efficacy (IE) and adverse events (AE) in Japanese patients with rheumatoid arthritis (RA) who are receiving etanercept (ETN). Methods. Data were collected from 588 patients treated with ETN as a first biologic from the Tsurumai Biologics Communication Registry. Baseline characteristics for the incidence of both IE and AE were analyzed using the Cox proportional-hazards regression model. Patients were divided into groups based on age and concomitant methotrexate (MTX). Drug retention rates were calculated using the Kaplan-Meier method and compared among groups using the log-rank test. Results. ETN monotherapy without concomitant MTX [MTX(–)] was significantly related to a higher incidence of discontinuation due to IE [hazard ratio (HR) = 2.226, 95% CI 1.363–3.634]. Older age and MTX(–) were significantly related to a higher incidence of discontinuation due to AE [HR = 1.040, 1.746, 95% CI 1.020–1.060, 1.103–2.763, respectively]. The MTX(–)/≥ 65 years group had the lowest retention rate (p < 0.001). The discontinuation rate due to IE was lower in the MTX(+)/< 65 years group compared to < 65 years/MTX(–), ≥ 65 years/MTX(–) group (p = 0.006, p < 0.001, respectively). The discontinuation rate due to AE was highest in the MTX(–)/≥ 65 years group (p < 0.001). Conclusion. Our findings suggest that the risk of discontinuation due to IE was high in the patients who did not use concomitant MTX and that the risk of discontinuation due to AE was high in elderly patients who did not use concomitant MTX.

Disease activity early in treatment as a predictor of future low disease activity in RA patients treated with iguratimod

Objectives. This retrospective observational study aimed to examine the efficacy of iguratimod with and without concomitant methotrexate (MTX) and to estimate the adequate observational period for predicting low disease activity (LDA) achievement at 24 weeks in patients with rheumatoid arthritis (RA). Methods. All patients treated with iguratimod were registered in a Japanese multicenter registry. Multivariate analyses were performed to identify predictive factors for LDA achievement at 24 weeks. Receiver operating characteristic (ROC) curve analyses were performed to estimate the association of 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) at each time point with achievement of LDA at 24 weeks and determine a cut-off for DAS28-ESR. Results. A total of 123 patients were treated with iguratimod with (n = 65) or without (n = 58) MTX. Iguratimod therapy resulted in significant clinical improvement in both groups. Multivariate analysis revealed that DAS28-ESR at each time point was an independent significant predictor of LDA achievement at 24 weeks. Cut-off values of DAS28-ESR at 12 weeks based on ROC curves were 3.2 and 3.6 in patients with and without MTX, respectively. Conclusions. Iguratimod was effective in RA patients in clinical practice. Our results suggest that 12 weeks may be a sufficient period to judge the medium-term efficacy of iguratimod in patients treated with and without MTX.

Use of a 12-week observational period for predicting low disease activity at 52 weeks in RA patients treated with abatacept: a retrospective observational study based on data from a Japanese multicentre registry study

OBJECTIVE Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.

Pneumococcal polyarticular septic arthritis after a single infusion of infliximab in a rheumatoid arthritis patient: a case report.

IntroductionWe present a case of Streptococcus pneumoniae polyarticular septic arthritis in a patient with rheumatoid arthritis receiving a single infusion of infliximab.Case presentationA 38-year-old Japanese man with a 5-year history of seronegative rheumatoid arthritis had previously received sulphasalazine and methotrexate therapies and was on regular low-dose prednisolone therapy. Despite these treatments, his disease activity remained high and infliximab was introduced in addition to methotrexate, prednisolone, and folic acid. However, he was admitted to hospital with a fever of 40.6°C, chills, and polyarthralgia eight days after the first infusion of infliximab. His joints were swollen, painful, and warm. Laboratory data showed marked acute inflammation. He was diagnosed with bacterial septic polyarthritis, and emergency surgical joint lavage and drainage was performed at the knees along with needle aspiration and lavage of the ankles and right wrist. He was then given intravenous antibiotic therapy for 31 days. He made a good recovery and was discharged on day 37.ConclusionsWe believe this is the first reported case of severe pneumococcal septic arthritis requiring hospitalization in a patient treated with infliximab. S. pneumonia is now a well-recognized but uncommon cause of polyarticular septic arthritis that can lead to cessation of therapy, as in our patients case.