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Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6-8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5-15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

To reduce costs of biological disease-modifying antirheumatic drugs (bDMARDs), we evaluated the efficacy of repeated etanercept (ETN) discontinuation and restarting in rheumatoid arthritis (RA) patients in a case-control study.Thirty-one bDMARD-naive RA patients with moderate to high disease activity received ETN until low disease activity (LDA) was achieved, after which ETN was discontinued. Upon flaring, ETN was readministered with observation every 2 months for 2 years, and radiographically evaluated in comparison with a historical control group treated continuously with ETN. Statistical methods including Fisher exact test, analysis of variance (ANOVA), Kruskal-Wallis test, multiple regression analysis, and Student t test were conducted as appropriate.Thirteen patients with inadequate response to ETN were withdrawn from the study, and 5 had no flare-up after ETN discontinuation. In the remaining 13 patients, ETN was used on-demand to maintain LDA. Multivariate analysis revealed that MTX was significantly correlated with ETN. All 13 patients achieved LDA at final follow-up. Although joint damage progressed in patients using ETN on-demand, structural damage progression in the on-demand group was not significantly different from that in controls.On-demand use of ETN for flaring reduced disease activity but not structural damage in 50% of patients (though not significantly). However, inhibition of joint damage was achieved in 50% of patients after 2 years, supporting on-demand use of ETN as a treatment option for patients with RA who cannot afford bDMARD or targeted synthetic DMARD therapy.

We investigated the influence of abatacept (ABT) on bone mineral density (BMD) and bone metabolic markers (BMMs) in patients with rheumatoid arthritis (RA) compared to other biologic disease-modifying anti-rheumatic drugs (bDMARDs). This prospective, comparative, non-randomized study (the AIRTIGHT study; UMIN000005570) investigated the effects of ABT and other bDMARDs on bone metabolism. A total of 165 RA patients were divided into ABT (n = 50) and non-ABT (n = 115). We evaluated percentage changes in BMD (%ΔBMD) at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Urinary levels of cross-linked N-telopeptide of type I collagen (uNTx) and bone-specific alkaline phosphatase (BAP) were used as markers of bone resorption and formation, respectively. No significant differences in 1-year completion rates were seen between ABT (64%) and non-ABT (72%; p = 0.387). The %ΔBMD at the femoral neck was significantly higher in the ABT group (0.97%) than in the non-ABT group (- 2.19%; p = 0.026). Whereas, no significant difference in %ΔBMD at the lumbar spine was observed between groups (ABT, - 0.40%; Non-ABT, - 1.67%; p = 0.524). No significant differences were observed in changes to uNTx or BAP. ABT treatment was significantly associated with increased BMD at the femoral neck (odds ratio (OR) 8.84; 95% CI 1.08-72.4; p = 0.04), and baseline lumbar osteoarthritis was significantly associated with BMD at the lumbar spine (OR 2.97; 95% CI 1.23-7.13; p = 0.02). The efficacy of ABT for increasing BMD at the femoral neck was superior to that of other bDMARDs. ABT may offer good efficacy for improving BMD at the femoral neck in patients with RA.

Although patients with rheumatoid arthritis (RA) are prone to osteoporosis, tight control of disease activity might have a positive effect on bone metabolism. We aimed to determine whether bisphosphonate use is still important to improve bone mineral density (BMD) in RA patients whose disease activity was tightly controlled and the dose of glucocorticoid was reduced. This study was a sub-analysis of the 10-year prospective cohort TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality: the TOMORROW which started from 2010. We compared BMD between 192 patients with RA and age- and sex-matched volunteers between 2010 and 2013 using dual-energy X-ray absorptiometry (DXA) in whole body mode. We then determined ratios of changes in BMD (%ΔBMD) to assess factors influencing increases in BMD among the patients using multivariate logistic regression analysis. The BMD was significantly lower in the patients than in the controls at all sites surveyed during 2010 and 2013. The %ΔBMD of the total spine was significantly higher among the patients treated with, than without bisphosphonate (6.2 vs. 1.8%, P = 0.0001). Multivariate logistic regression analysis revealed that use of bisphosphonate was a significant factor contributing to BMD increase (odds ratio 2.13; 95% confidence interval, 1.03-4.38, P = 0.041). Meanwhile, use of biologic agents, reducing glucocorticoid dose, and control of disease activity were not significant factors for gain of BMD. The BMD was lower among patients with RA than non-RA controls. Use of bisphosphonate significantly increased the BMD of the spine in patients over a period of 3 years and was important for maintaining the BMD among patients with RA under the control of inflammation and disease activity.

Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0 years; disease duration, 16.9 years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0 %, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; P = 0.045), prolonged surgery (OR, 1.02; P = 0.03), and preoperative white blood cell count >10,000/μL (OR, 3.66; P = 0.003). Those for delayed wound healing were advanced age (OR, 1.16; P = 0.001), prolonged surgery (OR, 1.02; P = 0.007), preoperative white blood cell count >10,000/μL (OR, 4.56; P = 0.02), and foot surgery (OR, 6.60; P = 0.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.

Predicting the responses of patients with rheumatoid arthritis (RA) to tocilizumab is difficult, because inflammatory markers such as C-reactive protein rapidly normalize regardless of clinical efficacy. We aimed to identify factors that could predict response to tocilizumab. Sixty-five patients completed 52 weeks of tocilizumab therapy. Serum fibrinogen, D-dimer and interleukin (IL)-1β levels were measured at baseline and after 4 weeks of therapy. Clinical responses to tocilizumab were assessed using disease activity score 28-erythrocyte sedimentation rate and the clinical disease activity index at baseline and after 52 weeks of therapy (UMIN Clinical Trials Registry No. UMIN000002246). Mean age was 60.5 years (range 22-85 years). Mean disease duration was 11.2 years (range 0-45 years). All patients had moderate-to-severe disease activity and were resistant to disease-modifying anti-rheumatic drugs and/or other biologics. Baseline IL-1β levels were significantly lower in responders than in non-responders (p = 0.045), but multiple logistic regression analysis found no significant difference (adjusted odds ratio 2.74; 95 % confidence interval 0.84-8.95; p = 0.096). Low D-dimer and IL-1β levels at 4 weeks predicted greater decrease in disease activity after 52 weeks of treatment (p = 0.005 and p < 0.001, respectively). Effects of tocilizumab at 52 weeks could be predicted from D-dimer and IL-1β levels after 4 weeks of tocilizumab treatment. These markers might be more useful than current inflammatory markers for early-stage prediction of response to tocilizumab in RA.

Objectives: Cervical spine instability (CSI) is commonly involved in patients with rheumatoid arthritis (RA). Although the treatment for RA has dramatically changed due to methotrexate and biologics, it is unclear whether this change contributes to the prevalence of CSI or not. Our objectives were to update the current prevalence of CSI and to investigate the factors associated with CSI., Methods: A cross-sectional study of patients with RA was conducted in our outpatient clinic. Clinical information and symptoms related to CSI were obtained. Plain radiography and magnetic resonance imaging were performed. CSI included atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS)., Results: Two hundred and twenty patients were analyzed, 93 (42%) of whom had CSI. A ≥ 10-year disease duration, Steinbrocker stage III, and three or more narrowed disc spaces from C2/3 to C6/7 were significantly associated with CSI. A neck pain VAS was associated with VS, but not with AAS and SAS. In contrast, methotrexate and biologics had no effect on CSI., Conclusion: The prevalence of CSI in this study was lower compared to previous reports before the approval of biologic, although we failed to detect the effect of biologics. Further prospective studies are needed to elucidate the efficacy.

We investigated the effects of biologics for rheumatoid arthritis (RA) patients on bone mineral density (BMD) and bone metabolic markers (BMM), retrospectively, and also clarified the effects of bisphosphonates (alendronate or risedronate 35 mg/week) and glucocorticoids. Participants in this study comprised 219 patients with RA, including 117 patients treated with biologics (infliximab, n = 90; etanercept, n = 27) and 102 patients with conventional disease-modifying anti-rheumatic drugs (DMARDs) for 1 year. Changes in BMD at the lumbar spine and total hip and BMMs [urinary type I collagen cross-linked N-telopeptide (NTX) and bone-specific alkaline phosphatase] were measured. BMD of the lumbar spine in both groups and total hip BMD in the biologics group were unchanged during treatment with biologics. However, BMD of the total hip was significantly decreased in the DMARDs group (from 0.731 ± 0.135 to 0.706 ± 0.135 g/cm2). Patients receiving glucocorticoids without bisphosphonates showed significant decrease in BMD of the total hip compared with patients not receiving glucocorticoids or receiving glucocorticoids with bisphosphonates in both biologics and DMARDs groups. Furthermore, BMD of the lumbar spine increased (p < 0.05) for patients in the biologics group who received bisphosphonates. NTX was significantly decreased only in the biologics group. Multiple regression analysis showed that BMD and bone metabolic marker levels correlated positively with bisphosphonate and biologics use and negatively with glucocorticoid use. BMD of the total hip was maintained in the patients using biologics without glucocorticoids or with bisphosphonates, but it was not maintained in the DMARDs patients, even without glucocorticoids or with bisphosphonates. Even if biologics have protective effect against bone loss of RA patients, we should consider reducing the dose of glucocorticoids and adding bisphosphonates for the treatment of osteoporosis.

Objective: To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA., Methods: In this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS-28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as ΔmTSS ≤0.5, and the non-progression rate was compared between groups., Results: Mean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean ΔmTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups., Conclusion: Low-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non-progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN., Trial Registration: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798.

Background: Screening and prophylactic treatment for hepatitis B virus (HBV) reactivation is recommended for patients who receive immunosuppressive or cytotoxic therapy. The aim of this study was to clarify the prevalence of HBV reactivation in rheumatoid arthritis (RA) patients who had received more than 1 year of immunosuppressive therapy. This study also evaluated guidelines for determining HBV reactivation in patients with RA., Methods: This was a prospective non-randomized, non-controlled study. We enrolled 50 patients with RA who had antibodies against hepatitis B core antigen (anti-HBc) and who had started treatment with disease-modifying anti-rheumatic drugs, including those who had additionally received anti-tumor necrosis factor-α (anti-TNF-α). HBV DNA levels were measured every 2-3 months by a real-time, polymerase chain reaction-based method. Entecavir was administered to patients with HBV DNA levels >2.1 log/ml., Results: The mean observation period was 23 months (range 12-32 months). HBV reactivation occurred in 2 of 5 patients with HBV surface antigen (HBsAg) and in 1 of 45 patients without HBsAg. In patients who received anti-TNF-α therapy, antibodies against HBsAg decreased significantly. Entecavir therapy inhibited HBV amplification and prevented HBV-associated flares of hepatitis., Conclusions: The incidence of HBV reactivation was low in RA patients in whom HBV infection had been resolved. Screening for HBV reactivation and prophylactic therapy with entecavir were effective means of preventing HBV-associated hepatic failure in patients with HBsAg, as well as in those with only anti-HBc who received immunosuppressive therapy for RA.

Pyoderma gangrenosum (PG) is characterized by ulcerative skin lesions. Infliximab (IFX) may promote PG healing in patients with inflammatory bowel disease, but whether IFX is effective for treating PG in patients with rheumatoid arthritis (RA) has not reported. We report the case of a 53-year-old woman with PG complicated by RA who was treated using IFX therapy. This case suggests that IFX therapy might offer effective treatment for such patients.

Objective: To investigate the effects of electrical pulses on the ability of methotrexate (MTX) to attenuate inflammation and subsequent joint destruction in rats with adjuvant-induced arthritis (AIA)., Methods: Rats in the experimental group received an intraperitoneal injection of MTX (0.125 mg/kg body weight), followed 30 minutes later by application of direct electrical pulses (50V, 8 Hz) to their left hind paws with an electroporation apparatus (M+/E+ group; n = 8). The procedure was repeated twice weekly for 3 weeks. Three control groups received the following treatments, respectively: MTX without electrical treatment (M+/E- group; n = 9), electrical treatment but no MTX (M-/E+ group; n = 10), or no electrical treatment and no MTX (M-/E- group; n = 9). Progression of AIA was monitored by joint swelling and radiologic and histologic changes in the ankle joint., Results: Three weeks after injection of the adjuvant, and at the height of the arthritic reaction, the swelling and radiologic and histologic changes in the left hind paws in the M+/E+ rats were significantly reduced, as compared with changes observed in the control groups., Conclusion: These results demonstrate that application of electrical pulses in combination with use of systemic low-dose MTX can ameliorate local arthritic reactions. This response probably occurs because electrical stimulation promotes transient passage of MTX through pores in the cell membranes, with a resultant local increase in the concentration of the drug within the cells. These results point to a potential use of electrochemotherapy to increase the efficacy of MTX or other drugs in an arthritic joint that is refractory to treatment, without increasing the dose of the drug.

Aim: Frailty is defined as the degradation of physical and cognitive function in older adults. The relationship between frailty and disease activity in patients with rheumatoid arthritis is unclear. Factors related to frailty in Japanese rheumatoid arthritis patients were investigated in a cross‐sectional analysis. Methods: Of 100 patients who entered the prospective, observational Correlation research of sarcopenia, skeletal muscle and disease activity in rheumatoid arthritis (CHIKARA) study, 95 completed a frailty check list (maximal score 25), and were classified as frail (8–25 points), pre‐frail (4–7 points) and normal (0–3 points). The relationship with disease activity was investigated in the frailty, pre‐frailty and normal groups. Relationships between clinical variables and frailty were evaluated by univariate and multiple logistic regression analyses. Results: The prevalences of frailty, pre‐frailty and normal were 18.9%, 38.9% and 42.2%, respectively. The disease activity score 28 erythrocyte sedimentation rate, matrix metalloproteinase 3 and modified health assessment questionnaire were higher in the frailty group. In remission, 66.6% were normal and 6.7% had frailty, but with moderate and high disease activity, 13.3% were normal and 46.7% had frailty. On univariate analysis, factors positively related to frailty were age, locomotive syndrome, disease activity score 28 erythrocyte sedimentation rate, matrix metalloproteinase 3, use of biological disease‐modifying antirheumatic drugs or targeted synthetic disease‐modifying antirheumatic drugs, Steinbrocker class and modified health assessment questionnaire; and the leg muscle score and grip strength were negatively related. Matrix metalloproteinase 3 was the only independent factor on multivariate logistic analysis. In patients aged >60 years, this tendency was similar. Conclusions: Frailty was found to be related to disease activity and physical function in rheumatoid arthritis. Control of disease activity appears important to prevent frailty. Geriatr Gerontol Int 2019; 19: 1220–1225. [ABSTRACT FROM AUTHOR]