Toshihiko Hidaka

Continuation of Methotrexate Resulted in Better Clinical and Radiographic Outcomes Than Discontinuation upon Starting Etanercept in Patients with Rheumatoid Arthritis: 52-week Results from the JESMR Study

Objective. The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA). Methods. In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6–8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score. Results. The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (–0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively). Conclusion. MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103)

Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy

Objectives We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). Methods A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4–6u2005weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. Results IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. Conclusions TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.

Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial

The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25xa0mg twice a week and MTX 6–8xa0mg/week (the Exa0+xa0M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the Exa0+xa0M group (52%) than in the E group (33%) at week 24 (pxa0=xa00.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the Exa0+xa0M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the Exa0+xa0M group (90%) than in the E group (64%; pxa0=xa00.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX.

Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis

Objectives We assessed the influence of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following influenza vaccination in patients with rheumatoid arthritis (RA). Methods A total of 194 RA patients received inactive trivalent influenza vaccination (A/H1N1, A/H3N2 and B/B1 strains). All patients were classified into the TCZ (n=62), TCZ+methotrexate (MTX) (n=49), MTX (n=65) and RA control (n=18) groups. Antibody titres were measured before and 4–6u2005weeks after vaccination using the haemagglutination inhibitory assay. Results For the A/H1N1 and A/H3N2 strains, the TCZ and TCZ+MTX groups achieved fold increases of 9.9–14.5, postvaccination seroprotection rates greater than 70% and seroresponse rates greater than 40%. For the B/B1 strain, seroresponse rates were approximately 30%, but fold increases and seroprotection rates were 5.0–5.4 and greater than 70%, respectively, in these treatment groups. MTX had a negative impact on vaccination efficacy, but adequate responses for protection were nevertheless demonstrated in the MTX group. Neither severe adverse effects nor RA flares were observed. Conclusions TCZ does not hamper antibody response to influenza vaccine in RA patients. Influenza vaccination is considered effective in protecting RA patients receiving TCZ therapy with or without MTX.

Leukocytapheresis (LCAP) decreases the level of platelet-derived microparticles (MPs) and increases the level of granulocytes-derived MPs: a possible connection with the effect of LCAP on rheumatoid arthritis.

Microparticles (MPs) are believed to play an important role in inflammatory diseases such as rheumatoid arthritis (RA). Leukocytapheresis (LCAP) is one of the options available for the treatment of RA. We analyzed the levels of MPs in RA, by flow cytometry, especially in relation to the effect of LCAP. Twenty female patients with RA were recruited into this study. Six of the 20 patients with RA further received LCAP. Plasma levels of platelet-derived MPs were high in patients with RA and are correlated with disease activity. LCAP significantly improved RA in all six patients. The numbers of platelet-derived MPs significantly decreased after the first session of LCAP, which was probably due to direct removal by LCAP. Mean numbers of platelet-derived MPs after four sessions of LCAP markedly decreased. The numbers of granulocyte-derived MPs, which are suggested to have an anti-inflammatory effect, were markedly increased after the first session of LCAP. These data suggest that removal of platelet-derived MPs and increase of granulocyte-derived MPs are novel mechanisms of LCAP as effective treatment in RA.

Effectiveness and safety of tocilizumab therapy for patients with rheumatoid arthritis and renal insufficiency: a real-life registry study in Japan (the ACTRA-RI study)

Renal involvement is frequently present in patients with rheumatoid arthritis (RA). Approximately 15–25% of patients with RA have renal insufficiency, defined as a glomerular filtration rate (GFR) <60u2005mL/min.1 Although concomitant use of methotrexate (MTX) has been proven to be more effective than administration of biological agents alone,2 MTX elimination is delayed in patients with renal insufficiency, which can increase the risk of adverse events.3 ,4 Therefore we often use MTX at reduced dosage for these patients in daily practice, which may result in inadequate responses.nnThe ACTRA-RI (Actemra for RA patients with renal insufficiency) study was designed to evaluate the efficacy and safety of tocilizumab (TCZ) therapy in the real-life registry of patients with RA and renal insufficiency. For this study, we registered all patients with RA who had begun TCZ therapy in participating hospitals as of January 2014 (total 405 patients with RA: 102 with renal insufficiency and 303 without). An estimated GFR (eGFR) was first calculated using an equation that had been …

Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases

Objective Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. Methods We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. Results Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). Conclusions Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Treatment with anti–tumor necrosis factor biologic agents in human T lymphotropic virus type I–positive patients with rheumatoid arthritis.

To investigate the response to and safety of anti–tumor necrosis factor (anti‐TNF) therapy in human T lymphotropic virus type I (HTLV‐I)–positive patients with rheumatoid arthritis (RA).

A merged presentation of clinical and radiographic data using probability plots in a clinical trial, the JESMR study

In terms of the relationship between synovial inflammation and radiographic changes, including both joint damage repair and progression,1 in rheumatoid arthritis (RA), pre-existing joint damage and persistent synovitis may promote joint destruction, while in the absence of synovitis, damaged joints may heal.2 ,3 Although presentation of radiographic results using cumulative probability plots has substantially improved understanding of clinical trial data,4 the effects of treatments on radiographic progression and improvement (regression) in individual RA patients has not yet been fully explained.nnIn the JESMR study,5 ,6 151 active RA patients unresponsive to treatment with methotrexate (MTX) were randomised into 1 of 2 treatment groups: etanercept (ETN) 50u2005mg/week with 6–8u2005mg/week of MTX (the E+M group), or ETN alone (the E group). Radiographs of the hands and feet before ETN (baseline) and during the first year of treatment were available from 53 (72%) and 68 (88%) patients in the E and E+M groups, respectively. Baseline characteristics of patients were comparable between those with and without available radiographic data in each treatment group (data not shown). However, most patients without data did not complete the study up to Week 52 as per protocol, chiefly due to lack of efficacy in the E group.6 The mean baseline total Sharp-van der Heijde score (TSS)7 was 114.5 in the E group and 113.1 in the E+M …

Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan

Objective Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. Methods We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. Results A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6–8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78–3.04) for infliximab, 1.72 (0.88–3.34) for adalimumab, 1.11 (0.55–2.21) for abatacept, and 1.02 (0.55–1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1–5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72–11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. Conclusions The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.