Yukitomo Urata

Phase III Study of the Efficacy and Safety of Subcutaneous Versus Intravenous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ‐SC) monotherapy to intravenous TCZ infusion (TCZ‐IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease‐modifying antirheumatic drugs (DMARDs).

Treating to target matrix metalloproteinase 3 normalisation together with disease activity score below 2.6 yields better effects than each alone in rheumatoid arthritis patients: T-4 Study

Objectives To assess whether therapy to achieve both a disease activity score in 28 joints (DAS28) less than 2.6 and matrix metalloproteinase (MMP) 3 normalisation offers better outcomes than either target alone in early rheumatoid arthritis (RA) at 56 weeks: Treating to Twin Targets (T-4) Study. Methods 243 early RA patients were randomly allocated to one of four strategy groups: routine care (R group; n=62); DAS28-driven therapy (D group; n=60); MMP-3-driven therapy (M group; n=60); or both DAS28 and MMP-3-driven therapy group (twin; T group; n=61). Medication was started with sulfasalazine (1 g/day) in all intervention groups. Targets were DAS28 less than 2.6 for the D group, MMP-3 normalisation for the M group and both DAS28 less than 2.6 and MMP-3 normalisation for the T group. If the value in question did not fall below the previously measured level, medication was intensified, including methotrexate, other disease-modifying antirheumatic drugs and biological agents. Primary, secondary and outcome measures consisted of the proportions of patients showing clinical remission (DAS28 <2.6), radiographic non-progression (Δmodified total Sharp score ≤0.5), normal physical function (modified health assessment questionnaire score 0), or comprehensive disease remission defined as the combination of clinical remission, radiographic non-progression and normal physical function. Results Clinical remission at 56 weeks was achieved by more patients in the T group (56%) than in the R group (p<0.0005) or M group (p<0.0005). Conclusions Results of the T-4 Study reveal that a twin target strategy can achieve a high clinical remission rate in early RA.

Phase III, multicenter, open-label, long-term study of the safety of abatacept in Japanese patients with rheumatoid arthritis and an inadequate response to conventional or biologic disease-modifying antirheumatic drugs.

Abstract Objectives. To examine the long-term safety of intravenous (IV) abatacept treatment in Japanese patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or other conventional or biologic disease-modifying antirheumatic drugs. Methods. This Phase III, open-label, long-term study (NCT00484289) comprised Japanese patients with RA who had completed abatacept Phase I or Phase II studies, and new patients intolerant to MTX. Patients from Phase I and Phase II studies received a weight-tiered dosing equivalent of 10 mg/kg abatacept, with MTX at doses up to 8 mg/week; newly enrolled patients received weight-tiered 10 mg/kg abatacept monotherapy. Safety and efficacy were assessed. Results. A total of 217 patients (Phase I, n = 13; Phase II, n = 178; newly enrolled, n = 26) were treated with IV abatacept for a mean of 3 years. Serious adverse events occurred in 67/217 (30.9%) patients. Most adverse events were mild or moderate. For all cohorts combined, American College of Rheumatology 20% response rates ranged from 61.3 to 81.8% for as-observed and last observation carried forward analyses over 192 weeks. Following initial response, clinical and functional outcomes were maintained for up to 3 years. Conclusions. In Japanese patients with RA, IV abatacept with and without background MTX showed tolerable safety and sustained efficacy over 3 years.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group

Abstract Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Swallowing and cough reflexes in patients with dementia

Sasaki’s group has extensively studied the association between aspiration pneumonia and cough/swallowing reflexes, and has demonstrated that these important reflexes are well maintained throughout the whole life, but decrease profoundly during the night and to a less extent during the day time in patients with vascular accidents such as basal ganglia infarction. In Japan, patients with dementia are increasing in number, therefore it seems to be very important to know the condition of their cough/swallowing reflexes. However, few reports dealing with cough/swallowing reflexes in patients with dementia could be found. Thus, we investigated the cough/swallowing reflexes in patients with dementia in the daytime. Subjects included 30 patients with dementia (age = 81.9 ± 1.5, 10 men, 20 women, vascular type 10, Alzheimer type 20) and 55 age-matched healthy nondementia volunteers (age = 79.8 ± 1.1, 23 men, 32 women). Nobody had taken either ACE inhibitors or levodopa. The swallowing reflex was induced by a bolus injection of tap water (0.5, 1.0, 2.0, 4.0 mL) into the pharynx through a nasal catheter. This reflex was evaluated by the volume injected that elicited a response within 4 s following the injection. The cough reflex was evaluated according to the method by Fujimura et al. using inhaled capsaicin (0.49–250 mmol/L). These two reflexes were examined on the same day (Tables 1, 2). In the swallowing reflex, the percentage of individuals who responded to 0.5 mL, 1.0 mL, 2.0 mL and 4.0 mL of water was 68%, 28%, 0% and 4%, respectively, in the dementia group (n = 25), and 84%, 12%, 2% and 2%, respectively, in the control group (n = 51). In the cough reflex, the dementia group (n = 28) also showed a slightly lower response rate than the control group (n = 54), but there was no statistically significant difference in these reflexes between dementia and control groups, and between vascular and Alzheimer types. In the present study, both swallowing and cough reflexes were demonstrated to be well maintained in patients with dementia in the daytime. Wada et al. reported that the swallowing reflex was significantly poorer in severe Alzheimer disease (AD) patients compared with that in a mild to moderate AD group, and that neuroleptics had a bad effect on the reflex. In our study, no individuals had a history of aspiration pneumonia within a year, and only one vascular dementia patient had a symptom of dysphagia. Neuroleptics were given to less than 10% of the individuals examined in the both groups. Most patients suffered from moderate to mild dementia, because very severe dementia patients Table 1 Swallowing reflex in the two groups

Is Methotrexate (MTX) Necessary in Combination Therapy with Tocilizumab and MTX for Rheumatoid Arthritis in Remission? Cohort Study Carried by the Michinoku Tocilizumab Study Group

Objectives: To determine the necessity of methotrexate (MTX) in patients with rheumatoid arthritis (RA) achieving clinical remission treated by tocilizumab (TCZ) and MTX (TCZ+MTX). Methods: A 3 year, multicenter, observational cohort study was performed. RA patients were treated by TCZ with or without MTX depending on the attending doctor’s decision. Of the patients treated with TCZ+MTX, the patients who discontinued MTX after achieving clinical remission (discontinued group: DISC) were compared with those who maintained the same dose of MTX after achieving clinical remission (maintained group: MAIN). Results: The DISC and MAIN consisted of 33 patients and 37 patients, respectively. The mean DAS28-ESR was significantly lower in the DISC than in the MAIN at 3 months, 6 months and 9 months (3 months: 1.8 ± 0.8 and 2.4 ± 1.0, p=0.018, 6 months: 1.5 ± 0.7 and 2.2 ± 1.0, p=0.009 and 9 months: 1.4 ± 0.6 and 2.0 ± 1.0, p=0.008, respectively). The DAS28-ESR remission rate and Boolean remission rate were significantly higher in the DISC than in the MAIN (93.8% and 64.5%, respectively in the DAS28-RSR, p=0.04; 51.6% and 17.2%, respectively in the Boolean, p=0.005) at 6 months. Conclusions: RA patients treated by the combination of TCZ and MTX who achieved deep remission (DAS28- ESR ≤ 1.98) at as early as 3 months could discontinue taking MTX.

SAT0157 Discontinuation of etanercept in rheumatoid arthritis patients in clinical remission: Two-year outcome

Background Tumor necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after achievement of clinical remission is important for safety and economic reasons. However there is limited data to confirm the effectiveness and safety over a longer time period after discontinuation of etanercept (ETN). Objectives We studied 2-year outcome in RA patients who achieved clinical remission (Disease activity score in 28 joints (DAS28) <2.6) by ETN and maintained without ETN to evaluate the clinical, radiographic and functional progression rate. Methods After patients had achieved DAS28<2.6, informed consent to discontinue ETN was obtained from 23 patients. Mean of characteristics at ETN addition time were as follows: age, 63.1 years; duration of disease, 49.9 months; CRP, 1.83 mg/dl; ESR, 30.6 mm/h; DAS-28, 4.93; simplified disease activity index (SDAI), 24.0; percentage taking methotrexate, 78% (mean dose, 6.19 mg/week); percentage taking prednisolone, 22% (mean dose, 4.0 mg/day); percentage taking DMARDs, 26%. After ETN was discontinued, DAS was measured every one to three months for 2 years. The following data were collected: relapse rate at year 2; the rate of radiographic remission (Dmodified total Sharp score (DTSS) ≤0.5) and functional remission (modified health assessment questionnaire score (mHAQ) <0.5) of patients with continued remission and those with relapse. Re-treatment with TNF inhibitors (including ETN) was considered as clinical relapse. TSS was determined using modified van der Heijde-sharp score. Results 9 (39.1%) patients maintained clinical remission and clinical relapse was observed in 14 patients (60.9%) at 2years. Re-treatment with TNF inhibitors in 4 patients (2 patients, ETN; 2 patients, adalimumab) was effective and the majority of patients reached DAS28<2.6 within 8weeks. Mean DAS, SDAI, mHAQ and TSS of patients with continued remission at year 2 were 2.03, 3.82, 0.09, and -2.26 respectively, those of patients with relapse were 3.11, 7.36, 0.27, and 0.37. Radiographic and functional remission rates of patients with continued remission at year 2 were 55.6%, 77.8% respectively, those of patients with relapse were 50%, 64.3%. Conclusions Some patients could maintain clinical, radiographic and functional remission upto two years after discontinuation of ETN. This study result proves that discontinuation of ETN after achieving of DAS<2.6, subsequently could lead to the possibility of bio-free remission in RA. Even if relapse occurred, remission could be achieved again with monitoring of disease activity and adequate treatment after ETN discontinuation. References Brocq O, Millasseau E, Albert C, et al. Effect of discontinuing TNFalpha antagonist therapy in patients with remission of rheumatoid arthritis. Joint Bone Spine. 2009;76:350-5. Miyamura T, Sonomoto K, Nakamura M, et al. Discontinuationof etanercept in patients with rheumatoid arthritis who were in clinical remission. Clin Rheumatol. 2010;29:87-90. Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis. 2010;69:1286-91. van Vollenhoven RF. Unresolved issues in biologic therapy for rheumatoid arthritis. Nat Rev Rheumatol. 2011;7:205-15. Disclosure of Interest None Declared

Relation of age and smoking to serum levels of total testosterone and dehydroepiandrosterone sulfate in aged men

Background:  Hormonal factors have been extensively investigated in the area of geriatric medicine in the search for potential anti‐aging agents or useful biomarkers for senescence in men. However, inconsistent results have been published so far concerning the relation of anthropometric and life‐style factors to endocrine factors. To confirm the relationships between epidemiological parameters and sex hormone levels, we examined the relation of age and smoking to serum levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEA) in aged men.