Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting

<p><b>Objectives:</b> The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan.</p> <p><b>Methods:</b> This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naïve or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation.</p> <p><b>Results:</b> Overall 784 (78.1%) were TCZ naïve and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naïve: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naïve patients died. TCZ-naïve patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks.</p> <p><b>Conclusions:</b> There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naïve patients and maintaining remission in TCZ-IV-SC patients.</p

Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event-reporting database

<p><b>Objective:</b> To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients.</p> <p><b>Methods:</b> Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008–10 April 2015) assuming the following: treated in Japan; TCZ RA treatment; ≥1 SI; unable to exclude causality between TCZ and SIs.</p> <p><b>Results:</b> The database included 7653 RA patients; 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date; 60.7% of patients had signs/symptoms ≤28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection.</p> <p><b>Conclusion:</b> This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

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Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

table_3.doc

Objective<p>The aim of this study was to examine the fluctuations in CD4⁺ T cells, CD8⁺ T cells, and natural CD4⁺CD25⁺FoxP3⁺T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM).</p>Methods<p>19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4⁺, CD8⁺, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min.</p>Results<p>Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4⁺, CD8⁺, and Treg were observed between the DM group and the non-DM group. The proportion of CD8⁺ was significantly reduced, whereas the proportion of CD4⁺ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC_{0–120 min} of CD8⁺ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin.</p>Conclusion<p>The proportion of CD4⁺ T cells was increased and that of CD8⁺ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.</p

Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials

<p><b>Objectives:</b> To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations.</p> <p><b>Methods:</b> Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs).</p> <p><b>Results:</b> For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate.</p> <p><b>Conclusion:</b> Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.</p