Supplemental Material - Upregulation of PD-1 and its ligands and expansion of T peripheral helper cells in the nephritic kidneys of lupus-prone BXSB-<i>Yaa</i> mice

Supplemental Material for Upregulation of PD-1 and its ligands and expansion of T peripheral helper cells in the nephritic kidneys of lupus-prone BXSB-Yaa mice by Rina Moriyama, Yasuhiro Katsumata, Yuko Okamoto, and Masayoshi Harigai in Lupus</p

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T)

<p><b>Objective:</b> To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy.</p> <p><b>Methods:</b> This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed.</p> <p><b>Results</b> 116/878 patients received sirukumab 50 mg/4 weeks (q4w, <i>n</i> = 35), 100 mg/2 weeks (q2w, <i>n</i> = 44) or placebo (<i>n</i> = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; <i>p</i> < .001, 100 mg q2w:24 [54.5%]; <i>p</i> = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs.</p> <p><b>Conclusion:</b> Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.</p

Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study

<p><b>Objective:</b> To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.</p> <p><b>Methods:</b> This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).</p> <p><b>Results:</b> A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, <i>n</i> = 58), 100 mg/every 2 weeks (q2w, <i>n</i> = 54), or placebo (<i>n</i> = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; <i>p</i> < .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, <i>p</i> = .024; 100 mg q2w: 0.0, <i>p</i> = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52.</p> <p><b>Conclusion:</b> Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.</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

Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study

<p><i>Objective</i>: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes.</p> <p><i>Methods</i>: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed.</p> <p><i>Results</i>: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection.</p> <p><i>Conclusion</i>: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.</p

Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan

<p><i>Objective.</i> To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice.</p> <p><i>Methods.</i> A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application.</p> <p><i>Results.</i> Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations.</p> <p><i>Conclusion</i>. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.</p

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120

<p><b>Objective:</b> Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs.</p> <p><b>Methods</b>: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, <i>n</i> = 105), golimumab 50 mg (Group 2, <i>n</i> = 101), or golimumab 100 mg (Group 3, <i>n</i> = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120.</p> <p><b>Results</b>: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE.</p> <p><b>Conclusion:</b> Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.</p

Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study

<p><b>Objectives:</b> We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA).</p> <p><b>Methods:</b> This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52.</p> <p><b>Results:</b> Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52.</p> <p><b>Conclusion:</b> Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.</p

Eligible patient population from the JMDC claims database (ABA-1L vs. ABA-2L+).

1L, first line; 2L+, second or later line; ABA, abatacept; df, degrees of freedom; JMDC, Japan Medical Data Center Inc; SD, standard deviation. aMcNemar’s chi-squared test or paired t-tests were used. bDisease duration (from date of initial diagnosis to ABA start date). (DOCX)</p

Effectiveness from the IORRA database (ABA-1L <i>vs</i>. ABA-2L+).

1L, first line; 2L+, second or later line; ABA, abatacept; ACR50, American College of Rheumatology response of at least 50% improvement; CDAI, Clinical Disease Activity Index; IORRA, Institute of Rheumatology, Rheumatoid Arthritis; J-HAQ, Japanese version of Health Assessment Questionnaire; SDAI, Simplified Disease Activity Index. (DOCX)</p