http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2013; Early Online: 1–9 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.843756

ORIGINAL ARTICLE

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: An open-label extension of a randomized, double-blind, placebo-controlled trial Masako Hara1, Naoki Ishiguro2, Kou Katayama3, Masakazu Kondo4, Takayuki Sumida5, Tsuneyo Mimori6, Satoshi Soen7, Kota Nagai8, Tomonobu Yamaguchi9, Kazuhiko Yamamoto10, and Iguratimod-Clinical Study Group 1Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, 2Department of Orthopaedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan, 3Katayama Orthopedic Rheumatology Clinic, Asahikawa, Japan, 4Kondo Clinic of Rheumatology and Orthopaedic Surgery, Fukuoka, Japan, 5Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, 6Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 7Department of Orthopaedic Surgery and Rheumatology, Nara Hospital, Kinki University School of Medicine, Ikoma, Japan, 8Eisai Co., Ltd., Tokyo, Japan, 9Toyama Chemical Co., Ltd., Tokyo, Japan, and 10Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Abstract Objective. To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA). Methods. Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod ⫹ MTX group continued treatment. Patients treated with placebo ⫹ MTX switched to iguratimod ⫹ MTX [the (placebo/iguratimod) ⫹ MTX group]. Results. In the iguratimod ⫹ MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod ⫹ MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod ⫹ MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred. Conclusion. Efficacy and tolerance of iguratimod ⫹ MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.

Introduction Iguratimod, known as T-614, is a small-molecule antirheumatic drug with unique mechanisms of action. Iguratimod was shown to suppress tumor necrosis factor (TNF)-alpha-induced production of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein 1 via the inhibition of nuclear factor-kappa B activation in cultured human synovial cells and human acute monocytic leukemia cells [1–3]. It was also shown to reduce immunoglobulin (Ig) production by acting directly on human B lymphocytes without affecting B lymphocyte proliferation [4]. In patients with active rheumatoid arthritis (RA), iguratimod monotherapy significantly decreased rheumatoid factor and the production of IgG, IgM and IgA compared with placebo [5]. Correspondence to: Masako Hara, Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. Tel: ⫹ 81-3-5269-1725. Fax: ⫹ 81-3-5269-1726. E-mail: [email protected]

Keywords Disease-modifying antirheumatic drug, Iguratimod, Methotrexate, Rheumatoid arthritis, T-614 History Received 13 March 2013 Accepted 23 May 2013 Published online 5 November 2013

Methotrexate (MTX), a disease-modifying antirheumatic drug (DMARD), has been the anchor drug in the selection of agents for initial RA treatment. An increased release of extracellular adenosine and a decreased production of lymphotoxins such as ammonia and superoxide were shown to be involved in the anti-inflammatory mechanisms of MTX [6–8]. The American College of Rheumatology (ACR) 2012 guideline recommends use of nonbiologic and biologic DMARDs based on RA disease duration, RA disease activity, prognostic factors for RA and previous experience of DMARDs [9]. When MTX monotherapy has found to be insufficient, combination therapy with other DMARDs such as biological agents has been recommended [10]. However, there are not a few patients who cannot be treated with biologic DMARDs due to comorbidities, sideeffects and costs. Therefore, a new efficacious combination therapy of MTX with other small-molecule DMARD that has antirheumatic mechanisms different from those of MTX is still needed. We recently reported results of a 24-week study on the efficacy and safety of combination therapy with iguratimod ⫹ MTX in Japanese patients with active RA who had shown an inadequate

2

M. Hara et al.

response to MTX alone [11]. This 24-week, multicenter, randomized, double-blind, placebo-controlled trial showed that combination therapy with iguratimod ⫹ MTX was efficacious and had a manageable safety profile. The rate of 20% improvement in ACR criteria (ACR20) at week 24 was 69.5% in the iguratimod ⫹ MTX group compared with 30.7% in the placebo ⫹ MTX control group (P ⬍ 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score 28 (DAS28) ⬍ 3.2, and rheumatoid factor level were also observed. The most commonly reported adverse events to week 24 were nasopharyngitis, lymphocyte decrease, and blood iron decrease; these adverse events were mild or moderate in severity. Here, we aimed to obtain additional safety and efficacy data on iguratimod ⫹ MTX combination therapy in an open-label, 24-week extension of our randomized, double-blind, placebocontrolled trial. Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

Materials and methods Study design This study was conducted in 99 medical institutions in Japan between August 2009 and September 2011. The study was conducted in compliance with the Declaration of Helsinki. The institutional review board at each institute approved the study protocol. This study was registered at http://clinicaltrials.gov (NCT00965757). Patients who completed an initial 28-week, randomized, double-blind trial of adding placebo or iguratimod to stable MTX therapy were allowed to enter an additional 24-week, open-label, extension study (Figure 1). In the extension phase, patients in the iguratimod ⫹ MTX group continued iguratimod ⫹ MTX treatment and patients in the (placebo/iguratimod) ⫹ MTX group who were randomized to placebo ⫹ MTX treatment in the initial phase switched to iguratimod ⫹ MTX treatment. The initial randomization used in the double-blind portion of this study was maintained in the open-label extension phase. During the open-label 24-week extension period, patients in the iguratimod ⫹ MTX group were administered 50 mg/day of iguratimod (25 mg twice daily), and patients in the (placebo/iguratimod) ⫹ MTX group were administered 25 mg iguratimod/day (25 mg once daily) for the first 4 weeks of the extension period and 50 mg/day (25 mg twice daily) for the subsequent 20-week extension period. MTX at stable low doses of 6 or 8 mg/week and folic acid at a dose of 5 mg/week were administered to patients in both groups for the entire treatment period (double-blind and extension periods).

Mod Rheumatol, 2013; Early Online: 1–9

of active RA for less than 10 years, based on 1987 ACR criteria [12]. Patients were aged from 20 to ⬍ 70 years and had active RA despite MTX therapy (ⱖ 6 mg/week) for more than 12 weeks, including stable low dosages of MTX (6–8 mg/week) for at least 8 weeks before study enrollment. Eligible patients also fulfilled the following criteria: at least six tender joints based on a 68-joint assessment, at least four swollen joints based on a 66-joint assessment and an erythrocyte sedimentation rate (ESR) of at least 28 mm/h or a blood C-reactive protein (CRP) concentration of at least 1.0 mg/dL. Exclusion criteria were a history or present manifestation of impaired hepatic function, as shown by abnormal results on liver function tests [elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels above the upper limit of normal], known hematopoietic disorder (absolute leukocyte count, ⬍ 4000/μL; platelet count, ⬍ 100,000/μL; and hemoglobin level, ⬍ 9.0 g/dL), positive results on serologic tests for hepatitis B or C, pregnancy (including wanting to be pregnant) or breast feeding, persistent or severe infection, active digestive diseases, body weight of ⬍ 40 kg and RA with Steinbrocker’s functional class IV. All patients provided written informed consent. The concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids at a prednisolone-equivalent dose of 7.5 mg/day or less was permitted at stable doses until week 24 and at necessary doses less than 7.5 mg/day from weeks 25 to 52. Concomitant use of DMARDs other than MTX, biological agents, and investigational new drugs was not allowed. Efficacy assessment For patients entering the open-label extension, ACR20, ACR50, ACR 70, ACR core components, Disease Activity Score using 28 joint counts (DAS28) [13], HAQ-DI [14] and immunological test values (rheumatoid factor, IgG, IgM and IgA) were assessed to identify trends with continued iguratimod ⫹ MTX therapy or following a switch to iguratimod ⫹ MTX therapy. ACR20 response was defined as at least a 20% improvement in tender joint count and swollen joint count, and in three of five of the following measures: patient pain intensity assessment, patient global assessment, physician global assessment, HAQ-DI, and an acute phase reactant (ESR or CRP). A decrease in HAQ-DI scores shows improvement and a decrease greater than 0.22 represents the minimum clinically important difference [15]. The state of disease activity was evaluated based on DAS28 score as follows: remission (⬍ 2.6), low disease activity (⬍ 3.2), moderate disease activity (ⱖ 3.2 and ⱕ 5.1) or high disease activity (⬎ 5.1) [16]. These efficacy assessments were undertaken at week 0 (baseline), 8, 16, 24, 28, 36, 44 and 52.

Patients

Safety assessment

Inclusion and exclusion criteria for the complete 52-week trial were described previously [11]. In short, all patients had a diagnosis

Safety was assessed using adverse event reports, physical examination including blood pressure measurements, and clinical laboratory Figure 1. Study design of the doubleblind and open-label extension phases of the trial. IGU, iguratimod; MTX, methotrexate; and PLA, placebo.

DOI 10.3109/14397595.2013.843756

Safety and efficacy of combination therapy of iguratimod with methotrexate

tests including hematology, blood chemistry examination and urinalysis. These safety assessments were undertaken at screening and at weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 30, 32, 34, 36, 38, 40, 44, 48 and 52. Adverse events were coded according to the primary system organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities/Japanese (MedDRA/J) (Version 13.1).

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

Statistical analysis Demographic and baseline characteristics were compared between groups using the t-test for continuous variables and Fisher’s exact test for categorical variables. All efficacy analyses were primarily performed on the full analysis set, defined as all randomized patients who received at least one dose of study drug and from whom at least one assessment of efficacy was available. Efficacy variables were calculated using the last-observation-carried-forward (LOCF) method. For intragroup comparisons, McNemar’s test, the paired t-test or the sign test was used as indicated. For intergroup comparisons, Fisher’s exact test, t-test or Wilcoxon rank sum test was used as indicated. All safety analyses were performed on the safety analysis set, defined as all randomized patients who received at least one dose of study drug and from whom at least one assessment of safety was available. Safety variables in the iguratimod ⫹ MTX group and in the extension phase of the (placebo/iguratimod) ⫹ MTX group were summarized on the safety-evaluable population, defined as all patients who received at least one dose of iguratimod. Safety variables in the initial phase of the (placebo/iguratimod) ⫹ MTX group were summarized on the safety-evaluable population, defined as all patients who received at least one dose of placebo. Significance levels in the tests were as follows: two-sided 15% for uniformity between groups and two-sided 5% for intergroup and intragroup comparisons.

Results

3

a 2:1 ratio. Of the 165 patients enrolled in the iguratimod ⫹ MTX group, 148 completed the initial double-blind 24-week therapy, 142 entered the open-label extension phase from week 29, and 132 completed the 24-week extension phase. Of the 88 patients enrolled in the (placebo/iguratimod) ⫹ MTX group, 70 completed the initial double-blind 24-week therapy with placebo ⫹ MTX, 68 entered the (placebo/iguratimod) ⫹ MTX extension phase from week 29, and 64 completed the 24-week extension phase. The percentage of patients who did not complete the 52-week treatment in the iguratimod ⫹ MTX group was 20.0% (33/165): 4.8% (8/165) of patients discontinued due to aggravation of symptoms and 12.1% (20/165) of patients discontinued due to adverse events. The percentage of patients who did not complete the 24-week extension phase in the (placebo/iguratimod) ⫹ MTX group was 5.9% (4/68): 1.5% (1/68) of patients discontinued due to aggravation of symptoms and 2.9% (2/68) of patients discontinued due to adverse events. In terms of reasons for withdrawal in the open-label phase (weeks 29–52) in the iguratimod ⫹ MTX group, adverse events lead to withdrawal in 4.9% (7/142) and aggravation of symptoms lead to withdrawal in 0.7% (1/142). The rate of discontinuation appeared to be lower during the open-label phase [7.0% (10/142) in the iguratimod ⫹ MTX group and 5.9% (4/68) in the (placebo/iguratimod) ⫹ MTX group] compared with the rate in the initial double-blind phase [13.9% (23/165) in the iguratimod ⫹ MTX and 22.7% (20/88) in the (placebo/iguratimod) ⫹ MTX group]. Table 1 shows baseline demographics in the iguratimod ⫹ MTX group, the (placebo/iguratimod) ⫹ MTX group treated with placebo ⫹ MTX, and the (placebo/iguratimod) ⫹ MTX group treated with iguratimod ⫹ MTX. No statistically significant differences were observed between groups at baseline. One patient in the iguratimod ⫹ MTX group was excluded from the safety analysis set and the full analysis set because data on efficacy and safety were not available. ACR response rates

Patient disposition and demographics Eligible patients were randomly assigned to the iguratimod ⫹ MTX group and to the (placebo/iguratimod) ⫹ MTX group in

Efficacy data for iguratimod ⫹ MTX therapy and (placebo/iguratimod) ⫹ MTX therapy in the initial 24-week, double-blind phase have been published previously [11].

Table 1. Demographics at baseline of patients with active rheumatoid arthritis (full analysis set).

Female, n (%) Age (SD), years Age ⱖ 65 years, n (%) Duration of RA (SD), months Positive for rheumatoid factor, n (%) Positive for anti-CCP antibodies, n (%) Previous therapy with DMARDs except for MTX, n (%) Concomitant medication, n (%) NSAIDs Corticosteroids Folic acid MTX at baseline, n (%) 6 mg/week 8 mg/week

IGU⫹ MTX* (n ⫽ 164) 134 (81.7) 54.8 ⫾ 9.9 32 (19.5) 53.8 ⫾ 35.0 128 (78.0) 144 (87.8) 61 (37.2)

(PLA/IGU) ⫹ MTX** (n ⫽ 88) 70 (79.5) 53.5 ⫾ 10.0 16 (18.2) 50.3 ⫾ 34.0 67 (76.1) 78 (88.6) 28 (31.8)

(PLA/IGU) ⫹ MTX*** (n ⫽ 68) 52 (76.5) 53.7 ⫾ 10.5 14 (20.6) 55.6 ⫾ 35.3 54 (79.4) 60 (88.2) 23 (33.8)

151 (92.1) 86 (52.4) 164 (100)

81 (92.0) 48 (54.5) 88 (100)

63 (92.6) 39 (57.4) 68 (100)

51 (31.1) 113 (68.9)

27 (30.7) 61 (69.3)

22 (32.4) 46 (67.6)

Values are number of patients (%) or mean ⫾ SD. IGU, iguratimod; MTX, methotrexate; PLA, placebo; RA, rheumatoid arthritis; CCP, cyclic citrullinated peptides; DMARDs, disease-modifying antirheumatic drugs; and NSAIDs, nonsteroidal anti-inflammatory drugs. *One patient in the IGU ⫹ MTX group (n ⫽ 165) was excluded from the safety analysis set and full analysis set because data on efficacy and safety were not available. **Data are based on patients who were randomized to the (PLA/IGU) ⫹ MTX group. ***Data are based on patients who entered the 24-week, open-label extension phase, and were treated with IGU ⫹ MTX. Baseline values at week 0 in the (PLA/IGU) ⫹ MTX group were calculated based on 68 patients who entered the extension phase.

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

4

M. Hara et al.

ACR20 in the iguratimod ⫹ MTX group reached almost a steady state around week 16 and maintained its steady level at least until week 52. Figure 2a shows that the ACR20 response rate at week 52 was 71.3%, which was similar to that at week 24 (69.5%, using LOCF method). The ACR50 and ACR70 at week 52 were 49.4 and 23.8%, respectively, which were significantly greater than rates of 38.4 and 17.1% at week 24, respectively (P ⫽ 0.003 and P ⫽ 0.048, respectively; intragroup comparison, McNemar’s test) (Figure 2b, c). A total of 68 patients switched from placebo ⫹ MTX to the iguratimod ⫹ MTX treatment at week 29. ACR20 at week 52 was 72.1%, which was significantly greater than that at week 24 (36.8%) (P ⬍ 0.001, intragroup comparison), which indicated the efficacy of 24-week therapy with iguratimod ⫹ MTX in the extension phase (Figure 2a). ACR50 and ACR70 at week 52 were 45.6 and 22.1%, respectively, which were significantly greater than rates of 17.6 and 5.9% at week 24, respectively (P ⬍ 0.001, intragroup comparison) (Figure 2b, c). ACR20, ACR50 and ACR70 rates at week 52 in the (placebo/iguratimod) ⫹ MTX group were not significantly different from those at week 52 in the iguratimod

Mod Rheumatol, 2013; Early Online: 1–9

⫹ MTX group, respectively, indicating the efficacy of 24-week extension phase with iguratimod ⫹ MTX. Changes from baseline in individual ACR core components and immunological test values In the iguratimod ⫹ MTX group, significant improvements were observed in tender joint count, swollen joint count, patient’s global assessment of disease activity, HAQ-DI and IgA at week 52 compared with those at week 24 (p values are listed in Table 2; intragroup comparisons). Patient’s assessment of pain, physician’s global assessment of disease activity, CRP, ESR, rheumatoid factor, IgG, IgM and HAQ-DI responders at week 52 showed similar levels to values at week 24. The mean change of ⫺ 0.41 in HAQ-DI from baseline to week 52 was significantly improved compared with that of ⫺0.35 from baseline to week 24 (P ⫽ 0.003, intragroup comparisons). At week 52, 65.2% of patients achieved a minimum clinically important difference (⫺0.22) in HAQ-DI, which was similar to 63.4% at week 24. In the group switched from placebo ⫹ MTX to iguratimod ⫹ MTX, significant improvements were observed in ACR core components, rheumatoid factor, IgG, IgM, IgA and HAQ-DI responders; that is, changes from baseline to week 52 were significantly improved compared with those from baseline to week 24 (intragroup comparison). Furthermore, values for those variables at week 52 in the (placebo/iguratimod) ⫹ MTX group were not significantly different from those at week 52 in the iguratimod ⫹ MTX group [p values for these inter-group comparisons are not listed in Table 2; Fisher’s exact test (ACR response), t-test (ACR core components), or Wilcoxon rank sum test (immunological test)]. The mean change of ⫺ 0.29 in HAQ-DI from baseline to week 52 was significantly improved compared with that of ⫺ 0.10 from baseline to week 24 (P ⬍ 0.001). At week 52, 52.9% of patients achieved a minimum clinically important difference (⫺0.22) in HAQ-DI. Assessment of DAS28

Figure 2. Rate of response for patients who achieved 20% improvement in American College of Rheumatology rheumatoid arthritis criteria (ACR20), ACR50, and ACR70 in the IGU ⫹ MTX group (n ⫽ 164) and the (PLA/IGU) ⫹ MTX group (n ⫽ 68) at week 24 and 52 (LOCF). P values are calculated using the McNemar test (intragroup comparisons). a. ACR20 response rate, b. ACR50 response rate and c. ACR70 response rate. LOCF, last observation carried forward; and NS, not significant.

In the iguratimod ⫹ MTX group, the mean change of ⫺ 1.73 in DAS28-CRP from baseline to week 52 was significantly improved compared with that of ⫺ 1.51 at week 24 (P ⫽ 0.001, intragroup comparisons) (Table 2). Rates of high disease activity (DAS28CRP ⬎ 5.1) at week 24 and 52 significantly decreased compared with those at week 0 (P ⬍ 0.001, intragroup comparison) (Figure 3). Furthermore, the rates of remission (DAS28-CRP ⬍ 2.6) and low disease activity (DAS28-CRP ⬍ 3.2) at week 24 and 52 were significantly greater than those at week 0 (P ⬍ 0.001, intragroup comparison). The proportion of patients in remission (DAS28-CRP ⬍ 2.6) at week 52 (34.1%) was numerically greater than that at week 24 (27.4%); however, this difference was not significant (P ⫽ 0.085, intragroup comparison). These results indicate maintenance of efficacy across 52 weeks of combination therapy with iguratimod ⫹ MTX. In the group switched from placebo ⫹ MTX to iguratimod ⫹ MTX, the mean change of ⫺ 1.81 in DAS28-CRP from baseline to week 52 was significantly improved from that (⫺0.95) from baseline to week 24 (P ⬍ 0.001). The rates of high disease activity (DAS28-CRP ⬎5.1) at week 52 significantly decreased compared with those at week 0 and 24 (P ⬍ 0.001 and P ⫽ 0.012, respectively, intragroup comparison) (Figure 3). Furthermore, the rates of remission (DAS28-CRP ⬍ 2.6) and low disease activity (DAS28CRP ⬍ 3.2) at week 52 were significantly greater than those at week 0 and 24 (P ⬍ 0.001, intragroup comparison). At week 52, 33.8% of patients showed remission (DAS28-CRP ⬍ 2.6) in the (placebo/iguratimod) ⫹ MTX group, which was similar to 34.1% in the iguratimod ⫹ MTX group. Similarly, at week 52, 55.9% of patients showed low disease activity (DAS28-CRP ⬍ 3.2) in the (placebo/iguratimod) ⫹ MTX group, which was similar to 53.7% in the iguratimod ⫹ MTX group.

DOI 10.3109/14397595.2013.843756

Safety and efficacy of combination therapy of iguratimod with methotrexate

5

Table 2. Baseline values and changes in individual efficacy valuables from baseline to week 24 and 52 (LOCF).

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

IGU ⫹ MTX (n ⫽ 164) Tender joint count, n Baseline Change from baseline at week 24 Change from baseline at week 52 Swollen joint count, n Baseline Change from baseline at week 24 Change from baseline at week 52 Patient’s assessment of pain, mm VAS Baseline Change from baseline at week 24 Change from baseline at week 52 Patient’s global assessment of disease activity, mm VAS Baseline Change from baseline at week 24 Change from baseline at week 52 Physician’s global assessment of disease activity, mm VAS Baseline Change from baseline at week 24 Change from baseline at week 52 HAQ-DI Baseline Change from baseline at week 24 Change from baseline at week 52 CRP, mg/dL Baseline Change from baseline at week 24 Change from baseline at week 52 ESR, mm/h Baseline Change from baseline at week 24 Change from baseline at week 52 Immunological test values RF, U/mL Baseline Change from baseline at week 24 Change from baseline at week 52 IgG, mg/dL Baseline Change from baseline at week 24 Change from baseline at week 52 IgM, mg/dL Baseline Change from baseline at week 24 Change from baseline at week 52 IgA, mg/dL Baseline Change from baseline at week 24 Change from baseline at week 52 HAQ-DI responders (⬎ 0.22), n (%) Week 24 Week 52 DAS28-CRP Baseline Change from baseline at week 24 Change from baseline at week 52

12.5 ⫾ 6.5 ⫺7.4 ⫾ 6.0 ⫺8.4 ⫾ 6.1 11.5 ⫾ 6.3 ⫺6.5 ⫾ 5.9 ⫺7.1 ⫾ 6.8 47.5 ⫾ 22.2 ⫺22.0 ⫾ 23.8 ⫺24.0 ⫾ 24.1 47.7 ⫾ 24.3 ⫺21.2 ⫾ 26.4 ⫺24.3 ⫾ 26.0 52.6 ⫾ 18.3 ⫺27.1 ⫾ 19.3 ⫺29.1 ⫾ 22.4 0.82 ⫾ 0.55 ⫺0.35 ⫾ 0.45 ⫺0.41 ⫾ 0.46 1.84 ⫾ 1.94 ⫺0.53 ⫾ 2.07 ⫺0.61 ⫾ 1.84 45.6 ⫾ 21.0*** ⫺9.3 ⫾ 20.8*** ⫺9.4 ⫾ 21.3*** 117.1 ⫾ 181.9 ⫺37.4 ⫾ 63.0 ⫺34.9 ⫾ 69.3 1534.8 ⫾ 376.5 ⫺152.1 ⫾ 190.4 ⫺166.6 ⫾ 214.3 129.2 ⫾ 154.1 ⫺14.7 ⫾ 25.3 ⫺9.3 ⫾ 27.8 310.8 ⫾ 123.1 ⫺41.9 ⫾ 41.2 ⫺47.6 ⫾ 42.4 104 (63.4) 107 (65.2) 4.87 ⫾ 0.89 ⫺1.51 ⫾ 1.22 ⫺1.73 ⫾ 1.20

p value*

(PLA/IGU) ⫹ MTX** (n ⫽ 68)

p value*

0.005

13.8 ⫾ 8.5 ⫺6.3 ⫾ 7.0 ⫺9.9 ⫾ 7.6

⬍ 0.001

0.045

10.9 ⫾ 5.8 ⫺4.0 ⫾ 6.3 ⫺6.3 ⫾ 6.5

⬍ 0.001

0.060

44.8 ⫾ 22.4 ⫺7.0 ⫾ 24.7 ⫺21.4 ⫾ 26.6

⬍ 0.001

0.010

48.4 ⫾ 23.6 ⫺9.7 ⫾ 26.8 ⫺23.1 ⫾ 27.7

⬍ 0.001

0.063

52.1 ⫾ 17.9 ⫺15.7 ⫾ 26.1 ⫺29.9 ⫾ 24.4

⬍ 0.001

0.003

0.72 ⫾ 0.53 ⫺0.10 ⫾ 0.45 ⫺0.29 ⫾ 0.47

⬍ 0.001

0.544

1.71 ⫾ 1.61 0.12 ⫾ 1.74 ⫺0.58 ⫾ 1.87

0.010

0.937

40.1 ⫾ 23.2 ⫺0.1 ⫾ 17.5 ⫺8.8 ⫾ 21.5

0.002

0.261

155.7 ⫾ 295.9 33.3 ⫾ 215.1 ⫺23.6 ⫾ 135.7

⬍ 0.001

0.134

1518.9 ⫾ 363.2 6.2 ⫾ 157.3 ⫺173.2 ⫾ 197.5

⬍ 0.001

0.177

⬍ 0.001

129.0 ⫾ 62.6 5.5 ⫾ 24.3 ⫺7.2 ⫾ 24.8

⬍ 0.001

310.3 ⫾ 106.4 ⫺3.6 ⫾ 40.2 ⫺43.2 ⫾ 46.0

⬍ 0.001

0.466

27 (39.7) 36 (52.9)

0.001

4.96 ⫾ 0.87 ⫺0.95 ⫾ 1.21 ⫺1.81 ⫾ 1.31

0.020

⬍ 0.001

Values are mean ⫾ SD. VAS, visual analog scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; HAQ-DI, Health Assessment Questionnaire Disability Index; DAS28, Disease Activity Score using 28 joint counts. *P value for the difference between changes from baseline to week 24 and to week 52 (intragroup comparison). Paired t-test was used for ACR core components, and sign test was used for immunological evaluation. **Data are based on patients who entered the extension phase and were treated with IGU ⫹ MTX. ***n ⫽ 163.

Safety Adverse events in the initial 24-week treatment with iguratimod ⫹ MTX were reported previously and are also listed in Table 3 for comparison [11]. In the iguratimod ⫹ MTX group, adverse events occurred in 95.1% of patients for the 52-week treatment,

and 80.5% of patients for the initial 24-week treatment. The percentages of adverse events in older patients (ⱖ 65 years) and in younger patients (⬍ 65 years) for the 52-week treatment were 96.9% (31/32) and 94.7% (125/132), respectively. Adverse events in the (placebo/iguratimod) ⫹ MTX group from weeks 29 to 52

6

M. Hara et al.

Mod Rheumatol, 2013; Early Online: 1–9

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

Figure 3. Percentage of patients in remission and with low, moderate and high disease activity at week 0 (baseline), 24 and 52 (LOCF). The measure of the disease activity is the DAS28-CRP: remission (DAS28 ⬍ 2.6); low disease activity (DAS28 ⬍ 3.2), moderate disease activity (DAS28 ⱖ 3.2 and ⱕ 5.1) and high disease activity (DAS28 ⬎ 5.1). DAS28, Disease Activity Score using 28 joint counts; CRP, C-reactive protein.

were observed in 79.4% of patients, which was similar to that (80.5%) in the iguratimod ⫹ MTX group from weeks 1 to 24. The percentages of adverse events in older patients (ⱖ 65 years) and in younger patients (⬍ 65 years) in the extension phase of the (placebo/iguratimod) ⫹ MTX treatment were 85.7% (12/14) and 77.8% (42/54), respectively. The most common adverse events coded by MedDRA SOC were infections and infestations, gastrointestinal disorders, and investigations for the iguratimod ⫹ MTX and (placebo/iguratimod) ⫹ MTX groups (Table 3). The percentages of these common adverse events in the extension phase of the (placebo/iguratimod) ⫹ MTX treatment (weeks 29–52) were not significantly different from those for iguratimod ⫹ MTX treatment (weeks 1–24), respectively. Table 3 shows adverse events coded by MedDRA PT and observed in ⱖ 5% of patients during the 52-week iguratimod ⫹

MTX treatment. Increases in adverse events of more than 5% during the period from weeks 24 to 52 were observed for nasopharyngitis, upper respiratory tract inflammation, AST increase, ALT increase and γ-glutamyltransferase increase. These adverse events were mild or moderate in severity. The most commonly reported adverse events in the extension phase of the (placebo/iguratimod) ⫹ MTX treatment were nasopharyngitis, lymphocyte count decrease and blood iron decrease, which were similar to the findings for the 24-week initial phase of iguratimod ⫹ MTX treatment. In the iguratimod ⫹ MTX group, serious adverse events were observed in 2.4% of patients (4/164) from weeks 25 to 52. These events included pneumonia bacterial, breast cancer, anaphylactic shock (insect stings) and supraventricular tachycardia, and were judged not to be related to iguratimod treatment. No deaths were reported. In the extension phase of the (placebo/iguratimod)

Table 3. Summary of adverse events and classification coded by MedDRA system organ class and preferred term. Weeks 1–24*

Total adverse events Age ⱖ 65 years Age ⬍ 65 years Infections and infestation Nasopharyngitis Pharyngitis Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation Gastrointestinal disorders Diarrhea Stomatitis Skin and subcutaneous tissue disorders Rash Musculoskeletal and connective tissue disorders Back pain Investigations Lymphocyte count decreased Aspartate aminotransferase increased Alanine aminotransferase increased γ-Glutamyltransferase increased β2-Microglobulin increased β2-Microglobulin urine increased Blood urea increased Blood iron decreased Serious adverse events Adverse events leading to discontinuation

IGU ⫹ MTX (n ⫽ 164) 132 (80.5) 31 (96.9) 101 (76.5) 45 (27.4) 28 (17.1) 7 (4.3) 17 (10.4)

(PLA/IGU) ⫹ MTX (n ⫽ 88) 66 (75.0) 13 (81.3) 53 (73.6) 26 (29.5) 14 (15.9) 6 (6.8) 4 (4.5)

Weeks 1–52

Weeks 29–52

IGU ⫹ MTX (n ⫽ 164) 156 (95.1) 31 (96.9) 125 (94.7) 86 (52.4) 52 (31.7) 10 (6.1) 34 (20.7)

(PLA/IGU) ⫹ MTX (n ⫽ 68) 54 (79.4) 12 (85.7) 42 (77.8) 26 (38.2) 15 (22.1) 0 (0.0) 5 (7.4)

9 (5.5) 43 (26.2) 6 (3.7) 11 (6.7) 15 (9.1) 4 (2.4) 14 (8.5)

2 (2.3) 15 (17.0) 4 (4.5) 2 (2.3) 13 (14.8) 3 (3.4) 6 (6.8)

20 (12.2) 65 (39.6) 11 (6.7) 18 (11.0) 31 (18.9) 9 (5.5) 33 (20.1)

4 (5.9) 23 (33.8) 2 (2.9) 4 (5.9) 8 (11.8) 2 (2.9) 8 (11.8)

3 (1.8) 81 (49.4) 23 (14.0) 16 (9.8) 9 (5.5) 4 (2.4) 13 (7.9) 11 (6.7) 7 (4.3) 35 (21.3) 5 (3.0) 7 (4.3)

2 (2.3) 39 (44.3) 8 (9.1) 5 (5.7) 7 (8.0) 2 (2.3) 2 (2.3) 1 (1.1) 2 (2.3) 16 (18.2) 3 (3.4) 3 (3.4)

11 (6.7) 102 (62.2) 29 (17.7) 27 (16.5) 24 (14.6) 15 (9.1) 15 (9.1) 15 (9.1) 13 (7.9) 43 (26.2) 9 (5.5) 20 (12.2)

1 (1.5) 31 (45.6) 7 (10.3) 3 (4.4) 5 (7.4) 2 (2.9) 5 (7.4) 4 (5.9) 3 (4.4) 9 (13.2) 2 (2.9) 2 (2.9)

Values are number of patients (%). The percentages were calculated based on the safety analysis set.MedDRA, Medical Dictionary for Regulatory Activities. *No statistically significant differences were seen in the incidence percentages between IGU ⫹ MTX and (PLA/ IGU) ⫹ MTX groups for any of the listed adverse events in the initial 24-week treatment.

Safety and efficacy of combination therapy of iguratimod with methotrexate

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

DOI 10.3109/14397595.2013.843756

⫹ MTX treatment, Meniere’s disease, a serious adverse event, occurred in 2 of 68 patients (2.9%); this was judged not to be related to the study drug. Twenty patients discontinued due to adverse events during the 52-week iguratimod ⫹ MTX treatment. Among them, 13 patients discontinued from weeks 25 to 52 due to carbon monoxide poisoning, pneumonia, gastric ulcer, eczema, lymphoid tissue hyperplasia, breast cancer, osteomyelitis, malaise, gastrointestinal disorder/parosmia, lymphocyte decrease, white blood cell decrease, β-2 microglobulin urine increase and AST increase/ ALT increase. In the 24-week extension phase of the (placebo/ iguratimod) ⫹ MTX treatment, two patients discontinued due to adverse events, including hemorrhagic diathesis and white blood cell decrease. In the iguratimod ⫹ MTX group, one patient each showed a notable decrease in leukocyte (⬍ 2.0 ⫻ 103/μL) and erythrocyte (⬍ 2.5 ⫻ 106/μL) counts from weeks 1 to 24; these two abnormal laboratory findings resolved after the patients stopped the study treatment. No patient showed notable decreases in leukocyte or erythrocyte counts from weeks 25 to 52. In the extension phase of the (placebo/iguratimod) ⫹ MTX treatment, no patient showed a notable decrease in leukocyte (⬍ 2.0 ⫻ 103/μL) or erythrocyte (⬍ 2.5 ⫻ 106/μL) counts. Most AST and ALT changes were less than 100 U/L (Table 4). In the iguratimod ⫹ MTX group, four patients showed AST levels ⱖ 100 U/L in the total 52 weeks, and 75% of these events occurred from weeks 25 to 52. Similarly, seven patients showed ALT levels ⱖ 100 U/L in the 52 weeks, and 71% of these events occurred from weeks 25 to 52. Both AST and ALT levels of more than 100 U/L were observed in three patients in the total 52 weeks. As described above, one patient with abnormal laboratory findings in ALT and AST levels discontinued treatment; values resolved after treatment was stopped. In the extension phase of the (placebo/iguratimod) ⫹ MTX treatment, ALT levels ⱖ 100 U/L were observed in one patient. No patient discontinued treatment due to abnormal AST/ALT findings.

Discussion Our previous 24-week, randomized, double-blind, placebocontrolled study showed that combination treatment with two small-molecule RA agents, iguratimod and MTX, was associated with statistically and clinically meaningful improvements in patients with active RA with an inadequate response to MTX when compared with placebo ⫹ MTX treatment [11]. Here, we studied the safety and efficacy of an open-label extension of the iguratimod ⫹ MTX therapy to week 52. The ACR20 response rate at week 52 was 71.3%, which was similar to that of 69.5% at week 24. However, the ACR50 response at week 52 (49.4%) was significantly greater than that at week 24 (38.4%) (P ⫽ 0.003;

intragroup comparison). The present value of ACR50 (49.4% at week 52) with the combination therapy of iguratimod ⫹ MTX is comparable, for example, with that of 47.5% in the 52-week study of additional use of tacrolimus in Japanese patients with early RA with inadequate response to DMARDs, mostly MTX (about 70%), although patient background and study design in the tacrolimus study was different from those of the present study [17]. In addition, the ACR50 response at week 24 (38.4%) of iguratimod ⫹ MTX therapy was also similar to 41.9% of golimumab 50 mg ⫹ MTX therapy in the 24-week study of golimumab in Japanese patients with active RA despite MTX therapy [18]. In the present study, ACR70, HAQ-DI and DAS28-CRP at week 52 were also significantly higher than the values at week 24. These present results indicate that the efficacy of the combination iguratimod ⫹ MTX therapy was maintained at least to week 52. ACR20 in the (placebo/iguratimod) ⫹ MTX group at week 52 was 72.1%, which was similar to 71.3% observed at week 52 in the iguratimod ⫹ MTX group. The switch from placebo to iguratimod improved scores of ACR20, ACR50, ACR70, ACR core components, rheumatoid factor, IgG, IgM, IgA, DAS-CRP and HAQ-DI responders; that is, changes from baseline to week 52 significantly improved compared with those of the placebo ⫹ MTX treatment from baseline to week 24 (intragroup comparisons). These results indicate efficacy of the 24-week switched treatment with iguratimod ⫹ MTX. Iguratimod monotherapy significantly decreased rheumatoid factor and the production of IgG, IgM, and IgA compared with placebo in active RA patients [5]. Furthermore, the combination iguratimod ⫹ MTX therapy significantly decreased rheumatoid factor and the production of IgG, IgM and IgA compared with placebo at week 24 [11], and in this study, these decreased levels were found to be maintained until at least week 52. Thus, iguratimod has been demonstrated to be a clinically useful DMARD with unique immunological mechanisms. One safety concern of the combination iguratimod ⫹ MTX therapy was potential hepatotoxicity. Occurrences of AST and/or ALT increases were not significantly different between iguratimod ⫹ MTX and (placebo/iguratimod) ⫹ MTX groups during the initial 24 weeks (Table 3). In the iguratimod monotherapy study for 52 weeks, AST and/or ALT increases were mostly evident between week 4 and 8, and were resolved spontaneously during treatment or upon discontinuation of treatment [19]. In the present iguratimod ⫹ MTX study, AST and ALT increases were found in 9.8 and 5.5% of patients at week 24, respectively, and in 16.5 and 14.6% of patients at week 52, respectively. Furthermore, AST and ALT levels ⱖ 100 U/L were found in 0.6 and 1.2% of patients at week 24, and in 2.4 and 4.3% of patients at week 52, respectively. One patient with abnormal AST and ALT levels discontinued treatment; values resolved after treatment was stopped. These results indicate the need for regular liver enzyme monitoring with iguratimod ⫹ MTX treatment.

Table 4. Distribution of patients with higher and highest increases in liver enzymes. Weeks 1–24 IGU ⫹ MTX (n ⫽ 164) AST ⱖ 50 U/L and ⬍ 100 U/L ⱖ 100 U/L ALT ⱖ 50 U/L and ⬍ 100 U/L ⱖ 100 U/L AST and ALT ⱖ 50 U/L and ⬍ 100 U/L ⱖ 100 U/L Values are number of patients (%).

7

(PLA/IGU) ⫹ MTX (n ⫽ 88)

Weeks 1–52

Weeks 29–52

IGU ⫹ MTX (n ⫽ 164)

(PLA/IGU) ⫹ MTX (n ⫽ 68)

15 (9.1) 1 (0.6)

5 (5.7) 1 (1.1)

22 (13.4) 4 (2.4)

4 (5.9) 0 (0.0)

12 (7.3) 2 (1.2)

10 (11.4) 1 (1.1)

21 (12.8) 7 (4.3)

6 (8.8) 1 (1.5)

8 (4.9) 0 (0.0)

3 (3.4) 0 (0.0)

12 (7.3) 3 (1.8)

4 (5.9) 0 (0.0)

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

8

M. Hara et al.

Twenty patients discontinued due to adverse events during the 52-week iguratimod ⫹ MTX treatment. Among them, four patients each were due to abnormal hematologic laboratory values and gastrointestinal disorders, suggesting the need for caution regarding these adverse events. Furthermore, attention should be paid to adverse events during iguratimod ⫹ MTX treatment, especially for patients aged ⱖ 70 years and patients with low body weight (⬍ 40 kg) who were excluded from this study. Previously impaired renal function in elderly patients was reported to be an adverse event risk factor in MTX therapy [20,21], and hepatic enzyme elevation in patients with low body weight was reported using iguratimod monotherapy [19]. In 2012, the present combination of iguratimod with MTX therapy was firstly approved in Japan as the combination therapy with two small-molecule DMARDs for patients with active RA with inadequate response to MTX. Currently, treatment choices are dominated by patient and physician preferences, side-effects and costs [22]. Because a patient’s response to available medications shows variability in efficacy, toxicity and unpredicted necessity of discontinuation of therapy, combination therapy with iguratimod ⫹ MTX provides an additional therapeutic option, especially from points of view of changing medication and lower-cost treatment of RA compared with biological agents. One limitation of our study is that lower dosages of MTX (6 or 8 mg/week) were used compared with recommended dosages (7.5–20 mg/week) according to ACR guidelines [23]; these lower dosages were chosen because the approved maximum dosage in Japan was 8 mg/week at the beginning of this study [higher dosages of MTX (up to 16 mg/week) were approved in February 2011]. Despite the above-mentioned limitation, combination therapy of iguratimod with low-dose MTX was clinically efficacious, as shown here. It should be noted that it is difficult to increase the dosage of MTX in patients with comorbidities, such as renal dysfunction (e.g. elderly patients) [21]. However, a future study is valuable to know whether greater efficacy of combination iguratimod ⫹ MTX therapy is achieved when a higher dose of MTX is used instead of the present low doses. It is also important to confirm the efficacy of combination therapy with biologics and iguratimod for patients who cannot tolerate MTX. Furthermore, efficacy and safety of the combination therapy of iguratimod with DMARDs other than MTX may be interesting to explore. In summary, combination iguratimod ⫹ MTX therapy is efficacious and tolerated to 52 weeks in patients with active RA taking MTX alone. This combination presents a practical choice for patients who have an inadequate response to MTX and for patients who may not be able to use other DMARDs or biological agents due to primary failure, secondary failure, side effects and/ or costs.

Acknowledgements This study was funded by Toyama Chemical Co., Ltd., Tokyo, Japan and Eisai Co., Ltd., Tokyo, Japan. The authors wish to thank all the collaborating members of the Iguratimod-Clinical Study Group. Principal investigators and institutions were as follows: Kou Katayama (Katayama Orthopedic Rheumatology Clinic), Naoichiro Yukawa (Kyoto University Hospital), Satoshi Soen (Nara Hospital, Kinki University School of Medicine), Katsumi Eguchi, Atsushi Kawakami (Nagasaki University Hospital), Shuji Ohno (Ohno Clinic), Tomohiko Yoshida (Setagaya Rheumatology Center, Internal Medicine Department Yoshida Clinic), Takaaki Fukuda (Kurume University Medical Center), Keisuke Hashimoto (Hashimoto Clinic for Orthopedic or Rheumatic Diseases), Takashi Sato (Association of Medical Corporation Dainohara Orthopedic Surgery), Yuichi Takahashi (Yu Family Clinic), Eiji Sugiyama (Hiroshima University Hospital), Kenji Kohriyama (Shinsuma Hospital), Yasuhiko Munakata (Medical Corporation Biei Taihaku Sakura Hospital), Koichi Kitamura (Hakodate Goryokaku Hospital), Kanzo Amano (Hiroshima Clinic), Shigeo Miyashima (Miyashima RA

Mod Rheumatol, 2013; Early Online: 1–9

and Orthopaedic Clinic), Akira Sagawa (Sagawa Akira Rheumatology Clinic), Takeo Sakurai (Inoue Hospital), Hiroo Yamane (Toyooka-daiichi Hospital), Wataru Hirose (Hirose Clinic), Hiroshi Nakashima (Nakajima Orthopaedic Surgery), Tamami Yoshitama (Yoshitama Clinic Rheumatology and Internal Medicine), Koichi Hirota (Hirota Medical Clinic), Motohide Kaneko (Kaneko Internal Medicine Rheumatology Clinic), Kunio Matsuta (Matsuta Clinic), Atsushi Fujisaku (Tomakomai City Hospital), Masanobu Mine (Suga Orthopedic Hospital), Shintaro Yano (Sanyakai Medical Corporation Maebashi Hirosegawa Clinic), Ichiro Oki (Oki Medical Clinic), Tatsumi Chijiwa (Medical Corporation Takatakai Kochi-Kinen Hospital), Masaya Mukai (Sapporo City General Hospital), Kazutoshi Aoki (Saitama Social Insurance Hospital), Munetoshi Nakashima (The Japanese Red Cross Nagasaki Genbaku Hospital), Jun Kishi (Tokushima University Hospital), Toshihisa Kanamono (Nagano Red Cross Hospital), Shuji Ohta (Taga General Hospital), Toshiaki Tsukada (Isahaya Health Insurance General Hospital), Yukitaka Ueki (Sasebo Chuo Hospital), Seiji Tsuboi (Shizuoka Kousei Hospital), Hirobumi Takahashi (Takahashi Medical Clinic), Hiroki Tsuchiya (Nagoya Kyoritsu Clinic), Tomomasa Izumiyama (Higashisendai Rheumatology Medical Clinic), Yukiyoshi Oishi, Yuji Hirano (Toyohashi Municipal Hospital), Takefumi Kato (Medical Corporation Kato Orthopedic Surgery), Shinichi Yamaguchi (Yamaguchi Clinic), Takanori Nagamine (Nagamine Orthopedic Clinic), Isao Furugo (JR Kyushu Hospital), Yasutaka Takagi (Tonami General Hospital), Takayuki Sumida (Tsukuba University Hospital), Ryosuke Kanda (Kitasenzoku Orthopedic Clinic), Keiji Maeda (NTT West Osaka Hospital), Tomomi Tsuru (Medical Co.LTA PS Clinic), Masakazu Kondo (Kondo Clinic of Rheumatology and Orthopaedic Surgery), Masatoshi Naito (Fukuoka University Hospital), Makoto Nishinarita (Nishinarita Clinic Office), Masakazu Nagashima (Tokyo Metropolitan Bokutoh Hospital), Hiroyuki Miyake (Ichinomiya Municipal Hospital), Takehiko Ayabe (Ayabe Clinic), Hideki Amma (Social Insurance Chukyo Hospital), Takeshi Oguchi (Anjo Kosei Hospital), Mitsugu Takahashi (Takahashi Orthopedics Clinic), Hiroshi Morio, Masaki Hiraguri (Japanese Red Cross Narita Hospital), Minoru Kurihara (Funaboriekimaeseikeigekanaika), Haruhiko Matsumoto (Munehiro Hospital), Juhro Fujimori (The Hofu Clinic for Orthopaedics and Rheumatology), Hiroshi Tsurukami (Tsurukami Clinic of Orthopedic and Rheumatology), Hiroshi Nakamura (Nakamura Orthopedic Clinic), Akio Suda (Suda Memorial Orthopedic Clinic), Hiroyuki Hagiyama (Yokohama City Minato Red Cross Hospital), Akikatsu Nakashima (Ishikawa-ken Saiseikai Kanazawa Hospital), Teiji Kontani (Komatsu Municipal Hospital), Shigeru Kamei (Kamei Orthopaedics), Takashi Maruyama (Yaenosato Hospital), Fumio Shinomiya (Centre for Rheumatic Disease, Mima Hospital in Yoshinogawa City), Seiji Yoshizawa (Hamanomachi Hospital), Kazuhide Tanimura (Hokkaido Medical Center for Rheumatic Diseases), Koji Hashimoto (Yamauchi Hospital), Hajime Kawamura (Kawamura Medical Clinic), Hiroyuki Nara (Kokubunji Sakura Clinic), Hidetomo Sato (Nasu Kogen Clinic), Shigeki Hidaka (Hidaka Orthopedic Hospital), Kenichi Murase (Nishikasai South Gate Department of Orthopedic Surgery and Rheumatology CL), Minoru Irahara (Irahara Clinic), Sadamu Suzuki (Suzuki Clinic), Makoto Kawakami (Tamatsukuri Kosei-Nenkin Hospital), Eisuke Shono (Shono Rheumatology Clinic), Junichi Obata (Hikarichuo Clinic), Motohiro Oribe (Oribe Clinic of Rheumatism and Medicine), Shoji Uchida (Uchida Clinic), Masao Nakajima (Kasumigaseki Urban Clinic), Takuya Sawabe (Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital), Koichiro Ishikawa (Ishikawa Orthopaedic and Rheumatism Hospital), Shin Munesada (Asunaro Orthopedic Clinic), Takashi Ohira (Ohira Orthopedic Hospital), Masaaki Yoshida (Yoshida Orthopedic Rheumatology Clinic), Tsukasa Matsubara (Matsubara Mayflower Hospital, Association of the Medical Corporation of Matsubara Clinic), Shigeru Honjo (Honjo Rheumatism Clinic), and Yuji Yamanishi (Hiroshima Rheumatology Clinic).

Conflict of interest N.I. has received speakers bureau from AbbVie GK, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. M.K. has received speakers bureau from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Pfizer Japan Inc. T.S. has received grant and research support from Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Pfizer Japan Inc.; speakers bureau from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma

Mod Rheumatol Downloaded from informahealthcare.com by University of Groningen on 05/01/14 For personal use only.

DOI 10.3109/14397595.2013.843756

Safety and efficacy of combination therapy of iguratimod with methotrexate

Corporation, Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. T.M. has received grant and research support from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; speakers bureau from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. S.S. has received grant and research support from Asahi Kasei Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Sanofi Aventis K.K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Limited; speakers bureau from Astellas Pharma Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd. K.Y. has received grant and research support from Astellas Pharma Inc., BristolMyers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., and Santen Pharmaceutical Co., Ltd.; speakers bureau from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Santen Pharmaceutical Co., Ltd. K.N. is an employee of Eisai Co., Ltd. T.Y. is an employee of Toyama Chemical Co., Ltd. M.H., N.I., K.K., M.K., T.S., T.M., S.S., and K.Y. served for consultancy to Eisai Co., Ltd. and Toyama Chemical Co., Ltd.

References 1. Kawakami A, Tsuboi M, Urayama S, Matsuoka N, Yamasaki S, Hida A, et al. Inhibitory effect of a new anti-rheumatic drug T-614 on costimulatory molecule expression, cytokine production, and antigen presentation by synovial cells. J Lab Clin Med. 1999; 133(6):566–74. 2. Kohno M, Aikawa Y, Tsubouchi Y, Hashiramoto A, Yamada R, Kawahito Y, et al. Inhibitory effect of T-614 on tumor necrosis factor-alpha induced cytokine production and nuclear factorkappaB activation in cultured human synovial cells. J Rheumatol. 2001;28(12):2591–6. 3. Aikawa Y, Yamamoto M, Yamamoto T, Morimoto K, Tanaka K. An anti-rheumatic agent T-614 inhibits NF-kappaB activation in LPSand TNF-alpha-stimulated THP-1 cells without interfering with IkappaBalpha degradation. Inflamm Res. 2002;51(4):188–94. 4. Tanaka K, Yamamoto T, Aikawa Y, Kizawa K, Muramoto K, Matsuno H, et al. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology 2003; 42(11):1365–71. 5. Hara M, Abe T, Sugawara S, Mizushima Y, Hoshi K, Irimajiri S, et al. Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study. Mod Rheumatol. 2007;17(1):1–9. 6. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65(3):168–73. 7. Chan ES, Cronstein BN. Methotrexate–how does it really work? Nat Rev Rheumatol. 2010;6(3):175–8.

9

8. Akkari R, Burbiel JC, Hockemeyer J, Müller CE. Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. Curr Top Med Chem. 2006;6(13):1375–99. 9. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625–39. 10. Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010; 69(6):964–75. 11. Ishiguro N, Yamamoto K, Katayama K, Kondo M, Sumida T, Minori T, et al. Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Mod Rheumatol. 2013;23(3):430–9. 12. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. 13. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8. 14. Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol. 1982;9(5):789–93. 15. Kosinski M, Zhao SZ, Dedhiya S, Osterhaus JT, Ware JE Jr. Determining minimally important changes in generic and diseasespecific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum. 2000;43(7):1478–87. 16. Fransen J, van Riel PL. Outcome measures in inflammatory rheumatic diseases. Arthritis Res Ther. 2009;11(5):244. 17. Kawai S, Takeuchi T, Yamamoto K, Tanaka Y, Miyasaka N. Efficacy and safety of additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to DMARDs–a multicenter, double-blind, parallel-group trial. Mod Rheumatol. 2011;21(5):458–68. 18. Tanaka Y, Harigai M, Takeuchi T, Yamanaka H, Ishiguro N, Yamamoto K, et al. Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study. Ann Rheum Dis. 2012;71(6):817–24. 19. Hara M, Abe T, Sugawara S, Mizushima Y, Hoshi K, Irimajiri S, et al. Long-term safety study of iguratimod in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(1):10–6. 20. Rheumatoid Arthritis Clinical Trial Archive Group. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. J Rheumatol. 1995;22(2):218–23. 21. Borchers AT, Keen CL, Cheema GS, Gershwin ME. The use of methotrexate in rheumatoid arthritis. Semin Arthritis Rheum. 2004;34(1):465–83. 22. Tak PP, Kalden JR. Advances in rheumatology: new targeted therapeutics. Arthritis Res Ther. 2011;13 Suppl 1:S5. 23. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002;46(2):328–46.

Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: an open-label extension of a randomized, double-blind, placebo-controlled trial.

To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with a...
337KB Sizes 0 Downloads 0 Views

Recommend Documents