Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

Abstract Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules.


Introduction
TNF α plays a central role in the pathogenesis of rheumatoid arthritis (RA). After the introduction of TNF inhibitors in clinical practice, the management of RA has dramatically changed [1,2]. Early initiation of TNF inhibitors is benefi cial not only because they improve the signs and symptoms of RA, but also because they improve physical function and inhibit structural damage, particularly when used in combination with methotrexate (MTX) [3 -5]. TNF inhibitors control RA symptoms and suppress functional and clinical signs and symptoms including radiographic progression and safety was shown. The aim of the current study was to determine whether the benefi cial eff ects of CZP are sustained during long-term treatment in Japanese RA patients who showed an inadequate response to MTX treatment. To evaluate the longterm effi cacy and safety of CZP treatment, we conducted an open-label extension (OLE) study of the J-RAPID study. As a subsidiary objective, we also compared the effi cacy of two separate maintenance dosing schedules, CZP 200 mg given every 2 weeks (Q2W) and CZP 400 mg given every 4 weeks (Q4W). We hereby report the 52-week interim results and post-hoc analysis from the ongoing J-RAPID OLE study.

J-RAPID and J-RAPID OLE study design
The J-RAPID OLE study (NCT00851318) is an OLE study of the J-RAPID study (NCT00791999) [13]. In brief, the J-RAPID study [hereinafter referred to as " double-blind (DB) phase " ] was a 24-week, Phase II/III, DB study conducted in 66 centers across Japan. Eligible patients were aged from 20 to 74 years and had a diagnosis of RA by the ACR (1987) criteria [16] with at least nine tender and nine swollen joints at screening and baseline. Moreover, the patients must have met at least one of the following criteria at screening: erythrocyte sedimentation rate (ESR) of Ն 30 mm/ hour or C-reactive protein (CRP) of Ն 1.5 mg/dL. Patients must have received treatment with MTX (with or without folic acid) for Ն 6 months before study drug administration, with the MTX dose fi xed for Ն 2 months beforehand and within the range of 6 -8 mg/ week. Patients with extensive comorbidities were excluded from the study. Refer to [13] for detailed inclusion and exclusion criteria of the J-RAPID study. Japanese patients with active RA and an inadequate response to MTX received either CZP or placebo while continuing to receive stable doses of MTX. In the DB phase, the subjects were randomly assigned 1:1:1:1 into four groups: subcutaneous CZP 100, 200 or 400 mg plus MTX, or placebo (saline) plus MTX, every 2 weeks. Patients randomized to CZP plus MTX received induction doses of 200 mg (100 mg group) or 400 mg (200 and 400 mg groups) at weeks 0, 2 and 4. All patients continued to receive MTX at the same dosage taken at DB phase entry (6 -8 mg/week). The primary endpoint of this study was an ACR20 response at week 12.
The J-RAPID OLE study was conducted between April 1, 2009 and August 22, 2011. In the OLE phase, we divided J-RAPID DB phase patients into four groups based on responses to treatment during the DB phase. Patients who did not achieve an ACR20 response at both weeks 12 and 14 were withdrawn from the DB phase at week 16, assigned to Group I ( n ϭ 81) and treated with CZP 200 mg Q2W plus MTX thereafter. Patients who exhibited an ACR20 response at weeks 12 or 14 but failed to achieve an ACR20 response at week 24 were assigned to Group II ( n ϭ 19) and also received CZP 200 mg Q2W plus MTX. Patients who achieved an ACR20 response at week 12 or 14 as well as at week 24 were randomized 1:1 to either CZP 200 mg Q2W plus MTX (Group III, n ϭ 93) or CZP 400 mg Q4W plus MTX (Group IV, n ϭ 92) ( Figure 1). Of importance, we established this dosing schedule so that the total dose received by patients in Groups III and IV over a 1-month period was the same.
Week 0 of the OLE phase of Groups II, III and IV (J-RAPID DB phase completers: hereinafter referred to as DB completers) corresponds to week 28 of the DB phase and week 0 of the OLE phase of Group I (early escape) corresponds to week 16 of the DB phase. Patients assigned to the placebo group during the DB phase were also included in this OLE study. Discontinuation of concomitant MTX was not permitted during the OLE phase up to week 52. A change in MTX dosage was permitted after week 24 of the OLE phase, if it was not greater than the original dose (6 -8 mg/week).
The outcome of the study was the measurement of continuous effi cacy and safety monitoring during long-term treatment with CZP plus MTX. Effi cacy outcomes included ACR20 response rates, and changes in Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score in 28 Joints-Erythrocyte Sedimentation Rate (DAS28-ESR), the Short Form-36 Health Survey (SF-36) and Pain Visual Analog Scale (VAS) from J-RAPID pre-study baseline. In addition, to measure radiographic disease progression, changes in the modifi ed Total Sharp Score (mTSS) from OLE study entry was assessed by linear extrapolation. Comprehensive disease control (CDC) was defi ned by the simultaneous achievement of the following three criteria: low disease activity   Figure 1. J-RAPID OLE study design. The diagram depicts the breakdown of J-RAPID DB study patients into four groups for the OLE phase of the study. * Regardless of their initial DB phase group assignment, patients who achieved an ACR20 response at weeks 12 or 14 as well as at week 24 were randomized (1:1) to either CZP 200 mg Q2W (Group III, n ϭ 93) or CZP 400 mg Q4W (Group IV, n ϭ 92).
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and with the Pharmaceutical Aff airs Law Standards for the Conduct of Clinical Trials on Drugs (Ministry of Health, Labour and Welfare Ordinance no. 28, 27 March 1997) and related notifi cations. Institutional review board approval was obtained at all centers and all patients provided written informed consent.

Post-hoc analyses
Since the OLE study included patients who received placebo during the J-RAPID DB phase, an additional post-hoc analysis of clinical effi cacy was performed on patients who received CZP in the DB phase, to observe the eff ects of continuous CZP treatment during the combined DB and OLE phases of the study. This data set includes patients who were originally assigned to CZP 100, 200 and 400 mg treatment groups in the DB phase and completed the DB phase (CZP-DB completers). We focused on ACR20/ACR50/ ACR70 response rates, DAS28-ESR scores, HAQ-DI scores and the disease activity state (high: DAS28-ESR Ͼ 5.1, moderate: Ͼ 3.2 and Յ 5.1, low disease activity (LDA): Յ 3.2 and remission: Ͻ 2.6) in this post-hoc analysis.

Statistical analyses
The effi cacy analysis was performed on the full-analysis set (FAS) using the last observation carried forward (LOCF) to impute missing data. We used J-RAPID pre-study parameters as baseline values. Safety analyses were performed on all subjects who received at least one dose of CZP during the OLE study. Because the objective of the study was to evaluate the long-term effi cacy and safety of CZP treatment, inferential analyses were not performed.

Patient characteristics and disposition of the J-RAPID OLE study
We obtained informed consent from 286 J-RAPID DB phase patients to enter the OLE study. Because one patient withdrew from the OLE study before receiving CZP treatment, a total of 285 patients were included in the effi cacy and safety analyses. During the 52-week treatment, an additional 33 patients withdrew from the study resulting in a total of 252 patients (88.4%) completing the 52-week interim period of the OLE study. A few patients (2.5%) withdrew from the study due to an inadequate response (Table 1). All reasons for study withdrawal are listed in Table 1. A summary of patient demographics and J-RAPID pre-study baseline characteristics is shown in Table 2. Patients were divided into four groups in the OLE phase based on their response during the DB phase. It was important to distinguish patients with an ACR20 response at week 24 of the DB phase (DB responders: Groups III and IV) and DB non-responders (Groups I and II) to evaluate the sustained effi cacy of continued long-term CZP treatment. As shown in Table 2, all of these groups included patients who were on placebo during the DB phase. The fraction of patients that received placebo during the DB phase was 55.6% (45 patients), 31.6% (6 patients), 10.8% (10 patients) and 9.8% (9 patients) in Groups I, II, III and IV, respectively. DB responders were further divided into two groups to evaluate the effi cacy of two diff erent dosing regimens. DB responder patients ( n ϭ 185) were randomized to either CZP 200 mg Q2W (Group III, n ϭ 93: 83 CZP patients, 10 placebo patients) or CZP 400 mg Q4W (Group IV, n ϭ 92: 83 CZP patients, 9 placebo patients) as shown in Table 2. At OLE study entry (OLE week-0), the mean DAS28-ESR scores of Groups I, II, III and IV were 6.08, 5.12, 3.22 and 3.20, respectively.

Clinical effi cacy is sustained by long-term CZP plus MTX treatment
The J-RAPID OLE study was designed to evaluate whether the benefi ts obtained after short-term CZP plus MTX treatment could be sustained by prolonged treatment. To this end, we analyzed the outcomes of Groups I, II, III, IV and overall DB completers (Groups II ϩ III ϩ IV) after up to 52 weeks of long-term CZP treatment in the OLE phase. ACR20/ACR50/ACR70 response rates, calculated from the J-RAPID pre-study baseline, were increased or sustained for up to 52 weeks in the OLE phase. At OLE study entry and at 52 weeks of the OLE phase, the ACR20 response rates were 7.5% and 76.5% for Group I, 36.8% and 84.2% for Group II, 95.7% and 98.9% for Group III, and 94.6% and 94.6% for Group IV, respectively ( Figure 2a). The ACR50 response rates were 0% and 48.1% for Group I, 0% and 57.9% for Group II, 77.4% and 87.1% for Group III, and 70.7% and 88% for Group IV, respectively ( Figure 2b). The ACR70 response rates were 0% and 30.9% for Group I, 0% and 31.6% for Group II, 39.8% and 64.5% for Group III, and 40.2% and 57.6% for Group IV, respectively ( Figure 2c). For overall DB completers  comprehensive disease remission (CDR: i.e. DAS28-ESR Ͻ 2.6, HAQ-DI Յ 0.5, and Δ mTSS Յ 0.5) at OLE study entry and at 52 weeks was 17.2% and 26.0%, respectively. Together, these data suggest that the clinical, functional and radiographic benefi ts obtained after short-term CZP treatment are sustained by longterm treatment with CZP.

The two dosing schedules (CZP at 200 mg Q2W vs. 400 mg Q4W) combined with MTX similarly sustain the clinical effi cacy of CZP
In both randomized arms (Groups III and IV), the high ACR20/ ACR50/ACR70 rates and the high changes from J-RAPID prestudy baseline in DAS28-ESR and HAQ-DI scores were sustained through 52 weeks of the OLE phase (Figures 2 and 3). For example, the ACR20 response rates at OLE study entry and at 52 weeks of the OLE phase were 95.7% and 98.9% for Group III and 94.6% and 94.6% for Group IV, respectively ( Figure 2a). In addition to clinical parameters, the Δ mTSS from OLE study entry between the two dosing regimens were similar throughout the OLE study (Figure 4). At week 52, 69.0% and 67.5% of patients had a Δ mTSS Յ 0.5 in Groups III and IV, respectively, suggesting that both regimens were similarly eff ective at inhibiting radiographic progression. Thus, both CZP maintenance regimens similarly sustained clinical effi cacy of CZP during the OLE study phase.

Assessment of sustained clinical effi cacy of combined long-term CZP plus MTX treatment by a post-hoc analysis through the DB and OLE phase
Since all arms of the OLE protocol (Groups I, II, II and IV) included patients who were originally randomized to the placebo group during the DB phase (Table 2), a post-hoc analysis was performed only on data from patients who were originally assigned to one of the CZP treatment groups in the DB phase and completed the DB phase with an ACR20 response at week 12 or 14 (CZP-DB completers). This was an important analysis to observe the eff ects (Groups II ϩ III ϩ IV), at OLE study entry and at 52 weeks of the OLE phase, the ACR20 response rates were 89.7% and 95.6%, the ACR50 response rates were 67.2% and 84.8%, and the ACR70 response rates were 36.3% and 58.3%, respectively ( Figure 2). A marked improvement in DAS28-ESR was also sustained for up to 52 weeks of the OLE phase for overall DB completers ( Figure 3a). DAS28-ESR remission rates (defi ned as DAS28-ESR Ͻ 2.6) for overall DB completers were 28.4% and 42.6% at OLE study entry and 52 weeks of the OLE phase, respectively. Improvements in quality of life indicators including HAQ-DI ( Figure 3b) and SF-36 were maintained by long-term CZP treatment. The HAQ-DI remission rates (defi ned as HAQ-DI Յ 0.5) for overall DB completers were 66.7% and 77.5% at OLE entry and at 52 weeks of the OLE phase, respectively, indicating that most patients achieved functional remission. The mean Ϯ SD changes of SF-36 scores from J-RAPID pre-study baseline at OLE study entry and at week 52 were 11.93 Ϯ 10.03 and 13.60 Ϯ 10.54 in physical component summary scores and 5.56 Ϯ 11.07 and 5.21 Ϯ 11.17 in mental component summary scores, respectively. In fact, an individual assessment of all eight domains of the SF-36 revealed sustained improvement in each component of the SF-36 score (data not shown). Moreover, the 100 mm pain VAS improvement was maintained, with a mean Ϯ SD change from J-RAPID pre-study baseline of Ϫ 33.8 Ϯ 22.1 at OLE study entry and Ϫ 39.2 Ϯ 23.2 at 52 weeks of the OLE phase.
In addition to signs and symptoms, and patient-reported outcomes, changes from OLE study entry in mTSS ( Δ mTSS) were assessed. The mean Ϯ SD and median Δ mTSS at week 52 were 1.15 Ϯ 4.80 and 0.00 in DB completers, respectively (Figure 4). At week 52, 68.3% of DB completers displayed radiographic nonprogression, that is a Δ mTSS Յ 0.5.
The proportion of DB completers achieving comprehensive disease control (CDC: i.e. DAS28-ESR Յ 3.2, HAQ-DI Յ 0.5, and Δ mTSS Յ 0.5) at OLE study entry and at 52 weeks was 25.5% and 35.8%, respectively. The proportion of DB completers achieving of continuous CZP treatment during the DB and OLE phases of the study. In this post-hoc analysis, we focused on ACR20/ACR50/ ACR70 response rates, DAS28-ESR scores, HAQ-DI scores and the disease activity state (LDA and remission). The effi cacy results are summarized in Figures 5 -7 for the patients who were originally randomized to either CZP 100, 200 or 400 mg in the DB phase and received either CZP 200 mg Q2W ϩ MTX (Groups II and III) or CZP 400 mg Q4W ϩ MTX (Group IV) in the OLE phase.
Moreover, the mean changes in DAS28-ESR scores and HAQ-DI scores, from J-RAPID pre-study baseline, were also sustained up to 52 weeks of the OLE phase (Figure 6a, b). Furthermore, the analysis of disease activity states demonstrated that both LDA and remission rates (defi ned as DAS28-ESR Յ 3.2 and Ͻ 2.6, respectively) were sustained during the 52-week period of the OLE phase. The proportion of patients who were in LDA and remission (DAS28-ESR Յ 3.2) was 47.1%, 52.4% and 57.0% at OLE entry, and 54.9%, 61.9% and 61.5% at week 52, in CZP-DB completers receiving 100, 200 and 400 mg CZP during the     I  II  III   IV  II+III+IV   I  II  III   IV  II+III+IV   I  II  III IV II+III+IV Figure 2. The ACR20/ACR50/ACR70 response rates in patients from each treatment group. The percentages of patients in Groups I ( n ϭ 81), II ( n ϭ 19), III ( n ϭ 93), IV ( n ϭ 92) and patients in Groups II ϩ III ϩ IV combined (DB completers, n ϭ 204) who achieved an (a) ACR20, (b) ACR50, or (c) ACR70 response were plotted over time for the DB and the OLE phase of the study (FAS population, LOCF imputation). Of note, week 0 of the OLE phase of Group I (early escape) corresponds to week 16 of the DB phase. There are no points in the missing section of the graph for Group I. most common AEs were nasopharyngitis, pharyngitis and upper respiratory tract infections. Most AEs were mild to moderate (84.6%). The rate, severity and distribution of AEs were similar among all groups (Groups I -IV), suggesting that no obvious diff erences in AEs are observed based on the CZP treatment schedule. No tuberculosis infections or deaths were reported. No unanticipated AEs occurred in any of the groups. Thus, over 52 weeks of the OLE phase, CZP coadministered with MTX was well tolerated, with no new safety precautions when compared with the DB phase (Table 3).

Discussion
The 24-week treatment of CZP has been shown to be effi cacious in improving RA disease activity [11 -14]. This was also true in patients who showed an inadequate response to MTX. In the DB placebo-controlled J-RAPID study, the combination of CZP plus MTX for 24 weeks improved disease outcome in RA patients who showed an inadequate response to MTX [13]. Although several data on short-term CZP plus MTX treatment have been available [17 -19], the clinical effi cacy and safety of long-term CZP plus MTX treatment is unknown in Japanese RA patients. Thus, we conducted an OLE study of the J-RAPID study to evaluate the safety of combined long-term CZP plus MTX treatment and to investigate whether the clinical benefi t obtained from the 24-week DB phase of the J-RAPID study could be sustained by extending the treatment for another 52 weeks. In addition, we used the OLE herein to assess the effi cacy of two diff erent maintenance dosing schedules, the standard dosing (CZP 200 mg Q2W) and an alternative regimen (CZP 400 mg Q4W), both with concomitant MTX. Our data demonstrate that long-term CZP treatment sustains the clinical effi cacy obtained in overall DB completers. This was DB phase, respectively (Figure 7). The remission rates (DAS28-ESR Ͻ 2.6) were 31.4%, 25.4% and 38.5% at OLE entry, and 47.1%, 34.9% and 49.2% at week 52, in CZP-DB completers receiving 100, 200 and 400 mg CZP during the DB phase, respectively (Figure 7). Therefore, this post-hoc analysis demonstrates that the effi cacy of CZP can be sustained in long-term CZP treatment, even when the analysis set is restricted to patients who have achieved an ACR20 clinical response after 12 -14 weeks of CZP treatment.

Adverse events (AE)s reported during long-term CZP plus MTX treatment
During the 52 weeks of the OLE phase, 253 patients (88.8%) experienced AEs and 31 patients (10.9%) experienced serious AEs (Table 3). Among SAEs, two patients (0.7%) exhibited abnormal hepatic function, two patients (0.7%) developed bronchitis, three patients (1.1%) displayed RA exacerbations and two patients (0.7%) developed subarachnoid hemorrhage. Two patients (0.7%) developed a malignancy (breast cancer, colon cancer). The  Figure 5. Post-hoc analysis of ACR20/ACR50/ACR70 response rates in patients from Groups II, III and IV excluding those who were in the placebo group during the DB phase (CZP-DB completers). The ACR20, ACR50 and ACR70 response rates of post-hoc analysis patients treated with (a) 100 mg ( n ϭ 51), (b) 200 mg ( n ϭ 63) or (c) 400 mg ( n ϭ 65) of CZP during the DB phase were plotted against time for the DB and the OLE phase of the study (LOCF imputation). radiographic progression between groups. On a separate note, the disconnect between the improvements in signs and symptoms and changes in radiographic manifestations of disease has been previously reported in patients treated with TNF antagonists [20].
Together, these results suggest that long-term CZP treatment is eff ective at controlling RA disease progression, even with the relatively low dose of concomitant MTX (6 -8 mg/week). The low withdrawal rate (2.5%) of patients from the study due to lack of effi cacy further supports this notion. This was true even for patients that were initially treated with the lower dose of CZP true for ACR response rates, DAS28-ESR, SF-36 scores and the pain VAS. In addition, clinical remission was observed in 42.6% of patients with long-term treatment at 52 weeks of the OLE study. Functional remission was also observed in 77.5% at 52 weeks of the OLE. Moreover, an analysis of mTSS scores showed that radiographic non-progression ( Δ mTSS Յ 0.5) was achieved in 68.3% of the patients. In terms of the radiographic scores, as described in the Materials and Methods, all patients received CZP in this OLE, and the changes in mTSS scores were within the 52 weeks of the OLE. Therefore, there are no signifi cant diff erences seen in  seen with other TNF inhibitors such as infl iximab, etanercept, adalimumab and golimumab. As an added benefi t, the local skin reaction to subcutaneous injection of CZP tends to be lower than other subcutaneously administered TNF inhibitors. Together, these data suggest that if the patient obtains a positive response to CZP treatment after 12 -14 weeks, clinicians can expect sustained effi cacy without additional risks by continuing onto long-term use of CZP plus MTX. In summary, our data suggest that continuous long-term CZP treatment is a benefi cial option in patients with active RA and an inadequate response to MTX, by providing long-term clinical, functional and radiographic disease control. This was true for both the Q2W and Q4W maintenance dosing schedules of CZP. Moreover, long-term treatment was well-tolerated with no new unexpected adverse events observed. One limitation of our study was that this was an OLE study and therefore not blinded. However, we believe that our data still suggest that long-term CZP treatment is benefi cial for continued suppression of RA. Thus, we propose that patients with active RA and an inadequate response to MTX should undergo continuous combined long-term treatment with either a CZP 200 mg Q2W or CZP 400 mg Q4W schedule with MTX to achieve long-lasting suppression of RA symptoms. approximately 7% lower in patients treated with 100 mg CZP during the DB phase compared with patients treated with 200 mg CZP at 52 weeks of the OLE phase, there were no overall significant diff erences in disease activity state regardless of the dose received during the DB phase (Figure 7). This is the fi rst study that demonstrates the benefi ts of continued long-term treatment of CZP administration in Japanese RA patients. Similar studies have been conducted internationally. In the RAPID1 trial, sustained benefi t in clinical signs and symptoms and radiographic progression was observed after 2 years of continuous CZP treatment [15]. More recently, the 5-year OLE study from the RAPID1 trial showed continued effi cacy up to 256 weeks with no new safety signals identifi ed [21]. Our data presented here suggest that Japanese patients continue to receive relief from RA symptoms after long-term TNF α inhibition by CZP. Importantly, long-term CZP plus MTX treatment was well-tolerated as no unexpected new AEs were detected in patients compared with those observed in previous clinical studies involving short-term CZP plus MTX treatment.
CZP is a novel anti-TNF α monoclonal antibody consisting of a humanized Fab ' fragment fused to a 40-kD PEG moiety [22,23]. One drawback of Fab ' fragments is that the clearance of Fab ' fragments is accelerated in the absence of the Fc region, leading to shorter in vivo half-lives compared with full antibodies. However, by attachment of the PEG moiety to the Fab ' fragment, the plasma half-life of CZP was extended to about 2 weeks. Because of the extended half-life, a more spaced out CZP maintenance dosing schedule is possible. Our current study provides evidence that extending the interval to Q4W for CZP maintenance therapy is as eff ective as the Q2W regimen. No obvious diff erences in clinical effi cacy and safety were observed between patients treated with CZP 200 mg Q2W and CZP 400 mg Q4W (Group III vs. Group IV). Thus, patients and physicians have the fl exibility of choosing either of two maintenance dosing schedules based on their needs. For example, a Q4W dosing schedule might decrease the number of doctor visits and thus, might be an attractive option for some patients.
The design of the J-RAPID OLE study included patients that were previously on placebo during the DB phase of the J-RAPID study. To observe the eff ects of continuous CZP treatment through the DB and OLE phases of the study (80 weeks), an additional post-hoc analysis was performed on CZP-DB completers (Groups II -IV) who received CZP during the DB phase. Restricting our analysis to these patients clearly showed that long-term CZP plus MTX treatment sustained the clinical, radiographic and functional effi cacy against disease. Thus, we conclude that long-term CZP plus MTX treatment for up to 80 weeks results in a sustained positive response.
Administration of MTX remains the cornerstone for treatment of RA [24,25]. However, some patients do not achieve the desired response when MTX is used as monotherapy [25]. Thus, it is important to identify drugs that can be used in conjunction with MTX to more eff ectively treat the symptoms of RA. The J-RAPID study demonstrated that CZP is clinically eff ective in combination with MTX for treatment of patients who failed to achieve a satisfactory response with MTX alone. Our current study is the fi rst to investigate the clinical effi cacy of CZP with MTX treatment over an ~ 80-week period (28 weeks during the DB phase ϩ 52 weeks during the OLE phase) in Japanese RA patients. Our data demonstrate that long-term CZP plus MTX treatment sustains the benefi cial eff ect of CZP plus MTX aff orded after 24 weeks of therapy. Moreover, no new unexpected AEs were discovered during the OLE phase, suggesting that additional risks are not incurred by long-term treatment with CZP plus MTX. Based on results from clinical trials and from post market surveys, the AEs observed with long-term CZP treatment are comparable to those