Abstract
Introduction
Short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that etanercept (ETN) is effective and well tolerated in patients with radiographic axial spondyloarthritis (r-axSpA) with long-term efficacy and safety continuing for up to 7 years after treatment start. Short-term randomized controlled trials (RCTs) have shown the efficacy of ETN after 12–24 weeks, with statistically significant improvements as early as week 2. This post hoc analysis investigated the timeframe (i.e., temporal responses) in which patients with r-axSpA achieved their first clinical response with ETN and how patients responded over a longer period according to different temporal responses in index studies.
Methods
Data were analyzed from three phase 3/4 PBO- or sulfasalazine-controlled RCTs of ETN for the treatment of r-axSpA (index studies). Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses (“Early,” “Intermediate,” “Late,” or “Non-response”) in their corresponding index studies.
Results
Within each index study, patient responses differed significantly between ETN and control arms for achievement of Assessment in SpondyloArthritis international Society (ASAS) 20 and other measures of treatment response. In general, the proportion of responders in the OLE studies was high for those with “Early” and “Intermediate” responses as defined in the index studies. Despite patients being considered non-responders in the index studies, a large proportion achieved response on continued treatment in the OLE studies over the longer term, including through 48 weeks.
Conclusions
Response in the index studies was maintained in the long term, and continued treatment was warranted in a large proportion of patients despite initial non-response. Absence of an early response in index studies did not predict non-response over the long term, and early response to treatment was not always a predictor for later response.
Trial Registration
NCT00421915; NCT00247962; NCT00356356; NCT00421980; NCT00410046.
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Why carry out this study? |
Although the association of early achievement of clinical responses with better long-term outcomes in radiographic axial spondyloarthritis (r-axSpA) has been demonstrated with etanercept treatment, this analysis further explored the timeframe in which patients achieve clinical responses with etanercept treatment. |
Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses (“Early,” “Intermediate,” “Late,” or “Non-response”) in their corresponding index studies. |
What was learned from the study? |
Response in short-term index studies (up to 24 weeks’ duration) was maintained in the long-term OLE studies. Overall, an early response during the index studies appeared to be associated with response in the long-term OLE studies. Where no response had occurred in the index studies, continued treatment led to a response in a large proportion of patients. |
These findings add to the body of evidence on the efficacy of anti-tumor necrosis factor therapy in r-axSpA and provide fresh insights into the long-term outcomes for patients, with data that may aid treatment decisions. |
Introduction
Radiographic axial spondyloarthritis (r-axSpA) is a subset of axial spondyloarthritis (axSpA), which is the main form of chronic inflammatory arthritis that affects the axial skeleton [1]. The 2022 update of the Assessment of SpondyloArthritis International Society (ASAS)–European Alliance of Associations for Rheumatology recommendations for the treatment of r-axSpA and nonradiographic axSpA recommends tumor necrosis factor inhibitors (TNFi) such as etanercept (ETN) for adults with active axSpA despite treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) [2].
Seven short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that treatment with ETN is effective and well tolerated in patients with r-axSpA [3,4,5,6,7,8,9]. The efficacy and safety of ETN has been shown to be maintained for up to 7 years after the start of treatment [10]. The clinical efficacy and safety of ETN has also been demonstrated in real-world studies, both retrospectively [11] and prospectively [12]. Six of the seven short-term randomized controlled trials (RCTs) of ETN in r-axSpA were designed to demonstrate efficacy of ETN treatment versus a control arm from 12 to 24 weeks. In addition to meeting primary endpoints at the specified timepoints, all six studies reported statistically significant improvements with ETN versus controls at earlier timepoints. The initial phase 2 trial of ETN for r-axSpA reported improvements with ETN 1 month after the start of treatment [3], and four phase 3/4 studies all reported improvements with ETN as early as 2 weeks after treatment initiation [5,6,7, 9]. In the SPINE study, Dougados et al. reported significant improvements with ETN after 8 weeks, with no difference observed between ETN and PBO at weeks 2 or 4; however, this study differed from the others as enrollment was restricted to patients with advanced disease [8].
As the association of early achievement of clinical responses with better long-term outcomes in r-axSpA has been demonstrated [11], this analysis was designed to further investigate the timeframe in which patients achieve clinical responses with ETN. In particular, temporal achievement of initial Assessment in SpondyloArthritis International Society 20 (ASAS20) or initial Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) < 1.3 (inactive disease/best possible response) in patients with r-axSpA randomly assigned to the ETN or control arms was compared across three clinical trials (or index studies). In addition, data from open-label extension (OLE) studies assessed how patients, defined by their different temporal responses (“Early,” “Intermediate,” “Late,” or “Non-response”) in the index studies, responded over the longer term.
Methods
Studies
Index Studies
This post hoc and exploratory analysis used data from three phase 3/4 PBO- or sulfasalazine (SSZ)-controlled RCTs of ETN (25 mg twice weekly or 50 mg once weekly, subcutaneously) for the treatment of r-axSpA, in which the primary endpoint was the proportion of patients achieving ASAS20 response. Patients received ≥ 12 weeks of ETN treatment plus optional stable background therapy (NSAIDs and/or SSZ [a disease-modifying antirheumatic drug (DMARD)], hydroxychloroquine [HCQ], or methotrexate [MTX]).
Study 16.0037 (Protocol 16.0037) was a phase 3, double-blind, 24-week trial that took place from December 2001 to October 2002, in which patients received PBO (n = 139) or ETN 25 mg (n = 138) twice weekly. The primary outcome measures were the percentages of patients achieving ASAS20 at weeks 12 and 24. Although stable doses of NSAIDs were permitted prior to and during the study as per protocol, no NSAID use was reported in this study [5]. Study 311 (NCT00421915) was a phase 3 RCT that took place from March 2002 to August 2002. Patients received ETN 25 mg (n = 45) or matched PBO (n = 39) twice weekly for 12 weeks. Evaluations were performed at weeks 2, 4, 8, and 12; 87% of patients used concomitant oral NSAIDs [6]. Study 402 (NCT00247962) was a phase 4 RCT that took place between December 2005 and February 2008. Patients received ETN 50 mg once weekly (n = 379) or SSZ titrated to a maximum of 3 g/day (n = 187) for 16 weeks. Evaluations were performed at weeks 2, 4, 8, 12, and 16; 84% of patients used concomitant oral NSAIDs. Background SSZ was not permitted [9, 13].
OLE Studies
This analysis used data from the OLE studies of the three respective index studies: Study 16.0040 (NCT00356356; OLE of Study 16.0037), Study 312 (NCT00421980; OLE of Study 311), and Study 405 (NCT00410046; OLE of Study 402). ETN was the only study treatment in the OLE studies. The visits assessed in the OLE studies were month 6 (week 24), month 8 (week 36; week 38 for Study 405), and year 1 (week 48 only for Studies 312 and 16.0040).
Study Design
Index Studies
This exploratory analysis assessed short-term responses by comparing the proportions of patients achieving early, intermediate, late, or no clinical response with ETN versus controls in the three index studies. Patients were categorized according to when they first achieved specific clinical improvement criteria: (1) the ASAS 5/6 criteria, (2) the ASAS40 improvement criteria, (3) improvement in ASDAS-CRP score ≥ 1.1 from baseline, and (4) improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 20 from baseline [14]. The ASAS 5/6 improvement criteria include six domains: patient global, pain, function (assessed by Bath Ankylosing Spondylitis Functional Index [BASFI]), inflammation (mean of BASDAI questions 5 and 6), CRP, and spinal mobility (assessed by lateral spinal flexion). To meet an ASAS 5/6 improvement, there should be an improvement of at least 20% in at least five of these six domains. The ASAS improvement criteria include four domains: patient global, pain, function (assessed by BASFI), and inflammation (mean of BASDAI questions 5 and 6). To meet an ASAS40 response, three of the four domains should improve by at least 40% and a minimum of 2 units on a scale of 0–10. In the remaining domain, there should be no worsening of ≥ 20% and a minimum of 1 unit, on a 0–10 scale. ASDAS improvement was defined as a score change of ≥ 1.1 units (equivalent to a clinically important improvement) on a 0–10 scale. BASDAI improvement was defined as a score change of ≥ 20 on a 0–100 scale [14]. An “Early” response was defined as initially occurring at week 4, and an “Intermediate” response at week 8. A “Late” response was a response initially occurring at week 12 (Studies 16.0037 and 311) or week 16 (Study 402). Patients were categorized as having a “Non-response” if they had not achieved clinical improvement by week 12 (or week 16 for Study 402). The proportions of patients achieving “Early,” “Intermediate,” “Late,” or “Non-response” for ASAS 5/6, ASAS40, ASDAS ≥ 1.1, and BASDAI ≥ 20 were compared between ETN and control arms within each study.
In the analysis of three index studies, patients were categorized according to their time to initial response (ASAS20 or ASDAS-CRP < 1.3) as “Early,” “Intermediate,” “Late,” or “Non-response” defined as described above. The time to initial response categories were subsequently stratified by concomitant DMARD use at baseline (yes vs. no) and by primary (r-axSpA) disease duration (early [< 3 years] vs. late [≥ 3 years]) because these variables are considered to have an effect on r-axSpA disease progression [15].
OLE Studies
Long-term outcomes were analyzed by determining the proportions of patients achieving clinical response in the OLE studies based on their different temporal response (i.e., “Early,” “Intermediate,” “Late,” or “Non-response”) in the corresponding index studies. Clinical response was defined as ASAS20, ASAS40 (including ASAS20), ASDAS-CRP < 1.3, and ASDAS-CRP < 2.1 (including ASDAS-CRP < 1.3) [14]. In addition to the four index response categories, patients were reported according to their corresponding treatment sequences in index/OLE, respectively: ETN/ETN, PBO/ETN, and SSZ/ETN.
The final protocol, any amendments, and informed consent were reviewed and approved by the institutional review boards or institutional ethics committees at each of the investigational centers participating in the study. Details of the ethics committees are available upon request. All patients provided written informed consent for participation in the study. This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines.
Statistical Analyses
Index Studies
This was an exploratory analysis based on observed cases. The analysis population was defined as all patients who had at least one dose of study drug and at least one post-baseline observation of interest. The proportions of patients achieving “Early,” “Intermediate,” “Late,” or “Non-response” in the different treatment arms within each study were compared using Cochran–Mantel–Haenszel tests without adjustment for multiplicity.
OLE Studies
The analysis population of each OLE study was defined as all enrolled patients who received at least one dose of study drug in the OLE study and had data for at least one of the endpoints at month 6. Patients were removed from the analyses if they had an enrollment gap ≥ 12 weeks off study treatment between index and OLE studies.
Each of the four endpoints were analyzed for each OLE study: ASAS20, ASAS40, ASDAS-CRP < 1.3, and ASDAS-CRP < 2.1, reported by index response category and treatment sequence. Endpoints were analyzed at month 6, month 8, and year 1 of the OLE study stratified by four ASAS20 groups as well as by four ASDAS-CRP < 1.3 groups as defined in the index studies. Proportions of month 6, month 8, and year 1 responders and their exact 95% confidence intervals were presented using the Clopper–Pearson exact method. For each OLE study and treatment sequence, the index response categorical variable was tested using a univariate logistic regression model to determine if it predicted the month 6 response, testing the pairwise difference for each response category (“Early,” “Intermediate,” “Late”) versus the “Non-response” group per the treatment sequence, through the index and OLE studies. The same logistic regression models were used for month 8 and year 1 analyses.
The univariate logistic regression models were not adjusted for any covariates, as previous analyses showed no association between the possible covariates such as concomitant DMARDs use at baseline (Y/N) or disease duration (< 3 years vs. ≥ 3 years) and the index study response categorical variable.
Results
Index Studies
Within each index study, patient responses differed significantly between the ETN and control arms for achievement of ASAS 5/6 (Fig. 1A), ASAS40 (Fig. 1B), improvement in ASDAS ≥ 1.1 (Fig. 1C), and improvement in BASDAI ≥ 20 (Fig. 1D).
Within each index study, the proportion of patients who achieved either “Early” ASAS20 (Fig. 2A) or “Early” ASDAS-CRP < 1.3 (Fig. 2B) was greater in the ETN arms compared with the control arm (SSZ or PBO), and the difference among response categories was significant between treatment groups. Across the three index studies, 50–65% of patients in the ETN arms and 13–41% of patients in the control arms achieved “Early” ASAS20 response, with lower proportions achieving “Intermediate” or “Late” ASAS20 responses (Fig. 2A). The proportions of patients who achieved “Early” ASDAS-CRP < 1.3 response was 12–24% in the ETN arms and ≤ 4% in the control arms, while those for patients achieving “Intermediate” or “Late” ASDAS-CRP < 1.3 responses were similar between treatments (Fig. 2B).
Overall, 50–59% and 48–74% of patients with concomitant DMARD use (yes vs. no, respectively) achieved “Early” ASAS20 response in the ETN treatment arms, compared with 13–28% and 13–43% of patients, respectively, in the control arms (Fig. 3A). For patients stratified by primary disease duration (< 3 years vs. ≥ 3 years), 44–83% and 52–62% of patients achieved “Early” ASAS20 response in the ETN treatment arms compared with 10–44% and 14–40%, respectively, of patients in the control arms (Fig. 3B).
“Early” ASDAS-CRP < 1.3 response was achieved by 6–26% and 15–23% of patients with concomitant DMARD use (yes vs. no, respectively) in the ETN treatment arms compared with ≤ 6% and ≤ 5% of patients, respectively, in the control arms (Fig. 4A). Similarly, a higher proportion of patients achieved “Early” ASDAS-CRP < 1.3 response in the ETN treatment arms, when stratified by primary disease duration (< 3 years vs. ≥ 3 years): 17–22% versus 11–27% of patients, respectively, compared with ≤ 5% versus ≤ 4% of patients in the control arms (Fig. 4B).
OLE Studies
In general, the proportion of responders in the OLE studies was high for “Early” and “Intermediate” responders based on the index studies. The proportions of patients with ASAS20 response were 87–100% and 69–100% for “Early” and “Intermediate” responders, respectively, in OLE studies 16.0040 and 312 based on their ASAS20 response category in the corresponding index study (Study 16.0037 and Study 311, respectively) and were 67–83% (“Early”) and 0–100% (“Intermediate”) for Study 405 (Fig. 5). The proportion of ASAS20 response was 50–80% for “Late” responders in Study 16.0037 (OLE Study 16.0040), and amongst those patients in the ASAS20 “Non-response” category in the index studies the proportions ranged from 33 to 68% across OLE Studies 16.0040 and 312.
The proportions of patients with ASAS20 response were 75–100% for both “Early” and “Intermediate” responders in all three OLE studies based on their ASDAS-CRP < 1.3 response category in the corresponding index study (Fig. 6). The proportion of ASAS20 was 50–100% for “Late” responders, and amongst those patients in the ASDAS-CRP < 1.3 “Non-response” category in the index studies the proportions ranged from 62 to 83% in Studies 16.0037 (OLE Study 16.0040) and 311 (OLE Study 312), at the timepoints analyzed.
A similar pattern was seen for all other parameters (Supplementary Tables 1–6). The proportion of responders in the OLE studies ranged from 25 to 83% for the different measures shown in Figs. 5 and 6 for the “Non-response” category from index studies.
Discussion
Although studies of ETN and other anti-TNFs have shown early responses in patients with r-axSpA, long-term data assessing outcomes of anti-TNF therapy following early response or non-response are lacking. This analysis investigated the timeframe in which patients achieved clinical responses with ETN. In particular, temporal achievement of initial ASAS20 (minimal response) or initial ASDAS-CRP < 1.3 (inactive disease/best possible response) in patients with r-axSpA randomly assigned to the ETN or control arms was compared across three clinical trials (or index studies). In addition, data from the OLE studies assessed how patients defined by their different temporal responses (“Early,” “Intermediate,” “Late,” or “Non-response”) in the index studies responded over the longer term.
In the current analyses, the better clinical response to ETN among patients with r-axSpA in the index studies was particularly reflected by significantly greater proportions of ETN-treated patients achieving early ASAS20 or early ASDAS-CRP < 1.3. The proportion of patients with no response to treatment was smaller in the ETN arms than the control arms throughout the three studies analyzed. There were no clear differences in early response rates between patients who did and did not use concomitant DMARDs, or between patients with early (< 3 years) or late (≥ 3 years) primary disease duration. Regardless of DMARD use or primary disease duration, more patients taking ETN achieved an early ASAS20 response compared with the control arms. Previous analysis of pooled data from the index studies described here found that very high baseline CRP is predictive of response to treatment [16]. In the long-term OLE studies, overall, early response appeared to be associated with long-term response. However, where no response had occurred in the index studies, continued treatment led to a response in a large proportion of patients.
In a small, double-blind RCT (n = 30) in patients with active r-axSpA, treatment with ETN led to ≥50% regression of disease activity (BASDAI50) in 57% of patients at week 6 compared with 6% of PBO-treated patients (p = 0.004) [4]. ASAS20 was 79% (ETN) versus 25% (PBO) after 6 weeks [4]. In a study in patients with advanced r-axSpA, after 12 weeks of treatment ASAS 5/6 was 21% (ETN) versus 5% (PBO), p = 0.044; ASAS40 was 44% (ETN) versus 23% (PBO), p = 0.053; and improvement in ASDAS ≥1.1 was 64% (ETN) versus 17% (PBO), p < 0.0001 [8]. Change in BASDAI over time first showed a significant difference between ETN and PBO at week 8 (− 26.1 ± 19.8 vs. − 13.6 ± 19.7; p = 0.005), and this was sustained until week 12 (− 26.4 ± 19.8 vs. − 14.4 ± 19.7; p = 0.008) [8].
In an RCT of ETN and SSZ in patients with r-axSpA from Eastern/Central Europe, Latin America, and Asia, the proportion of patients achieving ASAS40 and ASAS 5/6 increased from week 2 to week 16 in both the ETN (34 vs. 65% for ASAS40 and 33 vs. 48% for ASAS 5/6) and the SSZ (6 vs. 35% and 4 vs. 26%, respectively) treatment groups [17]. By week 16, the proportion of patients achieving 50% improvement in BASDAI (BASDAI50) was significantly greater (p < 0.001) in the ETN group (66%) than the SSZ group (42%) [17].
In a study of 40 patients with r-axSpA, 80% of patients treated with ETN showed improvement at 4 months compared with 30% in patients who received PBO; separation between groups was observed at 1 month, but significance was not reported [3]. In another study, patients with r-axSpA were randomly assigned to receive infusions of PBO or 5 mg/kg infliximab (INF) at weeks 0, 2, 6, 12, and 18 [18]. Clinical benefit was observed in patients receiving INF as early as week 2, and this was maintained over the 24-week study [18].
A multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study evaluated adalimumab (ADL) versus PBO for 24 weeks in patients with r-axSpA [19]. At week 12, 58.2% of ADL-treated patients achieved an ASAS20 response, compared with 20.6% of PBO-treated patients (p < 0.001). Significance between groups was reported as early as week 2 [19]. A comparison of INF versus PBO described by Barkham and co-authors [20] showed that the mean reduction in BASDAI score at 16 weeks was significantly greater in the INF group (– 3.41) than in the PBO group (– 0.75) (p = 0.002) [20].
Two 14-week studies of golimumab (GOL) versus PBO reported that ASAS20 separation between groups occurred as early as week 4 [21] and week 2 [22, 23], and in a retrospective study with no control, early changes in disease activity outcomes occurred with three TNFis (ETN, ADL, and INF; Bath AS Metrology Index [BASMI10]) [11].
Other studies of patients with nonradiographic axSpA (nr-axSpA) and r-axSpA have reported similar data. For example, in a phase 3 trial including patients with r-axSpA or nr-axSpA, ASAS20 response at week 12 was significantly higher with certolizumab pegol versus PBO, with improvements observed as early as week 1 [24]. In a study of patients with early, active axSpA including r-axSpA, patients were randomly assigned (2:1) to receive naproxen (NPX) plus either INF or PBO at weeks 0, 2, 6, 12, 18, and 24 [25]. A greater percentage of patients achieved ASAS partial remission (ASAS-PR) in the INF+NPX group (61.9%; 65/105) than in the PBO+NPX group (35.3%; 18/51) at week 28 (p = 0.002) and at all other visits, and improvements with INF+NPX versus PBO+NPX were first seen at week 2 [25]. In patients with nr-axSpA, a significantly greater proportion of those in the ETN group achieved ASAS40 response by week 12 than those in the PBO group, and the response was achieved as early as week 2 of treatment (p < 0.01) [26]. In patients with active axSpA, PBO versus ADL was administered for 12 weeks, followed by an OLE that continued up to week 52 [27]. At week 12, an ASAS40 response was achieved by 54.5% of the ADL-treated patients, compared with 12.5% of the PBO group (p = 0.004), and efficacy was maintained in all patients until week 52 [27].
In a study on the efficacy and safety of ADL in patients with nr-axSpA, a significantly greater percentage treated with ADL achieved the primary endpoint of ASAS40 response at week 12 (33/91, 36%) compared with patients treated with PBO (14/94, 15%; p < 0.001) [28]. In another study of patients with nr-axSpA, the percentage of patients achieving ASAS20 response at week 16 was significantly higher in the GOL group versus PBO (71.1 vs. 40.0%; p < 0.0001). Marked improvements (p < 0.0001) were observed in BASDAI and ASDAS at week 4 after one injection of GOL [29].
Limitations
The main limitations of this exploratory analysis were the relatively small numbers of patients in Study 311 and in the subgroup of patients who used DMARDs across all studies. There were considerably fewer participants included in the OLE Study 405 than the corresponding index study (Study 402) since it was conducted only in a subset of sites in Nordic countries and the UK. However, we are not aware of any other analysis of this kind in r-axSpA involving a large number of patients, with standardized and well-organized data collection owing to the clinical protocols followed.
Conclusions
These findings add to the body of literature on the efficacy of anti-TNF therapy in r-axSpA and provide new insights into the long-term outcomes for patients, with data that may help treatment decisions for patients and prescribers. The percentage of patients who had long-term responses was high for those who had early responses in index studies, although a lack of an early response did not necessarily preclude a future response in the long term.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
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Acknowledgements
The authors would like to thank all patients, investigators, and medical personnel who participated in the original clinical studies that led to this analysis. We acknowledge the valuable contributions made to the design of this study by Cinzia Curiale of Pfizer Italy.
Medical Writing/Editorial Assistance
Medical writing support was provided by Lorna Forse, PhD, of Engage Scientific Solutions and David Sunter, PhD, of Engage Scientific Solutions, and was funded by Pfizer.
Funding
Studies 311, 312, 402, and 405 were funded by Wyeth. Studies 16.0037 and 16.0040 were funded by Immunex. Pfizer funded the Rapid Service Fee.
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XB, AES, KKK, BV, and CEB made substantial contributions to the drafting of the manuscript, interpretation of data, and have substantively revised the manuscript. All authors read and approved the final manuscript and have agreed to be personally accountable for their contributions.
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X. Baraliakos: Research Support: AbbVie, Novartis, MSD; Consultant, Speakers Bureau, Scientific Advisory Board, and Honoraria: AbbVie, Amgen, BMS, Chugai, Galapagos, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, UCB; A.E. Szumski: was an employee of Syneos Health and was contracted by Pfizer to provide statistical support for the development of this paper; K.K. Kwok, B. Vlahos, C.E. Borlenghi: employees of Pfizer and hold stock in Pfizer.
Ethical Approval
The final protocol, any amendments, and informed consent were reviewed and approved by the institutional review boards or institutional ethics committees at each of the investigational centers participating in the study. Details of the ethics committees are available upon request. All patients provided written informed consent for participation in the study. This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines.
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Baraliakos, X., Szumski, A.E., Kwok, K.K. et al. Long-term Etanercept Response for Patients with Radiographic Axial Spondyloarthritis Based on Achievement of Early, Intermediate, or Late Responses During Index Studies. Rheumatol Ther 11, 583–597 (2024). https://doi.org/10.1007/s40744-024-00656-3
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DOI: https://doi.org/10.1007/s40744-024-00656-3