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Abstract
Objective There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients’ baseline MRI and CRP status.
Methods C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP−, MRI−/CRP+ and MRI+/CRP+).
Results Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI−/CRP+ and MRI+/CRP− patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI–/CRP+: 52.2%, MRI+/CRP–: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI–/CRP+: 62.5%, MRI+/CRP–: 65.2%).
Conclusions In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI−/CRP+ and MRI+/CRP− subgroups.
- Spondylitis, Ankylosing
- Magnetic Resonance Imaging
- Certolizumab pegol
Data availability statement
Data are available on reasonable request. Qualified researchers whose proposed use of the data has been approved by an independent review panel will be given access to anonymised individual participant data and redacted study documents. Additional information is available at www.clinicalstudydatarequest.com.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Many local and regional authorities require patients diagnosed with non-radiographic axial spondyloarthritis (nr-axSpA) to show active sacroiliitis on MRI and/or an elevated and C-reactive protein (CRP) level for them to be considered for tumour necrosis factor inhibitor (TNFi) treatment.
WHAT THIS STUDY ADDS
This post hoc analysis of the C-axSpAnd trial (NCT02552212) evaluated the efficacy of certolizumab pegol (CZP) in patients with nr-axSpA stratified into subgroups based on the presence of active sacroiliitis on MRI and CRP level at baseline. It is, to our knowledge, the first analysis to assess long-term (3-year) clinical outcomes in TNFi-treated patients with nr-axSpA according to their baseline MRI/CRP status.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Across all outcome measures, MRI+/CRP+ CZP-treated patients demonstrated numerically higher clinical responses at Week 156 compared with MRI−/CRP+ and MRI+/CRP− patients, although the magnitude of the differences between subgroups varied between outcomes. However, substantial improvements were also observed in CZP-treated patients who had active sacroiliitis on MRI but had normal levels of CRP (MRI+/CRP−), and in those who did not have active sacroiliitis on MRI but had elevated CRP (MRI−/CRP+). This suggests that patients in all MRI/CRP subgroups assessed in this analysis can receive sustained benefit from CZP treatment.
Introduction
Axial spondyloarthritis (axSpA) is a chronic inflammatory condition affecting the sacroiliac (SI) joints and spine, which is subdivided into non-radiographic (nr-axSpA) and radiographic disease (r-axSpA or ankylosing spondylitis [AS]).1 Patients with nr-axSpA show largely similar clinical characteristics and disease burden to those diagnosed with r-axSpA, often test positive for human leucocyte antigen B27 (HLA-B27) and have inflammatory lesions in the axial skeleton but do not exhibit signs of definitive radiographic sacroiliitis.1 2 If the disease is active, patients with nr-axSpA usually have objective signs of inflammation, such as active inflammation of the SI joints (active sacroiliitis) on MRI and/or elevated levels of C-reactive protein (CRP) above the upper limit of normal (ULN).
Several biologics with different modes of action have demonstrated efficacy and acceptable safety in the treatment of nr-axSpA, including certolizumab pegol (CZP).3–10 CZP is a PEGylated, Fc-free tumour necrosis factor inhibitor (TNFi), indicated for the treatment of adult patients with active axSpA by several regulatory authorities, and is the only FDA-approved TNFi for both AS and nr-axSpA.11 12 Previous studies have shown CZP to be safe and efficacious across the axSpA spectrum, including in patients with nr-axSpA.4–10
However, deciding which patients with nr-axSpA are eligible for therapy can be challenging since the decision relies on a number of clinical, imaging and laboratory features.1 Using objective signs of inflammation, such as active sacroiliitis on MRI and elevated CRP levels, can, therefore, provide well-defined prognostic factors for patient populations who are more likely to benefit from TNFi therapies.
Active sacroiliitis on MRI, often assessed with the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores and/or elevated CRP levels, has been shown to be correlated with disease progression and are predictors of response to TNFi therapy.13–20 Patients with nr-axSpA who lack elevated CRP or sacroiliitis on MRI, especially those who lack both objective signs of inflammation, have also been shown to be less likely to respond to TNFi treatment or to progress to r-axSpA.19 20 As a result, many local and regional authorities require patients diagnosed with nr-axSpA to show active sacroiliitis on MRI and/or an elevated CRP level for them to be considered for TNFi treatment.11 12 Understanding the impact of baseline MRI/CRP status on treatment response is therefore important to ensure TNFi treatment is accessible to patients who will benefit from therapy.
Previously reported data demonstrated improvements in clinical outcomes following 52 weeks of CZP treatment for patients who had positive MRI and/or CRP status at baseline.21 There remains, however, a paucity of data on the long-term response to biological treatment in patients with nr-axSpA stratified by baseline MRI/CRP status, particularly from interventional controlled studies. This presents an unmet need, since long-term suppression of inflammation and the prevention of structural damage are important goals for the treatment of nr-axSpA.22 23 Here, we report clinical outcomes to Week 156 of the C-axSpAnd study, stratified by patients’ baseline MRI/CRP status, with a focus on the 2-year safety follow-up extension (SFE) that occurred from Week 52 to Week 156.
Patients and methods
Study design and patients
C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated CZP 200 mg every 2 weeks in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. Eligible patients were ≥18 years of age with confirmed adult-onset nr-axSpA meeting the Assessment of SpondyloArthritis international Society (ASAS) classification criteria,24 but without radiographic sacroiliitis meeting the modified New York classification criteria.25 For inclusion, patients were required to have ≥12 months symptom duration and active disease at screening (defined as a Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]26 score of ≥4 and spinal pain score of ≥4 on a 0–10 scale). Patients were also required to have objective signs of inflammation, that is, either active sacroiliitis at screening (according to the 2009 ASAS definition of MRI positivity)27 or a baseline CRP level above 10.0 mg/L. CRP levels were determined by a central laboratory which used a cut-off of 10.0 mg/L as the ULN. Pelvic radiographs and MRI scans were read centrally by two readers and an adjudicator; patients were categorised as MRI+ if they had active inflammation on MRI that was highly suggestive of sacroiliitis associated with spondyloarthritis as determined by the central readers. Patients were classified as CRP+ if their CRP measurement at their second screening visit was classified above 10 mg/L; patients were classified as CRP− if their CRP level was ≤10 mg/L. In the unlikely event that a patient had an unavailable recorded CRP result prebaseline, they were considered CRP+ for analyses of efficacy but missing for other CRP summaries.
Enrolled patients entered a 52-week, double-blind period in which they were randomised 1:1 to CZP (400 mg loading dose at Weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo, in addition to their current non-biological background medication (NBBM). If the investigator deemed that a patient’s disease activity required escalation treatment, patients in both groups could make changes to their NBBM or switch to open-label CZP at any time during the study. At Week 52, patients from both treatment groups (including those who had switched to open-label CZP) who had completed the double-blind period and consented to enter the SFE received open-label CZP 200 mg every 2 weeks for an additional 104 weeks on top of their NBBM. Therefore, CZP-randomised patients who finished the SFE received CZP for the entire duration of the trial (3 years), while placebo-randomised patients could receive CZP for 2–3 years, depending on when they switched from placebo to CZP. During the SFE, clinical outcomes were assessed at Weeks 52 and 156 only.
Full details of the C-axSpAnd study design and patient inclusion criteria have been reported previously.10
Outcomes
The primary objective of the C-axSpAnd SFE was to assess the long-term safety of CZP treatment; these results have been reported previously.28 In this post hoc analysis, outcomes are reported to Week 156 of the C-axSpAnd trial (with Weeks 52–156 representing the SFE) for patients stratified into subgroups according to their MRI and CRP status at baseline, that is, Week 0 (MRI+/CRP−, MRI−/CRP+ and MRI+/CRP+; due to the inclusion criteria of the C-axSpAnd trial, patients who were MRI−/CRP− at baseline were not eligible to take part in the study).
The following outcomes are reported at Weeks 52 and 156: ASAS≥40% response (ASAS40); BASDAI ≥50% response (BASDAI50); patients achieving a major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI; ≥2.0-point decrease from baseline or lowest possible score [0.6]); ASDAS; BASDAI; Bath Ankylosing Spondylitis Functional Index (BASFI); SPARCC MRI SI joint inflammation score; Patient Global Assessment of Disease Activity (PGADA); nocturnal spinal pain; total spinal pain Numerical Rating Scale; the Ankylosing Spondylitis Quality of Life (ASQoL) score (with a scale of 0–1) and ASDAS disease states. ASDAS disease states were defined as follows: very high disease activity (vHDA): ASDAS >3.5; HDA: ASDAS ≥2.1 to ≤3.5; low disease activity (LDA): ASDAS <2.1; inactive disease (ID): ASDAS <1.3.
Additionally, in the subset of patients who had achieved MRI remission (defined as SPARCC score=0) and/or CRP remission (defined in this analysis as CRP <5 mg/L, chosen to represent a 50% reduction from the CRP ULN used in this study; many other laboratories also use 5 mg/L as their ULN) at Week 52 (beginning of the SFE), we report the proportion of patients achieving ASAS40, ASDAS-MI and mean BASDAI and BASFI change from baseline at Week 156.
Statistical analysis
Data are reported for all patients who entered the C-axSpAnd SFE at Week 52. Outcomes were compared numerically across both the CZP-randomised and placebo-randomised treatment arms for each patient subgroup. Dichotomous outcomes were calculated relative to study baseline (Week 0) at Weeks 52 and 156 and are reported as observed case (OC) and using non-responder imputation (NRI). Because of the 2-year gap in data collection between Weeks 52 and 156, continuous outcomes are reported as OC only.
Results
Patient disposition and baseline characteristics
Of the 159 patients randomised to CZP at baseline, 120 (75.5%) consented to enter the SFE at Week 52; 36/120 (30.0%) were MRI+/CRP+ at baseline, 32/120 (26.7%) were MRI–/CRP+ and 52/120 (43.3%) were MRI+/CRP–. In total, 123/158 (77.8%) patients randomised to placebo at baseline consented to enter the SFE; 30/123 (24.4%) were MRI+/CRP+ at baseline, 34/123 (27.6%) were MRI–/CRP+ and 59/123 (48.0%) were MRI+/CRP–.
Patients could switch to open-label CZP at any time during the blinded period of the study (Weeks 0–52; online supplemental table 1, figure 1). 10/120 (8.3%) CZP-randomised patients who entered the SFE had switched to open-label CZP during the double-blind period; the other 110/120 (91.7%) had completed the CZP treatment blinded. Of the 158 patients in the placebo-randomised group, 96 patients switched to open-label CZP during the double-blind period, with the average (mean (SD)) time between initial randomisation and switching to open-label CZP being 18.0 (6.4) weeks. In the placebo-randomised group that entered the SFE, 75/123 (61.0%) had switched to open-label CZP before Week 52; the remaining 48/123 (39.0%) patients completed the double-blind period on placebo. Consequently, by the end of the blinded period (Week 52), across all patients who entered the SFE, 110/243 (45.3%) were receiving CZP blinded, 85/243 (35.0%) were receiving open-label CZP, and 48/243 (19.8%) completed the entire double-blind period on placebo. Baseline demographics and disease characteristics by Week 52 are given in online supplemental table 2; patients who completed the double-blind period on placebo had a longer mean disease duration and generally lower disease activity at baseline compared with those who were initially randomised to placebo but switched to open-label CZP. At Week 52, all patients who entered the SFE (both CZP randomised and placebo randomised) switched to open-label CZP.
Supplemental material
In total, 102/120 (85.0%) patients from the CZP-randomised group and 104/123 (84.6%) from the placebo-randomised group completed the SFE to Week 156 (online supplemental table 1, figure 1). In the MRI+/CRP+ subgroup, 30/36 (83.3%) of CZP-randomised patients and 25/30 (83.3%) of placebo-randomised patients completed the SFE. Among MRI−/CRP+patients, 25/32 (78.1%) and 30/34 (88.2%) in CZP-randomised and placebo-randomised groups finished the SFE, respectively. In the MRI+/CRP− subgroup, SFE was completed by 47/52 (90.4%) CZP-randomised patients and 49/59 (83.1%) placebo-randomised patients.
Baseline characteristics stratified by MRI/CRP status for patients who entered the SFE are shown in table 1.
Baseline (Week 0) patient demographics and characteristics for patients participating in the safety follow-up extension study stratified by MRI/CRP status
Treatment response by MRI/CRP subgroup
At both Weeks 52 and 156, ASDAS-MI responses were highest in the MRI+/CRP+ subgroup, followed by the MRI–/CRP+ and MRI+/CRP− subgroups, as expected given the weight of CRP in the calculation of ASDAS. In the CZP-randomised group, ASDAS-MI response rates (from Week 0) were generally sustained at Week 156 compared with Week 52 across all MRI/CRP subgroups. In the placebo-randomised group, after all patients switched to CZP at Week 52, the placebo-randomised group had comparable or higher ASDAS-MI values than the CZP-randomised group at Week 156 in the MRI+/CRP+ and MRI−/CRP+subgroups, and lower ASDAS-MI values in the MRI+/CRP− subgroup (figure 1).
The proportion of patients achieving ASDAS-MI stratified by baseline MRI/CRP status. Data are reported for patients entering the SFE at Week 52; OC and NRI data at Week 156 reported. MRI+ was defined according to the 2009 ASAS definition,27 and CRP+ was defined as baseline CRP level above 10.0 mg/L. PBO-randomised patients include patients who switched to open-label CZP before Week 52; all PBO randomised patients switched to open-label CZP at Week 52. ASDAS, Ankylosing Spondylitis Disease Activity Score; ASDAS MI, Ankylosing Spondylitis Disease Activity Score Major Improvement (reduction of ≥2 units from baseline or lowest possible score (0.6)); CRP, C-reactive protein; CZP, certolizumab pegol; NRI, non-responder imputation; OC, observed case; PBO, placebo; Q2W, every 2 weeks; SFE, safety follow-up extension.
Across all MRI/CRP subgroups, ASAS40 responses were generally sustained to Week 156 compared with Week 52 in CZP-randomised patients who entered the SFE (MRI+/CRP+: 29/36 (80.6%) at Week 52 vs 20/26 at Week 156 (76.9%); MRI–/CRP+: 18/32 (56.3%) vs 15/24 (62.5%); MRI+/CRP–: 37/52 (71.2%) vs 30/46 (65.2%)). In placebo-randomised patients across all MRI/CRP subgroups, ASAS40 responses (from Week 0) maintained improvement to Week 156 (MRI+/CRP+: 20/30 (66.7%) at Week 52 vs 18/25 (72.0%) at Week 156; MRI–/CRP+: 17/34 (50.0%) vs 22/29 (75.9%); MRI+/CRP–: 28/59 (47.5%) vs 29/46 (63.0%); online supplemental figure 2). Similar results were seen for BASDAI50 for CZP-randomised patients (online supplemental figure 3).
Improvements in continuous outcomes such as ASDAS, BASDAI, BASFI, PGADA, SI-SPARCC and ASQoL scores at Week 52 (vs baseline) for the CZP-randomised group were sustained at Week 156 (figure 2, online supplemental figure 4,5, table 2), across all MRI/CRP subgroups. In patients randomised to placebo at baseline, including those who subsequently switched to open-label CZP in the double-blind period, numerical decreases in continuous clinical outcomes were also observed at Week 52 compared with Week 0 in all MRI/CRP subgroups. Additional decreases in these scores or sustained responses were observed at Week 156.
Mean ASDAS scores stratified by baseline MRI/CRP status. Mean values for clinical outcomes at Weeks 0, 52 and 156. OC data reported. MRI+ was defined according to the 2009 ASAS definition,27 and CRP+ was defined as baseline CRP level above 10.0 mg/L. PBO-randomised patients include patients who switched to open-label CZP before Week 52; all PBO-randomised patients switched to open-label CZP at Week 52. ASDAS, Ankylosing Spondylitis Disease Activity Score; CRP, C-reactive protein; CZP, certolizumab pegol; OC, observed case; PBO, placebo; Q2W, every 2 weeks.
Clinical outcomes stratified by baseline (Week 0) MRI/CRP status
In all MRI/CRP subgroups, the proportion of patients who achieved ASDAS LDA (<2.1) at Week 52 (LDA; including those with ID) was numerically higher for the CZP-randomised group (figure 3). At Week 156, a greater proportion of patients in the MRI+/CRP+ and MRI+/CRP− subgroups achieved ASDAS LDA or ID compared with patients in the MRI−/CRP+ subgroup (CZP randomised: 77.0% MRI+/CRP+, 71.8% MRI+/CRP−, compared with 56.5% MRI−/CRP+; placebo randomised: 72.0% MRI+/CRP+, 69.6% MRI+/CRP−, compared with 60.7% MRI−/CRP+).
The proportion of patients in each ASDAS disease state stratified by baseline MRI/CRP status. OC data reported. ASDAS scores used to assign disease activity were as follows: vHDA: >3.5; HDA: ≥2.1–≤3.5; LDA: ≥1.3–2.1; ID: <1.3. MRI+ was defined according to the 2009 ASAS definition,27 and CRP+ was defined as baseline CRP level above 10.0 mg/L. ASAS, Assessment of SpondyloArthritis international Society; ASDAS, Ankylosing Spondylitis Disease Activity Score; CRP, C-reactive protein; CZP, certolizumab pegol; HDA, high disease activity; ID, inactive disease; LDA, low disease activity; MRI, magnetic resonance imaging; OC, observed case; PBO, placebo; Q2W, every 2 weeks; vHDA, very HDA.
Treatment response in patients who were in MRI and/or CRP remission at Week 52
Of the total 120 CZP-randomised patients who entered the SFE, 76 (63.3%) were in MRI and/or CRP remission (defined as MRI SPARCC=0 or CRP <5 mg/L) at Week 52 (MRI+/CRP+: 21/36, 58.3%; MRI−/CRP+: 18/32, 56.3%; MRI+/CRP−: 37/52, 71.2%); of the total 123 placebo-randomised patients who entered the SFE, 27 (22.0%) had achieved MRI and/or CRP remission at Week 52 (MRI+/CRP+: 2/30, 6.7%; MRI−/CRP+: 10/34, 29.4%; MRI+/CRP−: 15/59, 25.4%). ASAS40 and ASDAS-MI response rates were higher or comparable in the subgroup of patients who achieved either MRI or CRP remission at Week 52 (figure 4) compared with the total SFE population (figure 1; online supplemental figure 2).
Clinical outcomes at Week 156 in patients who achieved MRI and/or CRP remission at Week 52 stratified by baseline MRI/CRP status. Data are reported for patients who had achieved either MRI or CRP (defined as CRP<5 mg/L) at Week 52; data reported as OC. Full population data for SFE can be found in figure 1. MRI+ was defined according to the 2009 ASAS definition,27 and CRP+ was defined as baseline CRP level above 10.0 mg/L. MRI remission at Week 52 was defined as SPARCC=0; CRP remission at Week 52 was defined as CRP<5 mg/L. ASAS, Assessment of SpondyloArthritis international Society; ASAS40, Assessment of SpondyloArthritis international Society ≥40% improvement; ASDAS-MI, Ankylosing Spondylitis Disease Activity Score Major Improvement (reduction of ≥2 units from baseline or lowest possible score [0.6]); BASDAI, Bath Ankylosing Spondylitis Disease Activity Index ≥50% improvement; BASFI, Bath Ankylosing Spondylitis Functional Index; CfB, change from baseline; CRP, C-reactive protein; CZP, certolizumab pegol; OC: observed case; PBO, placebo; Q2W, every 2 weeks.
Discussion
To our knowledge, this analysis from the C-axSpAnd study is the first to assess long-term (3-year) clinical outcomes in TNFi-treated patients with nr-axSpA according to their baseline MRI/CRP status. Clinical responses to CZP treatment were generally sustained from Week 52 to Week 156 in the patients who entered the SFE across all MRI/CRP subgroups. Across all outcome measures, MRI+/CRP+ CZP-treated patients demonstrated numerically higher clinical responses compared with MRI−/CRP+ and MRI+/CRP− patients, although the magnitude of the differences between subgroups varied between outcomes. However, substantial improvements were also observed in CZP-treated patients who had active sacroiliitis on MRI but had normal levels of CRP (MRI+/CRP−), and in those who did not have active sacroiliitis on MRI but had elevated CRP (MRI−/CRP+). The long-term (3-year) data reported here, together with the previously reported C-axSpAnd Week 52 data21 and short-term data for other TNFi treatments,14 15 29 show the potential efficacy of TNFi treatment in patients with nr-axSpA who are either MRI+ or CRP+but do not meet both of these criteria.
Consistent with previously published Week 52 results,21 in the SFE population, CZP-randomised patients showed numerically better responses at Week 52 compared with placebo-randomised patients across all outcome measures and MRI/CRP subgroups. At Week 156, this varied between different outcomes and subgroups, however, the outcomes in the patients who were initially randomised to placebo and then switched to CZP generally approached those in the CZP-randomised group, as expected due to all patients receiving CZP in the SFE period.
The percentage of patients achieving ASDAS-MI was numerically lower at Week 156 compared with Week 52 across MRI/CRP subgroups (both OC and NRI data); this contrasts with the low mean ASDAS sustained throughout the SFE period. These differences likely reflect the disadvantage of a dichotomous response measure, and are consistent with data previously reported from the C-axSpAnd SFE.28 ASDAS and BASDAI scores are arguably more relevant in clinical practice for disease activity monitoring than change from baseline improvements as measured by ASDAS-MI or ASAS40, which do not necessarily reflect the current status of the patient at a given time point.
The ASDAS-MI response rate was also notably higher in the MRI+/CRP+and MRI−/CRP+ subgroups relative to the MRI+/CRP− subgroup for both the data reported as OC and NRI at Week 156. This was expected given that CRP is weighted heavily in the calculation of ASDAS; due to this, patients with normal CRP at baseline had lower baseline ASDAS, and therefore, less scope to improve through a reduction in CRP.30 It is important to note, consequently, that the role of ASDAS-MI in comparing treatment responses in MRI/CRP patient subgroups is inherently limited. Patients were classified as MRI+ if they had active inflammation on MRI that was highly suggestive of sacroiliitis associated with spondyloarthritis as determined by the central readers. However, applying a different cut-off for MRI positivity would not be expected to notably impact differences in outcomes between subgroups, especially when comparing MRI+/CRP+ and MRI+/CRP− patients.
In this study, patients were able to switch to open-label CZP at any point during the double-blind period (however, no patients switched before Week 12). Outcomes reported for placebo-randomised patients by MRI/CRP subgroup, therefore, include patients who received CZP prior to entering the SFE at Week 52. A notable proportion of patients continued and completed the study despite high or vHDA (out of N=194 patients who completed the SFE across all subgroups, 25.3% had ASDAS HDA and 6.2% had ASDAS vHDA at Week 156). The reasons for these patients not choosing to discontinue participation may include receiving benefits that the measured outcomes do not capture, or the psychological benefit of participating in a study and being professionally observed via follow-ups. It is also possible for the self-reported measures included in BASDAI and ASDAS to capture other factors not directly caused by axSpA.
In this study, all MRI measurements were assessed by experienced readers, with the screening radiographs and MRIs being assessed centrally by two experienced readers and an adjudicator. This helped to ensure patients’ baseline MRI statuses were correctly categorised and that only patients with nr-axSpA according to absence of definite radiographic sacroiliitis on their pelvic X-rays were included in the C-axSpAnd study. One limitation of this analysis, however, was that clinical assessments were only performed at Weeks 52 and 156 during the SFE; as no assessments were made in the intervening period, clinical improvements at additional time points cannot be inferred. Despite this, clinical outcomes at Week 156 suggest that efficacy after 1 year was sustained at 3 years in patients who continued CZP treatment in all MRI/CRP subgroups. Another limitation of this study is the exclusion of patients who are MRI–/CRP– at baseline; clinical outcomes in this patient group should be studied to further build the body of evidence for optimal nr-axSpA treatment-prescribing criteria. In addition, it would be of interest to further study the progression of structural lesions on MRI and compare it between patients who do and do not achieve remission of inflammation. Finally, we have not reported incidence of adverse events related to SpA, such as psoriasis, IBD and uveitis. Incidence of such adverse events over the 156 weeks C-axSpAnd SFE has been reported previously28—as these extra musculoskeletal manifestations were uncommon, there was no pattern to imply a trend of these adverse events in any MRI/CRP subgroup.
In conclusion, in patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI−/CRP+and MRI+/CRP− subgroups. This suggests that patients in all MRI/CRP subgroups assessed in this analysis can receive sustained benefit from CZP treatment.
Supplemental material
Data availability statement
Data are available on reasonable request. Qualified researchers whose proposed use of the data has been approved by an independent review panel will be given access to anonymised individual participant data and redacted study documents. Additional information is available at www.clinicalstudydatarequest.com.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and the study protocol, amendments and patient-informed consent were reviewed by a national, regional, or independent ethics committee (IEC) or institutional review board (IRB). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors thank the patients, investigators and their teams who took part in this study. The authors also acknowledge Jane Spingardi, DPhil and Alexandra Vasilyeva, DPhil, from Costello Medical, UK, for medical writing and editorial assistance based on the authors’ input and direction. This study was funded by UCB Pharma. This article is dedicated to the memory of our colleague Professor Dr Philip Robinson who passed away in January 2023, during development of this manuscript. His contributions to this analysis were invaluable and he will be greatly missed by the authors, as well as the wider rheumatology community.
References
Supplementary materials
Supplementary Data
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Footnotes
X @walter maks
Contributors Substantial contributions to study conception and design: MR, AD, LB, LG, BH, TK, SEA, MK and WM; substantial contributions to analysis and interpretation of the data: MR, AD, LB, LG, BH, TK, SEA, MK and WM; drafting the article or revising it critically for important intellectual content: MR, AD, LB, LG, BH, TK, SEA, MK and WM; final approval of the version of the article to be published: MR, AD, LB, LG, BH, TK, SEA, MK and WM; manuscript guarantor: MK.
Funding This study was sponsored by UCB Pharma. This article was based on the C-axSpAnd study (NCT02552212) sponsored by UCB Pharma. Support for third-party writing assistance for this article, provided by Costello Medical, UK, was funded by UCB Pharma in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Competing interests MR: Personal fees from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, and UCB Pharma. AD: Speaker for Janssen, Novartis, and Pfizer; consulting fees from AbbVie, Amgen, Aurinia, Bristol Myers Squibb, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma; research grants from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Moonlake, Novartis, Pfizer, and UCB Pharma. LB, BH, TK, SEA and MK: Employees and stockholders of UCB Pharma. LG: Grants from Novartis and UCB Pharma paid to institution. Consulting fees from AbbVie, Acelyrin, Fresenius Kabi, Janssen, Novartis, Pfizer and UCB Pharma. WM: Honoraria/consulting fees from AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma; research grants from AbbVie, Pfizer and UCB Pharma; educational grants from AbbVie, Janssen, Novartis and Pfizer; Chief Medical Officer for CARE Arthritis.
Provenance and peer review Not commissioned; externally peer reviewed.
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