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The human leukocyte antigen (HLA)-B27 is associated with axial spondyloarthritis (axSpA) and is a predictor of response to tumor necrosis factor inhibitors. However, limited data are available on HLA-B27 and interleukin-17 inhibitors. We evaluated the influence of HLA-B27 status on ixekizumab response through 52 weeks in patients with axSpA.
Methods
Data were analyzed from three randomized placebo-controlled trials: COAST-V (NCT02696785), COAST-W (NCT02696798), and COAST-X (NCT02757352). Patients fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria for radiographic (r)-axSpA or non-radiographic (nr)-axSpA. Patients were randomized to receive 80 mg ixekizumab every 2 weeks, 80 mg ixekizumab every 4 weeks, or placebo. This post hoc analysis assessed the intent-to-treat population. The magnitude of benefit was calculated as the value for ixekizumab minus placebo.
Results
Among ixekizumab-treated patients with r-axSpA at week 16, ASAS ≥ 40% improvement (ASAS40) was achieved by 39.6% (n = 118/298) of HLA-B27-positive and 29.3% (n = 12/41) of HLA-B27-negative patients. The magnitude of benefit (ixekizumab–placebo) was 23.5% for HLA-B27-positive and 15.2% for HLA-B27-negative patients. At week 52, 44% of HLA-B27-positive and 31.7% of HLA-B27-negative patients achieved ASAS40. Similar trends were seen for Axial Spondyloarthritis Disease Activity Score low disease activity (ASDAS LDA; < 2.1) and Bath Ankylosing Spondylitis Disease Activity Index ≥ 50% improvement (BASDAI50).
In ixekizumab-treated patients with nr-axSpA at week 16, ASAS40 response was achieved by 41.7% (n = 55/132) of HLA-B27-positive and 28.0% (n = 14/50) of HLA-B27-negative patients. The magnitude of benefit was 19.2% for HLA-B27-positive and 16.0% for HLA-B27-negative patients. At week 52, 52.3% of HLA-B27-positive and 32.0% of HLA-B27-negative patients achieved ASAS40. Similar trends were seen among patients with nr-axSpA for ASDAS LDA and BASDAI50.
Conclusions
In patients with r-axSpA and nr-axSpA, ixekizumab improved response through 52 weeks for both HLA-B27-positive and HLA-B27-negative patients. However, the magnitude of benefit for ixekizumab versus placebo was numerically greater for HLA-B27-positive patients.
Trial Registration
ClinicalTrials.gov identifiers, NCT02696785, NCT02696798, and NCT02757352.
Prior Presentation: Data from this manuscript were previously presented at the European Alliance of Associations for Rheumatology Congress (EULAR 2021) held virtually on June 2–5, 2021.
Key Summary Points
Why carry out this study?
Presence of the major histocompatibility complex allele human leukocyte antigen (HLA)-B27 is widely reported to correlate with development of disease and to predict response to treatment in axial spondyloarthritis (axSpA).
We carried out this study to evaluate the efficacy of ixekizumab in patients with radiographic (r)-axSpA and non-radiographic (nr)-axSpA through up to 52 weeks of treatment stratified by HLA-B27 carrier status.
What was learned from the study?
We demonstrated that ixekizumab improved disease activity outcomes for patients with r-axSpA and nr-axSpA regardless of HLA-B27 status, as assessed by Assessment in SpondyloArthritis international Society ≥ 40% improvement (ASAS40), Axial Spondyloarthritis Disease Activity Score low disease activity (ASDAS LDA [< 2.1]), and Bath Ankylosing Spondylitis Disease Activity Index ≥ 50% improvement (BASDAI50) responses, with greater improvements seen for HLA-B27-positive patients.
Introduction
Axial spondyloarthritis (axSpA) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses [1]. AxSpA comprises two subtypes: radiographic (r-axSpA; historically referred to as ankylosing spondylitis) and non-radiographic (nr-axSpA) [2‐4]. The presence of the major histocompatibility complex allele human leukocyte antigen (HLA)-B27 is widely reported to correlate with susceptibility to axSpA [5‐7]. HLA-B27 fills a prominent role in the Assessment of SpondyloArthritis international Society (ASAS) criteria for axSpA classification, but while the presence of HLA-B27 can be a useful discriminator, it has limitations; up to 25% of patients with axSpA are not HLA-B27 carriers, especially in patients with nr-axSpA [3, 8‐10].
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Prior research has found that HLA-B27 status can predict clinical response to tumor necrosis factor inhibitors (TNFi). Patients who were HLA-B27-positive tended to have better outcomes compared with those who were HLA-B27 negative [11]. However, there is sparse evidence on the ability of HLA-B27 status to predict clinical response to interleukin (IL)-17 inhibitors.
Ixekizumab is a high-affinity IL-17A monoclonal antibody and has demonstrated efficacy in both r-axSpA and nr-axSpA [12, 13]. This report explores the association between HLA-B27 status and response to ixekizumab treatment in three separate clinical trials in patients with r-axSpA or nr-axSpA.
Methods
Study Design
The study designs, including full inclusion/exclusion criteria, treatment protocols, safety outcomes and adverse events, for the COAST-V (NCT02696785), COAST-W (NCT02696798), and COAST-X (NCT02757352) studies have been previously published [12‐14]. Briefly, COAST-V, COAST-W, and COAST-X were phase 3, multicenter, randomized, double-blind, and placebo-controlled trials evaluating the efficacy and safety of ixekizumab in patients with r-axSpA (COAST-V and COAST-W) or nr-axSpA (COAST-X). COAST-V and COAST-W were double-blinded from baseline to week 16; COAST-X was double-blinded from baseline to week 52.
Patients were randomly allocated to receive 80 mg ixekizumab every 2 weeks (Q2W), 80 mg ixekizumab every 4 weeks (Q4W), or placebo via subcutaneous administration. Patients randomized to the ixekizumab treatment regimens were randomized (1:1) to receive either an 80‐mg or 160‐mg starting dose of ixekizumab at week 0. In COAST-V, there was an additional active-reference arm in which patients were treated with 40-mg adalimumab Q2W. At week 16 in the COAST-V and COAST-W studies, patients who initially received adalimumab (COAST-V only) or placebo were re-randomized 1:1 in a double-blinded manner to receive ixekizumab Q2W or ixekizumab Q4W through week 52. In COAST-X, patients could switch to open-label ixekizumab Q2W after week 16 at the discretion of the principal investigator.
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Ethical Approval
COAST-V, COAST-W, and COAST-X (ClinicalTrials.gov identifiers: NCT02696785, NCT02696798, and NCT02757352, respectively) were approved by the institutional review board or ethics committee at each site and were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice Guidelines (CPMP/ICH/135/95). The master ethics committee was Schulman Associates IRB, (Cincinnati, OH, USA). Full listings of investigators and sites are available in previously published manuscript supplements [14, 15, 17]. All patients gave written informed consent before the trials started. No additional ethical approval was sought to conduct the current post hoc analysis.
Patients
Patient eligibility criteria have been described in previous publications [12, 13, 15]. Briefly, eligible patients were ≥ 18 years of age with a diagnosis of axSpA. In COAST-V (N = 341) and COAST-W (N = 316), patients were required to meet ASAS criteria for r-axSpA (with a centrally read radiograph showing sacroiliitis using the modified New York criteria and at least one spondyloarthritis feature; the central reading was conducted by two readers and an adjudicator in case of a discrepancy). In COAST-W, patients were required to have a treatment history for axSpA of at least 12 weeks. In COAST-X (N = 303), patients were required to meet ASAS criteria for nr-axSpA and have a treatment history for axSpA of at least 12 weeks; all magnetic resonance imaging (MRI) scans and radiographs for COAST-X were centrally read. Patients with radiographic sacroiliitis meeting the modified New York criteria were excluded from COAST-X.
Patients in COAST-V and COAST-X were required to be bDMARD (biologic disease-modifying antirheumatic drug)-naïve. In COAST-W, patients were required to have discontinued one or two TNFi therapies because of intolerance or inadequate response.
Assessments
In this post hoc analysis of patients in COAST-V and COAST-W (r-axSpA) and COAST-X (nr-axSpA), we assessed the efficacy of ixekizumab in patient subgroups based on HLA-B27 carrier status (positive/negative) through week 16 and descriptively summarized efficacy response by HLA-B27 status subgroups through week 52.
Efficacy was measured by the proportion of patients who achieved ≥ 40% ASAS improvement (ASAS40), the proportion of patients with an Axial Spondyloarthritis Disease Activity Score (ASDAS) of low disease activity (LDA [defined as < 2.1]), mean change from baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the proportion of patients with ≥ 50% improvement from baseline in the BASDAI score (BASDAI50). We also assessed the mean change from baseline in the Short Form-36 Health Survey Physical Component Summary (SF-36 PCS) score.
Statistical Analysis
Patients in the intent-to-treat population who met protocol eligibility criteria were included in this analysis (i.e., patients with protocol deviations related to inclusion and exclusion criteria were excluded). Data from COAST-V and COAST-W were integrated, and COAST-X data were analyzed separately. In COAST-X, patients who received ixekizumab or placebo could switch to open-label ixekizumab Q2W after week 16 at the discretion of the principal investigator [13]. Patients initially randomized to ixekizumab who switched to open-label treatment were included in analyses for the total ixekizumab group (combined Q4W and Q2W treatment arms).
Baseline demographics, disease characteristics, and MRI results of the spine were described by HLA-B27 status for the placebo and total ixekizumab groups.
We evaluated the proportion of patients who achieved ASAS40, ASDAS LDA, BASDAI50, and the mean change from baseline in BASDAI and SF-36 PCS through week 16, including statistical comparisons versus placebo, and summarized the data through week 52.
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For the integrated COAST-V and COAST-W analyses, the treatment comparison between the ixekizumab treatment arms and placebo at week 16 within each HLA-B27 subgroup was performed using the Cochran–Mantel–Haenszel test for categorical variables, stratified by study, and an analysis of covariance model for continuous variables with baseline value, study, and treatment as variables. For the COAST-X analyses, the treatment comparison between the ixekizumab treatment arms and placebo at week 16 within each HLA-B27 subgroup was performed using Fisher’s exact test for categorical variables and the analysis of covariance model for continuous variables with baseline value and treatment as variables. Missing data were imputed using non-responder imputation and modified baseline observation carried forward for categorical and continuous variables, respectively. The magnitude of benefit was calculated as the response rate or change from baseline for ixekizumab-treated patients minus that for placebo-treated patients at week 16. Analyses were conducted with SAS® version 9.2 or higher (SAS Institute, Cary, NC, USA).
Results
r-axSpA
Baseline Characteristics by HLA-B27 Status
In the integrated COAST-V (bDMARD-naïve patients) and COAST-W (TNFi-experienced patients) data set, 453 patients (88%) were positive for HLA-B27 (total ixekizumab, n = 298; placebo, n = 155) and 62 patients (12%) were negative for HLA-B27 (total ixekizumab, n = 41; placebo, n = 21) (Table 1). Baseline characteristics were similar between HLA-B27-positive and HLA-B27-negative patients, except HLA-B27-positive patients were younger at study entry and approximately 8 years younger at symptom onset relative to HLA-B27-negative patients. Disease activity scores were similar between HLA-B27-positive and HLA-B27-negative patients (Table 1).
Table 1
Baseline demographics and disease characteristics categorized by HLA-B27 status in patients with r-axSpA and nr-axSpA
Baseline characteristic
Patients with r-axSpA (COAST-V/W)
Patients with nr-axSpA (COAST-X)
HLA-B27-positive
HLA-B27-negative
HLA-B27-positive
HLA-B27-negative
Placebo (N = 155)
Total ixekizumab (N = 298)
Placebo (N = 21)
Total ixekizumab (N = 41)
Placebo (N = 71)
Total ixekizumab (N = 132)
Placebo (N = 25)
Total ixekizumab (N = 50)
Age (years)
43.6 (12.0)
43.1 (12.0)
51.1 (12.5)
50.1 (13.3)
38.4 (11.7)
39.5 (13.0)
42.8 (12.7)
44.4 (13.2)
Male, n (%)
133 (86)
241 (81)
18 (86)
30 (73)
33 (47)
68 (52)
5 (20)
23 (46)
BMI (kg/m2)
28.1 (5.6)
27.2 (5.1)
29.5 (6.1)
27.7 (6.2)
27.3 (6.1)
27.4 (5.2)
26.6 (5.0)
28.1 (5.9)
Current smoker, n (%)
54 (35)
96 (32)
2 (10)
12 (29)
13 (18)
26 (20)
8 (32)
15 (30)
Age at symptom onset (years)
25.2 (9.3)
26.3 (8.4)
35.4 (8.4)
34.6 (10.3)
29.2 (10.3)
28.6 (8.9)
32.6 (8.2)
33.0 (10.0)
Duration of symptoms since onset (years)
18.7 (11.8)
17.1 (10.4)
16.0 (9.7)
15.9 (12.4)
9.4 (7.9)
11.4 (10.8)
10.7 (7.9)
11.9 (10.1)
ASDAS score
4.0 (0.8)
4.0 (0.8)
4.3 (0.8)
4.1 (0.7)
3.9 (0.9)
3.9 (0.8)
3.5 (0.9)
3.8 (0.7)
BASDAI score
7.1 (1.2)
7.2 (1.4)
7.6 (1.1)
7.4 (1.4)
7.3 (1.5)
7.1 (1.3)
6.8 (1.6)
7.4 (1.3)
MRI of SIJ SPARCC score ≥ 2,an/Nx (%)
29/70 (41.4)
52/138 (37.7)
1/6 (16.7)
0/3 (0)
34/67 (50.7)
61/130 (46.9)
19/25 (76.0)
31/49 (63.3)
MRI of spine SPARCC score ≥ 2,bn/Nx (%)
61/112 (54.5)
135/225 (60.0)
9/12 (75.0)
3/9 (33.3)
NA
NA
NA
NA
SF-36 PCS score
33.7 (7.5)
33.2 (7.6)
34.0 (7.8)
31.4 (7.7)
31.9 (8.5)
32.9 (6.8)
35.3 (7.9)
32.2 (8.5)
Total ixekizumab = pooled ixekizumab 80 mg every 4 weeks and every 2 weeks. Data are displayed as mean (standard deviation) unless otherwise noted
ASDAS Axial Spondyloarthritis Disease Activity Score, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BMI body mass index, HLA-B27 human leukocyte antigen-B27, MRI magnetic resonance imaging, N number of patients in the analysis population, nr-axSpA non-radiographic axial spondyloarthritis, NA not available, Nx number of patients with non-missing values, r-axSpA radiographic axial spondyloarthritis, SF-36 PCS Short Form-36 Health Survey Physical Component Summary, SIJ sacroiliac joint, SPARCC SpondyloArthritis Research Consortium of Canada
aData displayed for r-axSpA are from patients in COAST-V only; these data were not obtained in COAST-W
bIn COAST-W, only a subset of patients participated in an MRI addendum; these data were not obtained in COAST-X
Efficacy by HLA-B27 Status
Among patients treated with ixekizumab at week 16, 39.6% (n = 118/298) of HLA-B27-positive patients and 29.3% (n = 12/41) of HLA-B27-negative patients achieved an ASAS40 response (Fig. 1A). The magnitude of benefit (difference between ixekizumab and placebo) was 23.5% for HLA-B27-positive patients and 15.2% for HLA-B27-negative patients. For ASDAS, LDA (< 2.1) was achieved at week 16 with ixekizumab by 31.5% of HLA-B27-positive patients and 7.3% of HLA-B27-negative patients (Fig. 1C), with a magnitude of benefit of 21.8% and 7.3%, respectively. Similar results were observed at week 16 for BASDAI50, with a magnitude of benefit of 21.1% for HLA-B27-positive patients and 2.8% for HLA-B27-negative patients (Fig. 2A). Trends were similar for continuous measures at week 16, with a magnitude of benefit for HLA-B27-positive and HLA-B27-negative patients of 1.4 and 0.3, respectively, for mean change from baseline in BASDAI (Fig. 2C) and of 4.5 and 1.9, respectively, for mean change from baseline in the SF-36 PCS score (Fig. 3A).
Fig. 1
ASAS40 (A, B) and ASDAS LDA < 2.1 9 (C, D) response rates by HLA-B27 status (COAST-V/COAST-W [integrated] and COAST-X) using non-responder imputation. In COAST-X, patients receiving PBO could switch to open-label IXE every 2 weeks after week 16 at the discretion of the principal investigator; data collected after the switch were included in the analyses and in the Total IXE arm. p values are based on the Cochran–Mantel–Haenszel test for COAST-V/COAST-W (stratified by study) and on Fisher’s exact test for COAST-X. **p < 0.01, ***p < 0.001 IXE vs. PBO; Δ IXE vs. PBO. ASAS40 Assessment of SpondyloArthritis international Society ≥ 40% improvement, ASDAS LDA Axial SpondyloArthritis Disease Activity Score low disease activity, HLA-B27 human leukocyte antigen-B27, IXE ixekizumab, nr-axSpA non-radiographic axial spondyloarthritis, PBO placebo, r-axSpA radiographic axial spondyloarthritis
BASDAI50 response rates (A, B) and BASDAI change from baseline (C, D) by HLA-B27 status (COAST-V/COAST-W [integrated] and COAST-X) using non-responder imputation. In COAST-X, patients receiving PBO could switch to open-label IXE every 2 weeks after week 16 at the discretion of the principal investigator; data collected after the switch were included in the analyses and in the Total IXE arm. p values are based on the Cochran–Mantel–Haenszel test for COAST-V/COAST-W (stratified by study) and on Fisher’s exact test for COAST-X. **p < 0.01, ***p < 0.001 IXE vs. PBO; Δ IXE vs. PBO. BASDAI50 Bath Ankylosing Spondylitis Disease Activity Index ≥ 50% improvement, HLA-B27 human leukocyte antigen-B27, IXE ixekizumab, nr-axSpA non-radiographic axial spondyloarthritis, PBO placebo, r-axSpA radiographic axial spondyloarthritis
SF-36 PCS change from baseline by HLA-B27 status (COAST-V/COAST-W [integrated] and COAST-X) using modified baseline observation carried forward. In COAST-X, patients receiving PBO could switch to open-label IXE every 2 weeks after week 16 at the discretion of the principal investigator; data collected after the switch were included in the analyses and in the Total IXE arm. p values are based on an analysis of covariance model including baseline value, treatment, subgroup, and treatment-by-subgroup interaction, and in the COAST-V/COAST-W study. **p < 0.01, ***p < 0.001 IXE vs. PBO; Δ IXE vs. PBO. HLA-B27 human leukocyte antigen-B27, IXE ixekizumab, nr-axSpA non-radiographic axial spondyloarthritis, PBO placebo, r-axSpA radiographic axial spondyloarthritis, SF-36 PCS Short Form-36 Health Survey Physical Component Summary
At week 52 among ixekizumab-treated patients, response rates for HLA-B27-positive patients and HLA-B27-negative patients, respectively, were 44% and 31.7% for ASAS40 (Fig. 1A), 38.6% and 24.4% for ASDAS LDA (Fig. 1C), and 39.3% and 31.7% for BASDAI50 (Fig. 2A). Moderate continued improvement was seen between week 16 and week 52 in both the HLA-B27-positive and HLA-B27-negative subgroups for mean change from baseline in BASDAI (Fig. 2C) and for SF-36 PCS change from baseline, where values at week 52 were 7.97 for HLA-B27-positive patients and 5.81 for HLA-B27-negative patients (Fig. 3A).
nr-axSpA
Baseline Characteristics by HLA-B27 Status
Among patients with nr-axSpA in COAST-X, 203 (73%) were positive for HLA-B27 (total ixekizumab, n = 132; placebo, n = 71) and 75 (27%) were negative for HLA-B27 (total ixekizumab, n = 50; placebo, n = 25) (Table 1). Baseline characteristics were similar between HLA-B27-positive and HLA-B27-negative patients, except that HLA-B27-positive patients were younger at study entry and approximately 4 years younger at symptom onset relative to HLA-B27-negative patients, and a higher percentage of HLA-B27-negative patients in the placebo group were women (80%) compared to the other three groups (approximately 50%). Disease activity scores were similar between HLA-B27-positive and HLA-B27-negative patients (Table 1).
Efficacy by HLA-B27 Status
Among patients treated with ixekizumab at week 16, 41.7% (n = 55/132) of HLA-B27-positive patients and 28.0% (n = 14/50) of HLA-B27-negative patients achieved an ASAS40 response (Fig. 1B); the magnitude of benefit was 19.2% for HLA-B27-positive patients and 16.0% for HLA-B27-negative patients. For ASDAS, LDA was achieved at week 16 with ixekizumab by 32.6% of HLA-B27-positive patients and 20.0% of HLA-B27-negative patients (Fig. 1D), with a magnitude of benefit of 22.7% and 0%, respectively. Similar results were observed for BASDAI50, with a magnitude of benefit of 20.0% for HLA-B27-positive patients and 12.0% for HLA-B27-negative patients (Fig. 2B). For mean change from baseline in BASDAI, magnitude of benefit for HLA-B27-positive and HLA-B27-negative patients was 0.9 and 0.7, respectively, (Fig. 2D) and was 2.6 and 3.0, respectively, for mean change from baseline in SF-36 PCS score (Fig. 3B).
At week 52 among ixekizumab-treated patients, response rates for HLA-B27-positive patients and HLA-B27-negative patients, respectively, were 52.3% and 32.0% for ASAS40 (Fig. 1B), 47.7% and 26.0% for ASDAS LDA (Fig. 1D), and 45.5% and 26.0% for BASDAI50 (Fig. 2B). Moderate continued improvement was seen between week 16 and week 52 in both the HLA-B27-positive and HLA-B27-negative subgroups for mean change from baseline in BASDAI (Fig. 2D) and for SF-36 PCS change from baseline, where values at week 52 were 9.48 for HLA-B27-positive patients and 9.13 for HLA-B27-negative patients (Fig. 3B).
Discussion
In this study, we evaluated the response to ixekizumab versus placebo treatment through week 16 and continued response to ixekizumab through week 52 within the subgroups of patients defined by HLA-B27-positive or -negative status. HLA-B27-positive patients were younger at study entry and at symptom onset relative to HLA-B27-negative patients, consistent with previous results showing a younger age of symptom onset in HLA-B27-positive patients [16]. Improvements were seen for ixekizumab versus placebo for both HLA-B27-positive and HLA-B27-negative patients; however, they were more robust for HLA-B27-positive patients. This was also reflected in the magnitude of benefit results, which generally showed numerically greater improvements for ixekizumab versus placebo in the HLA-B27-positive subgroup compared with the HLA-B27-negative subgroup. Continued improvements were seen with ixekizumab dosing through week 52 in both HLA-B27-positive and HLA-B27-negative patients.
One of the challenges of subgroup analysis based on HLA-B27 status in controlled clinical trials has been that relatively few patients with r-axSpA are HLA-B27-negative. As a result, insights from registry studies may be valuable, though the analyses often do not distinguish between r-axSpA and nr-axSpA and mostly pertain to TNFi treatment. A study of 1109 patients with axSpA from the prospective Swiss Clinical Quality Management Registry (831 HLA-B27-positive patients and 278 HLA-B27-negative patients) found a higher risk of TNFi discontinuation in HLA-B27-negative patients even after adjusting for potential confounders [17]. Another study of 21,196 patients with axSpA from 15 European registries found HLA-B27 positivity to be a predictor of ASDAS inactive disease, ASDAS clinically important improvement at 6 months, and drug retention at 12 months after initiating TNFi treatment [18]. A study from the DESIR (DEvenir des Spondylarthropathies Indifférenciées Récentes) cohort found that among several variables examined, only HLA-B27 positivity was independently associated with ASAS40 response after a first TNFi switch at an early stage of axSpA [19]. In a study of 1250 TNFi-naïve patients with axSpA from the Danish DANBIO registry, HLA-B27 negativity was associated with poorer treatment adherence and lower response rates in both nr-axSpA and r-axSpA patients who initiated TNFi treatment [20]. However, this trend is not seen everywhere. A United States study from the Department of Veterans Affairs (VA) Program to Understand the Long-term Outcomes in SpondyloARthritis registry (PULSAR) did not find that HLA-B27 predicted either TNFi persistence or discontinuation in patients with axSpA [21].
Data from controlled clinical trials addressing the role of HLA-B27 status in treatment response are more available for nr-axSpA than for r-axSpA due to higher proportions of HLA-B27-negative patients with nr-axSpA, though as with the registry studies, most analyses pertain to TNFi treatment [17‐19, 21‐23]. In the ABILITY-3 trial of open-label adalimumab therapy in 673 adult patients with nr-axSpA who had objective evidence of inflammation by MRI or elevated high-sensitivity C-reactive protein at screening, HLA-B27 positivity was an independent predictor of remission by week 12 [23]. A randomized clinical trial of certolizumab pegol in 317 patients with nr-axSpA with elevated C-reactive protein and/or active sacroiliitis on MRI at baseline found HLA-B27 positivity to be predictive of long-term (week 52) clinical response [22]. The relationship between HLA-B27 status and response to an IL-17 inhibitor in nr-axSpA was assessed in a post hoc analysis of the phase 3 PREVENT trial with secukinumab [24]. In that study, treatment responses for HLA-B27-positive and HLA-B27-negative patients were comparable to the response rates by HLA-B27 status for patients with nr-axSpA in the ixekizumab COAST-X study, as presented in this paper.
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The results of this post hoc analysis reinforce the trend observed in previous studies of better response to biological treatment in HLA-B27-positive versus HLA-B27-negative patients with axSpA. The reasons for this trend are not clear. Indeed, the molecule HLA-B27 could play a direct role in mediating better responses to anti-inflammatory biological therapy. Predisposing genes, including HLA-B27 may contribute to excess innate immune activation and IL-23 production, altered IL-23 responses, and increased production of IL-17 and related cytokines. Alternatively, the risk of misdiagnosis is clearly greater in HLA-B27-negative patients with back pain than in HLA-B27-positive patients. Making a correct diagnosis of axSpA in daily practice is challenging in general, and depends on clinical experience and correct interpretation of clinical findings and imaging (X-rays, MRI) [25].
Given a prevalence of HLA-B27 of 60% to 90% among patients with axSpA, HLA-B27 is considered a disease marker in axSpA and can be effectively used for diagnostic and screening purposes [6, 26, 27]. Consequently, any misinterpretation of clinical or imaging findings has a greater impact on misdiagnosis among HLA-B27-negative than HLA-B27-positive patients. Importantly, the frequency of HLA-B27 worldwide is the lowest in regions closest to the equator such as Africa and the Middle East and the highest in circumpolar regions populated by Inuit and other indigenous groups [28]. Among patients with axSpA, 85 to 95% of White, Hispanic, and Chinese patients are HLA-B27-positive, but Middle Eastern, North African, and American Black patients have a lower HLA-B27 frequency of 50–84% [26].
Limitations of the current analyses included the relatively small number of HLA-B27-negative patients, particularly in the r-axSpA studies, limiting the value of some statistical comparisons. In addition, there was no placebo comparator after week 16 in two of the three studies assessed; therefore, for consistency purposes, we limited comparisons to placebo to week 16 across all three trials.
Conclusions
For patients with either r-axSpA or nr-axSpA, ixekizumab treatment improved response through 52 weeks for both HLA-B27-positive and HLA-B27-negative patients. However, the magnitude of benefit for ixekizumab versus placebo was numerically greater for HLA-B27-positive patients.
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Medical Writing/Editorial Assistance
Writing support was funded by Eli Lilly and Company and provided by Geraldine Fahy, Natalie Haustrup, Molly Tomlin, and Laura de Ugarte Corbalan, employees and stockholders of Eli Lilly and Company.
Declarations
Conflict of Interest
John D. Reveille has served as a consultant for Eli Lilly and Company and has received grant and/or research support from Eli Lilly and Company. Martin Rudwaleit has served as a speaker, consultant, and/or instructor for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB Pharma. Proton Rahman has served as a speaker and instructor for Abbott, AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB Pharma, and has received grant and/or research support from Janssen and Novartis. Jose A. Maldonado-Cocco has served as a speaker and consultant for and has received grant and/or research support from AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB Pharma, and Wyeth. Marina Magrey has served as a speaker and/or consultant for AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB Pharma. Rebecca Bolce, Khai Jing Ng, Theresa Hunter Gibble, Jeffrey Lisse, So Young Park, and Andris Kronbergs are current employees and shareholders of Eli Lilly and Company. Victoria Navarro-Compán has served as a speaker, consultant, and/or instructor for AbbVie, Alfasigma, Eli Lilly and Company, Fresenius Kabi, Galapagos, Janssen, Novartis, Pfizer, and UCB Pharma, and has received grant and/or research support from ASAS and Novartis.
Ethical Approval
COAST-V, COAST-W, and COAST-X (ClinicalTrials.gov identifiers: NCT02696785, NCT02696798, and NCT02757352, respectively) were approved by the institutional review board or ethics committee at each site and were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice Guidelines (CPMP/ICH/135/95). The master ethics committee was Schulman Associates IRB (Cincinnati, OH, USA). Full listings of investigators and sites are available in previously published manuscript supplements [12, 13, 15]. All patients gave written informed consent before the trials started. No additional ethical approval was sought to conduct the current post hoc analysis.
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Does HLA-B27 Status Influence Ixekizumab Efficacy in Axial Spondyloarthritis? Results From the COAST-V, COAST-W, and COAST-X Trials
Verfasst von
John D. Reveille
Martin Rudwaleit
Proton Rahman
Jose A. Maldonado-Cocco
Marina Magrey
Rebecca Bolce
Khai Jing Ng
Theresa Hunter Gibble
Jeffrey Lisse
So Young Park
Andris Kronbergs
Victoria Navarro-Compán
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