Abstract
Objectives
To study the impact of C reactive protein (CRP) level at treatment start on interleukin-17 inhibitor (IL-17i) and tumour necrosis factor inhibitor (TNFi) effectiveness, including treatment retention, in axial spondyloarthritis (axSpA).
Methods
Nationwide observational study including patients with axSpA from the DANBIO registry initiating their first IL-17i or first TNFi between 2015 and 2024. Outcomes were 12-month treatment retention and Bath Ankylosing Spondylitis Disease Activity Index remission stratified by CRP levels (<5 (low)/5–10 (intermediate)/>10 mg/L (high)) at treatment initiation (baseline). Kaplan-Meier plots (including substratification by sex and radiographic status) and Cox regression models were used to assess treatment retention and hazard of discontinuation for IL-17i and TNFi separately.
Results
Overall, 3387 patients were included (601 IL-17i, 2786 TNFi) with baseline CRP levels (low/intermediate/high) 57%/17%/26% for IL-17i and 48%/20%/32% for TNFi. For IL-17i, 95% of patients were TNFi-experienced; for TNFi, 99% were biologic-naïve.
The 12-month retention rates stratified by baseline CRP (low/intermediate/high) were 51%/53%/55% for IL-17i and 63%/66%/72% for TNFi, with similar results when stratified by sex and radiographic status. Cox models (reference: low CRP) showed no clear association between CRP level and treatment retention among patients receiving IL-17i (intermediate CRP: HR 0.96, 95% CI 0.68 to 1.19; high CRP: HR 0.90, 95% CI 0.68 to 1.19). In contrast, among patients receiving TNFi, intermediate and high CRP levels were associated with a lower risk of treatment discontinuation (HR 0.86, 95% CI 0.73 to 1.02 and HR 0.72, 95% CI 0.62 to 0.84, respectively). Remission rates were 6%/8%/11% for IL-17i and 19%/22%/32% for TNFi.
Conclusion
In routine care, IL-17i was mainly used in biologic-experienced patients, whereas TNFi was primarily used in biologic-naïve patients with axSpA. Higher baseline CRP levels were associated with higher retention for first TNFi but not for first IL-17i. Higher CRP was associated with higher remission rates for both IL-17i and TNFi.
Keywords: Axial Spondyloarthritis, Tumor Necrosis Factor Inhibitors, Interleukin-17, Inflammation, Biomarkers
WHAT IS ALREADY KNOWN ON THIS TOPIC
In axial spondyloarthritis (axSpA), previous trials showed better effect of tumour necrosis factor inhibitor (TNFi) in patients with elevated C reactive protein (CRP) at treatment start, whereas interleukin-17 inhibitor (IL-17i) appeared effective regardless of CRP level.
In routine care settings, similar results were seen for TNFi, but evidence is lacking for IL-17i.
WHAT THIS STUDY ADDS
Using real-world data from a nationwide registry, we explored the effectiveness of a first TNFi or first IL-17i in patients with axSpA stratified by CRP level at treatment start. No head-to-head drug class comparisons were conducted.
The 12-month IL-17i retention was similar across CRP strata, whereas TNFi retention was higher in patients with elevated CRP.
Results were robust when stratified by sex and radiographic status.
IL-17i was mainly used in biologic-experienced patients.
For both IL-17i and TNFi, higher CRP was associated with higher remission rates.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
In axSpA, CRP level at treatment start may inform outcome expectations in routine care.
Introduction
Axial spondyloarthritis (axSpA) is a chronic, immune-mediated inflammatory disease affecting the axial skeleton, with both radiographic (r-axSpA) and non-radiographic (nr-axSpA) subtypes. Characterised by inflammatory back pain, stiffness and reduced mobility, axSpA has substantial impact on patient quality of life and physical function.1 2 Timely and effective disease-modifying therapy is essential to control symptoms.3
Tumour necrosis factor inhibitors (TNFi) are effective treatment options in axSpA, particularly for patients with objective signs of inflammation such as elevated C reactive protein (CRP) or MRI-confirmed sacroiliac joint inflammation.4 5 Thus, in previous trials and observational cohorts, elevated CRP levels at treatment initiation have consistently been associated with improved TNFi response,6,9 a relationship also emphasised in Assessment of SpondyloArthritis international Society (ASAS)-European Alliance of Associations for Rheumatology (EULAR) recommendations, which identify elevated CRP as the strongest predictor of a favourable treatment response in both r-axSpA and nr-axSpA.3 In these studies, TNFi effectiveness was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI),6 7 ASAS 20/40 response criteria,8 9 Axial Spondyloarthritis Disease Activity Score (ASDAS)-based response/remission8 and treatment retention in observational cohorts.6 7 However, in these studies, CRP was primarily analysed as a dichotomous variable or as a covariate in regression models rather than as a stratification variable, and most data originate from selected trial populations or earlier observational cohorts. Consequently, there is limited contemporary real-world evidence evaluating CRP-stratified treatment outcomes.
Biologic drugs targeting the interleukin-17 (IL-17) pathway have emerged as effective treatment alternatives.10 Unlike TNFi, the efficacy of IL-17 inhibitors (IL-17i) appears less dependent on elevated CRP levels. Clinical trials, including the COAST programme, the MEASURE and PREVENT trials,411,14 have demonstrated comparable treatment responses in patients with normal or elevated CRP levels at treatment start, in both r-axSpA and nr-axSpA populations. Specifically, post hoc analyses from the COAST-V and COAST-W trials showed that IL-17i (ixekizumab) demonstrated efficacy in patients with r-axSpA both with and without elevated baseline CRP and both with and without MRI evidence of spinal inflammation.4 These findings suggest that IL-17i may be of value for patients with normal CRP. However, real-world evidence on whether CRP influences IL-17i effectiveness is limited and with heterogeneous findings. Some studies suggest slightly poorer IL-17i retention among patients with elevated inflammatory markers, while others show no discernible CRP-related differences.15 16
Clarifying the relationship between CRP and biological disease-modifying antirheumatic drug (bDMARD) treatment effectiveness is clinically important, as approximately half of patients with axSpA present with normal CRP levels at the time of diagnosis.17 18 In this context, re-evaluating the association between CRP at treatment start and TNFi effectiveness is relevant, given today’s prescription patterns.
In addition to CRP, sex and radiographic status have also been suggested to influence treatment outcomes.19 20 In observational cohorts,19 20 women show poorer TNFi response and treatment retention than men, and a recent meta-analysis of randomised controlled trials (RCTs)21 found better treatment responses among male patients across both TNFi and IL-17i. Although TNFi are effective in nr-axSpA,22 more advanced radiographic changes have been associated with higher treatment response,23 whereas IL-17i appear to have similar efficacy in r-axSpA and nr-axSpA.24
High-quality observational data are essential to complement trial evidence and evaluate treatment outcomes in routine care.25 The DANBIO registry, a national clinical quality registry covering patients with inflammatory arthritis in Denmark, provides a unique platform to address this need.26 In the present study, we aimed to investigate the impact of the CRP level at treatment start on 1-year treatment effectiveness in patients with axSpA initiating either their first IL-17i or their first TNFi, respectively, defined as treatment retention (overall and stratified by sex and radiographic status) and treatment response, including remission. No head-to-head drug class comparisons were conducted.
Patients and methods
Study design
This was a nationwide observational cohort study based on prospectively collected data from the DANBIO registry. DANBIO contains clinical information as recorded by patients and treating rheumatologists. The registry has high data completeness and national coverage.27
Study population
Patients were included if they had a clinical diagnosis of axSpA in DANBIO, initiated a first IL-17i (bimekizumab, ixekizumab or secukinumab) or a first TNFi (adalimumab, certolizumab pegol, etanercept, golimumab or infliximab) between 1 January 2015 and 30 September 2024, were aged ≥18 years at the time of treatment initiation and had available registration of CRP in DANBIO at treatment start, that is, baseline. ‘First TNFi’ or ‘first IL-17i’ refers to the first treatment course of the respective drug class as recorded in DANBIO; patients could therefore have been previously treated with other bDMARDs/targeted synthetic (ts)DMARDs. The treatment duration should be ≥1 day (figure 1). The diagnosis was based on the treating physician’s judgement. Patients could contribute follow-up time to both treatment groups if they initiated a TNFi and later an IL-17i, or vice versa. Analyses were conducted separately for the two treatment groups (IL-17i, TNFi), and no head-to-head drug class comparisons were made. The following baseline CRP levels were used for stratification: low: <5 mg/L, intermediate: 5–10 mg/L, high: >10 mg/L.
Figure 1. Flow chart. axSpA, axial spondyloarthritis; CRP, C reactive protein; IL-17i, interleukin-17 inhibitor; TNFi, tumour necrosis factor inhibitor.
Study variables
The following baseline variables were identified in DANBIO: CRP (mg/L), age, sex (female/male), time since diagnosis, year of treatment start, patient-reported outcomes (visual analogue scale (VAS) for pain, fatigue, global assessment (0–100 mm)), physician global assessment (0–100 mm), BASDAI, ASDAS and functional status (Bath Ankylosing Spondylitis Functional Index (BASFI)). A predefined time window (−90 to +30 days after treatment start) for capturing baseline variables was applied. Furthermore, we identified human leucocyte antigen-B27 status (positive/negative), number of previous b/tsDMARDs and concomitant baseline methotrexate use (yes/no). Radiographic status (r-axSpA/nr-axSpA) was defined according to the International Statistical Classification of Diseases, 10th Revision codes used in DANBIO (see online supplemental table S1). These definitions reflect the diagnosis decided by the treating physician in routine care rather than formal classification criteria.
Outcomes
The primary outcome was 12-month treatment retention, defined as the proportion of patients maintaining treatment at 12 months. Secondary outcomes were 6-month retention and remission rates at 6 and 12 months. Treatment retention was calculated as the time from treatment initiation to discontinuation. Patients were censored at the last follow-up visit, death or end of data cut (30 September 2024). If no stop date was recorded, treatment was assumed to continue for up to 3 months after the last registered clinical visit, but not beyond the data cut date. If treatment was resumed within 90 days of discontinuation without initiation of another b/tsDMARD, the gap was ignored and the treatment course was considered continuous. Switches from an originator to a corresponding biosimilar or between biosimilars of the same originator were disregarded.
Disease activity was assessed according to BASDAI and ASDAS at baseline, 6 and 12 months. Disease remission was defined as BASDAI <20 mm or ASDAS <1.3.28 29 Group-level disease activity at 6-month and 12-month follow-up was analysed as medians (IQRs) at the two time points, no paired comparisons were made. Predefined 6-month (31–270 days) and 12-month (271–548 days) time windows were applied. LUNDEX-adjusted remission proportions were calculated to account for early withdrawal30 by multiplying the crude remission rate by the proportion of patients still on treatment.
Statistical analyses
Descriptive statistics were used to summarise baseline characteristics and disease activity at follow-up. Continuous variables were reported as medians (IQR), and categorical variables as counts and percentages. Treatment retention was assessed using Kaplan-Meier survival analyses with log-rank tests to estimate crude treatment retention rates across CRP strata. Cox proportional hazards models were used to estimate adjusted HRs for treatment discontinuation within 12 months, with the following covariates: sex, age, radiographic status (r-axSpA/nr-axSpA), number of previous b/tsDMARDs (0/1/≥2) and treatment start year.
The proportional hazards assumption was evaluated using Schoenfeld residuals and graphical diagnostics, with no violations observed. For robustness, we conducted additional analyses stratified by (1) sex (female vs male) and (2) radiographic status (r-axSpA vs nr-axSpA).
Analyses were conducted using available data with no imputation of missing values. All statistical analyses were performed using R (RStudio, V.2022.07.1). Reporting of results followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.31
Sensitivity analyses
To further assess robustness, we performed additional analyses including baseline BASDAI as a measure of disease activity. This did not substantially change the results or their interpretation. However, inclusion of BASDAI reduced the sample size due to missing data, and it was therefore not included in the final models. In addition, sensitivity analyses were performed using a dichotomised CRP definition (<5 mg/L vs ≥5 mg/L), including Kaplan-Meier analyses of treatment retention and corresponding Cox regression models.
Ethical considerations
The study was conducted in accordance with Danish data protection regulations. According to national legislation, ethical approval and informed consent are not required for observational registry studies.32
Results
Baseline characteristics
A total of 601 patients initiating a first IL-17i and 2786 patients initiating a first TNFi were included (table 1, online supplemental table S2).
Table 1. Baseline characteristics of patients with axSpA* initiating IL-17i or TNFi, stratified by CRP level.
| CRP <5 mg/L | CRP 5–10 mg/L | CRP >10 mg/L | Total | |
|---|---|---|---|---|
| Low | Intermediate | High | ||
| IL-17i group (n=601) | ||||
| Total number of patients, n (%) | 340 (57%) | 102 (17%) | 159 (26%) | 601 (100%) |
| Female, n (%) | 179 (53%) | 49 (48%) | 69 (43%) | 297 (49%) |
| Age (years), median | 46.9 (37.8, 54.6) | 46.5 (35.5, 54.8) | 45.8 (37.4, 56.6) | 46.6 (37.2, 55.3) |
| HLA-B27 positive, n (%) | 190 (61%) | 61 (67%) | 101 (71%) | 352 (65%) |
| CRP (mg/L) | 2.0 (1.0, 3.0) | 6.9 (5.6, 8.3) | 20.0 (14.0, 35.0) | 4.0 (2.0, 11.0) |
| BASDAI | 63 (48, 74) | 64 (47, 78) | 67 (54, 80) | 64 (49, 77) |
| BASFI | 53 (30, 69) | 57 (36, 71) | 64 (44, 78) | 56 (35, 73) |
| ASDAS | 3.1 (2.4, 3.5) | 3.7 (3.1, 4.1) | 4.4 (3.9, 4.9) | 3.4 (2.8, 4.1) |
| Disease duration, years | ||||
| Median (IQR) | 5.4 (2.3, 11.8) | 6.9 (3.2, 13.8) | 8.6 (4.1, 16.2) | 6.6 (2.6, 13.4) |
| 0–5 years, n (%) | 154 (48%) | 36 (39%) | 46 (32%) | 236 (42%) |
| >5 years, n (%) | 167 (52%) | 57 (61%) | 97 (68%) | 321 (58%) |
| Start year of treatment, n (%) | ||||
| 2015–2017 | 41 (12%) | 18 (18%) | 30 (19%) | 89 (15%) |
| 2018–2020 | 134 (39%) | 34 (33%) | 62 (39%) | 230 (38%) |
| 2021–2022 | 84 (25%) | 26 (25%) | 34 (21%) | 144 (24%) |
| 2023–2024 | 81 (24%) | 24 (24%) | 33 (21%) | 138 (23%) |
| Patient global assessment of disease activity—VAS (0–100) | 76 (58, 90) | 77 (55, 89) | 82 (70, 95) | 78 (59, 91) |
| Patient assessment of pain—VAS (0–100) | 69 (50, 84) | 71 (53, 86) | 75 (60, 85) | 71 (53, 84) |
| Patient assessment of fatigue—VAS (0–100) | 75 (54, 89) | 75 (54, 89) | 79 (60, 88) | 76 (55, 89) |
| MDHAQ | 0.90 (0.40, 1.30) | 1.00 (0.70, 1.30) | 1.20 (0.80, 1.60) | 1.00 (0.60, 1.38) |
| Physician global assessment—VAS (0–100) | 19 (10, 34) | 20 (11, 35) | 30 (18, 43) | 20 (10, 38) |
| Concomitant MTX, yes, n (%) | 31 (9%) | 9 (9%) | 30 (19%) | 70 (12%) |
| Prior b/tsDMARD, n (%) | ||||
| 0 treatments | 18 (5%) | 7 (7%) | 8 (5%) | 33 (5%) |
| 1 treatment | 68 (20%) | 20 (20%) | 25 (16%) | 113 (19%) |
| ≥2 treatments | 254 (75%) | 75 (73%) | 126 (79%) | 455 (76%) |
| Prior (ever) TNFi, n (%) | 326 (96%) | 93 (91%) | 153 (96%) | 572 (95%) |
| Patients also present in TNFi group, n (%) | 191 (56%) | 54 (53%) | 63 (40%) | 308 (51%) |
| Radiographic status, n (%) | ||||
| Radiographic | 179 (53%) | 54 (53%) | 62 (39%) | 295 (49%) |
| Non-radiographic | 161 (47%) | 48 (47%) | 97 (61%) | 306 (51%) |
| TNFi group (n=2786) | ||||
| Total number of patients, n (%) | 1336 (48%) | 563 (20%) | 887 (32%) | 2786 (100%) |
| Female, n (%) | 612 (46%) | 251 (45%) | 274 (31%) | 1137 (41%) |
| Age, years | 40.5 (30.8, 49.5) | 40.6 (30.6, 52.0) | 39.5 (29.9, 50.4) | 40.2 (30.6, 50.3) |
| HLA-B27 positive, n (%) | 795 (64%) | 351 (68%) | 591 (73%) | 1737 (68%) |
| CRP, mg/L | 2.0 (1.0, 3.2) | 7.0 (6.0, 8.6) | 20.6 (14.0, 34.0) | 5.0 (2.0, 14.0) |
| BASDAI | 57 (41, 69) | 59 (42, 72) | 58 (43, 72) | 57 (42, 71) |
| BASFI | 37 (20, 56) | 44 (25, 62) | 46 (27, 64) | 42 (23, 60) |
| ASDAS | 2.8 (2.2, 3.3) | 3.5 (2.9, 4.0) | 4.1 (3.5, 4.7) | 3.3 (2.7, 4.0) |
| Disease duration, years | ||||
| Median (IQR) | 1.0 (0.3, 4.2) | 1.0 (0.3, 4.3) | 0.6 (0.2, 3.8) | 0.8 (0.3, 4.1) |
| 0–5 years, n (%) | 926 (77%) | 400 (79%) | 638 (80%) | 1964 (74%) |
| >5 years, n (%) | 272 (23%) | 108 (21%) | 158 (20%) | 538 (26%) |
| Start year of treatment, n (%) | ||||
| 2015–2017 | 330 (25%) | 213 (38%) | 300 (34%) | 843 (30%) |
| 2018–2020 | 452 (34%) | 176 (31%) | 292 (33%) | 920 (33%) |
| 2021–2022 | 297 (22%) | 98 (17%) | 178 (20%) | 573 (21%) |
| 2023–2024 | 257 (19%) | 76 (14%) | 117 (13%) | 450 (16%) |
| Patient global assessment of disease activity—VAS (0–100) | 68 (49, 84) | 72 (54, 86) | 74 (55, 87) | 71 (51, 86) |
| Patient assessment of pain—VAS (0–100) | 60 (39, 75) | 64 (47, 77) | 66 (49, 80) | 63 (44, 77) |
| Patient assessment of fatigue—VAS (0–100) | 69 (46, 83) | 71 (51, 84) | 68 (47, 83) | 69 (47, 83) |
| MDHAQ | 0.70 (0.30, 1.00) | 0.80 (0.50, 1.20) | 0.80 (0.50, 1.20) | 0.70 (0.40, 1.10) |
| Physician global assessment—VAS (0–100) | 18 (8, 31) | 20 (10, 33) | 28 (16, 46) | 21 (10, 37) |
| Concomitant MTX, yes, n (%) | 93 (7%) | 69 (12%) | 111 (13%) | 273 (10%) |
| Prior b/tsDMARD, n (%) | ||||
| 0 treatments | 1324 (99%) | 559 (99%) | 880 (99%) | 2763 (99%) |
| 1 treatment | 10 (<1%) | 3 (<1%) | 7 (1%) | 20 (<1%) |
| ≥2 treatments | 2 (<1%) | 1 (<1%) | 0 (0%) | 3 (<1%) |
| Radiographic status, n (%) | ||||
| Radiographic | 784 (59%) | 301 (53%) | 420 (47%) | 1505 (54%) |
| Non-radiographic | 552 (41%) | 262 (57%) | 467 (53%) | 1281 (46%) |
Numbers are medians (IQR) unless otherwise stated. Results are based on available data; data completeness is shown in online supplemental table S2.
For International Statistical Classification of Diseases, 10th Revision codes, see online supplemental table S1.
ASDAS, Axial Spondyloarthritis Disease Activity Score; axSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; b/tsDMARD, biological/targeted synthetic disease-modifying antirheumatic drug; CRP, C reactive protein; HLA-B27, human leucocyte antigen-B27; IL-17i, IL-17 inhibitors; MDHAQ, Multi-Dimensional Health Assessment Questionnaire; MTX, methotrexate; TNFi, TNF inhibitors; VAS, visual analogue scale.
IL-17i group
Patients initiating IL-17i treatment had a median age of 46.6 years (IQR 37.2–55.3), 49% were female and 49% had r-axSpA. Patients were predominantly b/tsDMARD-experienced: 76% had received ≥2 prior b/tsDMARDs and 95% had prior TNFi exposure. Median baseline CRP was 4.0 mg/L (IQR 2.0–11.0), with 57% low, 17% intermediate and 26% high CRP.
Baseline disease activity was higher across increasing CRP levels, with BASDAI being 63, 64 and 67 in patients with low, intermediate and high CRP, respectively. Similarly, patients with high CRP had higher physician-assessed disease activity (19, 20 and 30 mm, respectively) and functional impairment (BASFI 53, 57, 64 mm, respectively).
TNFi group
Patients initiating TNFi treatment had a median age of 40.2 years (IQR 30.6–50.3), 41% were female, 54% had r-axSpA and most were b/tsDMARD-naïve (99%). Median baseline CRP was 5.0 mg/L (IQR 2.0–14.0), with 48% low, 20% intermediate and 32% high CRP. Baseline disease activity increased with higher CRP levels for physician-assessed disease activity (18, 20 and 28 mm, respectively) and BASFI (37, 44 and 46 mm, respectively), whereas BASDAI was similar (57, 59 and 58 mm, respectively).
Treatment retention
IL-17i group
Retention rates at 12 months were 51%, 53% and 55% for patients with low, intermediate and high baseline CRP, respectively (log-rank, p=0.68, figure 2A).
Figure 2. Twelve-month treatment retention in patients with axial spondyloarthritis initiating IL-17i (panel A) or TNFi (panel B). Kaplan-Meier analysis stratified by baseline CRP level. Kaplan-Meier curves stratified by baseline CRP level (low <5 mg/L, intermediate 5–10 mg/L, high >10 mg/L). CRP, C reactive protein; IL-17i, interleukin-17 inhibitor; TNFi, tumour necrosis factor inhibitor.
TNFi group
Among TNFi-treated patients, 12-month retention was 63%, 66% and 72% for patients with low, intermediate and high baseline CRP, respectively (log-rank, p<0.0001; figure 2B). Analyses using dichotomised CRP levels (<5 mg/L vs ≥5 mg/L) showed patterns similar to those observed in the primary analyses for both IL-17i and TNFi (online supplemental figure S1).
Sex and radiographic subgroup analyses
In Kaplan-Meier analyses with further stratification by sex and radiographic status, patterns similar to the overall analyses were found. Thus, for IL-17i, the retention for women, for men, for r-axSpA and for nr-axSpA were similar across CRP levels (log-rank, all p>0.05, figure 3). For TNFi, higher CRP levels were associated with longer retention for all four subgroups (log-rank, all p<0.01, figure 3). Detailed crude retention estimates for these subgroup analyses are provided in online supplemental table S3.
Figure 3. Twelve-month treatment retention stratified by sex and radiographic status in patients with axSpA initiating IL-17i (panel A–D) or TNFi (panel E–H). Kaplan-Meier curves stratified by baseline CRP level (low <5 mg/L, intermediate 5–10 mg/L, high >10 mg/L). axSpA, axial spondyloarthritis; CRP, C reactive protein; IL-17i, interleukin-17 inhibitor; TNFi, tumour necrosis factor inhibitor.
Factors associated with treatment retention
IL-17i group
Baseline CRP was not associated with 12-month treatment retention in patients initiating IL-17i. Similarly, female sex and radiographic status were not associated with treatment retention. Patients treated with two or more previous b/tsDMARDs tended to have increased risk of discontinuation (HR 1.86, 95% CI 0.98 to 3.51), but CIs were wide (multivariable Cox regression analysis, figure 4A).
Figure 4. Treatment discontinuation in patients initiating treatment with IL-17i (panel A) or TNFi (panel B). Results of multivariable Cox regression analyses including baseline CRP level (low <5 mg/L, intermediate 5–10 mg/L, high >10 mg/L), sex, radiographic status and number of previous b/tsDMARDs. Adjusted for age and calendar year. b/tsDMARDs, biological or targeted synthetic disease-modifying antirheumatic drugs; CRP, C reactive protein; IL-17i, interleukin-17 inhibitor; nr-axSpA, non-radiographic axial spondyloarthritis; r-axSpA, radiographic axial spondyloarthritis; Ref, reference; TNFi, tumour necrosis factor inhibitor.
TNFi group
For patients initiating TNFi, high CRP was associated with lower hazard of discontinuation (HR 0.72, 95% CI 0.62 to 0.84, p<0.01) compared with low baseline CRP (multivariable Cox regression analysis). For intermediate CRP, there was no significant difference of discontinuation compared with the low CRP (HR 0.86, 95% CI 0.73 to 1.02). Furthermore, female sex was associated with increased risk of discontinuation (HR 1.43, 95% CI 1.25 to 1.63), while radiographic status and number of previous b/tsDMARDs were not (figure 4B).
Analyses using dichotomised CRP levels (<5 mg/L vs ≥5 mg/L) in Cox regression models showed patterns similar to those observed in the primary analyses for both IL-17i and TNFi (online supplemental table S6).
Disease activity outcomes
IL-17i group
BASDAI remission (LUNDEX-adjusted) at 12 months was achieved by 6%, 8% and 11% of patients with low, intermediate and high CRP, respectively, with slightly higher remission rates in patients with high CRP. At 6 months, remission rates were nearly identical across CRP levels, with LUNDEX-adjusted rates of 8%, 9% and 9% for low, intermediate and high CRP, respectively (table 2). Similar patterns were seen for ASDAS remission (online supplemental table S4).
Table 2. BASDAI remission at 6 and 12 months in patients initiating IL-17i or TNFi, stratified by baseline CRP levels.
| 6 months | 12 months | |||||||
|---|---|---|---|---|---|---|---|---|
| Still on treatment | Data availability of BASDAI |
Crude remission rate | LUNDEX-adjusted remission rate | Still on treatment | Data availability | Crude remission rate | LUNDEX-adjusted remission rate | |
| IL-17i group | ||||||||
| Low CRP | 216/340 (64%) | 186/216 (86%) | 24/186 (13%) | 8% | 147/340 (43%) | 123/147 (84%) | 16/123 (13%) | 6% |
| Intermediate CRP | 59/102 (58%) | 47/59 (80%) | 7/47 (15%) | 9% | 47/102 (46%) | 43/47 (92%) | 7/43 (16%) | 8% |
| High CRP | 108/159 (68%) | 87/108 (81%) | 11/87 (13%) | 9% | 80/159 (50%) | 62/80 (78%) | 14/62 (23%) | 11% |
| TNFi group | ||||||||
| Low CRP | 950/1336 (71%) | 816/950 (86%) | 287/816 (35%) | 25% | 732/1336 (55%) | 608/732 (83%) | 213/608 (35%) | 19% |
| Intermediate CRP | 442/563 (79%) | 377/442 (85%) | 142/377 (38%) | 30% | 350/563 (62%) | 289/350 (83%) | 100/289 (35%) | 22% |
| High CRP | 724/887 (82%) | 625/724 (86%) | 273/625 (44%) | 36% | 589/887 (66%) | 475/589 (81%) | 227/475 (48%) | 32% |
Crude remission=number of patients achieving BASDAI remission divided by the number of patients with available BASDAI data at the corresponding time point.
LUNDEX-adjusted remission rate was calculated by multiplying the crude remission rate by the proportion of patients still on treatment at the corresponding time point (eg, for low CRP and IL-17i: 12.9%×63.5%=8.2%).
BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C reactive protein; IL-17i, interleukin-17 inhibitor; TNFi, tumour necrosis factor inhibitor.
TNFi group
BASDAI remission (LUNDEX-adjusted) was achieved by 19%, 22% and 32% of patients with low, intermediate and high CRP at 12 months, respectively, with remission rates increasing with higher CRP level. A similar pattern was observed at 6 months (table 2). Similar patterns were seen for ASDAS remission (online supplemental table S4).
The median disease activity (BASDAI and ASDAS) decreased over time for both IL-17i and TNFi groups (table 3). In the IL-17i group, the decrease of BASDAI and ASDAS was similar across CRP levels. In the TNFi group, the decrease in BASDAI was numerically higher in patients with higher CRP levels (table 3), whereas the decrease in ASDAS was similar across CRP levels (online supplemental table S5).
Table 3. Disease activity at baseline, 6 and 12 months in patients with axSpA initiating IL-17i or TNFi, stratified by baseline CRP levels.
| Low CRP | Intermediate CRP | High CRP | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline | 6 months | 12 months | Baseline | 6 months | 12 months | Baseline | 6 months | 12 months | |
| IL-17i group | |||||||||
| BASDAI, median (IQR) | 63 (48, 74) | 51 (33, 68) | 47 (29, 68) | 64 (47, 78) | 43 (27, 72) | 48 (28, 66) | 67 (54, 80) | 47 (30, 66) | 44 (23, 62) |
| Data availability, n (%) | 317 (93%) | 186 (86%) | 123 (84%) | 93 (91%) | 47 (80%) | 43 (92%) | 144 (91%) | 87 (81%) | 62 (78%) |
| TNFi group | |||||||||
| BASDAI, median (IQR) | 57 (41, 69) | 30 (14, 49) | 29 (14, 51) | 59 (42, 72) | 29 (12, 52) | 29 (12, 55) | 58 (43, 72) | 23 (10, 43) | 21 (8, 42) |
| Data availability, n (%) | 1247/1336 (93%) | 816/950 (86%) | 608/732 (83%) | 536/563 (95%) | 377/442 (85%) | 289/350 (83%) | 829/887 (93%) | 625/724 (86.3%) | 475/589 (81%) |
For each time point, patients who were still receiving treatment and had available data were included in the analysis.
axSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; IL-17i, interleukin-17 inhibitors; TNFi, tumour necrosis factor inhibitors.
Discussion
In this nationwide study of real-world patients with axSpA starting the first IL-17i or first TNFi, the treatment retention was independent of baseline CRP levels for IL-17i, whereas in patients treated with TNFi, the retention depended on CRP (best in patients with high CRP). These patterns were consistent across sex and radiographic status. Similarly, higher CRP was associated with higher remission rates for TNFi, whereas for IL-17i the association was weaker and less consistent. Taken together, these findings suggest that CRP at treatment start may help identify patients in routine care more likely to maintain treatment when initiating TNFi, whereas IL-17i appeared to provide clinical benefit irrespective of CRP levels. Given that up to half of patients with axSpA present with normal CRP,17 18 this distinction is clinically relevant and informs expectations on start of a new treatment.
This study is, to our knowledge, the first real-world study evaluating the impact of CRP levels on 12-month retention and disease activity in patients initiating IL-17i. The association between high baseline CRP and favourable TNFi outcomes aligns with results from both clinical trials and observational cohorts.5 8 9 Likewise, our finding that IL-17i outcomes appeared largely independent of baseline CRP levels is consistent with findings from clinical trials, for example, COAST subanalyses, showing that IL-17i (ixekizumab) demonstrated efficacy irrespective of baseline CRP level and MRI spine inflammation,4 and other phase III RCTs of IL-17i demonstrating similar responses across CRP levels.11 33 However, real-world data addressing the role of inflammatory markers in IL-17i treatment are scarce. Existing evidence, including the FORSYA study,15 has primarily relied on composite measures of objective inflammation combining CRP, erythrocyte sedimentation rate (ESR) and MRI findings, whereas our study evaluates the clinical relevance of CRP, a routinely available biomarker, in a routine-care setting. It should, however, be noted that no head-to-head comparison of IL-17i versus TNFi across CRP levels exists. Such a comparison was beyond the scope of the present paper due to the observational setting, which resulted in most IL-17i-treated patients being highly biologic experienced, whereas TNFi were often used as first-line b/tsDMARDs.27 This prescription pattern is in line with current international recommendations in the field.3
Another important contextual factor for treatment retention is sex. In the current study, we observed no clear sex differences among patients initiating IL-17i. However, in line with previous studies,19 20 we observed higher withdrawal rates in female patients initiating TNFi compared with males. Potential explanations include differences in disease phenotype, pain perception, comorbidities or drug tolerability, although the precise mechanisms remain unclear.19 20 These proposed explanations are primarily based on evidence from TNFi-treated populations, with limited corresponding data for IL-17i. These findings highlight the importance of considering sex when evaluating real-world TNFi treatment persistence.
In addition, treatment history represents an important contextual consideration. The IL-17i group in our study consisted predominantly of biologic-experienced patients, many with multiple prior treatment failures, in contrast to the mainly biologic-naïve TNFi group. This difference likely contributed to lower IL-17i retention overall, in line with previous rheumatology registry research showing higher discontinuation rates with increasing treatment line.7 16 Thus, the absence of a CRP-response gradient among IL-17i users should be interpreted in light of a more refractory disease population.
A major strength of this study is the use of DANBIO, a nationwide registry with prospective data collection, high coverage and high completeness of patient-reported outcomes, clinical scores and treatment data.26 The nationwide, largely unselected patient population and high registry coverage enhance the generalisability of the findings to routine clinical practice. The large sample size strengthens the statistical power, while the long follow-up period increases the robustness and clinical relevance of the retention estimates. Together, these features support the validity and applicability of the results. A further strength is that the findings were consistent across different CRP stratifications, including both three-level and dichotomised categories, which supports the robustness of the results.
In addition, BASDAI was used to evaluate disease activity across CRP strata. This was a deliberate methodological choice, as CRP is one of the variables in ASDAS algorithm,34 and would therefore be mathematically linked to the exposure of interest; using BASDAI allowed assessment of symptom burden independently of CRP level.
The study also has limitations. As an observational registry study, residual confounding cannot be excluded, including unmeasured indicators of objective inflammation such as MRI findings and extra-articular manifestations. In addition, data on comorbidities and coexisting pain conditions, such as fibromyalgia, were not available and may have influenced treatment outcomes, particularly in the IL-17i group, which likely represents a more treatment-refractory patient population. Incomplete follow-up may lead to missing outcome data, although LUNDEX adjustment mitigates this for remission analyses. No direct comparison between the two drug classes was performed. In routine clinical practice, treatment selection is influenced by disease characteristics and treatment history, resulting in systematic differences between patients initiating IL-17i and TNFi. In addition, analyses restricted to b/tsDMARD-naïve patients were not feasible for IL-17i, as IL-17i is predominantly used in b/tsDMARD-experienced patients in routine clinical practice in Denmark. Accordingly, almost all patients initiating IL-17i had failed prior therapies and therefore likely represented a more treatment-refractory patient population.
A direct comparative analysis would therefore be prone to confounding by indication,35 and findings should be interpreted within each treatment group rather than as comparative effectiveness estimates. Another limitation is that the relatively wide time windows applied during follow-up may introduce temporal variability in outcome assessment. However, these windows were chosen to maximise data completeness. Importantly, treatment retention was calculated based on the exact dates of treatment start and withdrawal. Finally, analyses at the individual drug level were not performed, and results should be confirmed in studies evaluating individual agents within each drug class, which was beyond the scope of this study.
Conclusion
In this nationwide real-world study of patients with axSpA, the majority of patients initiating first IL-17i were biologic-experienced, whereas patients initiating first TNFi were biologic-naïve. For IL-17i, treatment retention was independent of baseline CRP levels, while remission rates were only modestly higher in patients with higher CRP levels at 12 months. In contrast, among patients initiating TNFi, higher CRP levels were associated with higher retention and remission rates. CRP level at treatment start may therefore inform expectations regarding treatment outcomes in routine care.
Supplementary material
Acknowledgements
We are grateful to all patients and Danish Departments of Rheumatology that contribute to the DANBIO registry and to Niels Steen Krogh, ZiteLab, for the preparation of the raw data.
Eli Lilly had no role in the collection of data, statistical analyses or preparation of this manuscript and had no access to the raw data.
Footnotes
Funding: This study was partly sponsored by Eli Lilly.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Data availability statement
Data are available on reasonable request.
References
- 1.Navarro-Compán V, Sepriano A, El-Zorkany B, et al. Axial spondyloarthritis. Ann Rheum Dis. 2021;80:1511–21. doi: 10.1136/annrheumdis-2021-221035. [DOI] [PubMed] [Google Scholar]
- 2.Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390:73–84. doi: 10.1016/S0140-6736(16)31591-4. [DOI] [PubMed] [Google Scholar]
- 3.Ramiro S, Nikiphorou E, Sepriano A, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. 2023;82:19–34. doi: 10.1136/ard-2022-223296. [DOI] [PubMed] [Google Scholar]
- 4.Maksymowych WP, Bolce R, Gallo G, et al. Ixekizumab in radiographic axial spondyloarthritis with and without elevated C-reactive protein or positive magnetic resonance imaging. Rheumatology (Oxford) 2022;61:4324–34. doi: 10.1093/rheumatology/keac104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002;359:1187–93. doi: 10.1016/s0140-6736(02)08215-6. [DOI] [PubMed] [Google Scholar]
- 6.Arends S, Brouwer E, van der Veer E, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13:R94. doi: 10.1186/ar3369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Glintborg B, Ostergaard M, Krogh NS, et al. Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years’ surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis. 2010;69:2002–8. doi: 10.1136/ard.2009.124446. [DOI] [PubMed] [Google Scholar]
- 8.Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1) Ann Rheum Dis. 2013;72:815–22. doi: 10.1136/annrheumdis-2012-201766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Rudwaleit M, Schwarzlose S, Hilgert ES, et al. MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis. Ann Rheum Dis. 2008;67:1276–81. doi: 10.1136/ard.2007.073098. [DOI] [PubMed] [Google Scholar]
- 10.Braun J, Blanco R, Marzo-Ortega H, et al. Secukinumab in non-radiographic axial spondyloarthritis: subgroup analysis based on key baseline characteristics from a randomized phase III study, PREVENT. Arthritis Res Ther. 2021;23:231. doi: 10.1186/s13075-021-02613-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med. 2015;373:2534–48. doi: 10.1056/NEJMoa1505066. [DOI] [PubMed] [Google Scholar]
- 12.Deodhar A, van der Heijde D, Gensler LS, et al. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395:53–64. doi: 10.1016/S0140-6736(19)32971-X. [DOI] [PubMed] [Google Scholar]
- 13.Deodhar A, Blanco R, Dokoupilová E, et al. Improvement of Signs and Symptoms of Nonradiographic Axial Spondyloarthritis in Patients Treated With Secukinumab: Primary Results of a Randomized, Placebo-Controlled Phase III Study. Arthritis Rheumatol. 2021;73:110–20. doi: 10.1002/art.41477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Braun J, Deodhar A, Landewé R, et al. Impact of baseline C-reactive protein levels on the response to secukinumab in ankylosing spondylitis: 3-year pooled data from two phase III studies. RMD Open. 2018;4:e000749. doi: 10.1136/rmdopen-2018-000749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Dougados M, Lucas J, Desfleurs E, et al. Factors associated with the retention of secukinumab in patients with axial spondyloarthritis in real-world practice: results from a retrospective study (FORSYA) RMD Open. 2023;9:e002802. doi: 10.1136/rmdopen-2022-002802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Christiansen SN, Horskjær Rasmussen S, Ostergaard M, et al. Effectiveness of secukinumab in radiographic and non-radiographic axial spondyloarthritis: a European routine-care observational study. RMD Open. 2024;10:e004166. doi: 10.1136/rmdopen-2024-004166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Rudwaleit M, Haibel H, Baraliakos X, et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheum. 2009;60:717–27. doi: 10.1002/art.24483. [DOI] [PubMed] [Google Scholar]
- 18.Reveille JD. Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol. 2015;34:1009–18. doi: 10.1007/s10067-015-2949-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Rusman T, van Vollenhoven RF, van der Horst-Bruinsma IE. Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky. Curr Rheumatol Rep. 2018;20:35. doi: 10.1007/s11926-018-0744-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hellamand P, van de Sande M, Ørnbjerg LMi, et al. Sex differences in the effectiveness of first-line tumour necrosis factor inhibitors in axial spondyloarthritis: results from the EuroSpA Research Collaboration Network. RMD Open. 2023;9:e003325. doi: 10.1136/rmdopen-2023-003325. [DOI] [Google Scholar]
- 21.Gao A, Pardo Pardo J, Dang S, et al. Sex-Related Differences in Efficacy and Safety Outcomes in Axial Spondyloarthritis Randomized Clinical Trials: A Systematic Literature Review and Meta-Analysis. Arthritis Care Res (Hoboken) 2025;77:813–26. doi: 10.1002/acr.25512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Li D, Zhang X, Tian Y, et al. Efficacy and Safety of Tumor Necrosis Factor Inhibitors, Interleukin-17 Inhibitors, and Janus Kinase Inhibitors in Patients with Non-Radiographic Axial Spondyloarthritis: A Systematic Review and Network Meta-Analysis. Int Arch Allergy Immunol. 2025;186:784–801. doi: 10.1159/000542744. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Ciurea A, Kissling S, Bürki K, et al. Current differentiation between radiographic and non-radiographic axial spondyloarthritis is of limited benefit for prediction of important clinical outcomes: data from a large, prospective, observational cohort. RMD Open. 2022;8:e002067. doi: 10.1136/rmdopen-2021-002067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Webers C, Ortolan A, Sepriano A, et al. Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis. Ann Rheum Dis. 2023;82:130–41. doi: 10.1136/ard-2022-223298. [DOI] [PubMed] [Google Scholar]
- 25.Hyrich KL. Real world data in rheumatology. Semin Arthritis Rheum. 2019;49:S22–4. doi: 10.1016/j.semarthrit.2019.09.021. [DOI] [PubMed] [Google Scholar]
- 26.Ibfelt EH, Jensen DV, Hetland ML. The Danish nationwide clinical register for patients with rheumatoid arthritis: DANBIO. Clin Epidemiol. 2016;8:737–42. doi: 10.2147/CLEP.S99490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Jensen KY, Grøn KL, Hetland ML, et al. Effectiveness of ixekizumab in 709 real-world patients with axial spondyloarthritis and psoriatic arthritis: a nationwide cohort study. RMD Open. 2025;11:e005806. doi: 10.1136/rmdopen-2025-005806. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Machado P, Landewé R, Lie E, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011;70:47–53. doi: 10.1136/ard.2010.138594. [DOI] [PubMed] [Google Scholar]
- 29.Kwon OC, Park M-C. BASDAI cut-off values corresponding to ASDAS cut-off values. Rheumatology (Oxford) 2022;61:2369–74. doi: 10.1093/rheumatology/keab494. [DOI] [PubMed] [Google Scholar]
- 30.Kristensen LE, Saxne T, Geborek P. The LUNDEX, a new index of drug efficacy in clinical practice: results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern Sweden. Arthritis Rheum. 2006;54:600–6. doi: 10.1002/art.21570. [DOI] [PubMed] [Google Scholar]
- 31.von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573–7. doi: 10.7326/0003-4819-147-8-200710160-00010. [DOI] [PubMed] [Google Scholar]
- 32.Overblik over anmeldelsespligten. [08-Aug-2025]. https://videnskabsetik.dk/ansoegning-til-etisk-komite/overblik-over-anmeldelsespligten Available. Accessed.
- 33.Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2019;71:599–611. doi: 10.1002/art.40753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Lukas C, Landewé R, Sieper J, et al. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68:18–24. doi: 10.1136/ard.2008.094870. [DOI] [PubMed] [Google Scholar]
- 35.Kyriacou DN, Lewis RJ. Confounding by Indication in Clinical Research. JAMA. 2016;316:1818–9. doi: 10.1001/jama.2016.16435. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available on reasonable request.