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Background In clinical trials of axial spondyloarthritis (axSpA), composite measures such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response criteria, Assessment of Spondyloarthritis international Society (ASAS) response criteria, Ankylosing Spondylitis Disease Activity Score (ASDAS) disease activity states and ASDAS response criteria are used. However, these validated measures are largely based on patient (pt)-reported symptoms, which are likely to be confounded by other factors. In pts with active axSpA, certolizumab pegol (CZP) has demonstrated sustained clinical efficacy in clinical outcomes over 204 weeks [1]. However, we hypothesise that reduction of sacroiliac joint (SIJ) and spinal inflammation following treatment with CZP, as measured by MRI and C-reactive protein (CRP) levels, may not necessarily translate into clinical response [2].
Objectives A post-hoc analysis to evaluate the relationship between objective signs of inflammation (OSI), as measured by MRI/CRP, and clinical outcomes following 12 weeks of CZP treatment in pts with active axSpA.
Methods Data were analysed from the phase 3 RAPID-axSpA study (NCT01087762) [1]. To improve precision of pt-level estimates, data from two independent readers were pooled in a Mixed Model for Repeated Measures for each response variable; Manhattan plots are presented for ASDAS, BASDAI, CRP, Ankylosing Spondylitis spine MRI (ASspiMRI) Berlin Score and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ score. Outcomes are reported for pts (initially randomised to either CZP, or to placebo before switching to CZP) prior to CZP treatment (pre-CZP treatment) and following 12 weeks (wks) of treatment (post-CZP treatment).
Results 136 pts (radiographic axial spondyloarthritis [r-axSpA]: 76; non-radiographic axial spondyloarthritis [nr-axSpA]: 60) had a pre-CZP and ≥1 post-CZP MRI. Pre-CZP demographics for the r-axSpA and nr-axSpA populations are presented in Table 1. Following CZP treatment, CRP, ASspiMRI Berlin score, and SPARCC MRI SIJ score were reduced by >50%, in the majority of pts (CRP: 136/136 [100.0%]; BERLIN: 73/136 [53.7%]; SPARCC: 71/136 [52.2%]), and often by >75% (CRP: 18/136 [13.2%]; BERLIN: 53/136 [39.0%]; SPARCC: 50/136 [36.8%]) irrespective of pre-CZP value. However, only a minority of both r-axSpA and nr-axSpA pts (Figure 1), showed a >50% reduction in clinical responses (ASDAS: 66/136 [48.5%]; BASDAI: 64/136 [47.1%]). These results were also observed at the individual pt level; >50% improvements in MRI/CRP inflammatory measures did not translate into similar improvements in clinical responses for the majority of pts.
Conclusion This analysis revealed a potential disconnect between OSI, as measured by MRI and CRP, and clinical outcome responses. In most pts, CZP treatment resulted in a reduction of objective measures of inflammation, irrespective of improvements in clinical symptoms and measures of disease activity. The use of clinical response measures as clinical trial endpoints may therefore underestimate anti-inflammatory treatment effects.
Reference [1]van der Heijde. Ann Rheum Dis 2018;77:699–705; 2. Braun J. RMD Open 2017;3:e000430.
| r-axSpA (N=76) | nr-axSpA (N=60) | |
|---|---|---|
| Age, years, mean (SD) | 40.4 (11.6) | 37.3 (13.0) |
| Male, n (%) | 52 (68.4) | 31 (51.7) |
| BMI, kg/m2, mean (SD) | 27.0 (5.2)a | 26.8 (6.0)a |
| Symptom duration, years, median (min–max) | 10.3 (0.3–50.9) | 5.9 (0.3–39.6) |
| Symptom duration ≥5 years, n (%) | 51 (67.1) | 32 (53.3) |
| HLA-B27 positive, n (%) | 59 (77.6)b | 46 (76.7)c |
| ASDAS, mean (SD) | 4.0 (0.9) | 3.8 (0.9) |
| BASDAI, mean (SD) | 6.8 (1.5) | 6.6 (1.5) |
| CRP, mg/LMean (SD) |
21.2 (27.5) |
16.2 (17.0) |
| CRP, n (%)≤15 mg/L |
44 (57.9) |
37 (61.7) |
| MRI status, n (%)MRI+ |
76 (100) |
37 (61.7) |
MRI set. aData missing for 1 patient; observed case imputation used; bData missing for 1 patient; cData missing for 3 patients.
Image/graph:
Acknowledgements This study was funded by UCB Pharma. Medical writing support was provided by Costello Medical, funded by UCB Pharma.
Disclosure of Interests Martin Rudwaleit Speakers bureau: AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Novartis, and UCB Pharma, Filip van den Bosch Speakers bureau: AbbVie, BMS, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Helena Marzo-Ortega Speakers bureau: AbbVie, Eli-Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie, Eli-Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, Victoria Navarro-Compán Speakers bureau: AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Galapagos, Moonlake, MSD, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie and Novartis, Rachel Tham Employee of: Veramed statistical consultant for UCB Pharma, Thomas Kumke Shareholder of: UCB Pharma, Employee of: UCB Pharma, Lars Bauer Shareholder of: UCB Pharma, Employee of: UCB Pharma, Mindy Kim Shareholder of: UCB Pharma, Employee of: UCB Pharma, Lianne S. Gensler Consultant of: AbbVie, Acelyrin, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, and UCB Pharma, Grant/research support from: Novartis and UCB Pharma paid to institution.
Keywords: Outcome measures, Spondyloarthritis, Clinical trials
DOI: 10.1136/annrheumdis-2023-eular.3141