Baseline demographics and disease characteristics for COAST-V (N = 340) are summarized in Table S1. Briefly, most patients (N = 276, 81%) were male, the mean age was 41.7 ± 11.7 years, and 213 (63%) patients were of white race. A total of 781 patients were assessed for eligibility and 341 were randomly assigned to treatment. The trial profile up to week 16 is included in the supplement (Fig. S1).

In the first analysis when inflammation was controlled as assessed by MRI SPARCC SIJ < 4 at week 16 and MRI SPARCC Spine < 3 at week 16, both ixekizumab Q4W (mean = − 3.9 mm, p < 0.001) and adalimumab (mean = − 2.8 mm, p = 0.02) experienced significant reduction in SP-N at week 16 versus placebo (mean = − 1.6 mm, Fig. 1a, Table 1). In spinal pain, a significant difference was seen at week 16 between ixekizumab Q4W (mean = − 3.3 mm, p = 0.041) versus placebo (mean = − 2.3 mm); adalimumab (mean = − 2.4 mm) had a comparable reduction in spinal pain to placebo (Fig. 2a, Table 1). In the bodily pain domain, a significant difference was seen at week 16 between ixekizumab Q4W (mean = 22.5 mm, p = 0.01) versus placebo (mean = 11.9 mm); adalimumab (mean = 19.4 mm) had a greater, but nonsignificant, reduction in bodily pain compared to placebo (Fig. 3a, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures (Figs. 1a, 2a, and 3a, Table 1).

When inflammation was persisting as assessed by MRI SPARCC SIJ ≥ 4 at week 16 and MRI SPARCC Spine ≥ 3 at week 16, ixekizumab Q4W (mean = − 3.5 mm, p < 0.01) and adalimumab (mean = − 3.1, p = 0.02) experienced significant reduction in SP-N at week 16 (Fig. 1b, Table 1). In spinal pain, a significant difference was seen at week 16 between both ixekizumab Q4W (mean = − 3.2 mm, p = 0.004) and adalimumab (mean = − 3.0 mm, p = 0.012) versus placebo (mean = − 1.7 mm, Fig. 2b, Table 1). In the bodily pain domain, a significant difference was seen at week 16 between both ixekizumab Q4W (mean = 22.3 mm, p = 0.005) and adalimumab (mean = 23.0 mm, p = 0.001) versus placebo (mean = 10.9 mm, Fig. 3b, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures (Figs. 1b, 2b, and 3b, Table 1).

In the second analysis when inflammation was controlled as assessed by CRP, ixekizumab Q4W (mean = − 3.8 mm, p < 0.01) and adalimumab (mean = − 3.2 mm, p < 0.05) achieved significantly greater reduction in SP-N at week 16 versus placebo (mean = − 1.9 mm, Fig. 1c, Table 1). In spinal pain, a significant difference was seen at week 16 between both ixekizumab Q4W (mean = − 3.6 mm, p = 0.0038) and adalimumab (mean = − 2.9 mm, p = 0.0233) versus placebo (mean = − 1.5 mm, Fig. 2c, Table 1). In bodily pain, a significant difference was seen at week 16 between both ixekizumab Q4W (mean = 24.3 mm, p = 0.009) and adalimumab (mean = 23.7 mm, p = 0.009) versus placebo (mean = 11.8 mm, Fig. 3c, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures (Figs. 1c, 2c, and 3c, Table 1).

When inflammation was persisting as assessed by CRP, ixekizumab Q4W (mean = − 3.7 mm, p < 0.001) achieved a significant reduction in SP-N versus placebo (mean = − 1.7 mm) at week 16; the observed improvement with adalimumab (mean = − 2.2 mm, p = 0.4) was not significant. Furthermore, patients re-randomized to ixekizumab from adalimumab or placebo at week 16 had further reductions in SP-N at week 52 (Fig. 1d, Table 1). In spinal pain, a significant difference was seen at week 16 between ixekizumab Q4W (mean = − 2.9 mm, p = 0.018) versus placebo (mean = − 2.0 mm); adalimumab (mean = − 2.0 mm) had a comparable reduction to placebo (Fig. 2d, Table 1). In the bodily pain domain, a significant difference was seen at week 16 between ixekizumab Q4W (mean = 20.0 mm, p = 0.0063) versus placebo (mean = 10.6 mm); adalimumab (mean = 13.0 mm) had a greater, but nonsignificant, improvement in bodily pain compared to placebo (Fig. 3d, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures (Figs. 1d, 2d, and 3d, Table 1).

In the third analysis, when inflammation was controlled as assessed by both MRI and CRP, ixekizumab Q4W (mean = − 3.8 mm) and adalimumab (mean = − 3.1 mm) demonstrated a numerically greater reduction versus placebo (mean = − 2.4 mm, Fig. 1e, Table 1) in SP-N at week 16, although neither drug had a significant reduction versus placebo. In the bodily pain domain, ixekizumab Q4W (mean = 23.7 mm) and adalimumab (mean = 22.2 mm) treated patients experienced a nonsignificant reduction versus placebo at week 16 (mean = 16 mm, Fig. 3e, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures, except for placebo when inflammation was controlled as assessed by MRI and CRP, there was decrease at week 52 (mean = 12.2 mm) compared to week 16 (mean = 16.0, Figs. 1e, 2e, and 3e, Table 1).

When inflammation was persisting as assessed by MRI and CRP simultaneously, ixekizumab Q4W (mean = − 3.7 mm, p < 0.001) achieved a significant reduction in SP-N versus placebo at week 16 (mean = − 1.7 mm); the observed improvement with adalimumab (mean = − 2.6 mm, p = 0.06) was not significant (Fig. 1f, Table 1). Patients re-randomized to ixekizumab from adalimumab or placebo at week 16 had further reductions in SP-N at week 52 (Fig. 1f, Table 1). In spinal pain, a significant difference was seen at week 16 between ixekizumab Q4W (mean = − 3.2 mm, p < 0.001) versus placebo (mean = − 1.9); adalimumab (mean = − 2.5) had a greater but nonsignificant improvement compared to placebo (Fig. 2f, Table 1). In bodily pain, a significant difference was seen at week 16 between both ixekizumab Q4W (mean = 21.8 mm, p < 0.001) and adalimumab (mean = 18.3, p = 0.015) versus placebo (mean = 10.5, Fig. 3f, Table 1). Further improvements were experienced by patients in the adalimumab or placebo arm after they were re-randomized to ixekizumab at week 16 by week 52 in all three pain measures (Figs. 1f, 2f, and 3f, Table 1).

In the pathway analysis, while the total effect of ixekizumab on pain relief over placebo at week 16 was greater than that for adalimumab, treatment with ixekizumab versus placebo in patients with AS had a greater direct effect on spinal pain (ixekizumab = 70.8%, adalimumab = 45.7%), SP-N (ixekizumab = 75.4%, adalimumab = 60.7%), and bodily pain domain (ixekizumab = 71.7%, adalimumab = 69.4%) compared to adalimumab versus placebo at week 16 (Fig. 4). Pathway analysis enables a numerical comparison in the indirect effect between the two drugs, however no statistical comparison was conducted. Therefore, no statement regarding statistical significance can be made.

Pathway analysis of treatment effect on spinal pain, SP-N, and bodily pain domain in ixekizumab (N = 78) and adalimumab (N = 82) treated patients versus placebo (N = 79) in the intent to treat population at week 16. Bar plots present total treatment effect on pain relief decomposed by direct and indirect effects, for ixekizumab and adalimumab. a Pathway analysis of treatment effect on spinal pain in ixekizumab and adalimumab-treated patients versus placebo in the ITT population at week 16. b Pathway analysis of treatment effect on SP-N in ixekizumab and adalimumab-treated patients versus placebo in the ITT population at week 16. c Pathway analysis of treatment effect on SF-36 bodily pain domain in ixekizumab and adalimumab-treated patients versus placebo in the ITT population at week 16. Figures show mean (standard error). ADA adalimumab, CRP C-reactive protein, ITT intent to treat, IXE ixekizumab, MRI magnetic resonance imaging, SF-36 Medical Outcomes Study 36-item Short-Form Health Survey, SIJ sacroiliac joint, SP-N spinal pain at night, SPARCC Spondyloarthritis Research Consortium of Canada