Effects of ixekizumab treatment on structural changes in the sacroiliac joint: MRI assessments at 16 weeks in patients with non-radiographic axial spondyloarthritis.

There is limited understanding regarding the inhibition of structural damage in the sacroiliac joint of patients with non-radiographic axial spondyloarthritis. This study evaluated the effect of the interleukin-17A inhibitor ixekizumab versus placebo on structural lesions in the sacroiliac joints as assessed by MRI at week 16 in patients with non-radiographic axial spondyloarthritis from the COAST-X study. COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs. Patients were randomly allocated to placebo or double-blind ixekizumab 80 mg every 4 weeks (Q4W) or 2 weeks (Q2W), with an 80 mg or 160 mg starting dose. We report a post-hoc analysis of 266 patients with available MRI scans from baseline and week 16. MRI scans were scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint structural score (SSS) method independently by two masked readers. Treatment comparisons used analysis of covariance based on observed cases. Correlations were evaluated among changes in SPARCC SSS for erosion, fat lesions, and backfill, and between changes in SPARCC SSS and sacroiliac joint inflammation scores and clinical measures. COAST-X was registered with ClinicalTrials.gov, NCT02757352. Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled to the COAST-X study. 290 (96%) of 303 participants completed the week 16 visit (95 in the ixekizumab Q4W group, 98 in the ixekizumab Q2W group, and 97 in the placebo group), and MRI scans were available for 266 patients at baseline and week 16 (85 in the ixekizumab Q4W group, 91 in the ixekizumab Q2W group, and 90 in the placebo group). Changes from baseline to week 16 in mean SPARCC SSS for erosion were -0·39 for ixekizumab Q4W (p=0·003 vs placebo), -0·40 for ixekizumab Q2W (p=0·002), and 0·16 for placebo; for fat lesions: 0·16 for ixekizumab Q4W (p=0·013), 0·10 for ixekizumab Q2W (p=0·067), and -0·04 for placebo; and for backfill: 0·21 for ixekizumab Q4W (p=0·011), 0·22 for ixekizumab Q2W (p=0·006), and -0·10 for placebo. Ankylosis did not change. Effects of ixekizumab versus placebo on structural changes were most pronounced in patients with baseline inflammation in the sacroiliac joints. Changes from baseline at week 16 in erosion, fat lesions, and backfill were correlated. Although the clinical relevance is not yet clear, patients with non-radiographic axial spondyloarthritis receiving ixekizumab had significant reductions in erosions and increases in fat lesions and backfill in the sacroiliac joints versus placebo at week 16, suggesting an early repair process with ixekizumab treatment. Eli Lilly and Company.

Maksymowych WP ，Baraliakos X ，Lambert RG ，Landewé R ，Sandoval D ，Carlier H ，Lisse J ，Li X ，Hojnik M ，Østergaard M ... -  《Lancet Rheumatology》

Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial.

Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Eli Lilly and Company.

Deodhar A ，van der Heijde D ，Gensler LS ，Kim TH ，Maksymowych WP ，Østergaard M ，Poddubnyy D ，Marzo-Ortega H ，Bessette L ，Tomita T ，Leung A ，Hojnik M ，Gallo G ，Li X ，Adams D ，Carlier H ，Sieper J ，COAST-X Study Group ... -  《-》

Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 ra

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs. In this phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites (12 countries) in Europe, Asia, and North America. By use of a computer-generated random sequence, patients were randomly assigned (1:1:1:1) to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference group), or placebo. The primary objective was to compare the proportion of patients achieving an ASAS40 response, a composite measure of clinical improvement in axial spondyloarthritis, at week 16 for both ixekizumab treatment groups versus the placebo group. The adalimumab reference group was included as an in-study active reference for comparison with placebo to provide additional context to interpretation of the ixekizumab study results. Between June 20, 2016, and Aug 22, 2017, 341 patients were randomly assigned to either the placebo group (n=87), adalimumab group (n=90), ixekizumab Q2W (n=83), or ixekizumab Q4W (n=81). At week 16, compared with placebo (16 [18%] of 87), more patients achieved ASAS40 with ixekizumab Q2W (43 [52%] of 83; p<0·0001), ixekizumab Q4W (39 [48%] of 81; p<0·0001), and adalimumab (32 [36%] of 90; p=0·0053). One serious infection occurred in each of the ixekizumab Q2W (1%), ixekizumab Q4W (1%), and adalimumab (1%) groups; none were reported with placebo. One (1%) Candida infection occurred in the adalimumab group and one (1%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No treatment-emergent opportunistic infections, malignancies, or deaths occurred. Each dosing regimen of ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms in patients not previously treated with bDMARDs; the safety profile was consistent with previous indications of ixekizumab. Eli Lilly and Company.

van der Heijde D ，Cheng-Chung Wei J ，Dougados M ，Mease P ，Deodhar A ，Maksymowych WP ，Van den Bosch F ，Sieper J ，Tomita T ，Landewé R ，Zhao F ，Krishnan E ，Adams DH ，Pangallo B ，Carlier H ，COAST-V study group ... -  《-》

Evaluation of active inflammation, chronic structural damage, and response to treatment of sacroiliitis in axial spondyloarthritis using the Spondyloarthritis research consortium of Canada scoring system.

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting the spine and sacroiliac joints. To investigate whether there are differences in inflammatory and chronic structural damages, as assessed by a semiquantitative MRI scoring method, between non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) patients with active inflammation at baseline, and to evaluate the treatment response in these patients after 3 months of tumor necrosis factor-alpha (TNF-α) inhibitor treatment. Fifty-eight axSpA patients with active inflammation were included in the study. The patients were divided into nr-axSpA group and AS group. MRI examinations of the sacroiliac joints were performed before and after treatment. Inflammatory and structural damages in these patients were assessed using the established Spondyloarthritis Research Consortium of Canada (SPARCC) inflammation and sacroiliac joint structural (SSS) scoring methods, which are two MRI-based scoring methods. The SPARCC score, SSS score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level were compared between the two groups. At baseline, SPARCC scores for patients in the nr-axSpA and AS groups did not differ significantly (P > 0.05); however, SSS scores for fat metaplasia, erosion, and backfill for patients in the AS group were significantly higher (P < 0.001). Compared with baseline, SPARCC scores were significantly decreased in both groups after treatment (P < 0.001); however, after treatment, no statistically significant difference was found regarding SPARCC scores between the AS and nr-axSpA groups. Compared with baseline, a significant increase in the SSS scores for fat metaplasia and backfill (P < 0.001) and a significant decrease in the SSS scores for erosion (P < 0.001) were observed in all axSpA patients. Changes in the SPARCC score was inversely correlated with the changes in the SSS score for fat metaplasia (r = - 0.634, P < 0.001). Changes in the SSS score for backfill were positively correlated with the changes in the SSS score for fat metaplasia (r = 0.277, P < 0.05) and inversely correlated with those for erosion (r = - 0.443, P < 0.001). The SPARCC and SSS scoring systems can be used to assess inflammatory and chronic structural damages as well as treatment responses in patients with axSpA. More severe structural damages were seen in AS patients. TNF-α inhibitor treatment for 3 months could effectively reduce inflammation in axSpA patients.

Zhang Y ，Guo Z ，Zhan Y ，Qu J ，Lei X ... -  《BMC MUSCULOSKELETAL DISORDERS》

Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis.

To evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study). Patients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated. MRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (-0.57 vs -0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: -0.81 versus -0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo. Treatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further. NCT01258738; Post-results.

Maksymowych WP ，Wichuk S ，Dougados M ，Jones HE ，Pedersen R ，Szumski A ，Marshall L ，Bukowski JF ，Lambert RG ... -  《-》