In this study, patients with nr-axSpA treated with ixekizumab reported improved sleep, work productivity, and activity impairment. Primary results of the COAST-X trial have established the efficacy of ixekizumab in treating the signs of symptoms of nr-axSpA as demonstrated by significant improvements in ASAS40 response as early as Week 1 [1].
Patients with nr-axSpA are more likely to report poor sleep than the general population, and patients with nr-axSpA have reported worse sleep disturbance at baseline compared to patients with r-axSpA [15,16,17]. The baseline mean JSEQ score for patients naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) with nr-axSpA enrolled in the COAST-X trial was slightly higher than the scores for bDMARD-naïve patients with r-axSpA enrolled in the COAST-V trial, which may suggest worse sleep disturbance in bDMARD-naïve patients with nr-axSpA [1, 18]. However, TNFi-experienced patients with r-axSpA enrolled in COAST-W reported higher baseline JSEQ scores than bDMARD-naïve patients enrolled in COAST-X and COAST-V [18]. Factors contributing to the observation of greater sleep disturbance in nr-axSpA compared to r-axSpA may include a greater proportion of women being affected by nr-axSpA as well as a greater prevalence of diagnosed fibromyalgia in nr-axSpA patients [19]. Central sensitization, which is more common in female patients with axSpA and in patients with fibromyalgia, can also contribute to sleep disturbance [20]. Sleep disruption due to disease activity has also been tied to work impairment [15, 21]. Because sleep disruptions may exacerbate chronic inflammatory conditions or serve a marker of underlying inflammation, sleep quality could serve as a proxy for disease activity [15].
While there is not yet a full understanding of nr-axSpA’s impact on work disability and economic consequences, nr-axSpA’s effects are estimated to be equivalent to those of r-axSpA because both disease states share similar severity in disease activity, pain, and fatigue [11, 16]. Baseline absenteeism, overall work impairment, and activity impairment scores were slightly higher in bDMARD-naïve patients with nr-axSpA enrolled in the COAST-X trial compared to the bDMARD-naïve patients with r-axSpA enrolled in the COAST-V trial [22]. TNFi-experienced patients with r-axSpA enrolled in COAST-W reported higher baseline WPAI-SpA scores across all domains than bDMARD-naïve patients enrolled in COAST-X and COAST-V [22]. As described above, central sensitization can affect work impairment because it can worsen sleep disruption [19, 20].
Maintaining employment is an important factor in patients’ quality of life, influencing additional psychosocial, societal, and financial impacts [14, 23, 24]. In a 2015 study evaluating the baseline burden of early nr-axSpA and the effect of treatment with etanercept, 69.7% (129/185) of patients were employed at baseline; a similar proportion was found in the present analysis with 64.7% (196/303) of patients enrolled in COAST-X reporting part- or full-time employment [16]. European patients with nr-axSpA had greater work productivity loss compared with the general population, and bDMARD-naïve patients reported worse presenteeism, overall work impairment, and activity impairment than bDMARD-experienced patients [25].
Fatigue and sleep are inherently linked, and patients with axSpA consider both important for overall health [6]. Results from a study of patients with AS and rheumatoid arthritis (RA) treated with etanercept showed a significant association between fatigue and presenteeism and activity impairment (but not overall work impairment or absenteeism) in patients with AS as well as an association between fatigue and all WPAI-SpA domains in patients with RA [9]. A study of patients with axSpA in the United Kingdom found an association between absenteeism and worse fatigue, which was more likely in those with nr-axSpA; presenteeism, work impairment, and activity impairment were also associated with higher levels of fatigue [26]. In another study using data from the British Society for Rheumatology Biologics Register, fatigue was associated with absenteeism and presenteeism in patients with axSpA [21]. Results from the European Map of Axial Spondyloarthritis survey suggested that worse patient-reported outcomes, particularly greater disease activity and psychological distress, were associated with work-related issues [27].
In a recent study using data from 2 trials of patients with r-axSpA naïve to bDMARDs and those who were intolerant of or who had inadequate response to TNFi (COAST-V and COAST-W, respectively), treatment with ixekizumab improved work productivity and activity impairment as measured by WPAI-SpA with sustained and consistent results through Week 52 [22]. In the context of nr-axSpA, the efficacy of ixekizumab treatment in improving signs and symptoms in the COAST-X trial has been demonstrated [1]. A recent study using COAST-X trial data demonstrated that treatment with ixekizumab improved patient-reported outcomes in nr-axSpA, including patient global disease activity, spinal pain, function, stiffness, fatigue, and spinal pain at night [13]. An additional recent study using COAST-X trial data showed that treatment with ixekizumab improved patient-reported functioning and health in nr-axSpA [28]. Overall, these data suggest that ixekizumab has significant efficacy on patient-reported outcomes across the axSpA disease spectrum. Beyond axSpA, ixekizumab has also shown effectiveness in improving work productivity in patients with moderate-to-severe plaque psoriasis and psoriatic arthritis [29,30,31].
The results of this study show improvements in sleep, work productivity, and activity impairment and are consistent with previously reported results demonstrating the efficacy of ixekizumab in treating nr-axSpA [1, 13]. Collectively, these results suggest treatment with ixekizumab can improve patient-reported outcomes as well as overall HRQoL in the specific context of nr-axSpA.
Limitations of this study include the absence of specific predefined criteria to switch to open label, which followed regulatory requirements. At investigator discretion, substantial proportions of patients who achieved clinical response were switched from their blinded ixekizumab treatment to open-label ixekizumab and were considered non-responders. In addition, while over 60% of patients enrolled in COAST-X reported paid work, WPAI-SpA requires part- or full-time employment for absenteeism, presenteeism, and overall work impairment scores. The limited number of patients reporting paid work may have impacted analyses determining the statistical significance of changes from baseline in WPAI-SpA scores, particularly in absenteeism.
Strengths of the COAST-X trial included the enrollment of patients from multiple global regions. In addition, enrolled patients had objective signs of inflammation confirmed by screening MRI/CRP status. Patients enrolled in COAST-X also experienced disease symptoms that lasted over 10 years without transition to r-axSpA. This analysis used scores from the validated instruments JSEQ and WPAI-SpA. The presence and consistency of a placebo arm through Week 52 allowed for a true comparison of the effects of ixekizumab against placebo on sleep, work productivity, and activity impairment. COAST-X met ethical requirements by allowing patients to modify background therapy or switch to open-label ixekizumab Q2W after Week 16 (at investigator discretion).