Discussion
pain, inflammatory bowel disease, UC
DISEASE, INFLAMMATORY BOWEL DISEASE, RECTAL BLEEDING, PGA
This post hoc analysis of data from OCTAVE Induction 1 and 2 examined interrelationships among tofacitinib treatment, disease activity (as measured by Mayo subscores), and SF-36/IBDQ domain scores in patients with UC. The majority of tofacitinib treatment effects on HRQoL, as measured using either the generic HRQoL instrument SF-36 or the disease-specific IBDQ, were indirect effects mediated via improvements in Mayo subscores. However, indirect effects via improvements in Mayo subscores did not fully explain the effects of tofacitinib on HRQoL as statistically significant direct effects were also observed and reported. Specifically, tofacitinib directly improved certain aspects of general health status (bodily pain, role-physical, and vitality) and disease-specific HRQoL (bowel symptoms, systemic symptoms, and social function) outside the benefit of improving stool frequency, rectal bleeding, endoscopic appearance, or PGA, as measured by the Mayo score. This suggests that the treatment effect of tofacitinib on HRQoL is due to mediators beyond the Mayo subscores. For example, a cross-sectional study of patients with inflammatory bowel disease in the USA found that high levels of stress were predictive of low HRQoL; thus, high levels of stress could be considered an additional mediator of the relationship between tofacitinib treatment and patient-reported outcomes [Guidance issued by the US Food and Drug Administration in 2016, and by the European Medicines Agency in 2018, recognizes the importance of HRQoL outcomes by recommending HRQoL measurements as key to the assessment of the signs and symptoms of UC, alongside clinician-reported endoscopic and histologic evaluation [Mediation modeling frameworks have been used previously to determine the associations between different exposures and treatment satisfaction among patients with inflammatory bowel disease. A post hoc analysis of data from a double-blind, placebo-controlled phase 2 trial used two mediation models, a clinician-reported outcomes-based model (which used the Mayo subscores as the mediator) and a patient-reported outcomes-based model (which used the IBDQ score domains as the mediator) to investigate the direct and indirect effects of tofacitinib treatment on patient satisfaction among patients with UC. The study found that in the clinician-reported outcomes-based model, the effect of tofacitinib treatment on patient satisfaction was predominantly mediated by improvements in the Mayo subscores; however, in the model with patient-reported mediators, the effect of tofacitinib treatment on patient satisfaction was only partially mediated by improvements in the IBDQ domains [The interpretation of this analysis was limited by biases that may influence patient-reported outcomes data, such as patient tendencies to select values at the extremes of HRQoL scales, regardless of the item content (extreme response style) [Furthermore, the results of this analysis must be interpreted with the understanding that no technique, including mediation analyses and other forms of structural equation models, can determine causation. The purpose of this mediation analysis was to quantify the hypothesized causal relationships (e.g., changes in disease activity affect SF-36/IBDQ domain scores). Mediation modeling often requires multiple iterations since assumptions must be refined if the results of a mediation model contradict the initially hypothesized model. Even if the results of a mediation model are consistent with the hypothesized relationships between model elements, this does not prove causation; instead, it shows that the assumptions made may be valid. Additionally, inclusion of data from patients from various countries and regions who were enrolled in OCTAVE Induction 1 and 2 may have been a potential confounder in this analysis, and the factors that mediate the effects of treatment on HRQoL may vary across different geographic regions.In conclusion, the results of these analyses indicate that Mayo scores and Mayo subscores are significant but incomplete contributors to the effects of tofacitinib on HRQoL in patients with moderate to severe UC. The results also indicate that additional mechanisms and/or pathways can affect how tofacitinib influences HRQoL outcomes and that HRQoL measurements may play an important role in the assessment of the signs and symptoms of UC. These results reinforce the value of clinicians using patient-reported HRQoL measures in addition to clinical measures, such as the Mayo score and its subscores, when assessing treatment outcomes in patients with UC. Additionally, prospectively designed studies are required to more fully elucidate other mediators of tofacitinib treatment effects on HRQoL, such as the cognitive-affective processes that may influence patient-reported outcomes.