Discussion
AD lesions, itch, anxiety, Dupilumab, atopic dermatitis, Skin Pain, skin pain, pruritus, atopic, non-herpetic skin infections, depression, AD, skin lesions
DISEASE, ATOPIC DERMATITIS, THIGH DISEASE, PATHOPHYSIOLOGY, SECONDARY, SKIN LESION, ATOPIC, SYSTEMIC INFECTION, PATHOGENESIS, SKIN LESIONS, CHRONIC DISEASE
Management of PN is challengingGiven the seminal role of pruritus and resultant scratching in the patient experience with PN, as exemplified by the ‘butterfly sign’ where there is an absence of lesions in regions of the body that the patient cannot easily reach, this was chosen as the primary endpoint for the trialDespite previous use of topical and, in over 60% of patients, systemic therapies, the patients enrolled in PRIME and PRIME2 had a high disease burden at baseline, with severe itch and skin lesions impacting sleep, QoL and mental health. All primary and key secondary endpoints addressing itch and number of skin lesions were met in both trials. Non-multiplicity-controlled significant itch improvement started as early as week 3 or 4, with progressively larger treatment differences from placebo throughout the 24-week treatment period. From an initial baseline of 20 to >100 nodules, 32.0% (PRIME) and 25.6% (PRIME2) of dupilumab-treated patients showed a reduction to ≤5 nodules, corresponding to a response of ‘clear’ or ‘almost clear’ skin at week 12, compared to 11.8% and 12.2% of placebo-treated patients; the treatment effect on skin lesions continued to improve after week 12, with 48.0% (PRIME) and 44.9% (PRIME2) of patients achieving ≤5 nodules at week 24 with dupilumab versus 18.4% and 15.9%, respectively, with placebo. Approximately one-third of dupilumab-treated patients met the composite pruritus and skin lesion endpoint at the end of treatment. Dupilumab treatment also led to fewer patients using rescue medication compared to placebo in both trials.Improvements in skin pain mirrored those in itch throughout both trials, with non-multiplicity-controlled significant improvement starting at week 3 and week 4 in PRIME and PRIME2, respectively. Dupilumab-treated patients experienced non-multiplicity-controlled significant improvement in DLQI from week 4 and, by the end of the treatment, achieved mean DLQI scores at the threshold between ‘small’ and ‘moderate’ impact on life in both trials, whereas the ‘very large’ impact of PN on QoL at baseline was maintained in placebo groups to week 24. Improvements (non-multiplicity-controlled significance in PRIME2) were also seen for HADS anxiety and depression.The safety profile of dupilumab observed in PN was consistent with its known safety profileMore than 50% of patients enrolled did not have an atopic background, and only 4% had concomitant mild AD. Efficacy was consistent regardless of the assessed atopic or non-atopic status, although patients with moderate-to-severe atopic dermatitis were not included in this study. These results support PN as a disease independent from AD. Thus, whether one has concomitant AD or not, the pathophysiology of PN may be highly conserved in terms of nodules yet distinct from AD lesions.Concomitant TCS/TCI therapy was allowed especially because topical treatments are the standard of care in clinical practice, and patients who experienced severe disease could continue with the standard of care, but higher placebo responses were observed in patients who did not use concomitant TCS/TCI compared to those who did. Possible reasons include the fact that patients who continued TCS/TCI use during the trials in each group were those with more severe disease. It is, therefore, not unexpected that improvements should come more easily in patients who started with less severe disease at baseline.Dupilumab, through its blockade of IL-4 and IL-13 signaling, may impact PN pathogenesis in multiple waysDupilumab specifically targets the IL-4/IL-13 cytokine axis and has not been associated with systemic immunosuppression, as suggested by the lower incidence of non-herpetic skin infections and absence of systemic infections in the dupilumab groups compared to placebo.In our studies, improvements in WI-NRS, Skin Pain NRS and DLQI increased progressively over 24 weeks of treatment without plateauing, indicating that further treatment could lead to continued improvements. The relatively short duration of treatment in this study for this chronic disease precluded assessment of efficacy maintenance beyond 24 weeks. Also, of the atopic population enrolled, mild, active AD was capped at 10%, limiting the strength of statistical analysis for this subpopulation. Lastly, although patients had high compliance with the daily diary, with over 90% at week 12 and 85% at week 24 completing the majority of the days for both studies (Supplementary Table In conclusion, dupilumab treatment in PRIME and PRIME2 led to significant improvements in multiple aspects of PN in patients with disease inadequately controlled with topical therapies, with a safety profile consistent with its known safety profile. These positive studies support the involvement of type 2 cytokines in driving PN disease pathogenesis and the targeting of the IL-4/IL-13 axis as a novel therapeutic paradigm for patients with PN.