Effectiveness and Safety of Upadacitinib in the Treatment of Moderate-Severe Atopic Dermatitis: A Multicentric, Prospective, Real-World, Cohort Study

Atopic dermatitis (AD) is a chronic-relapsing, highly itchy, inflammatory skin disease that is associated with a negative impact on patients’ quality of life (QoL) [1]. It represents a common skin condition with an increasingly higher prevalence in adulthood that in Italy is estimated at 8.1% [2]. Because of the complex immune mechanism underlying AD pathogenesis, topicals and/or conventional systemic immunosuppressive/immunomodulant therapies (i.e., cyclosporine) are prescribed, though their use is often limited by the lack of effectiveness or safety risks related with their long-term use [3, 4]. Dupilumab, a subcutaneous monoclonal antibody inhibiting the signaling of two pathogenic cytokines, interleukin (IL)-4 and IL-13 [5], is now available in most European countries for the treatment of moderate-to-severe AD in adults and adolescents/children. Although many patients benefit from dupilumab therapy, persistence of AD was reported in a consistent proportion of dupilumab-exposed patients in pivotal trials and in real-world studies [5‐8]. Moreover, about 31% of patients continued to have flares and 4–17% were unresponsive or showed an inadequate response to dupilumab [7‐11]. In addition, dupilumab-related adverse events might be commonly observed and the eventual cause of discontinuation, such as conjunctivitis, which was reported in up to 40% of subjects treated in a real-world setting [8, 12‐14], or dupilumab-associated facial and neck erythema, which occurred in 11% of cases [15]. Overall, these reports underline the need for therapeutic alternatives for the treatment of moderate-to-severe AD. New drugs are being investigated for the treatment of AD, in particular agents targeting Janus kinase (JAK)-1 represent a promising therapy to treat AD as multiple proinflammatory cytokines implicated in AD pathogenesis signal through this kinase [16]. Upadacitinib, an oral selective JAK inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 [17], has been recently approved by the European Medicines Agency (EMA) for the treatment of both adults and adolescents with moderate-to-severe AD. Trials demonstrated high efficacy and a favorable safety profile of upadacitinib in treating moderate-to-severe AD across two doses (15 mg and 30 mg), either as monotherapy or combined with topical corticosteroids with a substantial steroid-sparing effect [18‐20]. Moreover, a head-to-head trial comparing upadacitinib with dupilumab demonstrated superiority of upadacitinib in treating AD, with a significantly greater proportion of upadacitinib-treated patients achieving both primary and secondary endpoints [21]. Nevertheless, the trial setting implicates patient selection based on predetermined inclusion and exclusion criteria, which does not always reflect daily clinical practice. Thus, this study aimed to provide evidence of safety and effectiveness of upadacitinib in a heterogenous, real-world, AD patient cohort that mostly included patients failing available systemic therapies, in particular patients who discontinued dupilumab because of lack of efficacy or occurrence of adverse events.

Forty-three patients (15 females and 28 males) were treated with 30 mg upadacitinib daily for an observation period of 16 weeks. Baseline demographic and clinical characteristics of the study population are illustrated in Table 1. All patients had been previously treated with at least one systemic agent. In particular, dupilumab was prescribed in 42/43 patients, while in one case it was not prescribed as it was considered not indicated (severe conjunctivitis with marked facial involvement). The most common reason for dupilumab discontinuation was inefficacy (39 cases, 92.9%), followed by the occurrence of AEs (three cases: two for recalcitrant conjunctivitis and one for head/neck eczema).

Thirty-nine of 43 patients completed 16 weeks of treatment, whereas two withdrew from treatment due to Aes, while two were lost to follow-up.

Safety and effectiveness of upadacitinib have been shown in clinical trials, but real-world data are currently limited [18, 20‐24]. This prospective, multicentric study provides insights into the short-term safety and effectiveness of 30 mg upadacitinib in the treatment of moderate-to-severe adult AD patients in a real-world setting. In particular, our patient population consisted of difficult-to-treat patients who were unresponsive or had contraindications to several lines of systemic therapies including dupilumab, which in 92.9% of cases failed to obtain a satisfactory clinical response. Notably, patients previously exposed to dupilumab or JAK inhibitors were not included in the upadacitinib clinical trials [18, 20‐22].

Rapid and marked reduction of disease severity was observed from the first follow-up visit, corresponding to 4 weeks of treatment. Being a real-world study, intermediate follow-up visits (visit after 4 weeks of treatment, for instance) could be differently scheduled, thus, clinical data might result missing. In those patients evaluated after 4 weeks’ treatment, the clinical response obtained during the first weeks of treatment was maintained over time with further reductions in disease severity scores thereafter. According to therapeutic goals identified by an international expert consensus seeking to define treat-to-target recommendations for AD [19], we also detected the achievement of both early and late therapeutic goals in a large percentage of patients (above 88%). These goals were obtained in a shorter timeframe (within 4 months of treatment) compared to those timepoints (3 and 6 months) proposed by the international expert consensus [19], suggesting an eventual revision of the treat-to-target strategy and goals in the future that considers the upcoming therapeutic options available for the management of AD. At week 4 and week 16, our study revealed elevated percentages of patients achieving EASI 75, EASI 90, and EASI 100, which were higher than clinical trial outcomes [20, 21]. In the Measure Up 1 and Measure Up 2 trials, EASI 75 was obtained by 79.7% and 72.9% of patients treated with 30 mg upadacitinib, respectively, and the association with topical low-to-medium potency corticosteroids did not enhance upadacitinib efficacy in a phase III trial, AD Up (77.1% of EASI 75 response at week 16) [20, 21]. In our cohort, almost all subjects (97.5%) achieved EASI 75 after 16 weeks of treatment. Differences in clinical outcomes between trial setting and our real-world experience were more marked in terms of EASI 90 and EASI 100. In our study, EASI 90 at week 16 was reached by 82.1% of patients, reflecting a self-assessed clear or almost clear condition (POEM 0–2) reported in 79.5% of treated cases.

This high rate of effectiveness could be related to the characteristics of our patient cohort, which consisted of high-need patients with moderate-to-severe AD, who had shown multifailure to systemic therapies, and had no other valid therapeutic options than upadacitinib. Additional inclusion/exclusion criteria of the compassionate use program could possibly have selected a sub-population of great responders. Another factor that might contribute to the better responses documented in this real-world study is the allowed combination of topical potent-ultrapotent corticosteroids based on the physician’s choice. Similarly, real-world outcomes related to other targeted therapies used in AD, such as dupilumab, showed higher response rates in comparison with clinical trials [25‐27]. As is commonly seen, in our study the improvement of skin manifestations was associated with a decrease of itch, an amelioration of sleep disturbances, as well as better QoL. In particular, at week 4 about one-third of patients achieved DLQI 0/1, which was obtained by a greater number of patients (76.9% of cases) at week 16. A significant improvement in patients’ QoL was also reported in the Measure Up 1 trial, with 41.1% of patients reaching DLQI 0/1 at week 16 [20]. No upadacitinib-treated patients withdrew from therapy because of ineffectiveness; the two cases of discontinuation were due to the occurrence of AEs. Overall, the safety profile was favorable and in line with clinical trials, showing plasma creatine phosphokinase elevation, anemia, and acne as the most frequently reported treatment-emergent AEs, the majority of which were mild and transient and did not cause treatment withdrawal.

Our study describing the safety and effectiveness of upadacitinib in patients unresponsive to dupilumab provides evidence with meaningful clinical implications as no data are currently available on dupilumab-exposed patients [5, 28, 29]. Long-term data on a larger patient population will be of great interest to confirm the persistence of treatment response and safety in upadacitinib-treated patients [30].