Janus kinase of all trades? Treatment of ixekizumab and dupilumab-related paradoxical reactions with upadacitinib

Dear Editor, Atopic dermatitis (AD) and psoriasis (PsO) are prevalent inflammatory skin diseases characterized by distinct clinical manifestations.[1-3] While conventional therapies provide some relief, biologics play a crucial role in treatment, significantly improving the quality of life for affected individuals.[2] However, paradoxical reactions to biologics are increasingly reported in this patient population.[2,3] The lack of consensus on management strategies within this subgroup poses challenges for clinical approaches.[1] This study presents two cases, highlighting their respective treatment courses, to provide valuable insights into the evolving challenges associated with paradoxical reactions in AD and PsO. A 10-year-old East Asian girl with recurrent AD since childhood had previously tried moisturizers, topical corticosteroids (TCS), narrow-band Ultraviolet B (UVB) phototherapy (NBUVB), and oral antihistamines, all without significant improvement [Figure 1a and b]. Subcutaneous therapy with dupilumab (300 mg every 2 weeks) initially showed improvement, but a week after the 14th dose, lichenified psoriasiform plaques appeared on the scalp, abdomen, upper back, and lower limbs [Figure 1c]. PsO was diagnosed with a paradoxical reaction to dupilumab. Rescue therapy included alternating injections of secukinumab and dupilumab, as well as oral cyclosporine (100 mg daily). After 5 months of alternating treatment attempts, numerous refractory plaques persisted. Eventually, oral upadacitinib (15 mg daily) significantly improved both AD and PsO. The patient had stable conditions with occasional mild flare-ups under 15–30 mg daily upadacitinib in the next year.Figure 1: (a) Erythematous scaly patches and papules with significant scales and excoriation on the right forearm and elbow and (b) posterior knee, (c) several lichenified psoriasiform plaques on upper back after the fourteenth dose of dupilumab, (d) psoriasiform plaques with scales on left arm and (e) upper back, (f) multiple maculopapular eruptions on abdomen and scaly patches on bilateral flexural elbows after the twelfth dose of ixekizumab.A 31-year-old East Asian man with recurrent plaque PsO for more than 10 years had limited improvement with TCS, calcineurin inhibitors (TCI), and NBUVB phototherapy [Figure 1d and e]. Subcutaneous ixekizumab (80 mg every 2 weeks for six doses, then every 4 weeks) initially improved his condition, but 3 weeks after the twelfth dose, he developed acute eczema with redness on the face, neck, hands, and chest [Figure 1f]. AD was diagnosed with a paradoxical event related to ixekizumab. Rescue therapy involved ustekinumab (45 mg subcutaneously), oral cyclosporine (300 mg daily), and suspension of ixekizumab. Despite these interventions, a new relapse of AD occurred 5 months later, unresponsive to an increased dose of cyclosporine. Eventually, oral upadacitinib (15 mg daily) significantly improved both AD and PsO. The patient had stable conditions with occasional mild flare-ups under 15mg daily of upadacitinib in the next year. Conventionally, PsO has been classified as a T helper 1 (Th1) and Th17-driven disorder, while AD has been primarily associated with T helper 2 (Th2) cells.[1,2] However, recent studies have identified distinct subtypes of AD, including the Asian variant, where Th17 and Th22 cells also play a pivotal role in pathogenesis.[1,3,4] Moreover, the increasing incidence of paradoxical reactions induced by biologics suggests that PsO and AD may not be entirely separate entities but rather part of a spectrum with varying T-cell polarities.[3,5-7] In cases of moderate-to-severe plaque PsO and AD, biologics are typically prioritized after conventional treatments fail. Unfortunately, a subset of patients experiences limited efficacy or paradoxical reactions to these interventions.[3,5-7] Furthermore, consensus on the management of biologic-induced paradoxical reactions remains elusive. In specific scenarios, such as following the initiation of dupilumab or ixekizumab, paradoxical reactions – such as psoriasiform changes or eczematous reactions – prove challenging to control using conventional therapies or other biologics. These occurrences underscore the potential significance of the immunophenotype in patients exhibiting overlapping features of PsO and AD. Some literature has reported the possible hypotheses of the paradoxical reaction of dupilumab, including inhibition of interlukin (IL)-4 by dupilumab activates Th1 and Th17 cells, which are involved in PsO [Supplementary Figure 1].[1,2,4] For ixekizumab-induced eczematous eruptions, recent literature highlights limited reports of brodalumab-related eczematous eruptions compared to secukinumab and ixekizumab.[2] Brodalumab functions by inhibiting the IL-17 receptor A, effectively blocking multiple IL-17 cytokines. Studies have established that IL-17E plays a critical role in Th2-mediated inflammation, while IL-17C is closely associated with atopic eczema.[2] This suggests that ixekizumab-induced eczematous eruptions may be linked to other IL-17 family members, except IL-17A.[2]Supplementary Figure 1: Dupilumab-induced paradoxical psoriasiform eruptions.Prolonged administration of biologics can lead to cumulative exposure, potentially prompting immune system adaptations and paradoxical reactions over time. The onset of these reactions varies among individuals, with Yagiz et al. reporting a median onset time of 12 months (range: 1–132 months, mean: 21 months).[8] This delayed onset reflects the gradual nature of immune system changes triggered by continuous biologic use. Based on our clinical experience, patients with Asian-type AD, which indicates more demarcation of lesions, with more prominent scaling and lichenification, have higher possibilities for poor or paradoxical reactions to dupilumab.[1] Janus kinase inhibitors emerge as an alternative therapeutic option in such instances.[9] Notably, Upadacitinib appears to demonstrate favorable efficacy in both situations. The strategy of inhibiting Janus kinase rather than specific interleukins may yield better responses and help prevent paradoxical reactions in patients with concurrent PsO and AD features.[3] In conclusion, we presented two cases of paradoxical reactions to dupilumab and ixekizumab, both of which exhibited positive responses to upadacitinib. These findings highlight the potential role of upadacitinib as a management strategy for paradoxical reactions in the context of AD and PsO. Further research and additional clinical experiences are necessary to establish consensus therapeutic approaches and enhance our understanding of the underlying mechanisms. Declaration of patient consent The authors certify that they have obtained appropriate consent forms from the legal guardian of the patient in the first case and from the patient in the second case. In the forms, the guardian and the patient have given their consent for the images and other clinical information to be reported in the journal. They understand that the patient’s name and initials will not be published and that every effort will be made to conceal the patient’s identity, although anonymity cannot be guaranteed. Data availability statement The datasets generated during and/or analyzed during the current study are publicly available. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.