Targeted therapies with biologics blocking IL-13 and Janus kinase (JAK) inhibitors (JAKi) are frequently used for the treatment of moderate to severe atopic dermatitis (AD) 1. Although proven to be effective, they have the potential to mediate unwanted effects owing to the multiple functions of IL-13, and the broad expression of JAKs. This study aimed at investigating the spectrum of adverse reactions observed in AD patients treated with biologics and/or JAKi and discussing possible interferences of these anti-inflammatory therapies with the immune system. In a single-center retrospective study, data of 145 patients, in whom a new systemic therapy for AD was started (07/2017–07/2023), because of lack of efficacy or adverse reactions to previous topical or systemic therapies (data available 01/2000 on) were analyzed (Tables S1–S3). The median follow-up time was 40.0 months (IQR 25.0–63.5). Systemic therapies included immunosuppressants (ciclosporin, azathioprine), biologics (dupilumab, tralokinumab), and JAKi (baricitinib, upadacitinib, abrocitinib, tofacitinib). In total, 269 adverse events have been documented (Tables S4 and S5), of which most were mild (67.3%), but in 27.1% of cases, the culprit drug had to be stopped. The most common adverse reactions associated with dupilumab or tralokinumab were ocular surface disease (OSD) and head/neck dermatitis (HND), while others, such as the onset or worsening of inflammatory bowel disease or arthritis, sarcoidosis and uveitis, rapidly progressing vitiligo, psoriasiform dermatitis, infections (eczema herpeticum, varicella-zoster infection, impetigo), and weight gain were rare but clinically significant. Adverse reactions reported upon JAKi therapy were infections, including purulent arthritis and pneumonia, acne, psoriatic lesions, a worsening of Crohn's disease, weight gain, and abnormal laboratory results. Nephrotoxicity, hypertension, infections, headache and abdominal pain were the main reasons why ciclosporin therapy had to be stopped. Our results on the spectrum of adverse drug reactions to systemic therapies of AD, including biologics and JAKi, are in agreement with recent reports on real-world data 2. Next, we classified the adverse reactions observed upon treatment with biologics and other immunomodulatory agents according to the proposed categories of biologics-associated adverse reactions 3. Possible pathomechanisms include immune and cytokine imbalances and off-target reactions induced by biologics, effects on signaling pathways, and altered immune functions following JAKi therapy, and toxic effects of immunosuppressants (Table 1). Most adverse reactions observed upon the use of biologics blocking IL-4 and/or IL-13 function might be explained, at least partially, by a shift from the predominant type 2 inflammation in AD toward Th1, Th17, and Th22 immune responses 3. A switch from Th2/Th17 toward Th1/Th17 in OSD and an increase of type 22 markers in HND upon dupilumab therapy have been reported 4, 5. Also, for psoriatic dermatitis, inflammatory bowel disease, sarcoidosis, and vitiligo, a preponderance of type 1, 17, and 22 responses after blocking type 2 inflammation can be assumed as the underlying pathomechanism. Infections associated with systemic AD therapy might be a result of both immune imbalance and blocking the signaling of type I and type II interferons (IFN-α, IFN-γ). In addition, various adverse reactions resulting from interferences with physiological functions of the target molecule, inhibition of signaling pathways, or toxic effects have been noted upon therapy with biologics, JAKi, and immunosuppressants 3. Weight gain could be assigned to an inhibition of JAK/STAT signaling in the hypothalamus as well as the blockade of type 2 cytokine functions and thus their regulatory effects on adipose tissue 6. Blocking IL-13: Epithelial cell homeostasis ↓, Mucus production by goblet cells ↓ CD8+ T cells ↓ Treg ↑, IL-10↑ Blocking mTORC: impaired lipid secretion Blocking signaling of EGFR Blocking JAK2/STAT: Leptin signaling↓ in the hypothalamus Blocking signaling of IL-4, IL-13, IL-24: adipocyte maturation↓; lipid breakdown↓; insulin resistance JAK2 inhibition: Erythropoietin ↓, GM-CSF ↓, G-CSF ↓, Thrombopoetin ↓ The insights into the spectrum of adverse reactions upon therapy with biologics and JAKi suggest that these effects are most likely the result of an immune imbalance and/or interference with physiological functions of target molecules and signaling pathways. The data presented here have implications for the monitoring and therapeutic management of patients, in particular those with comorbidities. D.S., C.S., H.-U.S., and S.R.-H. were involved in the study concept, methodology, and design. K.T., C.A., Z.M., and M.L. were involved in the acquisition of data. K.T., C.A., and S.C. were involved in the analysis and interpretation of data. D.S. and S.R.-H. were involved in study supervision. K.T., C.A., D.S., and S.R.-H. were involved in drafting of the manuscript. K.T., C.A., H.-U.S., C.S., S.R.-H., and D.S. were involved in critical revision of the manuscript for important intellectual content. The authors have nothing to report. The study was approved by the Cantonal Ethics Committee Bern (2023–01598). General informed consent had been obtained from all patients prior to the study. C.A., Z.M., M.L., S.C., H.-U.S.: no additional conflicts of interest. C.S.: Advisor or speaker for AbbVie, Almirall, BMS, GSK, Incyte, LEO Pharma, Lilly, Kiowa Kirin, Novartis, Pfizer, and Sanofi, research funding from PPM Services. D.S.: Advisor for AbbVie, Amgen, Astra Zeneca, Galderma, Incyte, LEO, Novartis, Sanofi. Participation in clinical trials of Sanofi, Elli Lilly, Pfizer, AbbVie, Amgen, Incyte. S.R.-H.: Advisor or speaker for Almirall, Incyte, LEO Pharma, Galderma, GSK, Sanofi. K.T.: Advisor for Galderma, LEO, AbbVie, received support for travel from Almirall, Sanofi. The data that support the findings of this study are available from the corresponding author upon request. Table S1: Demographics and severity of atopic dermatitis of patients included in the study. Table S2: Concomitant diseases and previous atopic dermatitis therapies of study patients. Table S3: Therapies for atopic dermatitis prescribed at baseline and follow-up visits. Table S4: Description of all treatment-emergent adverse events observed, and related actions taken. Table S5: Description of treatment-emergent adverse events observed, and related actions taken by pharmaceutical product groups (immunosuppressants ciclosporin, azathioprine, biologics dupilumab, tralokinumab, small molecules JAK inhibitors (upadacitinib, abrocitinib, baricitinib, tofacitinib), apremilast). 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Thormann et al. (Fri,) studied this question.