Bakker, Daphne S

Boesjes, Celeste M

de Bruin-Weller, Marjolein S

de Graaf, Marlies

Knol, Edward F

van Wijk, Femke

Utrecht University Repository

294  |    Clin Exp Allergy. 2024;54:294–296.wileyonlinelibrary.com/journal/ceaReceived: 18 September 2023  | Revised: 22 November 2023  | Accepted: 6 December 2023DOI: 10.1111/cea.14442  R E S E A R C H  L E T T E RDifferential dynamics of TARC during JAK- inhibitor therapy compared to biological therapies targeting type 2 inflammationTo the editor,Atopic dermatitis (AD) is a complex inflammatory skin disease whose pathogenesis is primarily driven by CD4+ T helper (Th)2 cell- mediated responses. One of the involved type 2 chemokines is thymus and activation- regulated chemokine (TARC)/CCL17 which is constitutively expressed in the thymus, and mainly produced by dendritic and endothelial cells. It is therefore highly expressed in the dermis of both acute and chronic AD lesions.1 Consequently, higher serum TARC levels are found in AD patients compared to healthy controls, and levels significantly correlate with disease se-verity.2 Moreover, serum TARC levels significantly decrease dur-ing AD treatment including dupilumab and tralokinumab.3,4 TARC is therefore identified as most reliable severity biomarker for AD.2 Janus kinase (JAK) inhibitors (JAKi) baricitinib, upadacitinib and abrocitinib, targeting multiple cytokine pathways, have recently entered the market and have shown to be effective treatments for AD.5 Two recently published studies reported that serum TARC lev-els substantially decrease during upadacitinib and abrocitinib treat-ment.6,7 However, in our clinical practice, we found persistently high or increased serum TARC levels in AD patients despite disease improvement during JAKi treatment. Therefore, we determined serum TARC levels, which were measured during routine diagnos-tics, of AD patients treated with JAKi at the University Medical Center Utrecht, and compared those with serum TARC levels of AD patients treated with biologicals (i.e. dupilumab or tralokinumab). All patients participated the Dutch BioDay registry and visited the outpatient clinic at baseline and after 4, 8 (only JAKi) and 16 weeks of treatment and then every 3 months, between October 2017 and July 2023. Clinical effectiveness was measured by the Eczema Area Severity Index (EASI). TARC was also measured in plasma in a subgroup of JAKi patients (n = 10) and a dupilumab control group (n = 5), at baseline and week 8 or 16. Furthermore, platelet, lympho-cyte and monocyte counts were determined. All patients provided written informed consent.A total of 95 AD patients with 134 baricitinib, upadacitinib or abrocitinib treatment episodes, 622 AD patients with 643 dupilumab episodes and 60 tralokinumab treated patients, were included. Gender and age were equally distributed between the treatment groups (JAKi patients: 63.2% male, median age 33.0 years [interquartile range (IQR) 26–49]; dupilumab patients: 57.1% male, median age 43.0 years [IQR 30–56]; tralokinumab patients: 46.7% male, median age 40.0 years [IQR 29–52]). The baseline EASI was 13.0 (IQR 8.0–18.9) in the JAKi patients, and 14.0 (IQR 9.4–20.8) and 10.2 (IQR 6.6–16.5) in dupilumab and tralokinumab patients, respectively. In the JAKi cohort, the me-dian EASI decreased during 52 weeks of treatment with all me-dians beneath the cutoff score (EASI ≤ 7), indicating mild disease. However, median serum TARC levels either remained relatively stable or demonstrated a propensity to increase, which persisted during long- term treatment. In contrast, in the dupilumab and tralokinumab group both EASI and serum TARC levels substan-tially decreased during treatment (Figure 1).So far, we have not found an explanation for the high serum TARC levels in AD patients treated with JAKi. Recently the European Medicines Agency (EMA) issued a warning stating that JAKi treat-ment may lead to an increased risk of thrombo- embolic events. Platelets have been demonstrated to store and release TARC, how-ever, mean platelet counts were within normal range at baseline and follow- up measurements.8 Also, serum/plasma TARC ratios were stable and similar in both JAKi and dupilumab subgroups, indicating that the JAKi did not influence TARC levels by affecting the platelet population. In addition, no changes in lymphocyte (i.e. binds TARC to CCR4) or monocyte (i.e. produces TARC) counts were found during JAKi treatment.1It is known that interleukin (IL)- 4 and IL- 13 are highly ex-pressed in active AD skin.5 One could hypothesize that the effect of JAKi on these TARC- inducing cytokines might be less effective. For example, JAK1 inhibition alone may not be sufficient to com-pletely block IL- 4 and IL- 13 signaling. While JAK1 is involved in the signaling pathways of these cytokines, they also rely on other JAKs, such as JAK3 (IL- 4) and JAK2 (IL- 13). Therefore, baricitinib (JAK1/2 inhibitor), upadacitinib and abrocitinib (both selective JAK1 inhibitors) likely do not provide a comprehensive blockade of TARC- inducing cytokines. Dupilumab and tralokinumab, both monoclonal antibodies specifically and strongly inhibiting IL- 4 and/or IL- 13 receptor binding, might therefore be more effective in reducing serum TARC levels.2,3,5 Larger studies are needed to confirm our findings as in contrast to our study, two previous This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.    | 295RESEARCH LETTERstudies reported a decrease in serum TARC levels during upad-acitinib and abrocitinib treatment in AD patients.6,7 Interestingly, a phase 3 clinical trial with nemolizumab, an IL- 31 receptor alpha antagonist, also reported that serum TARC levels increased while AD severity decreased. However, this was only found in the first 16 weeks, whereas in our study, it remained up to at least 52 weeks of treatment.9 Another hypothesis could be that despite disease improvement, remission at immune level is limited in some patients (i.e. subclinical response), leading to persistently high serum TARC levels. These patients might be prone for relapsing of the disease, and serum TARC would then still be an adequate biomarker of per-sistent immune dysregulation.In conclusion, we found persistently high and increased serum TARC levels in AD patients treated with baricitinib, upadacitinib or abrocitinib despite a good clinical response, implying a limitation of the use of TARC as clinical biomarker in these patients. Translational research on TARC levels in both blood and AD skin is essential to gain insight into the underlying mechanism and to evaluate the safety of these JAKi.Summary box• Elevated TARC levels were found in AD patients treated with JAK inhibitors despite a good clinical response.• The use of TARC as a clinical biomarker in these patients is therefore questionable.F I G U R E  1  (A) Median EASI and serum TARC levels in AD patients up to 52 weeks of baricitinib, upadacitinib or abrocitinib treatment. (B) Median EASI and serum TARC levels in AD patients up to 52 weeks of dupilumab or tralokinumab treatment. TARC levels were log- transformed, and bars represent interquartile ranges. EASI, Eczema Area and Severity Index; TARC, Thymus and activation- regulated chemokine; n, number of treatment episodes.05101520100100010000BaricitinibEASIscoreTARC(pg/ml)0n=324n=328n=2516n=1628n=1440n=952n=6Weeks05101520100100010000DupilumabEASIscoreTARC(pg/ml)0n=6434n=60816n=59028n=54340n=47952n=451Weeks05101520100100010000UpadacitinibEASIscoreTARC(pg/ml)0n=654n=628n=5216n=4628n=4040n=3052n=23Weeks05101520100100010000TralokinumabEASIscoreTARC(pg/ml)0n=604n=5516n=3828n=2840n=1852n=13Weeks05101520100100010000AbrocitinibEASIscoreTARC(pg/ml)0n=374n=378n=3116n=3028n=1940n=1252n=7Weeks(A) (B) 13652222, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.14442 by Utrecht University, Wiley Online Library on [03/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License296  |    RESEARCH LETTERAUTHOR CONTRIBUTIONSConceptualization: CB, DS, MG, EK, MdBW, FvW; Formal Analysis: CB; Funding Acquisition: MG, MdBW; Investigation: CB, DS, MG, MdBW; Methodology: CB, MdBW, FvW; Resources: CB; Supervision: MG, EK, MdBW, FvW; Visualization: CB, EK, MdBW, FvW; Writing—Original Draft Preparation: CB; Writing—Review and Editing: DS, MG, EK, MdBW, FvW.ACKNO WLE DG E MENTSWe would like to thank our patients included in this manuscript for participating in the BioDay registry. This study has no funding, but the BioDay registry is supported by Eli Lilly and Company, Sanofi, Leo Pharma, AbbVie and Pfizer.CONFLIC T OF INTERE S T S TATEMENTC.M. Boesjes is a speaker for AbbVie and Eli Lilly and Company. Dr. D.S. Bakker is a speaker for Sanofi and LEO Pharma. Dr. E.F. Knol is a speaker and/consultant for Sanofi, Thermo Fisher Scientific and GSK. Dr. M. de Graaf is a consultant, advisory board member and/or speaker for AbbVie, Almirall, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals and Sanofi. Prof. F. van Wijk is a speaker and/or a consultant for Janssen, Johnson&Johnson and Takeda and has received grants from Regeneron Pharmaceuticals, Leo Pharma, Sanofi, BMS, Galapagos and Takeda. Prof. Dr. M. S. de Bruin- Weller is a consultant, advisory board member and/or a speaker for AbbVie, Almirall, Aslan, Arena, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron Pharmaceuticals and Sanofi.IRB S TATEMENTThe study was part of the BioDay registry which was approved by the local Medical Research Ethics Committee as a non- interventional study (METC 18–239) and was performed according to the Declaration of Helsinki.DATA AVAIL ABILIT Y S TATEMENTData are available upon reasonable request from the corresponding author.Celeste M. Boesjes1Daphne S. Bakker1Edward F. Knol2Marlies de Graaf1Femke van Wijk2Marjolein S. de Bruin- Weller11Department of Dermatology and Allergology, National Expertise Center for Atopic Dermatitis, University Medical Center Utrecht, Utrecht, The Netherlands2Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The NetherlandsCorrespondenceCeleste M. Boesjes, Department of Dermatology and Allergology, National Expertise Center for Atopic Dermatitis, University Medical Center Utrecht, Utrecht, The Netherlands.Email: c.m.boesjes-2@umcutrecht.nlORCIDCeleste M. Boesjes  https://orcid.org/0000-0002-3371-6414 Daphne S. Bakker  https://orcid.org/0000-0002-0193-5794 R E FE R E N C E S 1. Catherine J, Roufosse F. What does elevated TARC/CCL17 ex-pression tell us about eosinophilic disorders? Semin Immunopathol. 2021;43(3):439- 458. 2. Renert- Yuval Y, Thyssen JP, Bisonette R, et al. Biomarkers in atopic dermatitis—a review on behalf of the international eczema council. J Allergy Clin Immunol. 2021;147(4):1174- 1190. 3. Bakker DS, Ariens LFM, Giovanonne B, et al. EASI p- EASI: pre-dicting disease severity in atopic dermatitis patients treated with dupilumab using a combination of serum biomarkers. Allergy. 2020;75(12):3287- 3289. 4. Olydam JI, de Wijs LEM, Ropke MA, et al. EASI p- EASI: predict-ing disease severity in patients with atopic dermatitis treated with Tralokinumab. J Invest Dermatol. 2022;142(12):3335- 3337. 5. Dubin C, Del Duca E, Guttman- Yassky E. The IL- 4, IL- 13 and IL- 31 pathways in atopic dermatitis. Expert Rev Clin Immunol. 2021;17(8):835- 852. 6. Hagino T, Saeki H, Kanda N. The efficacy and safety of upadacitinib treatment for moderate to severe atopic dermatitis in real- world practice in Japan. J Dermatol. 2022;49(11):1158- 1167. 7. Gooderham M, Girolomoni G, Moore JO, et al. Durability of re-sponse to Abrocitinib in patients with moderate- to- severe atopic dermatitis after treatment discontinuation in a phase 2b trial. Dermatol Ther. 2022;12(9):2077- 2085. 8. Fujisawa T, Fujisawa R, Kato Y, et al. Presence of high contents of thymus and activation- regulated chemokine in platelets and ele-vated plasma levels of thymus and activation- regulated chemokine and macrophage- derived chemokine in patients with atopic derma-titis. J Allergy Clin Immunol. 2002;110(1):139- 146. 9. Kabashima K, Matsumara T, Komazaki H, et al. Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate- to- severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: results from two phase III, long- term studies. Br J Dermatol. 2022;186(4):642- 651. 13652222, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.14442 by Utrecht University, Wiley Online Library on [03/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Differential dynamics of TARC during JAK-inhibitor therapy compared to biological therapies targeting type 2 inflammation

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Differential dynamics of TARC during JAK-inhibitor therapy compared to biological therapies targeting type 2 inflammation

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