Tralokinumab as a Therapeutic Alternative for Dupilumab-associated Arthralgia in Atopic Dermatitis: A Multi-center Case Series

J Clin Aesthet Dermatol. 2025;18(5):16–19.

by Ana B.W. Greenberg, BS; Mona Shahriari, MD; Michael C. Cameron, MD; Michael Payette, MD, MBA; Diego Ruiz Dasilva, MD; Giovanni Damiani, MD, PhD; Edward I. Herman, MD, PhD; Lindsay A. Eminger, MD; Naiem T. Issa, MD, PhD; Adrian Rodriguez, MD; James Q. Del Rosso, DO; Youna Kang, PharmD; Jeffrey M. Cohen, MD; and Christopher G. Bunick, MD, PhD

Ms. Greenberg and Dr. Shahriari are with Yale School of Medicine in New Haven, Connecticut. Drs. Shahriari and Payette are with Central Connecticut Dermatology in Cromwell, Connecticut. Dr. Cameron is with Cameron Dermatology PLLC in New York, New York, and the Department of Dermatology at Mount Sinai in New York, New York. Dr. Dasilva is with Forefront Dermatology in Virginia Beach, Virginia, and Eastern Virginia Medical School in Virginia Beach, Virginia. Dr. Damiani is with the Department of Biomedical, Surgical and Dental Sciences at the University of Milan in Milan, Italy, and the Italian Center of Precision Medicine and Chronic Inflammation at the University of Milan in Milan, Italy. Drs. Herman and Eminger are with South Shore Dermatology Physicians in North Easton, Massachusetts. Dr. Issa is with Forefront Dermatology in Vienna, Virginia, the Dr. Philip Frost Department of Dermatology and Cutaneous Surgery at the Leonard M. Miller School of Medicine in Miami, Florida, and the Department of Dermatology at the George Washington University School of Medicine and Health Sciences in Washington, District of Columbia. Dr. Rodriguez is with the Nashville Skin Comprehensive Dermatology Center in Nashville, Tennessee. Dr. Del Rosso is with the Department of Dermatology at Touro University Nevada in Henderson, Nevada, JDR Dermatology Research in Las Vegas, Nevada, and Advanced Dermatology and Cosmetic Surgery in Maitland, Florida. Dr. Kang is with Yale-New Haven Hospital Pharmacy in New Haven, Connecticut. Drs. Kang, Cohen, and Bunick are with the Department of Dermatology at the Yale School of Medicine in New Haven, Connecticut. Dr. Cohen is also with the Department of Biomedical Informatics and Data Science at the Yale School of Medicine in New Haven, Connecticut. Dr. Bunick is with the Program in Translational Biomedicine at the Yale School of Medicine in New Haven, Connecticut.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Shahriari has served as a consultant for AbbVie, Apogee, Arcutis, Bristol Myers Squibb, Dermavant, Galderma, Incyte, Janssen, Leo Pharma, Lilly USA, Novartis, Novan, Ortho Dermatologics, Sanofi-Genzyme, Regeneron, and UCB; a speaker for Abbvie, Arcutis, Bristol Myers Squibb, Lilly USA, Janssen, Dermavant, Leo Pharma (former), Sanofi-Genzyme, Regeneron, and UCB; and an investigator at AbbVie, CorEvitas Psoriasis Registry, CorEvitas Atopic Dermatitis Registry, Dermira, Lilly USA, Cara, Dermavant, Novartis, Union, and Mindera. Dr. Cameron has served as a consultant for Abbvie, Apogee, Arcutis, Bristol Myers Squibb, CorEvitas Atopic Dermatitis Registry, CorEvitas Alopecia Areata Registry, Dermavant Sciences, Eli Lilly, Evelo, Galderma, Incyte, Journey Medical, Leo Pharma, Regeneron, Sanofi, Sun, Union Therapeutics, Verrica; a promotional speaker for Abbvie, Amgen, Bristol Myers Squibb, Dermavant Sciences, Eli Lilly, Incyte, Journey Medical, Leo Pharma, Pfizer, Regeneron, Sanofi, Ortho Pharmaceutical, Verrica; an investigator for Abbvie, Alumis, Apogee, Incyte, Eli Lilly, Novartis, Sanofi, Sun Pharma. Dr. Payette has served as consultant for Abbvie, Amgen, Arcutis, Boehringer Ingelheim, Bristol Meyers Squibb, Castle Biosciences, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, Leo Pharmaceuticals, Novartis, ONVIV, Ortho-Dermatologics, Pfizer, Sanofi-Genzyme, Sun Pharmaceuticals, Regeneron, Takeda, and UCB; a speaker for Abbvie, Amgen, Arcutis, Bristol Meyers Squibb, Eli Lilly, Galderma, Incyte, Janssen, Novartis, Pfizer, Sanofi-Genzyme, Sun Pharmaceuticals, Regeneron, and UCB; and an investigator for Abbvie, Cara, CorEvitas Atopic Dermatitis Registry, CorEvitas Psoriasis Registry, Dermavant, Dermira, Eli-Lilly, Incyte, Mindera, and Novartis. Dr. Dasilva has served as a speaker or consultant for AbbVie, Arcutis, Dermavant, Eli Lilly, Galderma, Janssen, LEO pharma, Pfizer, Sanofi and Regeneron, UCB, Verrica. Dr. Damiani has served as a consultant for Almirall, Galderma, Funziona, and a speaker for Almirall, Galderma, Funziona, and Sanofi. Dr. Herman has served as a consultant, speaker, or investigator for AbbVie, Bristol Myers Squibb, LEO Pharma, Lilly, Regeneron, and Sanofi. Dr. Issa has served as a speaker, consultant, advisor, or investigator for Abbvie, Almirall, Apogee, Bristol Myers Squibb, Castle Biosciences, Dermavant Sciences, DermTech, Galderma, Incyte, Janssen, Journey, LEO Pharma, Lilly, Novartis, Ortho Dermatologics, Pfizer, Primus, Regeneron, Sanofi, SUN Pharmaceuticals Industry, Topix, UCB, Verrica Pharmaceuticals. Dr. Rodriguez has served as a consultant, research investigator and/or speaker for Abbvie, Arcutis, Almirall, Bristol Myers Squibb, Dermavant, Galderma, Incyte, Janssen, Johnson & Johnson, Leo Pharma, Lilly, Mindera, Novan, Novartis, Sanofi, Sun, and UCB. Dr. Del Rosso has served as a consultant, research investigator, and/or speaker for Abbvie, Amgen, Arcutis, Almirall, Bausch Health, Botanix, Bristol Myers Squibb, Cara, Dermavant, Evommune, Ferndale, Galderma, Incyte, Journey Leo Pharma, Lilly USA, Mindera, Moonlake, Nektar, Novan, Novartis, Primus, Regeneron, Sanofi-Genzyme, Sun Pharma, UCB and Vyne. Dr. Cohen serves on a data and safety monitoring board for Advarra and has served as a consultant for Novartis, Takeda, and GSK. Dr. Bunick has served as an investigator for AbbVie, Almirall, Apogee, Daiichi Sankyo, LEO Pharma, Ortho Dermatologics, Sun Pharma, Timber, and Palvella; a consultant for AbbVie, Almirall, Apogee, Arcutis, Connect BioPharma, Eli Lilly, EPI Health/Novan, Incyte, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer, Sanofi-Regeneron, Takeda, and UCB; and a speaker for and received honoraria from Allergan, Almirall, LEO Pharma, and UCB.

ABSTRACT: Atopic dermatitis (AD) is a chronic inflammatory skin condition that often requires systemic treatment to achieve optimal clinical outcomes. The clinical and immunological heterogeneity of AD necessitates the use of various therapies to maximize efficacy while minimizing adverse events (AEs). Dupilumab, the first biologic agent approved by the United States Food and Drug Administration (FDA) for moderate-to-severe AD, targets interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways. Although effective, some patients experience dupilumab-associated musculoskeletal AEs, such as arthralgia, arthritis, or enthesitis, which may lead to discontinuation of treatment. Recent studies suggest that IL-4 inhibition disrupts T-cell populations, promoting a skewed T-helper 17 (Th17)-dominant immune response that may contribute to arthralgia. Switching to alternative therapies, such as tralokinumab—an IL-13-specific inhibitor—has shown promise in alleviating these AEs while maintaining control of AD signs and symptoms. Case reports indicate that patients with dupilumab-associated arthralgia have improved after switching to tralokinumab, suggesting the potential of tralokinumab as a safer alternative for these individuals. We present a series of 15 AD patients treated with tralokinumab following discontinuation of dupilumab due to arthralgia. All 15 patients achieved clear or nearly clear skin and demonstrated reductions in AD signs and symptoms as measured by Investigator’s Global Assessment (IGA), body surface area of involvement (BSA), and/or patient reported measures of pruritus. Importantly, all patients experienced resolution of arthralgia without recurrence while on tralokinumab. These findings support the use of tralokinumab as an effective and safe alternative therapy for patients with dupilumab-induced arthralgia.

Keywords: Joint pain, eczema, prurigo nodularis, biologic therapy, adverse event

Introduction

Atopic dermatitis (AD) is a chronic relapsing and remitting inflammatory skin disease that often requires systemic therapy to achieve optimal clinical response. The clinical and immunological heterogeneity of this systemic skin disease requires multiple therapeutics with varying mechanisms of action to optimize patient management and minimize adverse events (AEs). Dupilumab, a first-generation interleukin 4 (IL-4) receptor alpha blocker with targeted inhibition of IL-4/interleukin 13 (IL-13) signaling, received its initial approval in 2017 as the first biologic agent to treat moderate-to-severe AD.

While dupilumab is effective for managing moderate-to-severe AD, some patients might experience AEs that necessitate discontinuing treatment. Several recent studies have demonstrated that some patients treated with dupilumab develop new musculoskeletal symptoms, specifically arthralgia, arthritis, and enthesitis (for purposes herein, arthralgia will be used).^1–4 Bridgewood et al^5,6 and Hughes et al⁷ hypothesize that IL-4 inhibition, not IL-13, may lead to a shift toward a T-helper 17 (Th17)-driven immune response because of the necessity of IL-4 for T-helper 2 (Th2) cell differentiation. Consequently, inhibiting IL-4 may imbalance T-cell populations leading to expansion of Th17 cells, which could provoke arthralgia symptoms. Real-world experience suggests that blocking both IL-4 and IL-13 with dupilumab may inadvertently drive a Th17-skewed immune response in select patients. This shift has been associated with the onset of Th17-mediated psoriasiform dermatitis during dupilumab therapy.⁸ The Th17-driven inflammation described in reported cases may also contribute to the development of other conditions, such as symptomatic inflammatory arthropathy, due to shared underlying immunopathological mechanisms.⁹ In these patients, a medication with a different mechanism of action may control the signs and symptoms of AD and resolve the arthalgia symptoms. Therefore, investigation into real-world switching to alternate therapies to ameliorate symptoms of arthropathy is warranted. Based on multiple reports, tralokinumab, an IL-13 specific inhibitor, is a reasonable option to consider as an alternative agent in patients experiencing adverse effects with dupilumab.¹⁰

The current literature regarding therapeutic switch to tralokinumab in AD patients with dupilumab-associated side effects includes several case reports suggesting that tralokinumab may be able to maintain AD response while allowing the dupilumab associated AEs to resolve.^10,11 In a recent case series, all nine AD patients who discontinued dupilumab due to inadequately controlled AD or AEs such as conjunctivitis and joint pain reported maintenance of AD control and improvement of these AEs upon switching to tralokinumab.¹² Our objective is to further study the potential efficacy and safety of tralokinumab in a larger multi-center real-world case series of AD patients following dupilumab discontinuation specifically due to the emergence of arthralgia.

Fifteen patients with AD (8 female; median age (years), 50 [Interquartile Range: 42–75]; Table 1) who discontinued dupilumab due to arthralgia and were subsequently initiated on tralokinumab before resolution of arthralgia were included. Notably, 67 percent (n=10/15) of patients at the cessation of dupilumab (or lebrikizumab for one patient) had skin severity equal to Investigator’s Global Assessment (IGA) score of 3 (moderate) (Table 2). After switching to tralokinumab, all 15 patients achieved clear or almost clear skin (ie, IGA 0/1) and experienced reduced AD signs and symptoms as measured by body surface area of involvement (BSA) and/or patient-reported measures of pruritus. Achievement of AD skin clearance with tralokinumab is highlighted in Figure 1. Importantly, all 15 patients experienced resolution and no exacerbations of arthralgia on tralokinumab. Regarding pruritus, 73 percent (n=11/15) of tralokinumab-treated patients reported an itch-numerical rating scale (NRS) score of 0, while 27 percent (4/15) patients experienced mild pruritus (1, 2 or 3 itch-NRS score; “mild pruritus”). Aside from one patient who reported initial symptoms of skin burning and headache with tralokinumab after the first injection, which resolved with continued treatment, the remaining patients reported no other tralokinumab-associated AEs.

Our case series of 15 patients supports tralokinumab as an alternative therapy for patients experiencing dupilumab-induced arthralgia. With its IL-13-specific blockade, tralokinumab effectively controls the signs and symptoms of AD in a targeted manner that allows for resolution of dupilumab-induced arthralgia without exacerbation of these joint symptoms. The American Academy of Dermatology AD guidelines give a strong recommendation in favor of using tralokinumab and dupilumab as first-line biologics for AD;¹³ our findings, along with these guidelines, suggest that tralokinumab may offer a suitable alternative for patients who have dupilumab-induced AEs so that they can maintain AD control while avoiding such AEs. 

Interestingly, one patient in our cohort experienced arthralgia on dupilumab and lebrikizumab, the latter being a newly FDA-approved IL-13 targeted monoclonal antibody whose mechanism of IL-13 inhibition differs from that of tralokinumab.¹⁴ One proposed hypothesis which may explain these findings is lebrikizumab may exhibit indirect IL-4 inhibition via reduction of IL13-Rα1 protein available to form competent type II receptors.¹⁴ This single case suggests that tralokinumab, as opposed to lebrikizumab, may potentially be the preferred alternative biologic for patients developing arthralgias on dupilumab; additional data and clinical experience are needed to better understand whether this will hold true for larger populations. 

Conclusion

The patient cases outlined in this case series lend evidence supporting tralokinumab as an effective and safe treatment option for patients with AD who develop musculoskeletal adverse reactions with IL-4/IL-13 blockade.

References

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