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

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.

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.

TABLE 1.

Participant demographics and clinical characteristics

PATIENT	GENDER	AGE, Y	ETHNICITY	PREVIOUS TREATMENTS*	MORPHOLOGIC AND TOPOGRAPHIC AD PHENOTYPE**	DURATION OF AD	TIME ON DUPILUMAB (BEFORE ARTHRALGIA-CAUSED DISCONTINUATION)
1	F	50	White	Prednisone	AD	1–2 years	41 months
2	M	30	White	TCS, TCI	AD	>6 years	48 months
3	F	78	White	Topical corticosteroids, oral antihistamines	AD	>2 years	24 months
4	M	69	White	Ruxolitinib cream	AD, worse on hands	6 months	13 months
5	M	48	White	Cyclosporine	AD	17 years	26 months
6	M	39	White	Cyclosporine	AD	24 years	12 months
7	F	57	White	Prednisone	Primarily chronic hand eczema	4 years	7 months
8	F	77	White	TCS, phototherapy, antibiotics, prednisone	Primarily prurigo nodularis	>10 years	3 months, 8 months***
9	F	83	Hispanic	TCS, TCI, prednisone	AD	2 years	1 month
10	F	44	Black	TCS, TCI, prednisone	AD	40 years	2 months
11	F	66	Black	TCS, TCI, prednisone	AD	3 years	6 months
12	M	84	White	TCS, TCI, prednisone, phototherapy	AD	6 years	4 months
13	F	26	White	TCS, TCI, roflumilast, crisaborole, prednisone	AD	5 years	4 months
14	M	62	Hispanic	TCS, TCI, prednisone	AD	2 years	8 months
15	M	35	White	Lebrikizumab-lbkz****	AD	>15 years	1 month

AD: Atopic dermatitis; F: Female; M: Male; TCI: Topical calcineurin inhibitor; TCS: Topical corticosteroid

*In addition to dupilumab

**Patients were categorized according to morphographic or topographic variants as follows: Morphologic variants: atopic prurigo / prurigo nodularis; Topographic variants: hand eczema

***Patient had two separate courses of dupilumab about 2 years apart, both of which were discontinued due to arthralgia.

****Patient developed shoulder and ankle pain 5 days after initial dupilumab loading injections; this occurred again 5 days after a second dupilumab injection. Patient switched to lebrikizumab and developed the same but milder shoulder and ankle pain, plus transient eyelid swelling, 3 days after initial injection. The patient then switched to tralokinumab and experienced none of these symptoms.

TABLE 2.

Treatment with and clinical response to tralokinumab

PATIENT	BASELINE IGA	IGA AT TRALOKINUMAB START	BASELINE BSA, %	BSA AT TRALOKINUMAB START, %	TIME ON TRALOKINUMAB (DOSING FREQUENCY)	OUTCOMES ON TRALOKINUMAB
						IGA	BSA, %	PATIENT-REPORTED OUTCOMES	AEs
1	3	3	10	10	8 months (Q4W)	0	0	Clear	None
2	3	0	40	0	13 months (Q4W)	0	0	Clear, no pruritus	None
3	4	0	90	0	15 months (Q2W)	0	0	Clear, no pruritus	Skin burning,* headache*
4	3	3	10	10	19 months (Q2W)	0	0	No pruritus	None
5	3	3	15	15	10 months (Q2W)	0	0	Almost clear, no pruritus	None
6	3	2	10	10	6 months (Q2W)	0	0	Almost clear, no pruritus	None
7	4	1	4	2	7 months (Q2W)	0	0	Clear, no pruritus	None
8	4	3	15	10	4 months (Q2W)	1	1	Improvement in pruritus and appearance	None
9	4	3	40	30	6 months (Q2W)	0	0	No pruritus	None
10	4	3	50	20	5 months (Q2W)	1	2	Mild pruritus	None
11	4	3	25	18	10 months (Q2W)	0	0	Mild pruritus	None
12	4	3	40	22	6 months (Q2W)	1	4	Mild pruritus	None
13	3	3	12	10	4 months (Q2W)	0	0	No pruritus	None
14	4	1	18	2	2 months (Q2W)	0	0	No pruritus	None
15	3	3	8	8	3 months (Q2W)	1	3	Mild pruritus	None

Abbreviations: AEs: Adverse events; BSA: Body surface area; F: Female; IGA: Investigator’s Global Assessment; M: Male; q2w: Every two weeks; q4w: Every 4 weeks

*Symptom resolved

FIGURE 1.

(A) Clinical images of Patient #7 prior to dupilumab therapy presenting with erythematous, scaly patches on the hands characteristic of atopic dermatitis. She developed arthralgia shortly after starting treatment, prompting discontinuation of dupilumab. (B) Images of the hands of the same patient who demonstrated complete resolution of eczematous patches and arthralgia symptoms after switching biologic treatment to tralokinumab.

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.