Introduction

Atopic dermatitis (AD) is a chronic, inflammatory skin disease, affecting up to 25% of children and from 2.0% to 17.6% of adults worldwide.1,2 Clinically, AD is usually characterized by eczema and itch, typically affecting the face, neck, and the flexures of the limbs.1,2 However, several clinical phenotypes can be distinguished.3 Moreover, AD can strongly affect patients’ quality of life, thus requiring a prompt and effective treatment.4

As regards AD pathogenesis, the impairment of cutaneous barrier and the hyperactivation of T helper (Th) 2 cells seem to play a key role.5 Recent knowledge on the overexpressed cytokines belonging to the Th2 pathway, such as interleukin (IL) 13 and 4, led to the development of new effective and targeted drugs, completely changing therapeutic scenario.5 Indeed, even if mild forms of AD are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging.6 In particular, the conventional systemic drugs used for AD management such as systemic immunosuppressant may be contraindicated for patients’ comorbidities or the development of adverse events (AEs).7 In this scenario, tralokinumab is a fully human monoclonal antibody targeting interleukin IL13, recently licensed for the treatment of moderate-to-severe AD in adult and adolescent patients 12 years and older who are candidates for systemic therapy.8

Despite its effectiveness and safety have been widely reported in both clinical trials and real-life experiences,9–17 studies regarding its use on “special populations” (SPs), are scant. These populations include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials.18,19 As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. It should be underlined that real-world data plays a crucial role because patients involved in clinical trials often differ from those encountered in routine clinical practice.20 Indeed, real-life subjects exhibit a broader range of characteristics, whereas the stringent inclusion and exclusion criteria employed in clinical trials can limit the representation of diverse clinical scenarios and individual variability.20

In this context, the aim of our study was to evaluate the effectiveness and safety of tralokinumab for the management of SPs affected by AD.

Material and Methods Study Population

A retrospective dual-center study was conducted, analyzing data from patients with moderate-to-severe AD who received tralokinumab treatment and attended the outpatient clinic of the Dermatology Unit at the University Federico II of Naples and University Magna Graecia of Catanzaro, Catanzaro, Italy.

The inclusion criteria comprised individuals aged ≥18 years with a diagnosis of moderate-to-severe AD who had undergone tralokinumab treatment for a minimum of 24 weeks and the presence of a comorbidity and/or age ≥65 years, which allow to consider these subjects as “SPs”.

In addition to age, the following criteria were considered to categorize patients as SPs: severe cardiovascular disease, severe neurological disease, severe psychiatric disorder, severe pulmonary disorder, history of cancer, severe infection. Comorbidities were defined as “severe” when they significantly impact a patient’s overall health, complicate the treatment of the primary condition, or increase the risk of adverse outcomes.

Exclusion criteria were: history of allergy to any component of tralokinumab, absence of a comorbidity and/or age <65 years which does not allow to categorize these patients as “SPs”.

Tralokinumab has been administered at labelled dosage as subcutaneous injection [600 mg (four 150 mg injections) at baseline followed by 300 mg (two 150 mg injections) administered every other week] in all the patients.

For each subject, the demographic (age, sex) and clinical data (medical history, AD comorbidities, previous treatments for AD, concomitant disease, medications or procedures) were recorded.

The efficacy of tralokinumab treatment was measured evaluating AD severity using the following score: Eczema Area Severity Index (EASI), and Pruritus–Numerical Rating Scale (P-NRS). Moreover, the impact of AD on quality of life was evaluated by using Dermatology Life Quality Index (DLQI). Clinical and demographic data, as well as EASI, P-NRS and DLQI were evaluated at baseline. Moreover, AD severity scores and DLQI were also evaluated following 4 and 16 weeks of treatment.

Regarding safety data, any new clinical symptoms reported by the patient or observed during physical examinations were documented at each visit and assessed for potential side effects.

Statistical Analysis

Categorical variables were presented as frequencies and percentages, while continuous variables were expressed as mean ± standard deviation (SD). Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student’s t-test. Statistical analyses were performed using GraphPad Prism software (v.8.0; GraphPad Software Inc., La Jolla, CA, USA), with significance set at p < 0.05.

Additionally, data analysis employed the last observation carried forward method, wherein if a patient discontinued the study, the last available value was extrapolated forward until the end of the treatment period.

Ethical Considerations

The study adhered to the principles of the Declaration of Helsinki, and all patients provided informed consent for the collection of their personal and clinical data, authorizing the treatment of their anonymized clinical records, as was the case of the Campania region web-based platform used for biologic drug prescription (SANIARP; www.saniarp.it). Moreover, for non-interventional studies, the Directive (2001/20/EC) stipulates that they should be conducted in accordance with the Declaration of Helsinki, but they are generally exempt from the stringent requirements applied to interventional clinical trials, including the need for formal ethical approval.

Results Demographics

A total of 112 patients were screened. Of these, 93 (83.04%) had a follow-up period of at least 24 weeks. Then, 66 (70.97%) subjects were excluded since they did not respect inclusion criteria. Finally, 27 patients [17 males (62.96%), mean age: 71.26 ± 11.32 years, range 33–87 years] were included in the study, respecting all the inclusion and exclusion criteria. Rhinitis was the commonest AD comorbidity, reported in 10 (37.04%) patients, followed by conjunctivitis (n = 4, 14.81%) and asthma (n = 2, 7.41%).

Clinical and demographical data of patients are reported in Table 1.

Table 1 Demographic Data and Clinical Outcomes of SPs Patients Treated with Tralokinumab

Twenty-three out of 27 (85.19%) subjects were over 65 years old. Of these, only 5/23 (21.74%) had not relevant concomitant disease.

Globally, history of cancer (prostatic cancer, breast cancer, non-Hodgkin’s lymphoma, colorectal cancer, lung cancer) was found in 7 (25.93%) patients, whereas 3 (11.11%) psychiatric disorder (depression, bipolar syndrome), 2 (7.41%) neurological disorder (Parkinson’s disease or epilepsy), 11 (40.74%) cardiovascular disease (ischemic heart disease, cerebral vasculopathy, idiopathic thrombosis lower limbs, ictus, pacemaker, congenital thrombophilia), 3 (11.11%) pulmonary disease (chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary emphysema), and 1 (3.70%) case of severe infection (hepatitis C) were collected, with 6 (22.22%) patients reporting more than 1 severe comorbidity.

Detailed clinical history is reported in Table 2.

Table 2 Demographic Data and Clinical History of SPs

All the patients with neurological, psychiatric, pulmonary, or cardiovascular disease were on various pharmacological treatments during the administration of tralokinumab. Among the 6 patients with a history of cancer, 5 received concomitant therapy. Finally, the subject with Hepatitis C was previously treated with Interferon.

Regarding previous treatments, phototherapy was the most common (n = 13, 48.15%), followed by systemic corticosteroids (n = 6, 22.22%), and cyclosporine (n = 5, 18.51%). Of interest, 1 (3.70%) patient previously failed dupilumab for conjunctivitis.

Clinical Effectiveness and Safety

At baseline, mean EASI and P-NRS were 25.96 ± 2.81 and 9.04 ± 1.46. Moreover, a high impact on quality of life was reported with a DLQI of 26.12 ± 3.19. All of the patients completed week 4, week 16 and week 24 follow-up. Clinical results were summarized in Table 1 and Figure 1.

Figure 1 Improvement of EASI, P-NRS and DLQI at baseline, Week 4, Week 16, and Week 24.EASI: Eczema Area Severity Index; DLQI: Dermatology Life Quality Index; P-NRS: Pruritus – Numerical Rating Scale.

In particular, a statistically significant reduction of EASI was observed at week 4 (14.92 ± 5.67, p < 0.0001), week 16 (5.24 ± 4.71, p < 0.0001), and week 24 (3.08 ± 3.11, p < 0.0001) as compared with baseline.

Similarly, P-NRS significantly decrease following 4 (6.28 ± 2.01, p < 0.0001), 16 (4.04 ± 2.91, p < 0.0001) and 24 weeks of treatment (2.92 ± 2.41, p < 0.0001).

As regards the impact of tralokinumab on quality of life, DLQI significantly reduced at each follow-up visit (p < 0.0001 for both), resulting as 14.52 ± 6.48 at week 4, 5.52 ± 4.89 at week 16, and 2.12 ± 2.51 at week 24, respectively.

Finally, no cases of tralokinumab discontinuation for inefficacy were collected, as well as no patients reported at least one AE during the study period.

Discussion

Recent knowledge on AD pathogenesis allowed the development of selective drugs specifically targeting ILs involved in the disease.2 Among these, tralokinumab, specifically targeting IL13, has been recently licensed, showing promising results in terms of safety.8 Indeed, the only contraindication for its administration is hypersensitivity to the active substance or to any of the excipients.8 However, studies regarding its use in SPs are scant. These data are essential since SPs usually require additional consideration in treatment selection as the comorbidities or concomitant drugs may interfere with the use of the investigated drug.18 Moreover, these patients may exhibit a different response to treatment and frequency of AEs.19 Therefore, physicians frequently exhibit reluctance to utilize certain drugs, particularly those that are newly introduced, in SPs.

In this context, differently from dupilumab, the other monoclonal antibody approved for AD,21–24 data on SPs patients undergoing treatment with tralokinumab are scant.

Our study enrolling 27 SPs patients, showed a significant improvement of EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decrease at each timepoint as compared to baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease.

Reviewing current literature, data on tralokinumab use in SPs are limited. Indeed, as reported by drug insert package, there are limited data on tralokinumab use in elderly patients, or subjects with renal or hepatic impairment.8

A post hoc analysis of Phase III trials (ECZTRA 1, ECZTRA 2, ECZTRA3) enrolling 75 adults 65 years or older showed that efficacy and safety outcomes in this population were similar as compared with the younger patient cohorts after 16 weeks of treatment.25 Moreover, the proportions of patients experiencing AEs in the tralokinumab and placebo groups were similar in elderly cohort.25

Currently, real-life experiences are limited to a case report, which reported a case of an 83-year-old male patient affected by AD and vitiligo, hypertension, heart rhythm abnormalities requiring pacemakers, recurrent conjunctivitis, benign prostatic hypertrophy, and idiopathic Raynaud’s phenomenon successfully treated with tralokinumab, without AEs collected.26

Of interest, a Phase II study (ECZTRA 5) enrolling 215 patients receiving tralokinumab (n = 107) or placebo (n = 108) for 16 weeks showed that tralokinumab was not inferior to placebo for immune response to Tdap (tetanus/diphtheria/pertussis) (91.9% vs 96.1%) and meningococcal (86.0% vs 84.2%) vaccines administered at week 12.27

Finally, a case series enrolling AD patient who participated in the ECZTEND trial, showed that tralokinumab does not seem to be associated with more severe COVID-19 disease as well as tralokinumab does not seem to reduce the effectiveness of COVID-19 vaccines.28

Globally, the introduction of new drugs targeting AD pathogenesis has revolutionized the management of this disease.29–34 However, more and more studies are required to offer patients a personalized approach.

To sum up, data on tralokinumab use in SPs are scant. Despite limited, our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.

Main strengths of our study are the data accuracy and the homogeneity of clinical evaluation. However, main limitations should be stated such as the retrospective design, the reduced follow-up period, the reduced cohort, and the lack of a control group.

Conclusion

In our study, the effectiveness and safety of tralokinumab have been evaluated in elderly AD patients or patients affected by malignancies, severe neurological, psychiatric, pulmonary, and/or cardiovascular disease, and C hepatitis. A statistically significant improvement was reported for each investigated score (EASI, P-NRS, DLQI) since week 4, continuing to improve up to week 24. Moreover, no AEs were collected. Despite promising, further observational data with more patients or longer follow-up periods are needed to confirm our results.

Data Sharing Statement

Data that support the findings of this study are available from the corresponding author, LP, upon reasonable request.

Informed Consent Statement

The patients in this manuscript have given written informed consent for the publication of their case details.

Disclosure

Cataldo Patruno reports personal fees from LeoPharma, outside the submitted work. The authors report no other conflicts of interest in this work.

References

1. Eichenfield LF, Stripling S, Fung S, Cha A, O’Brien A, Schachner LA. Recent Developments and Advances in Atopic Dermatitis: a Focus on Epidemiology, Pathophysiology, and Treatment in the Pediatric Setting. Paediatr Drugs. 2022;24(4):293–305. doi:10.1007/s40272-022-00499-x

2. Mandlik DS, Mandlik SK. Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies. Immunopharmacol Immunotoxicol. 2021;43(2):105–125. doi:10.1080/08923973.2021.1889583

3. Patruno C, Potestio L, Napolitano M. Clinical phenotypes of adult atopic dermatitis and related therapies. Curr Opin Allergy Clin Immunol. 2022;22(4):242–249. doi:10.1097/ACI.0000000000000837

4. Ali F, Vyas J, Finlay AY. Counting the Burden: atopic Dermatitis and Health-related Quality of Life. Acta Derm Venereol. 2020;100(12):adv00161. doi:10.2340/00015555-3511

5. Li H, Zhang Z, Zhang H, Guo Y, Yao Z. Update on the Pathogenesis and Therapy of Atopic Dermatitis. Clin Rev Allergy Immunol. 2021;61(3):324–338. doi:10.1007/s12016-021-08880-3

6. Facheris, Paola, Jeffery, Jane, Del Duca, Ester et al The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol. 2023;20(5):448–474. doi:10.1038/s41423-023-00992-4

7. Frazier W, Bhardwaj N. Atopic Dermatitis: diagnosis and Treatment. Am Fam Physician. 2020;101(10):590–598.

8. ADRALTZA. Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/adtralza-epar-product-information_en.pdf. Accessed April4, 2024.

9. Potestio L, Patruno C, Napolitano M. Efficacy and Safety of Tralokinumab in Real Life: possible Predictive Rapid Response Factors. Dermatitis. 2024;35(S1):S77–S80. doi:10.1089/derm.2023.0261

10. Domínguez-Santana CM, Viedma-Martínez M, Ríos-Sánchez E. Tralokinumab in Atopic Dermatitis: real-Life Data from a Spanish Tertiary Referral Center. Actas Dermo Publ Febr. 2:2024. doi:10.1016/j.ad.2023.12.005

11. De Greef A, Ghislain PD, de Montjoye L, et al. Tralokinumab improves clinical scores in adolescents with severe atopic dermatitis: a real-life multicentric observational study. J Eur Acad Dermatol Venereol. 2024;38(3):e288–e290. doi:10.1111/jdv.19605

12. Pezzolo E, Sechi A, Tartaglia J, Naldi L. A critical evaluation of suitability of tralokinumab for treatment of moderate-to-severe atopic dermatitis in adolescents and adults. Expert Rev Clin Immunol. 2024;20(3):255–266. doi:10.1080/1744666X.2023.2283585

13. Ferrucci S, Barei F, Tavecchio S, et al. Assessment of patient-reported outcomes at 24 weeks of treatment with tralokinumab for atopic dermatitis: a multicentric real-life experience. J DermatolTreat. 2023;34(1):2285243. doi:10.1080/09546634.2023.2285243

14. Gargiulo L, Ibba L, Vignoli CA, et al. Tralokinumab rapidly improves subjective symptoms and quality of life in patients with moderate-to-severe atopic dermatitis: a real-life 16-week experience. J DermatolTreat. 2023;34(1):2216815. doi:10.1080/09546634.2023.2216815

15. Pereyra-Rodríguez JJ, Herranz P, Ruiz-Villaverde R, et al. Treatment of severe atopic dermatitis with tralokinumab in clinical practice: short-term effectiveness and safety results. Clin Exp Dermatol. 2023;48(9):991–997. doi:10.1093/ced/llad153

16. De Greef A, Ghislain PD, Bulinckx A, et al. Real-Life Experience of Tralokinumab for the Treatment of Adult Patients with Severe Atopic Dermatitis: a Multicentric Prospective Study. Clin Drug Investig. 2023;43(4):299–306. doi:10.1007/s40261-023-01258-7

17. Wollenberg A, Blauvelt A, Guttman-Yassky E, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437–449. doi:10.1111/bjd.19574

18. Burkholder DM, Nash NB. Special Populations in Health Care. 1st ed. Jones & Bartlett Learning; 2013.

19. Davies EA, O’Mahony MS. Adverse drug reactions in special populations - The elderly. Br J Clin Pharmacol. 2015;80(4):796–807. doi:10.1111/bcp.12596

20. Cinelli E, Fabbrocini G, Megna M. Real-world experience versus clinical trials: pros and cons in psoriasis therapy evaluation. Int J Dermatol. 2022;61(3):e107–e108. doi:10.1111/ijd.15644

21. Napolitano M, Fabbrocini G, Potestio L, et al. A 24-weeks real-world experience of dupilumab in adolescents with moderate-to-severe atopic dermatitis. Dermatol Ther. 2022;35(8):e15588. doi:10.1111/dth.15588

22. Napolitano M, Fabbrocini G, Neri I, et al. Dupilumab Treatment in Children Aged 6-11 Years With Atopic Dermatitis: a Multicentre, Real-Life Study. Paediatr Drugs. 2022;24(6):671–678. doi:10.1007/s40272-022-00531-0

23. Nettis E, Ferrucci SM, Ortoncelli M, et al. Use of Dupilumab in 543 Adult Patients With Moderate-to-Severe Atopic Dermatitis: a Multicenter, Retrospective Study. J Investig Allergol Clin Immunol. 2022;32(2):124–132. doi:10.18176/jiaci.0641

24. Napolitano M, Maffei M, Patruno C, et al. Dupilumab effectiveness for the treatment of patients with concomitant atopic dermatitis and chronic rhinosinusitis with nasal polyposis. Dermatol Ther. 2021;34(6):e15120. doi:10.1111/dth.15120

25. Merola JF, Butler DC, Mark T, Schneider S, Kim Y, Abuabara K. Safety and Efficacy of Tralokinumab in Older Adults With Moderate-to-Severe Atopic Dermatitis: a Secondary Analysis. JAMA Dermatol. 2023;159(10):1119–1123. doi:10.1001/jamadermatol.2023.2626

26. Napolitano M, Potestio L, Menna L, Megna M, Fabbrocini G, Patruno C. Tralokinumab in elderly atopic dermatitis. Ital J Derm Ven. 2023;158(5):419–420. doi:10.23736/S2784-8671.23.07446-7

27. Merola JF, Bagel J, Almgren P, et al. Tralokinumab does not impact vaccine-induced immune responses: results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis. J Am Acad Dermatol. 2021;85(1):71–78. doi:10.1016/j.jaad.2021.03.032

28. Blauvelt A, Pink A, Worm M, et al. Outcomes of COVID-19 and Vaccination in Patients With Moderate to Severe Atopic Dermatitis Treated With Tralokinumab. JAMA Dermatol. 2022;158(11):1327–1330. doi:10.1001/jamadermatol.2022.3488

29. Hagino T, Saeki H, Fujimoto E, Kanda N. Long-term effectiveness and safety of upadacitinib for Japanese patients with moderate-to-severe atopic dermatitis: a real-world clinical study. J DermatolTreat. 2024;35(1):2344591. doi:10.1080/09546634.2024.2344591

30. Hagino T, Hamada R, Yoshida M, Saeki H, Fujimoto E, Kanda N. Sustained Effectiveness of Upadacitinib in Moderate-to-Severe Atopic Dermatitis: a 48-Week Real-World Study. Pharmaceuticals. 2024;17(4):519. doi:10.3390/ph17040519

31. Potestio L, Napolitano M, Bennardo L, Fabbrocini G, Patruno C. Atopic dermatitis exacerbation after Covid-19 vaccination in Dupilumab-treated patients. J Eur Acad Dermatol Venereol. 2022;36(6):e409–e411. doi:10.1111/jdv.17964

32. Paolino G, Narcisi A, Carugno A, et al. Successful use of tralokinumab for the treatment of atopic dermatitis on the genitals. J DermatolTreat. 2024;35(1):2351489. doi:10.1080/09546634.2024.2351489

33. Navarro-Triviño FJ, Salazar-Nievas M, Sanz-Cabanillas JL, Arjona-Aguilera C. Efficacy and safety of tralokinumab in the treatment of head and neck pattern atopic dermatitis: a multicentre study of 12 patients. Australas J Dermatol. 2024;65(3):260–265. doi:10.1111/ajd.14264

34. Paolino G, Carugno A, Frontera A, et al. Arrhythmias and other cardiovascular diseases in young patients (<40 years) with moderate/severe atopic dermatitis: a multicentric study in northern Italy. J Eur Acad Dermatol Venereol 2024. doi:10.1111/jdv.20184