Higher Levels of Immunoglobulin E and Thymus and Activation-Regulated Chemokine Are Associated with Conjunctivitis During Lebrikizumab Treatment in Patients with Moderate-to-Severe Atopic Dermatitis

Abstract

Abstract: Background: Treatment with anti-interleukin (IL)-13 antibody lebrikizumab is sometimes associated with the occurrence of conjunctivitis in patients with atopic dermatitis (AD). However, predictive factors for its occurrence are unknown.

Objective: To identify predictive factors for the occurrence of conjunctivitis during lebrikizumab treatment for AD.

Methods: A prospective study was conducted in 140 Japanese patients with moderate-to-severe AD who received lebrikizumab 500 mg at weeks 0 and 2, followed by 250 mg every 2 weeks until week 16, thereafter every 4 weeks for median 24 (ranging 12–36) weeks. We compared baseline clinical and laboratory indices, and background factors between patients who developed conjunctivitis and those who did not.

Results: Conjunctivitis occurred in 20 patients (14.3%) during lebrikizumab treatment. Patients with conjunctivitis had significantly higher immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC) compared to those without. Logistic regression analysis showed that the occurrence of conjunctivitis was associated with higher IgE (odds ratio [OR]: 1, 95% confidence interval [CI]: 1.0–1.0, P = 0.0287) and TARC (OR: 1, 95% CI: 1.0–1.0, P = 0.0441).

Conclusions: Higher IgE and TARC may predict conjunctivitis during lebrikizumab treatment for AD.

Capsule Summary

Conjunctivitis can occur in some patients with atopic dermatitis (AD) during lebrikizumab treatment, but predictive factors for its occurrence are unclear. Higher baseline immunoglobulin E and thymus and activation-regulated chemokine may predict the occurrence of conjunctivitis during lebrikizumab treatment for AD.

INTRODUCTION

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease, which occurs in a wide range of age, from children to adults. Its prevalence is reported to be about 2%–7% in adults and about 20% in children.^{1B2 -6} Atopic dermatitis is clinically characterized by intense pruritus, recurrent eczema, and disruption of skin barrier.^{7B8 -11} Chronic itching and skin inflammation in AD can cause sleep disturbances, psychological stress, and social isolation, which greatly reduces quality of life (QoL) of patients.¹² The pathogenesis of AD might involve genetic predisposition, environmental factors, and alterations of skin microbiome, which are mutually interacting.⁵ Type 2-skewed immune responses are considered as a main axis of its pathogenesis, and especially interleukin (IL)-13 might play a central role in promoting skin barrier disruption, tissue inflammation, and pruritus.^{13B14 -18} The levels of IL-13 in lesional skin with AD are highly elevated and correlate with disease severity.¹⁹

Recently, systemic and targeted therapies have been progressively developed for moderate-to-severe AD. The anti-IL-4Rα antibody dupilumab or Janus kinase (JAK) inhibitors (abrocitinib, baricitinib, and upadacitinib) have now been used for patients who did not improve sufficiently by topical treatments or phototherapy. These treatments are promising because they selectively downregulate major immune pathways for inflammation and itching in AD. However, these treatments cannot always provide long-term remission of AD, and there are still concerns about the safety of long-term usage of JAK inhibitors.

Under these circumstances, lebrikizumab, a high-affinity human immunoglobulin (Ig) G4 monoclonal anti-IL-13 antibody, has gained attention as a new treatment option.^{20B21 -24} Lebrikizumab selectively binds IL-13 and blocks the association of IL-13Rα1 with IL-4Rα on target cell surface, while allowing binding of IL-13 to the decoy receptor IL-13Rα2, so that other immune functions are not seriously compromised. Results of clinical trials showed that lebrikizumab improved clinical signs and pruritus of AD as evaluated by eczema area and severity index (EASI), investigator’s global assessment (IGA), and peak pruritus numerical rating scale (PP-NRS).^{25B26 -33} However, long-term effectiveness and safety in real-world treatment with lebrikizumab are still unknown, and should further be examined to seek safer and more durable treatments for AD.

Regarding safety, anti-IL-4Ra antibody dupilumab, inhibiting IL-4 and IL-13, can frequently cause ocular adverse events, such as conjunctivitis.³⁴ The conjunctivitis associated with dupilumab treatment in patients with AD might possibly be related to decreased mucus production and number of conjunctival goblet cells by inhibition of IL-4 and IL-13 by dupilumab.³⁴ Though much lower frequency compared to dupilumab, clinical trials also showed that treatment with lebrikizumab, inhibiting IL-13, is associated with conjunctivitis in patients with AD.^{25B26 -33} However, in real-world settings, long-term safety data are limited, and predictive factors are unknown for the occurrence of conjunctivitis during lebrikizumab treatment for AD. Identifying the predictive factors for conjunctivitis may be useful for detection of high-risk patients before treatment, and better risk management during lebrikizumab treatment, may contribute to its long-term continued usage and improvement of patients’ QoL, and may help select safer therapy for individual patients.

In this study, we aim to identify predictive factors for the occurrence of conjunctivitis during lebrikizumab treatment in patients with moderate-to-severe AD. We compared patients’ background factors, history of allergic diseases, baseline clinical and laboratory indices between patients who developed conjunctivitis during lebrikizumab treatment versus those who did not, in order to identify the characteristics of the former.

METHODS

Study Design and Data Collection

This prospective, single-center study was conducted from May 2024 to December 2024 at Nippon Medical School Chiba Hokusoh Hospital. We enrolled Japanese patients diagnosed with moderate-to-severe AD based on the “Japanese Atopic Dermatitis Guidelines 2024.”³⁵ Lebrikizumab 500 mg was administered subcutaneously at weeks 0 and 2 to all the patients, followed by 250 mg every 2 weeks (q2W) until week 16. Thereafter, all patients received lebrikizumab every 4 weeks (q4W). The duration of lebrikizumab treatment was median 24 (ranging 12–36) weeks. Topical corticosteroids of moderate- to strongest-potency were simultaneously administered twice daily to all the patients.

Data Collection

We recorded and evaluated the baseline characteristics of all patients, including age, sex, duration of AD, body mass index (BMI), and history of bronchial asthma, allergic conjunctivitis, or allergic rhinitis. Clinical and laboratory assessments included EASI, PP-NRS, immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), total eosinophil count (TEC), eosinophil-to-lymphocyte ratio (ELR), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and C-reactive protein. We also assessed systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI). SII was calculated as (platelet count × neutrophil count)/lymphocyte count, and SIRI was calculated as (neutrophil count × monocyte count)/lymphocyte count. These markers are known to reflect systemic inflammation and could serve as indicators of the severity in some diseases such as psoriasis, or as prognostic markers in cancer or cardiovascular diseases.^{36B37 -42}

Inclusion and Exclusion Criteria

Patients aged ≥15 years with moderate-to-severe AD, defined as total EASI score ≥16 or head and neck EASI score ≥2.4, were included. Adolescent patients aged ≥12 years with body weight ≥40 kg who had an inadequate response to topical therapy or for whom topical therapy alone was deemed inappropriate were included. Since this study was not a clinical trial, there was no strictly defined washout period for switching from other systemic therapies to lebrikizumab. Because the EASI score during prior systemic therapy was not tracked, the start of lebrikizumab administration was defined as week 0 (baseline). We excluded data from patients who restarted lebrikizumab after discontinuation. Other exclusion criteria were serious cardiovascular diseases (heart failure, myocardial infarction, or stroke), malignancy, active infection, a history of hypersensitivity to lebrikizumab or its components, and pregnant or breastfeeding women. Though lebrikizumab can be administered q4w after week 4 in Japan, patients who received q4W immediately after week 4 were excluded from this study to unify treatment conditions.

Comparison of Patients with and Without Conjunctivitis

We compared baseline clinical and laboratory indices and background factors between patients who developed conjunctivitis during lebrikizumab treatment and those who did not. The diagnosis of conjunctivitis was mainly made by dermatologists, and there was no systematic ophthalmological evaluation before, during, or after lebrikizumab therapy. In cases with conjunctivitis, symptomatic treatment was given using anti-allergy eye drops or fluorometholone eye drops.

Ethical Considerations

This study was carried out in accordance with the principles of the Declaration of Helsinki (2004 version) and was approved by the ethics committees of Nippon Medical School, and Nippon Medical School Chiba Hokusoh Hospital.

Statistical Analysis

Normally distributed variables were presented as mean ± standard deviation (SD), and nonparametric variables were presented as median and interquartile range (IQR). We used Fisher’s exact test to evaluate differences in the frequency of categorical variables. For comparisons between two groups, we used the Mann–Whitney U test for nonparametric variables. We evaluated the association between the occurrence of conjunctivitis and each variable using multivariate logistic regression analysis. In the above analysis, only variables with P < 0.05 in the univariate analysis were included, and results were adjusted for age, sex, and BMI. Variables with a variance inflation factor greater than 10 were excluded to avoid multicollinearity. Receiver-operating characteristic (ROC) analysis was performed to assess predictive accuracy, as evaluated by the area under the curve (AUC). A P value <0.05 was considered statistically significant. We conducted statistical analyses using Eazy R (Jichi Medical University Saitama Medical Center).

RESULTS

Baseline Characteristics

A total of 140 patients with AD were included in this study, of whom 87 (62.1%) were male (Supplementary Table S1). The age was median [IQR] 42.0 [18.0–61.0] years, and the disease duration was median [IQR] 16.0 (11.0–39.0) years. Among these patients, 34 patients (24.3%) had allergic conjunctivitis, 50 (35.7%) had allergic rhinitis, and 33 (23.6%) had bronchial asthma. Baseline total EASI score was median [IQR] 19.8 [16.2–27.9], and the PP-NRS score was median [IQR] 7.0 [5.0–9.0]. The median [IQR] of baseline laboratory indexes were serum IgE 3,088 [435.5–10409.5] IU/mL, TARC 1,248 [502.5–3354] pg/mL, LDH 242 [199–292] IU/mL, and TEC 435.6 [269.8–748]/μL.

Background Factors Associated with the Occurrence of Conjunctivitis During Lebrikizumab Treatment in Patients with AD

During lebrikizumab treatment, 20 patients (14.3%) developed conjunctivitis, and its onset was median [IQR] 4 [2–6] week. The duration of lebrikizumab treatment was median [IQR] 24 [12–32] weeks in patients with conjunctivitis while median [IQR] 24 [16–28] weeks in those without, and there were no significant differences (P = 0.862, by Mann–Whitney U test). Among the 20 patients with conjunctivitis, most cases were mild to moderate, and improved with topical eye drops. However, two patients presented with severe conjunctivitis, leading to a switch from lebrikizumab to tralokinumab, and their conjunctivitis resolved. No other patients required discontinuation of lebrikizumab due to conjunctivitis.

AD patients with conjunctivitis during lebrikizumab treatment had significantly higher baseline IgE levels compared to those without (median [IQR] 20,087 [6142.5–37990.3] vs 2,103 [279–7966] IU/mL, P = 0.0000179, by Mann–Whitney U test) (Supplementary Table S2). Patients with conjunctivitis also showed significantly higher baseline TARC levels (median [IQR] 6,064.5 [2865.3–8522.3] vs 1,107.0 [480.5–2652.0] pg/mL, P = 0.0000198, by Mann–Whitney U test), LDH levels (median [IQR] 297.5 [250–326.3] vs 238 [196.5–283.5] IU/mL, P = 0.001147, by Mann–Whitney U test), TEC (669 [496–1209.2] vs 405 [229.4–737.2]/mL, P = 0.00022, by Mann–Whitney U test), and ELR levels (0.5 [0.4–0.8] vs 0.3 [0.1–0.4], P = 0.00123, by Mann–Whitney U test) compared to those without conjunctivitis. There were no significant differences in sex or age distributions, and baseline EASI and PP-NRS between patients with conjunctivitis versus those without.

Logistic Regression Analysis for Predictive Factors of Conjunctivitis

Logistic regression analysis revealed that higher baseline IgE (odds ratio [OR]: 1, 95% confidential interval [CI]: 1.0–1.0, P = 0.0287) and TARC (OR: 1, 95% CI: 1.0–1.0, P = 0.0441) were significantly associated with the occurrence of conjunctivitis during lebrikizumab treatment in patients with AD (Supplementary Table S3). The other factors, including age, sex, BMI, LDH, and TEC, were not significantly associated with the occurrence of conjunctivitis in this model.

ROC Curve Analysis for Predictive Accuracy

ROC curve analysis was performed to assess the predictive abilities of baseline IgE and TARC in distinguishing patients with the occurrence of conjunctivitis from those without (Fig. 1). The AUC of IgE was 0.834 (95%CI: 0.734–0.933), with 60.7% specificity and 93.8% sensitivity by the cut-off value of 3,591 IU/mL. The AUC of TARC was 0.832 (95% CI: 0.74–0.924), with 88.8% specificity and 68.8% sensitivity by the cut-off value of 4,941 pg/mL. Thus, both IgE and TARC demonstrated moderate accuracies to predict the occurrence of conjunctivitis during lebrikizumab treatment.

Figure 1.

The receiver operating characteristic (ROC) curves for evaluating the predictive capability of baseline immunoglobulin E (IgE) (left panel) and thymus and activation-regulated chemokine (TARC) (right panel) levels for the occurrence of conjunctivitis during lebrikizumab treatment in patients with atopic dermatitis. The curve for IgE demonstrates an area under the curve (AUC) of 0.834 (95% confidence interval [CI] 0.734–0.933), a sensitivity of 93.8%, and a specificity of 60.7% at the cut-off value of 3,591 IU/mL. The curve for TARC demonstrates an AUC of 0.832 (95% CI 0.74–0.924), a sensitivity of 68.8%, and a specificity of 88.8% at the cut-off value of 4,941 pg/mL.

DISCUSSION

In this real-world study, we identified two key factors associated with the occurrence of conjunctivitis during lebrikizumab treatment for moderate-to-severe AD: IgE and TARC. Logistic regression analysis showed that both higher IgE and TARC levels were significantly associated with the occurrence of conjunctivitis during lebrikizumab treatment for AD. These results indicate that higher baseline IgE and TARC levels in patients with AD may predict the occurrence of conjunctivitis during lebritizumab treatment.

The incidence of conjunctivitis was 14.3% (20/140) during lebrikizumab treatment of median 24 (ranging 12–36) weeks in this study. In clinical trials and the real-world studies,^34,43 the occurrence of conjunctivitis up to 16 weeks of dupilumab treatment in patients with AD was 22.1% and 22.8%, respectively. Since lebrikizumab inhibits the effects of IL-13 but not of IL-4, it might generate a lower incidence of conjunctivitis compared to dupilumab. In a phase 3 randomized, double-blind, placebo-controlled study (ADhere-J; NCT04760314) of lebrikizumab q2W for 16 weeks in Japanese AD patients, the occurrence of allergic conjunctivitis and conjunctivitis was 17.1% and 9.8%, respectively.⁴⁴ In our real-world study, the diagnosis of conjunctivitis was done by dermatologists, and it is ambiguous if the occurrence of conjunctivitis (14.3%) includes allergic conjunctivitis or not. Further large-scale studies with evaluation by ophthalmologists are needed to investigate the incidence of conjunctivitis during lebrikizumab treatment for AD.

As well as lebrikizumab treatment, previous clinical trials and real-world studies demonstrated that higher IgE and TARC levels in AD patients are associated with the occurrence of conjunctivitis during treatment with dupilumab, inhibiting IL-13 and IL-4.^34,43 According to our present results of ROC, AD patients with IgE higher than 3,591 IU/mL or TARC higher than 4,991 pg/mL might be predicted to develop conjunctivitis during lebrikizumab treatment, and should be prepared in advance for the early detection and treatment of conjunctivitis. Further studies using larger cohorts are needed to determine more accurate cutoff values for predicting conjunctivitis.

TARC is generally known to increase as AD severity worsens, potentially raising the risk of conjunctivitis in more severe patients. However, while TARC and IgE showed significant associations with conjunctivitis in this study, EASI scores did not. A possible reason is the lack of a strict washout period, which may have lowered the EASI scores of more severe patients who had received prior systemic therapies. Larger cohorts with well-defined washout protocols are needed to clarify whether EASI influences the occurrence of conjunctivitis in lebrikizumab-treated AD patients.

This study has several limitations. First, the sample size was relatively small. Second, the study included only Japanese patients. Third, the treatment duration varied among patients. Fourth, mild or asymptomatic cases of conjunctivitis may have been overlooked since we did not perform systematic ophthalmological evaluations before, during, or after lebrikizumab treatment. Fifth, there was no strict washout period when switching from previous systemic treatments to lebrikizumab since this study was not a clinical trial. Sixth, we enrolled patients who received lebrikizumab in combination with topical corticosteroids, and did not include the patients treated with lebrikizumab alone. Seventh, the majority of our study population was male, which might limit the generalizability of our findings to a broader AD population.

CONCLUSION

The results of this study indicate that higher IgE and TARC levels in AD patients are associated with the occurrence of conjunctivitis during lebrikizumab treatment. These results highlight the importance of evaluating the above biomarkers before starting lebrikizumab to predict patients developing conjunctivitis.

Footnotes

SUPPLEMENTARY MATERIAL

References

1. Chiesa Fuxench

, Block

, Boguniewicz

, et al. Atopic dermatitis in America study: A cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J Invest Dermatol. 2019;139(3):583–590; doi: 10.1016/j.jid.2018.08.028

2. Harrop

, Chinn

, Verlato

, et al. Eczema, atopy and allergen exposure in adults: A population-based study. Clin Exp Allergy. 2007;37(4):526–535; doi: 10.1111/j.1365-2222.2007.02679.x

3. Sacotte

, Silverberg

. Epidemiology of adult atopic dermatitis. Clin Dermatol. 2018;36(5):595–605; doi: 10.1016/j.clindermatol.2018.05.007

4. Hadi

, Tarmizi

, Khalid

, et al. The epidemiology and global burden of atopic dermatitis: A narrative review. Life (Basel). 2021;11(9):936; doi: 10.3390/life11090936

5. Langan

, Irvine

, Weidinger

. Atopic dermatitis. Lancet. 2020;396(10247):345–360; doi: 10.1016/s0140-6736(20)31286-1

6. Diepgen

, Ofenloch

, Bruze

, et al. Prevalence of contact allergy in the general population in different European regions. Br J Dermatol. 2016;174(2):319–329; doi: 10.1111/bjd.14167

7. Honda

, Kabashima

. Reconciling innate and acquired immunity in atopic dermatitis. J Allergy Clin Immunol. 2020;145(4):1136–1137; doi: 10.1016/j.jaci.2020.02.008

8. Hagino

, Saeki

, Kanda

. 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; doi: 10.1111/1346-8138.16549

9. Uchiyama

, Fujiwara

, Inoue

, et al. Possible suppressive effects of baricitinib on serum IL-22 levels in atopic dermatitis. J Dermatol Sci. 2022;106(3):189–192; doi: 10.1016/j.jdermsci.2022.04.006

10.

10. Kosaka

, Uchiyama

, Ishikawa

, et al. Real-world effectiveness and safety of upadacitinib in Japanese patients with atopic dermatitis: A two-centre retrospective study. Eur J Dermatol. 2022;32(6):800–802; doi: 10.1684/ejd.2022.4365

11.

11. Nomura

, Sandilands

, Akiyama

, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol. 2007;119(2):434–440; doi: 10.1016/j.jaci.2006.12.646

12.

12. Silverberg

. Atopic dermatitis in adults. Med Clin North Am. 2020;104(1):157–176; doi: 10.1016/j.mcna.2019.08.009

13.

13. Kamata

, Tada

. Optimal use of Jak inhibitors and biologics for atopic dermatitis on the basis of the current evidence. JID Innov. 2023;3(3):100195; doi: 10.1016/j.xjidi.2023.100195

14.

14. Nakashima

, Yanagihara

, Otsuka

. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71(1):40–46; doi: 10.1016/j.alit.2021.10.004

15.

15. Bieber

. Interleukin-13: Targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020;75(1):54–62; doi: 10.1111/all.13954

16.

16. Marbach-Breitrück

, Kalledat

, Heydeck

, et al. Atopic patients show increased interleukin 4 plasma levels but the degree of elevation is not sufficient to upregulate interleukin-4-Sensitive Genes. Skin Pharmacol Physiol. 2019;32(4):192–200; doi: 10.1159/000499431

17.

17. Szegedi

, Lutter

, Res

, et al. Cytokine profiles in interstitial fluid from chronic atopic dermatitis skin. J Eur Acad Dermatol Venereol. 2015;29(11):2136–2144; doi: 10.1111/jdv.13160

18.

18. Tubau

, Puig

. Therapeutic targeting of the IL-13 pathway in skin inflammation. Expert Rev Clin Immunol. 2021;17(1):15–25; doi: 10.1080/1744666x.2020.1858802

19.

19. Tsoi

, Rodriguez

, Degenhardt

, et al. Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J Invest Dermatol. 2019;139(7):1480–1489; doi: 10.1016/j.jid.2018.12.018

20.

20. Smith

, Engel

, Wu

. Lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med. 2023;388(24):2299; doi: 10.1056/NEJMc2304782

21.

21. Loh

, Hsiao

, Shi

. Therapeutic potential of lebrikizumab in the treatment of atopic dermatitis. J Asthma Allergy. 2020;13:109–114; doi: 10.2147/jaa.S211032

22.

22. Bernardo

, Bieber

, Torres

. Lebrikizumab for the treatment of moderate-to-severe atopic dermatitis. Am J Clin Dermatol. 2023;24(5):753–764; doi: 10.1007/s40257-023-00793-5

23.

23. Labib

, Ju

, Yosipovitch

. Managing atopic dermatitis with lebrikizumab—the evidence to date. Clin Cosmet Investig Dermatol. 2022;15:1065–1072; doi: 10.2147/ccid.S295672

24.

24. Ultsch

, Bevers

, Nakamura

, et al. Structural basis of signaling blockade by anti-IL-13 antibody Lebrikizumab. J Mol Biol. 2013;425(8):1330–1339; doi: 10.1016/j.jmb.2013.01.024

25.

25. Silverberg

, Guttman-Yassky

, Thaçi

, et al. Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med. 2023;388(12):1080–1091; doi: 10.1056/NEJMoa2206714

26.

26. Blauvelt

, Thyssen

, Guttman-Yassky

, et al. Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials. Br J Dermatol. 2023;188(6):740–748; doi: 10.1093/bjd/ljad022

27.

27. Simpson

, Gooderham

, Wollenberg

, et al. Efficacy and safety of lebrikizumab in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis: A randomized clinical trial (ADhere). JAMA Dermatol. 2023;159(2):182–191; doi: 10.1001/jamadermatol.2022.5534

28.

28. Stein Gold

, Thaçi

, Thyssen

, et al. Safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis: An integrated analysis of eight clinical trials. Am J Clin Dermatol. 2023;24(4):595–607; doi: 10.1007/s40257-023-00792-6

29.

29. Hebert

, Flohr

, Hong

, et al. Efficacy of lebrikizumab in adolescent patients with moderate-to-severe atopic dermatitis: 16-week results from three randomized phase 3 clinical trials. J Dermatolog Treat. 2024;35(1):2324833; doi: 10.1080/09546634.2024.2324833

30.

30. Yosipovitch

, Lio

, Rosmarin

, et al. Lebrikizumab improved itch and reduced the extent of itch interference on sleep in patients with moderate-to-severe atopic dermatitis: Two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2024;190(2):289–291; doi: 10.1093/bjd/ljad435

31.

31. Simpson

, Flohr

, Eichenfield

, et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE). J Am Acad Dermatol. 2018;78(5):863–871.e11; doi: 10.1016/j.jaad.2018.01.017

32.

32. Tanaka

, Igawa

, Takahashi

, et al. Lebrikizumab combined with topical corticosteroids improves patient-reported outcomes in Japanese patients with moderate-to-severe atopic dermatitis. Acta Derm Venereol. 2024;104:adv34375; doi: 10.2340/actadv.v104.34375

33.

33. Soung

, Ständer

, Gutermuth

, et al. Lebrikizumab monotherapy impacts on quality of life scores through improved itch and sleep interference in two Phase 3 trials. J Dermatolog Treat. 2024;35(1):2329240; doi: 10.1080/09546634.2024.2329240

34.

34. Akinlade

, Guttman-Yassky

, de Bruin-Weller

, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019;181(3):459–473; doi: 10.1111/bjd.17869

35.

35. Saeki

, Ohya

, Arakawa

, et al. English version of clinical practice guidelines for the management of atopic dermatitis 2024. J Dermatol. 2025;52(2):e70–e142; doi: 10.1111/1346-8138.17544

36.

36. Dziedzic

, Gąsior

, Tuzimek

, et al. Investigation of the associations of novel inflammatory biomarkers-systemic inflammatory index (SII) and systemic inflammatory response index (SIRI)-with the severity of coronary artery disease and acute coronary syndrome occurrence. Int J Mol Sci. 2022;23(17):9553; doi: 10.3390/ijms23179553

37.

37. Hagino

, Saeki

, Fujimoto

, et al. Predictive factors for long-term high responders to upadacitinib treatment in patients with atopic dermatitis. Dermatitis. 2025;36(1):62–71; doi: 10.1089/derm.2024.0230

38.

38. Sugimoto

, Matsuda

, Shibata

, et al. Impact of pretreatment systemic inflammatory markers on treatment persistence with biologics and conventional systemic therapy: A retrospective study of patients with psoriasis vulgaris and psoriatic arthritis. J Clin Med. 2023;12(8):3046; doi: 10.3390/jcm12083046

39.

39. Topkan

, Mertsoylu

, Kucuk

, et al. Low systemic inflammation response index predicts good prognosis in locally advanced pancreatic carcinoma patients treated with concurrent chemoradiotherapy. Gastroenterol Res Pract. 2020;2020:5701949; doi: 10.1155/2020/5701949

40.

40. Ma

, Cui

, Cai

, et al. Association between systemic immune inflammation index, systemic inflammation response index and adult psoriasis: Evidence from NHANES. Front Immunol. 2024;15:1323174; doi: 10.3389/fimmu.2024.1323174

41.

41. Hagino

, Saeki

, Fujimoto

, et al. Real-world effectiveness and safety of bimekizumab in Japanese patients with psoriasis: A single-center retrospective study. J Dermatol. 2024;51(5):649–658; doi: 10.1111/1346-8138.17186

42.

42. Yang

, Wu

, Hsu

, et al. Systemic immune-inflammation index (SII) predicted clinical outcome in patients with coronary artery disease. Eur J Clin Invest. 2020;50(5):e13230; doi: 10.1111/eci.13230

43.

43. Uchida

, Kamata

, Nagata

, et al. Conjunctivitis in patients with atopic dermatitis treated with dupilumab is associated with higher baseline serum levels of immunoglobulin E and thymus and activation-regulated chemokine but not clinical severity in a real-world setting. J Am Acad Dermatol. 2020;82(5):1247–1249; doi: 10.1016/j.jaad.2019.12.039

44.

44. Katoh

, Tanaka

, Takahashi

, et al. Efficacy and safety of lebrikizumab combined with topical corticosteroids in Japanese patients with moderate-to-severe atopic dermatitis: A phase 3, double-blind, placebo-controlled, randomized clinical trial (ADhere-J). Curr Med Res Opin. 2025;41(1):1–12; doi: 10.1080/03007995.2024.2436982

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.02 MB

0.00 MB