提示: 手机请竖屏浏览!

nemolizumab并用外用药治疗特应性皮炎伴瘙痒的试验
Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus


Kenji Kabashima ... 其他 • 2020.07.09
NEJM 动画解读

nemolizumab治疗特应性皮炎

摘要


背景

nemolizumab是皮下注射的抗白细胞介素-31受体A的人源化单克隆抗体,而白细胞介素-31受体A与特应性皮炎的瘙痒和炎症相关。在2期研究中,nemolizumab减轻了特应性皮炎的严重程度。

 

方法

在一项为期16周的双盲3期试验中,我们将有中度至重度瘙痒且对外用药应答不足的日本特应性皮炎患者以2∶1的比例随机分组,两组分别每4周接受一次nemolizumab(60 mg)或安慰剂皮下注射,直到第16周,而且并用外用药。主要终点是瘙痒的视觉模拟量表(VAS)评分(范围,0~100分,评分较高表示瘙痒较严重)从基线至第16周的平均变化百分比。次要终点包括截至第4周时瘙痒VAS评分变化情况的时间过程,湿疹面积和严重程度指数(Eczema Area and Severity Index,EASI)评分(范围,0~72分,评分较高表示较严重)的变化,皮肤病学生活质量指数(Dermatology Life Quality Index,DLQI)评分(范围,0~30分,评分较高表示对日常生活的影响较大)≤4分,失眠严重程度指数(Insomnia Severity Index,ISI)评分(范围,0~28分,评分较高表示较严重)≤7分和安全性。

 

结果

共计143例患者被随机分配接受nemolizumab治疗,72例患者被随机分配接受安慰剂治疗。基线时瘙痒的中位VAS评分为75分。第16周时,nemolizumab组和安慰剂组VAS评分的平均变化百分比分别为-42.8%和-21.4%(差异,-21.5个百分点;95%置信区间[CI],-30.2~-12.7;P<0.001)。nemolizumab组和安慰剂组EASI评分的平均变化百分比分别为-45.9%和-33.2%。nemolizumab组和安慰剂组DLQI评分≤4分的患者百分比分别为40%和22%;ISI评分≤7分的患者百分比分别为55%和21%。nemolizumab组和安慰剂组的注射相关反应发生率分别为8%和3%。

 

结论

在这项为期16周的试验中,与特应性皮炎外用药并用安慰剂相比,外用药并用nemolizumab皮下注射更大幅减轻了患者瘙痒。nemolizumab的注射部位反应发生率高于安慰剂。我们有必要通过更长时间、更大规模的试验来确定nemolizumab对特应性皮炎是否具有持久疗效以及是否安全(由Maruho资助,在JapicCTI注册号为173740)。





作者信息

Kenji Kabashima, M.D., Ph.D., Takayo Matsumura, M.S., Hiroshi Komazaki, M.S., and Makoto Kawashima, M.D., Ph.D. for the Nemolizumab-JP01 Study Group*
From the Department of Dermatology, Graduate School of Medicine, Kyoto University (K.K.), and the Departments of Clinical Development (T.M.) and Data Science (H.K.), Maruho, Kyoto, and Tokyo Women’s Medical University, Tokyo (M.K.) — all in Japan. Address reprint requests to Dr. Kabashima at the Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan, or at kaba@kuhp.kyoto-u.ac.jp. *The members of the Nemolizumab-JP01 Study Group are listed in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers 2018;4:1-1.

2. Torres T, Ferreira EO, Gonçalo M, Mendes-Bastos P, Selores M, Filipe P. Update on atopic dermatitis. Acta Med Port 2019;32:606-613.

3. Avena-Woods C. Overview of atopic dermatitis. Am J Manag Care 2017;23:Suppl:S115-S123.

4. Klonowska J, Gleń J, Nowicki RJ, Trzeciak M. New cytokines in the pathogenesis of atopic dermatitis — new therapeutic targets. Int J Mol Sci 2018;19:3086-3086.

5. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: Part I. J Eur Acad Dermatol Venereol 2018;32:657-682.

6. Chrostowska-Plak D, Reich A, Szepietowski JC. Relationship between itch and psychological status of patients with atopic dermatitis. J Eur Acad Dermatol Venereol 2013;27(2):e239-e242.

7. Bridgman AC, Block JK, Drucker AM. The multidimensional burden of atopic dermatitis: an update. Ann Allergy Asthma Immunol 2018;120:603-606.

8. Dainichi T, Kitoh A, Otsuka A, et al. The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis. Nat Immunol 2018;19:1286-1298.

9. Wahlgren CF. Itch and atopic dermatitis: an overview. J Dermatol 1999;26:770-779.

10. Ramirez FD, Chen S, Langan SM, et al. Association of atopic dermatitis with sleep quality in children. JAMA Pediatr 2019;173(5):e190025-e190025.

11. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol 2014;71:116-132.

12. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: Section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol 2014;71:327-349.

13. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: Part II. J Eur Acad Dermatol Venereol 2018;32:850-878.

14. Katoh N, Ohya Y, Ikeda M, et al. Clinical practice guidelines for the management of atopic dermatitis 2018. J Dermatol 2019;46:1053-1101.

15. Matterne U, Böhmer MM, Weisshaar E, Jupiter A, Carter B, Apfelbacher CJ. Oral H1 antihistamines as ‘add-on’ therapy to topical treatment for eczema. Cochrane Database Syst Rev 2019;1:CD012167-CD012167.

16. Oyama S, Kitamura H, Kuramochi T, et al. Cynomolgus monkey model of interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor A by a humanized monoclonal antibody. Exp Dermatol 2018;27:14-21.

17. Nemoto O, Furue M, Nakagawa H, et al. The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br J Dermatol 2016;174:296-304.

18. Wong C-K, Leung KM-L, Qiu H-N, Chow JY-S, Choi AOK, Lam CW-K. Activation of eosinophils interacting with dermal fibroblasts by pruritogenic cytokine IL-31 and alarmin IL-33: implications in atopic dermatitis. PLoS One 2012;7(1):e29815-e29815.

19. Bağci IS, Ruzicka T. IL-31: a new key player in dermatology and beyond. J Allergy Clin Immunol 2018;141:858-866.

20. Singh B, Jegga AG, Shanmukhappa KS, et al. IL-31-driven skin remodeling involves epidermal cell proliferation and thickening that lead to impaired skin-barrier function. PLoS One 2016;11(8):e0161877-e0161877.

21. Ruzicka T, Hanifin JM, Furue M, et al. Anti–interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med 2017;376:826-835.

22. Silverberg JI, Pinter A, Pulka G, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J Allergy Clin Immunol 2020;145:173-182.

23. Kabashima K, Furue M, Hanifin JM, et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study. J Allergy Clin Immunol 2018;142(4):1121.e7-1130.e7.

24. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Dermatol Venereol (Stockholm) 1980;92:Suppl:44-47.

25. Kawashima M, Nakagawa H. Olopatadine hydrochloride in children: evidenced efficacy and safety for atopic dermatitis treatment in a randomized, multicenter, double-blind, parallel group comparative study. Nishinihon J Dermatol 2011;73:278-289.

26. Jacob SE, Steele T. Corticosteroid classes: a quick reference guide including patch test substances and cross-reactivity. J Am Acad Dermatol 2006;54:723-727.

27. Reich A, Heisig M, Phan NQ, et al. Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol 2012;92:497-501.

28. Barbier N, Paul C, Luger T, et al. Validation of the Eczema Area and Severity Index for atopic dermatitis in a cohort of 1550 patients from the pimecrolimus cream 1% randomized controlled clinical trials programme. Br J Dermatol 2004;150:96-102.

29. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) — a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-216.

30. Basra MKA, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology 2015;230:27-33.

31. Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep 2011;34:601-608.

32. Chopra R, Vakharia PP, Sacotte R, et al. Severity strata for Eczema Area and Severity Index (EASI), modified EASI, Scoring Atopic Dermatitis (SCORAD), objective SCORAD, Atopic Dermatitis Severity Index and body surface area in adolescents and adults with atopic dermatitis. Br J Dermatol 2017;177:1316-1321.

33. Yosipovitch G, Reaney M, Mastey V, et al. Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis. Br J Dermatol 2019;181:761-769.

34. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients’ perspective. Arch Dermatol 2004;140:1513-1519.

35. Schmitt J, Langan S, Williams HC. What are the best outcome measurements for atopic eczema? a systematic review. J Allergy Clin Immunol 2007;120:1389-1398.

36. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 1993;4:353-365.

37. Schram ME, Spuls PI, Leeflang MMG, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy 2012;67:99-106.

38. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375:2335-2348.

39. Shirley M. Dupilumab: first global approval. Drugs 2017;77:1115-1121.

40. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;389:2287-2303.

服务条款 | 隐私政策 | 联系我们