Beyond Suppression: Why Immunosuppressive Therapies Control – but Do Not Cure – Eczema 超越抑制: 免疫调节疗法为何只能控制而难以治愈湿疹

Do not stop at superficial tasting, do not cater to the mainstream, do not fear the pain of critical thinking, do not lose the soul of the humanities.

「不浅尝辄止，不迎合主流，不惧思辨之痛，不失人文之魂。」

What “cure” would actually mean

To cure eczema—principally atopic dermatitis—would require permanent abolition of the disease in the absence of ongoing treatment. That entails (i) durable restoration of the skin-barrier defect, (ii) a rewired immune profile that no longer over-reacts to innocuous stimuli, and (iii) elimination of the genetic/epigenetic proclivity that ignites flares. No current therapy—including immunosuppressants—fulfils all three conditions.

Pathophysiological logic

Why immunosuppressants fall short of “cure”

  1. Symptom extinguishers, not circuit rewires  Drugs such as topical corticosteroids, calcineurin inhibitors, methotrexate, cyclosporine, JAK inhibitors, and IL-4/IL-13 biologics act as dimmer switches on inflammatory circuits. When the pharmacologic pressure is lifted, the original circuitry re-brightens.
  2. Barrier remains structurally compromised  Even on perfect immune quiescence, FLG-mutant skin leaks moisture and admits irritants, re-stimulating immunity.
  3. Immunologic memory is resilient  T-cell and ILC-2 populations retain epigenetic programs that survive drug withdrawal, ready to re-launch cytokine cascades.
  4. Selective pressure can yield rebound  Abrupt cessation of systemic steroids or cyclosporine often triggers a rebound flare, illustrating the pendulum nature of suppression rather than eradication.

Can “disease modification” evolve into cure?

  1. Aggressive biologic therapy may elongate remission intervals (“window-of-opportunity” hypothesis), but long-term studies still record relapse once drugs cease.
  2. Gene-editing of FLG or targeted epigenetic editing of Th2 memory are theoretic future avenues; they are not current clinical reality.

Curated Primary Literature & Key Reviews

  1. Start with Simpson et al. for clinical trial design and endpoints—observe rapid clearance yet relapse on wash-out.
  2. Pair with Gao Q, Hao PS and to understand why relapse happens at the chromatin level.
  3. Integrate Hajar T et al. to appreciate real-world rebound when patients self-discontinue steroids.
  4. Consult Khatib CM et al. for the genetic architecture that any definitive therapy must rectify.

Take-Away

Immunosuppressive medicines are powerful firefighting foam—indispensable for controlling a blaze, but they do not rebuild the wiring that keeps sparking that blaze. They deliver control, sometimes long remission, yet cure remains contingent on solving deeper genetic-barrier-immune entanglements that the drugs merely mask.

 

1. 何谓“治愈”

真正的治愈意味着：停药后疾病永不复发，同时皮肤屏障、免疫系统及遗传易感全部恢复常态。现行任何免疫抑制药物皆未能同时满足此三项苛刻标准。

2. 病理逻辑逐层拆解

3. 免疫抑制药物难以“治愈”的原因

  1. 灭火非重接线路 糖皮质激素、钙调磷酸酶抑制剂、甲氨蝶呤、环孢素、JAK 抑制剂及生物制剂均仅暂时调暗炎症“灯光”。撤药后，线路仍旧亮起。
  2. 屏障结构未根本修复 FLG 缺失皮肤仍渗水、漏入刺激物，重新点燃免疫反应。
  3. 免疫记忆顽固 T 细胞与 ILC-2 的表观遗传程序能够跨过药物清除期，随时备战。
  4. 抑制后易反弹 系统激素或环孢素骤停常出现反跳性爆发，佐证“压制”而非“根除”。

4. “疾病修饰”能否迈向治愈？

早期高强度生物制剂或许能延长缓解（“机会窗口”假说），然停药后大多仍复发。FLG 基因编辑、Th2 记忆的精准表观遗传干预乃未来构想，尚未临床应用。

5. 核心结论

免疫抑制药物如同灭火泡沫：扑灭烈焰不可或缺，却无法重建不断走火的电线。
它们提供控制，甚至长期缓解，但要真正“治愈”湿疹，仍须破解遗传-屏障-免疫的深层纠缠，而现行药物仅是遮蔽其表。

6.  精选主要文献与关键综述

1. 首先阅读Simpson 等人的研究，了解临床试验的设计与终点指标——可见病灶迅速清除，但停药后又复发。

2. 随后结合 Gao Q、Hao P S 等人的工作，以阐明复发在染色质层面发生的机制。

3. 再整合 Hajar T 等人的研究，体会患者自行停用激素时在真实世界里出现的反弹现象。

4. 最后参阅 Khatib C M 等人的研究，了解任何根本性疗法必须矫正的遗传结构基础。

.

Reference

  1. Khatib CM, Klein-Petersen AW, Rønnstad ATM, Egeberg A, Christensen MO, Silverberg JI, Thomsen SF, Irvine AD, Thyssen JP. Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis. Exp Dermatol. 2024 Jul;33(7):e15130. doi: 10.1111/exd.15130. PMID: 38989976.
  2. Khatib CM, Klein-Petersen AW, Rønnstad ATM, et al. Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis. Exp Dermatol. 2024; 33:e15130.
  3. E.L. Simpson et al.Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis N Engl J Med 2016;375:2335-48.
  4. Emma Guttman-Yassky et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.The Lancet. Volume 397, Issue 10290, 5–11 June 2021, Pages 2151-2168
  5. Marlys S. Fassett et al. ,IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis.Sci. Immunol.8,eabi6887(2023).DOI:10.1126/sciimmunol.abi6887
  6. Orfali RL, Aoki V. Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis. Pharmaceutics. 2023 Feb 8;15(2):577. doi: 10.3390/pharmaceutics15020577. PMID: 36839897; PMCID: PMC9961325.
  7. Gao Q, Hao PS. Inflammatory Memory in Epidermal Stem Cells – A New Strategy for Recurrent Inflammatory Skin Diseases. J Inflamm Res. 2024 Sep 21;17:6635-6643. doi: 10.2147/JIR.S478987. PMID: 39323610; PMCID: PMC11423832.
  8. Danielidi A, Lygeros S, Anastogianni A, Danielidis G, Georgiou S, Stathopoulos C, Grafanaki K. Genetic and Epigenetic Interconnections Between Atopic Dermatitis, Allergic Rhinitis, and Rhinitis with Nasal Polyps. Allergies. 2025; 5(2):9. https://doi.org/10.3390/allergies5020009
  9. Taieb A. Topical Steroid Withdrawal: The Challenging Transition from Patient Self-Diagnosis on Social Media to Medical Science and Care. Acta Derm Venereol. 2025 Apr 3;105:adv43455. doi: 10.2340/actadv.v105.43455. PMID: 40178221; PMCID: PMC11986266.
  10. Kim K, Kim M, Rhee E, Lee MH, Yang HJ, Park S, Kim HS. Efficacy and Safety of Low-Dose Cyclosporine Relative to Immunomodulatory Drugs Used in Atopic Dermatitis: A Systematic Review and Meta-Analysis. J Clin Med. 2023 Feb 9;12(4):1390. doi: 10.3390/jcm12041390. PMID: 36835928; PMCID: PMC9959975.
  11. Jacobson ME, Seshadri RS, Morimoto R, Grinich E, Haag C, Nguyen K, Simpson EL. Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress. J Eur Acad Dermatol Venereol. 2024 Apr;38(4):665-672. doi: 10.1111/jdv.19699. Epub 2023 Dec 8. PMID: 38063244.
  12. Nicholas Stefanovic, Alan D. Irvine, Filaggrin and beyond: New insights into the skin barrier in atopic dermatitis and allergic diseases, from genetics to therapeutic perspectives, Annals of Allergy, Asthma & Immunology, Volume 132, Issue 2, 2024, Pages 187-195
  13. Bhat P, Garibyan L. The Potential of CRISPR-Guided Therapies in the Dermatology Clinic. JID Innov. 2022 Jan 25;2(2):100103. doi: 10.1016/j.xjidi.2022.100103. PMID: 35265937; PMCID: PMC8899042.