The expanding horizon of anti-IL-36 therapy

By Warren R. Heymann, MD, FAAD
Sept. 25, 2024
Vol. 6, No. 39

An abridged version of this commentary was published in “A Clinician’s Perspective” in the April 2024 issue of the JAAD.

We last explored the relationship between IL-36 and generalized pustular psoriasis (GPP) and the use of spesolimab (SPEVIGO an IL-36 receptor antagonist) six months prior to its September 2022 FDA approval for GPP. (1,2) Subsequent studies have affirmed that the IL-36 signaling pathway is the key driver in the pathogenesis of GPP. Spesolimab has demonstrated efficacy and safety in managing GPP, in the rapid control of the flares and in preventing their recurrence. (3)

A controversial point regarding the use of spesolimab focuses on (or if) screening for tuberculosis should be performed when the drug has been prescribed. The package insert states, “Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SPEVIGO.” According to Hackley et al. no cases of spesolimab-induced TB reactivation have been reported. The authors contend that treating GPP as soon as possible is a priority and propose that treatment with spesolimab should not be delayed for TB screening in patients with no significant risk factors for active or latent TB infection. (4)

As anticipated, the role of IL-36 in the pathogenesis of other dermatoses is an area of active inquiry. Understanding the biology of IL-36 is essential when considering how modifying its roles can be used to therapeutic advantage. The following abstract excerpt is from the review by Ahmad et al. on the IL-36/IL-36R axis. (5)

IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36β, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cascade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis.

Dramatic examples of off-label spesolimab have been reported in severe cases of pyoderma gangrenosum (PG). Guénin et al. reported two cases — a 72-year-old man with postoperative PG and a 39-year-old woman with overlapping connective tissue disorders and multiple refractory PG ulcers, respectively. Although the man responded to prednisone and cyclosporine, further improvement occurred with the addition of spesolimab, which was continued on monthly infusions, allowing for lower doses of prednisone and cyclosporine. The woman was treated with prednisone, cyclosporine, hydroxycholoroquine, and IVIG; her PG was recalcitrant to this regimen, at which point, spesolimab was administered. Importantly both patients noted improvement within 72 hours of the infusion. (6) Ma et al. reported a 44-year-old man with a 12-year history of PG that was worsening. His disease was recalcitrant to prednisone, tofacitinib, cyclosporine, and adalimumab. Within a month of a single infusion of spesolimab, all lesions healed, allowing for a tapering of his steroids. (7) Presumably, spesolimab breaks the inflammatory cycle in PG by decreasing neutrophil recruitment. (8)

As previously stated, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. (5) According to Palaniappan et al. “Spesolimab probably works by reducing IL-4 and IL-13, the primary triggers of Th2 inflammation in atopic dermatitis. In hidradenitis suppurativa, it likely decreases the release of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α that are released in an autocrine fashion and form an inflammatory loop.” (8)

Imsidolimab is a high-affinity humanized IgG4 monoclonal antibody that specifically binds IL-36R, antagonizing IL-36 signaling. Warren et al performed a phase II trial of imsidolimab that demonstrated a rapid resolution of symptoms and pustular eruptions in patients with a GPP flare. Eight patients were enrolled and 6 completed the study (One patient left because of a lack of improvement and the other switched to infliximab following a “nonserious” Staphylococcus aureus bacteremia). Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29, and through day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity (a flare of plaque psoriasis, sore throat). No deaths were reported. The drug is advancing to phase III trials. (9) In an accompanying editorial, Gleeson and Mahil emphasize the appeal of the mixed delivery method for imsidolimab with patients receiving an initial intravenous infusion followed by monthly subcutaneous dosing, allowing for convenient disease maintenance. (10) Imsidolimab is being investigated for ichthyosis and acne.

In my original commentary on IL-36, I noted that “In Jewish numerology (gematria), the number 18 (“chai”) means life (think of “L’chaim — to life!” from Fiddler on the Roof) — 36 is twice life.” The lifetime study of the IL36/IL-36R axis is in its adolescence. As stated by Hwang et al., “Future clinical trials on IL-36 antagonists are warranted and will further define their role in inflammatory skin disease while adding an important immunomodulating treatment pathway.” (11)

Point to Remember: The IL-36/IL-36R axis is crucial in the pathogenesis and treatment of generalized pustular psoriasis. Researchers have demonstrated that this pathway may be instrumental in several other inflammatory dermatoses, as already shown in pyoderma gangrenosum.

Our experts’ viewpoint

Fareed Ahmad, PhD
Department of Dermatology and Venereology
Dermatology Institute, Academic Health System
Translational Research Institute, Academic Health System
Hamad Medical Corporation, Doha, Qatar

Joerg Buddenkotte, MD, PhD
Department of Dermatology and Venereology
Dermatology Institute, Academic Health System
Translational Research Institute, Academic Health System
Hamad Medical Corporation, Doha, Qatar

Martin Steinhoff, MD, PhD
Department of Dermatology and Venereology
Dermatology Institute, Academic Health System
Translational Research Institute, Academic Health System
Hamad Medical Corporation, Doha, Qatar

School of Medicine, Qatar University, Doha, Qatar
School of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
Department of Health & Life Sciences, Hamad-bin Khalifa University, Doha, Qatar
Department of Dermatology, Weill Cornell Medicine

In 1996, human and rat IL-36R (IL1RL2) genes were first cloned and characterized as the sixth IL-1 receptor (IL-1R1). Three receptor activating cytokines (IL-36α, IL-36β, IL-36γ) and one antagonist (IL-36Ra) were identified in quick succession and associated with pro-inflammatory (IL-36α/γ) and anti-inflammatory (IL-36Ra) capacities in humans. About 30 years later, IL-36 cytokines have been described to drive mostly inflammatory disorders at all mucosal barrier sites, intestinal, pulmonary and in particular cutaneous. Initially associated with pustular psoriasis, IL-36 is now known to be involved in the pathology of hidradenitis suppurativa, pyoderma gangrenosum, and Netherton syndrome. Immunologically, there is a higher activation of the innate immune responses in an autoinflammatory manner compared to psoriasis vulgaris (characterized by excessive proliferation and abnormal differentiation of keratinocytes), and atopic dermatitis (characterized by ‘de-differentiation’ of keratinocytes). The pleiotropy of IL-36 to contribute to innate and the adaptive immune response in numerous skin dermatoses is astonishing; this might depend on the microinflammatory environment IL-36 isotypes. For example, IL-36R signaling remodels an immune-suppressive tumor microenvironment in solid tumors. In addition, engaging in the early, innate immunity stage of inflammatory skin disorders could probably explain the wide range of disease associations. The recent FDA approval of spesolimab, a humanized IgG1 monoclonal antibody blocking IL-36R, for the treatment of generalized pustular psoriasis (GPP) will very likely expand our therapeutic toolbox to treat patients with therapy-refractory atopic dermatitis, hidradenitis suppurativa, psoriasis vulgaris, and neutrophilic dermatoses (including pustular drug eruptions, pyoderma gangrenosum, Behcet’s disease, Sweet syndrome, and probably many more).

Spesolimab has already been used as an emergency intervention in two patients with refractory pyoderma gangrenosum. Recruitment for phase-II/III clinical trials of spesolimab in patients with Netherton syndrome is ongoing and being evaluated in phase-II/III clinical trials for ulcerative colitis. A phase-II clinical trial of spesolimab in patients with perianal fistulizing Crohn disease has been completed. Additional trials evaluating the long-term efficacy and safety data are required before spesolimab becomes a major player in the treatment of GPP and other inflammatory skin diseases. Currently, two new anti-IL-36R monoclonal antibodies, HB0034 (Huaota) and IMG008 (Inmagene Bio), are in progress. In future, preclinical, clinical, and ongoing trials data will further define the ideal target population for anti-IL-36R therapy in many more skin disorders beyond GPP.

1. Heymann WR. IL-36 and generalized pustular psoriasis: L’Chaim! Dermatology World Insights and Inquiries, March 9, 2022, volume 4, number 10. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2022/il-36-and-generalized-pustular-psoriasis

2. Blair HA. Spesolimab: First Approval. Drugs. 2022 Nov;82(17):1681-1686. doi: 10.1007/s40265-022-01801-4. Erratum in: Drugs. 2023 Jan;83(1):103. PMID: 36418672; PMCID: PMC9744699.

3. Bernardo D, Thaçi D, Torres T. Spesolimab for the Treatment of Generalized Pustular Psoriasis. Drugs. 2023 Dec 20. doi: 10.1007/s40265-023-01988-0. Epub ahead of print. PMID: 38114719.

4. Hackley M, Thampy D, Waseh S, Feldman SR, Blauvelt A, Weinberg JM, Schwartzman S, Liao W, Prussick R, Cohen JM, Hsu S; National Psoriasis Foundation Medical Board. Increased risk of severe generalized pustular psoriasis due to tuberculosis screening delay for spesolimab initiation. J Am Acad Dermatol. 2024 Feb;90(2):408-410. doi: 10.1016/j.jaad.2023.09.078. Epub 2023 Oct 10. PMID: 37821053.

5. Ahmad F, Alam MA, Ansari AW, Jochebeth A, Leo R, Al-Abdulla MN, Al-Khawaga S, AlHammadi A, Al-Malki A, Al Naama K, Ahmad A, Buddenkotte J, Steinhoff M. Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases. J Invest Dermatol. 2024 Jan 7:S0022-202X(23)03114-7. doi: 10.1016/j.jid.2023.11.004. Epub ahead of print. PMID: 38189700.

6. Guénin SH, Khattri S, Lebwohl MG. Spesolimab use in treatment of pyoderma gangrenosum. JAAD Case Rep. 2023 Feb 4;34:18-22. doi: 10.1016/j.jdcr.2023.01.022. PMID: 36936866; PMCID: PMC10015112.

7. Ma L, Chen X, Guo Q, Qiao Z, Wang N, Pai P, Liu X. Rapid response to spesolimab in a patient with severe refractory pyoderma gangrenosum. Clin Exp Dermatol. 2023 Dec 19;49(1):82-84. doi: 10.1093/ced/llad317. PMID: 37706345.

8. Palaniappan V, Gopinath H, Murthy AB, Radhakrishnan S, Karthikeyan K. Spesolimab: a comprehensive review on the anti-IL-36 receptor antibody in dermatology. Int J Dermatol. 2024 Jan;63(1):88-93. doi: 10.1111/ijd.16941. Epub 2023 Nov 29. PMID: 38031264.

9. Warren RB, Reich A, Kaszuba A, Placek W, Griffiths CEM, Zhou J, Randazzo B, Lizzul P, Gudjonsson JE. Imsidolimab, an anti-interleukin-36 receptor monoclonal antibody, for the treatment of generalized pustular psoriasis: results from the phase II GALLOP trial. Br J Dermatol. 2023 Jul 17;189(2):161-169. doi: 10.1093/bjd/ljad083. PMID: 37120722.

10. Gleeson D, Mahil SK. Imsidolimab: an emerging biological therapy for generalized pustular psoriasis. Br J Dermatol. 2023 Jul 17;189(2):153. doi: 10.1093/bjd/ljad128. PMID: 37079741.

11. Hwang J, Rick J, Hsiao J, Shi VY. A review of IL-36: an emerging therapeutic target for inflammatory dermatoses. J Dermatolog Treat. 2022 Sep;33(6):2711-2722. doi: 10.1080/09546634.2022.2067819. Epub 2022 Apr 26. PMID: 35470744.

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