# Successful therapy with secukinumab in a patient with generalized pustular psoriasis carrying homozygous IL36RN p.His32Arg mutation

Romain Gabeff, Roba Safar, Sophie Leducq, Annabel Maruani, Guillaume

Sarrabay, Isabelle Touitou, Mahtab Samimi

► To cite this version:

Romain Gabeff, Roba Safar, Sophie Leducq, Annabel Maruani, Guillaume Sarrabay, et al.. Successful therapy with secukinumab in a patient with generalized pustular psoriasis carrying homozygous IL36RN p.His32Arg mutation. International Journal of Dermatology, 2019, 58 (1), pp.e16-e17. 10.1111/ijd.14293 . hal-02566764

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Submitted on 14 Feb 2025

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## Successful therapy with secukinumab in a patient with generalized pustular psoriasis carrying homozygous IL36RN p.His32Arg mutation

Acute generalized pustular psoriasis (GPP) is a severe, multisystemic disease whose treatment is often challenging. In a subset of patients, the disease is related to homozygous or compound

<figure><img src="image_2.png" /><figcaption>**Figure 1** Treatment with secukinumab in a 32-year-old woman with generalized pustular psoriasis and carrying the IL36RN mutation. (a) Before treatment. (b) After secukinumab therapy for 3 months</figcaption></figure>

heterozygous mutations of the IL36RN gene impairing the expression of the interleukin 36 (IL-36) receptor antagonist (IL-36Ra), a negative regulator of the IL-36 signaling pathway.¹ IL-1 blockers, tumor necrosis factor antagonists, ustekinumab, and IL-17 inhibitors have been found efficient in GPP, regardless of IL36RN mutation status.²,³ However, to what extent the presence and type of IL36RN mutations affect the response to conventional and biological therapies is not well known. The efficacy of IL-17 inhibitors in the setting of GPP with IL36RN mutation has been reported only very recently in four single case reports, each patient carrying a different mutation⁴⁻⁷ (Table 1).

A dozen IL36RN mutations have been described in patients with pustular diseases, with a possible genotype-phenotype association. In this context, reporting the efficiency of therapies by patients' mutational status seems relevant for clinical practice. Here, we describe the efficiency of secukinumab, an IL-17 inhibitor, in a patient with GPP and carrying a homozygous IL36RN p.His32Arg mutation, previously described as a hypomorphic mutation, with reduced IL-36Ra protein expression.⁸

A 32-year-old Syrian woman had GPP since childhood, with intermittent acute flares of widespread erythema, pustules, and fever up to 39 °C. The condition was steroid-dependent and failed to respond to methotrexate, cyclosporine, adalimumab, and infliximab. Next-generation sequencing revealed that she was carrying a homozygous mutation in IL36RN (c.95A>G/ p.His32Arg), a heterozygous mutation in MEFV (c.442G>C/ p.Glu148Gln), and no mutations in CARD14 or AP1S3. Secukinumab was given subcutaneously (300 mg at weeks 0, 1, 2, 3, 4, and every 4 weeks thereafter). Before starting treatment, 70% of the body surface area (BSA) was affected, GPP area and severity index (GPPASI) was 32.7, and Dermatology Life Quality Index (DLQI) was 27/30 (Fig. 1a). Improvement was noted after 1 month, with almost complete clearance at

<table><caption>**Table 1** Case reports of patients with generalized pustular psoriasis carrying IL36RN mutations and receiving IL-17 antagonists, including the present case</caption><thead><tr><td>Author</td><td>Sex, age, years</td><td>Clinical findings</td><td>Prior treatments</td><td>IL-17 antagonist</td><td>Efficacy</td><td>IL36RN mutation</td><td>Impact on IL-36Ra expression*</td></tr></thead><tbody><tr><td>Kinoshita 4</td><td>M, 37</td><td>GPP, fever</td><td>CsA</td><td>Secukinumab</td><td>CR</td><td>Heterozygous c.115 + 6T&gt;C/c.142C&gt;T</td><td>Unknown</td></tr><tr><td>Molho-Pessach 5</td><td>NA, Adolescent</td><td>GPP, fever, arthralgia</td><td>Acitretin MTX</td><td>Secukinumab</td><td>CR</td><td>Homozygous c.368 C&gt;T</td><td>No expression</td></tr><tr><td>Köstner 6</td><td>M, 4</td><td>GPP, fever</td><td>CS MTX</td><td>Secukinumab</td><td>CR</td><td>Homozygous c.80 T&gt;C</td><td>No expression</td></tr><tr><td>Wilsmann-Theis 7</td><td>F, 56</td><td>GPP</td><td>IL-1 inhibitor CS, MTX</td><td>Secukinumab</td><td>CR</td><td>Heterozygous c.115 + 6T&gt;C/NA</td><td>Unknown</td></tr><tr><td>Present case</td><td>F, 35</td><td>GPP, fever, arthralgia</td><td>TNF antagonist FAE CsA MTX</td><td>Secukinumab</td><td>CR</td><td>Homozygous c.95A&gt;G</td><td>Reduced</td></tr><tr><td></td><td></td><td></td><td>TNF antagonist</td><td></td><td></td><td></td><td></td></tr></tbody></table>

F, female; M, male; GPP, generalized pustular psoriasis; CsA, cyclosporine; MTX, methotrexate; CS, corticosteroids; CR, complete response; TNF, tumor necrosis factor; FAE, fumaric acid ester; NA not available.

<footnote>*in vitro 8</footnote>
3 months (residual BSA 1%, GPPASI 2, and DLQI 2/30)
(Fig. 1b). No recurrence was noted after a 6-month follow-up.

A dozen previously identified *IL36RN* mutations have been assessed *in vitro* in terms of their impact on the expression of IL-36Ra protein and inhibition of NFκB, in order to identify a genotype–phenotype association.⁸ Null mutations (no protein) were associated with only severe “systemic” conditions (GPP and acute generalized exanthematous pustulosis), whereas hypomorphic mutations (reduced protein expression) were also associated with less severe, localized pustular variants (pustular palmoplantar psoriasis and acrodermatitis continua of Hallopeau). In this context, such mutations may also affect response to treatment.

In a few months, four cases of GPP in patients carrying *IL36RN* mutations with successful IL-17 inhibitor treatment were reported. Cases are described in Table 1. Two of these mutations had been described as null mutations, but the impact on protein expression had not been described for the two other cases. We describe the first case, to the best of our knowledge, of a marked response to secukinumab in a GPP patient carrying a mutation previously reported to be hypomorphic.⁸ These findings, although still sparse, suggest that IL-17 inhibitors are effective in the subset of GPP patients carrying *IL36RN* mutations, with no obvious impact of the type of mutation. However, the respective roles of genetic, epigenetic, and environmental factors that may affect clinical expression and response to treatment are still widely unknown and deserve further research.

Romain Gabeff ¹,²,*, MD
Roba Safar ¹, MD
Sophie Leducq ¹, MD
Annabel Maruani ¹, PhD, MD
Guillaume Sarrabay ³, MD
Isabelle Touitou ³, PhD, MD
Mahtab Samimi ¹,⁴, PhD, MD

¹Department of Dermatology, University Hospital of Tours,
University François-Rabelais, Tours, France
²Department of Dermatology, County Hospital, La Roche Sur
Yon, France

³Laboratory of Rare and Autoinflammatory Diseases,
University Hospital, INSERM U1183, Montpellier, France

⁴ISP1282 INRA, University of Tours, Tours, France

*E-mail: romain.gabeff@hotmail.fr

Conflict of interest: none

References

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2 Imafuku S, Honma M, Okubo Y, et al. Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: a

52-week analysis from phase III open-label multicenter Japanese study. *J Dermatol* 2016; **43**: 1011–1017.

3 Saeki H, Nakagawa H, Nakajo K, et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: results from a 52-week, open-label, phase 3 study (UNCOVER-J). *J Dermatol* 2017; **44**: 355–362.

4 Kinoshita M, Okamoto T, Sano S, et al. Deficiency of the interleukin-36 receptor antagonist dramatically improved by secukinumab. *J Dermatol* 2018; **45**: e280–e281.

5 Molho-Pessach V, Alyan R, Gordon D, et al. Secukinumab for the treatment of deficiency of interleukin 36 receptor antagonist in an adolescent. *JAMA Dermatol* 2017; **153**: 473–475.

6 Köstner K, Prelog M, Almanzar G, et al. Successful use of secukinumab in a 4-year-old patient with deficiency of interleukin-36 antagonist. *Rheumatology (Oxford)* 2018; **57**: 936–938.

7 Wilsmann-Theis D, Schnell LM, Ralser-Isselstein V, et al. Successful treatment with interleukin-17A antagonists of generalized pustular psoriasis in patients without IL36RN mutations. *J Dermatol* 2018; **45**: 850–854.

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Cutaneous sarcoidosis after Hodgkin lymphoma

Brinker reported first the nonfortuitous association of sarcoidosis preceding lymphoma in 1986 that named “sarcoidosis-lymphoma syndrome”.¹ Lymphoma can occur after sarcoidosis in patients with chronic active disease. In Scandinavia, there is an increased risk of Hodgkin lymphoma (HL) of 14.1% in patients with sarcoidosis. On the other hand, the onset of sarcoidosis after lymphoma is underreported.²⁻⁴ For some authors, this association may be nonfortuitous as well. We report a case in a Finnish patient revealed by skin manifestations.

A 62-year-old woman was referred for the suspicion of cutaneous sarcoidosis. Her past medical history was notable for a stage IIA HL of the left abdominal para-iliac chains in July 2016. At the time, positron emission tomography/computed tomography ruled out other suspicious localization. She received two cycles of Adriamycin-Bleomycin-Vinblastine-Dacarbazine (ABVD) on August 9 followed by local radiotherapy (20 Gy) in September and October 2016. At the turn of the year 2018, the patient reported subcutaneous nodules on both thighs that were neither inflamed nor painful. Soft-tissue ultrasound imaging ruled out lipomas, and no vascularization was noticed. Ultrason-guided needle biopsy revealed giant cell granulomas without necrosis or foreign bodies. The patient reported simultaneous changes within two previous old scars, one on the forehead and one on the left knee. Both were because of past trauma in her youth. The patient was sent with the suspicion of sarcoidosis. Upon examination, the patient presented an oval infiltration on a scar of the forehead. A 5 mm red orange papula was found on the right knee (Fig. 1a), and a 3 cm scar