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The first report of Tocilizumab for Darier disease with summer exacerbations Study conducted at the Wenzhou, Zhejiang, China.

Dear Editor,

Darier Disease (DD), also known as keratosis follicularis, is a rare dermatosis caused by mutations in the ATP2A2 gene. There are no currently validated curative treatments available, besides oral retinoids, and most cases are treated symptomatically.11 Haber RN, Dib NG. Management of Darier disease: a review of the literature and update. Indian J Dermatol Venereol Leprol. 2021;87:14-21. Here, we reported the first case of using a monoclonal antibody against human IL-6R (Tocilizumab) in the treatment of summer exacerbations of DD.

A 23-year-old woman presented with a more than 10-year history of multiple pruritic yellow-brown keratotic papules covered with greasy scales. Physical examination showed diffuse red, skin-colored corn-like papules with keratosis, confluence in a flaky distribution, and multiple pustules and crusts (Fig. 1A). During the summer or before menstruation, her symptoms became severe and were characterized by more papules and pustules visible on her forearm with a burning sensation and intense itching that made it impossible to sleep. The patient had no relevant medical or family background. The results of laboratory tests showed markedly increased levels of serum IL-6 24.40 pg/mL (normal: < 3.0 pg/ML) and TNF-α 6.71 pg/mL (normal: < 3.10 pg/ML), but IL-4 0.1 pg/mL (normal: < 3.0 pg/ML) and IL-10 3.37 pg/mL (normal: < 4.1 pg/ML) were in normal range. The light microscopy showed isolated dyskeratotic cells and spicules with hyperkeratosis, and focal hyperkeratosis suggestive of DD (Fig. 1B). In addition, skin immunohistochemistry showed weak positivity for IL-6 (Fig. 1C). Mutation (c.193T>G:p.L65V) in the ATP2A2 gene was identified using whole-exome sequencing. Finally, she was diagnosed with DD. Isotretinoin led to a slight improvement, but even at small doses, there were intolerable side effects. She was distressed by itching and desired more treatment. After signing the informed consent form, she received treatment with Tocilizumab (8 mg/kg, repeated at 2-week intervals). During that time, she used emollients to supplement treatment. After 2-months of follow-up, forearm lesions (Fig. 2 A‒D) and itching were reduced, and sleep quality improved significantly.

Figure 1
(A) Confluent red miliary papules on the back. (B) The light microscopy showed isolated dyskeratotic cells and spicules with hyperkeratosis and focal hyperkeratosis suggesting Darier disease. (C) Immunostaining with anti‐IL-6 (A11114, 1:200, ABclonal Biotech) showed weakly positive staining (x100).

Figure 2
(A‒B) Multiple papules on her forearm. (C‒D) After the treatment marked improvement.

In in vitro experiments, UV light decreased the expression of the ATP2A2 gene, which is consistent with DD exacerbated by heat and UV light, and the gene expression of ATP2A2 was increased after the use of an IL-6 antibody.22 Mayuzumi N, Ikeda S, Kawada H, Ogawa H. Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. Br J Dermatol. 2005;152:920-4. IL-6 antibodies have been proposed in the literature for the treatment of DD patients with summer exacerbations.33 Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016;43:275-9. Nevertheless, no cases of clinical use have been reported. Here, we found that Tocilizumab alleviates pruritus in summer exacerbations in DD patients and controls the further progression of skin inflammation. Biologicals can improve genodermatoses acting in the secondary inflammation and not in the mutation per se.

  • Financial support
    This work was supported by the Zhejiang Provincial Natural Science Foundation of China (LY22H160030).
  • Study conducted at the Wenzhou, Zhejiang, China.

References

  • 1
    Haber RN, Dib NG. Management of Darier disease: a review of the literature and update. Indian J Dermatol Venereol Leprol. 2021;87:14-21.
  • 2
    Mayuzumi N, Ikeda S, Kawada H, Ogawa H. Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. Br J Dermatol. 2005;152:920-4.
  • 3
    Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016;43:275-9.

Publication Dates

  • Publication in this collection
    31 May 2024
  • Date of issue
    2024

History

  • Received
    29 Sept 2022
  • Accepted
    25 Oct 2022
  • Published
    4 Mar 2024
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