Sir,

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions often triggered by medications. Although their pathogenesis remains incompletely understood, systemic corticosteroids and intravenous immunoglobulin (IVIG) are widely used, particularly in severe or progressive cases [1]. However, the immunological changes associated with these treatments, especially in combination, remain unclear. We report a patient with SJS in whom combined corticosteroid and IVIG therapy was associated with decreased serum levels of interleukin (IL)-12 and tumor necrosis factor (TNF)-α and increased IL-10, correlating with clinical improvement.

A Japanese man in his twenties developed a sore throat and fever and subsequently took acetaminophen. He presented with a 2-day history of erythema and oral erosions. Physical examination revealed conjunctival hyperemia, oral mucosal erosions, and erythematous macules with atypical target lesions on the trunk and extremities (Figs. 1a – 1c). Nikolsky’s sign was positive, and epidermal detachment involved less than 10% of the body surface area. Histopathological examination showed spongiosis, blister formation, and multiple necrotic keratinocytes in the epidermis, along with inflammatory cell infiltration composed mainly of neutrophils (Figs. 1d and 1e). Immunohistochemical staining demonstrated infiltration of CD8⁺ cytotoxic lymphocytes and CD68⁺ macrophages in the lesional skin (Figs. 1f and 1g). Blood cell counts were within normal limits, and liver enzymes were mildly elevated. Tests for infectious causes, including Epstein-Barr virus and Mycoplasma, were negative. The lymphocyte stimulation test for acetaminophen was positive. Based on these findings, acetaminophen-induced SJS was diagnosed.

Figure 1: Clinical, histopathological, and cytokine findings in a patient with Stevens-Johnson syndrome (a) Erythematous macules and atypical target lesions on the trunk, including confluent erythematous areas with dusky centers and flaccid blisters, with a positive Nikolsky sign. (b) Conjunctival hyperemia. (c) Oral mucosal lesions. (d) Skin biopsy site. (e) Histopathological findings of the arm lesion. (hematoxylin and eosin stain (H&amp;amp;amp;E), original magnification ×100) showing spongiosis, blister formation, and multiple necrotic keratinocytes in the epidermis, with inflammatory cell infiltration composed mainly of neutrophils. (f, g) Immunohistochemical staining showing infiltration of CD8+cytotoxic lymphocytes (f) and CD68+ macrophages (g) in the epidermal lesions. (h) Cytokine analysis before and after IVIG treatment. Serum IL-10 levels were significantly increased after IVIG treatment, whereas serum IL-12 and TNF-α levels were significantly decreased. IL-17 levels decreased slightly but without statistical significance. P-values less than 0.05 were considered statistically significant (t-test). *P < 0.05.

Methylprednisolone (1000 mg/day for 3 days) was administered, followed by prednisolone (80 mg/day, approximately 1 mg/kg/day). Because the skin lesions continued to worsen, IVIG (400 mg/kg/day for 5 days) was initiated. Following combined corticosteroid and IVIG therapy, skin symptoms progressively improved, and no new blister formation was observed. To evaluate cytokine changes associated with treatment, serum samples obtained immediately before and after IVIG therapy were analyzed using a multiplex ELISA-based Q-plex Human Cytokine array (Quansys Biosciences, Logan, Utah, USA). Each measurement was performed in triplicate using the patient’s serum samples. TNF-α and IL-12 levels decreased. IL-17 levels did not show a significant change (Fig. 1h).

Corticosteroids and IVIG are commonly used in SJS/TEN, although their combined immunological effects remain unclear. TNF-α is a key proinflammatory cytokine, and its inhibition has been proposed as a therapeutic strategy in SJS/TEN [2]. IVIG may exert anti-inflammatory effects by modulating macrophage activity, thereby reducing TNF-α and IL-12 production [3]. In the present case, combined corticosteroid and IVIG therapy may have contributed to these cytokine changes, supported by the presence of CD68⁺ macrophages in lesional skin. CD8⁺ cytotoxic T cells, which were observed in the lesional skin, may also have contributed to local inlammatory responses, including the production of proinflammatory cytokines such as TNF-α [4].

IL-10 is an anti-inflammatory cytokine produced by multiple immune cell types, such as regulatory T cells (Tregs), and acts through antigen-presenting cells to suppress inflammatory responses. Previous studies have shown that IVIG exerts immunomodulatory effects through both Fab- and Fc–dependent mechanisms, including interaction with the neonatal Fc receptor (FcRn) and expansion of Treg cells. Therefore, IVIG, together with corticosteroid therapy, may have indirectly enhanced anti-inflammatory pathways, leading to increased IL-10 production in our patient. This interpretation is supported by previous findings showing increased IL-10 levels after IVIG therapy in autoimmune disorders such as Kawasaki disease [5].

In summary, changes in TNF-α, IL-12, and IL-10 levels during combined corticosteroid and IVIG therapy may help reflect treatment response in SJS. However, as this is a single case, these changes may reflect the natural course, prior corticosteroid therapy, or the combined rather than isolated effects of IVIG, and further studies are required to clarify their clinical significance.

Consent

The examination of the patient was conducted according to the principles of the Declaration of Helsinki.

The authors certify that they have obtained all appropriate patient consent forms, in which the patients gave their consent for images and other clinical information to be included in the journal. The patients understand that their names and initials will not be published and due effort will be made to conceal their identity, but that anonymity cannot be guaranteed.

REFERENCES

1.  Schwab I, Nimmerjaahn F. Intravenous immunoglobulin therapy:how does IgG modulate the immune system. Nat Rev Immunol. 2013;13:176-89.

2.  Ao S, Gao X, Zhan J, Ai L, Li M, Su H, et al. Inhibition of tumor necrosis factor improves conventional steroid therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis in a cohort of patients. J Am Acad Dermatol. 2022;86;1236-1245.

3.  Das M, Karnam A, Stephen-Victor E, Gilardin L, Bhatt B, Kumar Sharma V, et al. Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy. Cell Death Dis. 2020;11:50.

4.  St Paul M, Ohashi PS. The Roles of CD8+T Cell Subsets in Antitumor Immunity. Trends Cell Biol. 2020;30:695-704

5.  Jane C.Burns, Alesssandra Franco. The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. Expert Rev Clin Immunol. 2015;11:819–25.