Lichenoid Drug Eruption due to Telmisartan–Hydrochlorothiazide Combination Progressing to Bullous Pemphigoid: A Case Report

Cases of drug-induced lichenoid skin inflammation, which triggered an autoimmune reaction and resulted in the development of bullous pemphigoid (BP), have been reported [1, 2]. We report a case of BP suspected to have progressed from lichenoid drug eruption due to the telmisartan–hydrochlorothiazide combination. An 85-year-old Japanese woman presented with erythema and violaceous flat-topped papules on the trunk and extremities for 8 months (Figure 1a–d). No mucosal involvement was observed. She had been administered the telmisartan (angiotensin II receptor blocker [ARB], 40 mg daily)–hydrochlorothiazide (thiazide, 12.5 mg daily) combination for 12 years. Laboratory tests, including glucagon level and chemiluminescent enzyme immunoassays of desmoglein 1 (Dsg1), Dsg3 and BP180, showed no abnormality. Computed tomography detected no visceral involvement. Histopathology showed vacuolar degeneration of basal cells and a band-like inflammatory lymphocytic infiltration in the upper dermis (Figure 1e). Direct immunofluorescence was negative. The drug-induced lymphocyte stimulation test for telmisartan was positive (stimulation index 2.6; normal < 1.8). These findings led to the diagnosis of lichenoid drug eruption induced by telmisartan. Although the telmisartan–hydrochlorothiazide combination was stopped, the erythema gradually increased and enlarged despite the treatment with a topical corticosteroid. We reexamined the frozen plasma obtained at the first visit to our clinic. While indirect immunofluorescence of 1 M NaCl-split normal human skin for both IgG and IgA antibodies, and IgG enzyme-linked immunosorbent assays of BP180 and BP230 (MBL, Nagoya, Japan) showed negative results, immunoblotting using recombinant protein of BP180 NC16a-domain was positive. Four months later, when blisters developed (Figure 1f–h), a skin biopsy showed subepithelial cleft with lymphocytic infiltration in the upper dermis (Figure 1i). Direct immunofluorescence showed positive C3c deposition to the basement membrane zone (BMZ) (Figure 1j), but not for IgG, IgA, or IgM. Chemiluminescent enzyme immunoassay of BP180 was positive (57.7; normal < 9.0 U/mL). The diagnosis of BP was made. After administration of oral prednisolone (20 mg daily), the skin lesions were resolved gradually. In our case, preexisting lichenoid drug eruption might induce damage to the BMZ and expose antigens such as BP180 to the immune system, leading to the development of drug-induced BP. Drug-induced BP has been reported to be induced by multiple drugs, including angiotensin-converting enzyme inhibitors [3], and immune checkpoint inhibitors [4], against either PD1 or PDL1. Lichenoid drug eruptions have been reported to induce BP in 5.4 years (range: 0.7–19 years) [3], or in 4.7 years (range: 1.2–13 years). However, there have been only a few reports of ARB-related drug-induced BP. In general, the time duration from drug initiation to skin rash is much longer in cases of drug eruption due to ARBs or angiotensin-converting enzyme inhibitors (4–30 months) than in other medications [5]. ARB can induce various pro-inflammatory cytokines in some diseases with visceral dysfunctions, such as CD8 + T-cell-associated acute myocardial inflammation [5]. Thus, at the earlier stage in our case, it might be speculated that ARB activated CD8 + T-cells, which damaged the BMZ and led to the production of low levels of anti-BP180 antibodies. In refractory BP case, we should consider long-term prescribed medications as possible candidates of causal drugs. We are grateful to the patient for giving the written informed consent to publication. We express our gratitude to Ms. Mayumi Tamada (Department of Dermatology, Kurume University School of Medicine) for performing immunological tests. Approval of the research protocol: The Committee of Medical Ethics of Hirosaki University Graduate School of Medicine approved the research study. This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan to S. Minakawa (project 25K10676) and the 2024 Hirosaki University Research Support System. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.