Drug-induced subacute cutaneous lupus erythematosus initially diagnosed as erythema annulare centrifugum

INTRODUCTION

Erythema annulare centrifugum (EAC) is a rare (prevalence: 1/100,000 population), recurrent, reactive dermatosis characterized clinically by the presence of outwardly spreading annular or arciform, slightly raised erythematous lesions with discrete marginal scaling along the inner edge, and with central clearing. EAC lesions usually occur on the trunk [1, 2].
The diagnosis of EAC relies on the clinical presentation of skin lesions, with diagnostic confirmation obtained through histopathological examination [2].
Subacute cutaneous lupus erythematosus (SCLE), accounting for 10–15% of cutaneous lupus erythematosus (CLE) cases, was first described in 1979 by Sontheimer et al. [3–5].
Based on clinical appearance, SCLE can be divided into two variants: annular (42%) and psoriasiform (39%). The disorder is most commonly diagnosed in women aged between 30 and 40 years. Symmetrical lesions are located primarily on sun-exposed skin areas, including the lateral surfaces of the neck, upper chest, upper back, extensor surfaces of the upper limbs, and dorsal surfaces of the hands. Notably, facial skin is rarely affected [6].
It is considered that the main factor triggering and exacerbating SCLE is exposure to natural sunlight and artificial light sources [7]. In immune tests, anti-Ro/SS-A antibodies (detected in 70–90% of patients) are recognized as an immune marker for SLCE. They can be accompanied by anti-La/SS-B antibodies (30–50%) [7–9].

OBJECTIVE

The aim of the study was to present the case of a patient with drug-induced subacute cutaneous lupus erythematosus (DI-SCLE), initially diagnosed as EAC, who was hospitalized in the Clinical Department of Dermatology.

CASE REPORT

An 89-year-old woman was admitted to the hospital in January 2023 due to disseminated, annular erythematous lesions with peripheral scaling, persisting since June 2022. The lesions were primarily located on the skin of the neck, trunk, and upper limbs (figs. 1 A–F). No concurrent oral mucosal changes or dry mucosa were observed.
Prior to the hospitalization, based on the results of histopathological examination, the patient received a diagnosis of EAC. Treatment included a 3-week course of methylprednisolone at 16 mg/day (with gradual dose reduction), non-sedating antihistamines (cetirizine, bilastine, fexofenadine), topical compounded ointments with 1% hydrocortisone, and lubrication with emollients.
Following short-term partial remission of skin lesions, the patient was referred to our department for an extended diagnostic workup and treatment.
The patient’s history revealed left mastectomy due to breast cancer (January 2021) preceded by four cycles of neoadjuvant chemotherapy, and arterial hypertension treated with ramipril 1.25 mg and amlodipine 2.5 mg.
During the patient’s hospitalization, active cancer and infection (based on gynecological, dental, ENT examination), which are the most prevalent causes of EAC, were excluded. Given the patient’s history, clinical characteristics of the skin lesions and their distribution, a diagnostic biopsy was done again to verify the diagnosis. The results indicated that the histological picture could be categorized within the spectrum of lupus erythematosus (LE) (figs. 2 A, B).
Following the identification of leukopenia (white blood cells (WBC): 2.95 × 10³/µl; 3.44 × 10³/µl) and a tendency toward normocytic anemia (erythrocyte level: 4.28 × 10⁶/µl; 3.81 × 10⁶/µl), along with the detection of ANA antibodies in a titer of 1:10 240 in basic tests, the immunological diagnostic workup was extended, giving the following results: anti-SSA native (60 kDa) +++ strongly positive, anti-SSB +++ strongly positive, anti-Ro-52 +++ strongly positive, other test results: complement components C3 and C4, and antiphospholipid antibodies in the normal range.
After excluding SLE according to the current EULAR/ACR criteria and the received data, DI-SCLE was diagnosed, provoked by antihypertensive drugs used by the patient for the previous several months.
During hospitalization, topical treatment with clobetasol and urea ointment was administered, and hydroxychloroquine at a dose of 200 mg/day was ordered. Gradual remission of the skin lesions was achieved (figs. 3 A–C).
Furthermore, since the patient’s blood pressure had returned to normal, antihypertensive treatment was discontinued. After 10 weeks, pronounced browning and remission of active skin lesions, along with normalization of WBC and RBC values, were observed.
The patient remains under the care of the Department’s outpatient dermatology clinic (figs. 4 A–D).

DISCUSSION

An unintended consequence of advances in modern medicine and pharmacology is the occurrence of drug reactions, presenting mainly as skin manifestations, of which every medical practitioner should be aware. Drug-induced cutaneous reactions account for approximately 70% of all clinical manifestations of adverse drug effects. This can be attributed to the fact that the skin, being the largest organ in the body, exhibits significant metabolic/immunological activity.
The reported case illustrates the challenges that can be encountered in clinical practice.
It is essential to note that the result of histopathological examination serves as an ancillary test, confirming the diagnosis when it is consistent with the clinical presentation of the disease. In cases where there is a lack of correlation – as in the presented case, where EAC was diagnosed – a differential diagnostic process should be considered [10].
Even though EAC can be diagnosed in any age group, the condition predominantly affects young adults. The skin lesions are typically located on the trunk and less commonly on the extremities [2]. While most cases of EAC are idiopathic, according to the literature, infections (generally fungal) and neoplastic processes are the most prevalent factors contributing to the development of the disorder [11, 12]. Less commonly considered triggers include food allergies and drugs. Also, isolated case reports have documented links between EAC and autoimmune diseases, pregnancy, and stress [1, 2, 13–16]. Even though the etiopathogenesis of EAC remains uncertain, the involvement of delayed type Id hypersensitivity reactions has been postulated [13, 16].
In patients with clinical and histopathological suspicion of EAC, the main considerations for differential diagnosis should be cutaneous mycosis and psoriasis. Other differential diagnostic options include sarcoidosis, urticaria vasculitis presenting with annular skin lesions, and erythema migrans [2, 10, 17].
In contrast, in patients with an autoimmune profile, EAC requires differentiation mainly from various forms of CLE and linear IgA bullous dermatosis (LABD) [2].
With respect to paraneoplastic EAC (paraneoplastic erythema annulare centrifugum eruptions – PEACE), in 60% of cases the process is believed to be associated with lymphoproliferative hematological processes, and in 40% with a solid hyperplastic tumor [2, 12]. In our patient leukopenia and erythrocytopenia were detected. After excluding active infectious and neoplastic processes, the diagnostic approach was extended to include an immunological panel. Following the preliminary diagnosis of SCLE, ultimately the patient was diagnosed with DI-SCLE.
At the same time, a toxic drug reaction was ruled out, as such reactions are dose-related, occur after 1–2 weeks of treatment, peak in intensity after 3–4 weeks of therapy, and subside after 2 weeks [18].
DI-SCLE was first described by Reed et al. in 1985 [5, 19]. DI-SCLE manifests as SCLE in 15–70% of cases. DI-SCLE and idiopathic SCLE share immunological and histological similarities [5]. In both disorders, the immune markers are anti-Ro/SS-A antibodies potentially coexisting with anti-La/SS-B antibodies. Importantly, the histological picture and DIF result (positive in 60% of patients) are not the basis for differentiation [20].
It is currently recognized that ANA are positive in over 80% of patients with DI-SCLE. Ro/SSA antibodies are detected in 80%, while La/SSB antibodies are found in less than 50% and antihistone antibodies only in 33% of patients [5, 20].
In clinical terms, both polycyclic and psoriasiform skin lesions in SCLE, when compared to DI-SCLE, are typically more extensive and confined to skin regions with the highest exposure to sunlight [5, 10, 21]. Several additional factors play an important role in diagnosing DI-SCLE. They include the patient’s gender (9 : 1 ratio of women to men) and age (average age approximately 60 years), and evidence for a temporal link between the initiation of drug treatment and onset of skin changes, together with their resolution upon discontinuation of the implicated medication. The average period of time between the commencement of treatment and the appearance of skin lesions typical of DI-SCLE is believed to be 8 weeks. Upon the discontinuation of treatment, the resolution of skin lesions is usually observed within nine weeks [5, 20, 21].
As of now, there is evidence of a link between at least 50 drugs and DI-SCLE (table 1). Interestingly, the significance of proton pump inhibitors (PPIs) as drugs inducing DI-SCLE has recently risen in parallel to the increased frequency of PPI use [5, 22–24] (table 1).
In the reported case, two cardiovascular drugs (amlodipine, rapiril) were identified as the causative agents of DI-SCLE based on the patient’s history and medical records. Both medications were eventually discontinued following the normalization of blood pressure values.
The patient had been taking ramipril and amlodipine for the past year due to hypertension, which was diagnosed after the completion of chemotherapy for breast cancer. Because the annular skin lesions appeared approximately 5–6 months after the initiation of hypertension treatment, taking into account the incubation periods of the drugs, 6 weeks to 6 months and 3 weeks to 6 years, respectively [10, 25, 26], it appears that both drugs were rightly identified as the causative agents of DI-SCLE. The decision was clinically validated by the fact that at the 10-week follow-up visit there was a considerable reduction of skin lesions without a tendency for recurrence.
At present, there are no standardized diagnostic criteria for DI-SCLE, but it is believed to be a lupus-like syndrome caused by chronic exposure to causative drugs and resolving after their discontinuation [5, 21].
While the precise mechanism underlying DI-SCLE remains unclear, it is currently hypothesized to involve the Köbner phenomenon and isomorphic response in individuals who are immunogenetically predisposed to SCLE. This hypothesis is substantiated by various factors, including reports indicating that the majority of drugs proven to be implicated in DI-SCLE have photosensitizing properties. There is also evidence demonstrating the presence of autoantibodies, including Ro/SSa, in individuals who do not yet present with symptoms of LE [20, 26–28].
The main diagnostic recommendations in patients with DI-SCLE are to identify and discontinue the causative drug. At the same time, it is generally recognized that pharmacological treatment is not necessary in the majority of patients with the condition. Therapeutic interventions should be reserved for refractory cases that are likely to represent early-stage LE [5]. In the majority of cases, remission of skin lesions is observed on average within 9 weeks after discontinuing the drug. Also, an approximately 40% decrease in the anti-Ro/SS-A titer is seen in approximately 50% of patients within 8 months [5, 26, 29].
From a clinical perspective, it is important to note that multiple analyses and pooled case reports have failed to identify a correlation between the clinical presentation of DI-SCLE and the dose of the drug [5, 20, 24].

CONCLUSIONS

Given that the prevalence of DI-SCLE appears to be considerably higher (70%) than previously estimated (20%), the diagnosis of DI-SCLE should also be considered when idiopathic SCLE is suspected, particularly in patients over 60 years taking medicaments encountered in table 1. In this age group in particular, before initiating treatment, an ANA test should be performed. If the result is positive, therapy with drugs that are not considered causative for DI-SCLE should be considered.

FUNDING

No external funding.

ETHICAL APPROVAL

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

References