Erythromycin as a Safe and Effective Treatment Option for Erythema Annulare Centrifugum

Abstract

Background:

Erythema annulare centrifugum (EAC) is an inflammatory dermatosis with unknown etiology. It is usually self-limited, but chronic disease may be difficult to treat. We observed incidentally the therapeutic effect of erythromycin for EAC among patients taking erythromycin for other diseases.

Aim:

To evaluate the treatment response of erythromycin for EAC.

Materials and Methods:

During the study period, from July 2007 to February 2011, all patients with EAC were assigned to erythromycin stearate tablet 1000 mg per day for two weeks. EAC was diagnosed by a constellation of clinical and pathological findings. The efficacy (before and after the treatment) was assessed clinically by one dermatologist and photographically by two blinded dermatologists. Secondary outcomes included adverse drug effects and recurrence.

Results:

Eight patients were enrolled in this study. Most patients had chronic relapsing disease with poor response to previous treatment. All the patients showed rapid response with profound reduction in the size of lesion and erythema two weeks after initiation of erythromycin treatment. The response was so obvious and complete that a coincidental response was less likely. Three patients had recurrence of disease and they tended to have more extensive lesions. Readministration of erythromycin was effective. All patients tolerated the treatment well.

Conclusion:

Our study documented erythromycin as a safe and cost-effective treatment for EAC.

What was known?

Treatment of erythema annulare centrifugum is variable and inconclusive.

Introduction

Erythema annulare centrifugum (EAC) is a benign inflammatory dermatosis with characteristic clinical manifestations. It affects either sex and can occur at any age, including neonates.[1] Typical presentations are erythematous papular lesions with peripheral enlargement and central clearance. Restricted perivascular infiltrate of lymphohistiocytes is the main finding on histology. Based on clinical and histological pattern, it is usually classified as superficial (pruritic and scaling) and deep (non pruritic and non scaling) types.[2]

The etiology is unclear, but putative associations with medication, infection, malignancy, and stress have been reported.[3,4,5] Rare associations include autoimmune disorders such as Graves’ disease, progesterone dermatitis, and hypereosinophilic syndrome.[6,7,8] The postulated pathogenesis of EAC is delayed type hypersensitivity and mediated by the interaction between inflammatory mediators. Sima Halevy et al. demonstrated progesterone-induced in vitro interferon-gamma release in a 28-year-old woman with deep type EAC.[7] Later, John Minni and Sarro. suggested the association between tumor necrosis factor-alpha cytokines and EAC.[9]

The treatment of EAC is variable and depends on different trigger factors. Topical or systemic glucocorticoids were traditionally used as initial treatment. However, the response was usually disappointing and relentless recurrence was the rule in many cases.[3,4] At our clinic, we incidentally observed the clearance of skin lesions in patients with EAC taking erythromycin for other diseases. However, few reports have mentioned about the treatment effect of erythromycin for EAC. Therefore, we conducted this study to include more patients and observe the response to erythromycin as the sole treatment.

Materials and Methods

The records of all patients with EAC in the Kaohsiung Chang Gung Memorial Hospital (a tertiary referral medical center in Taiwan) were collected from July 2007 to February 2011. A total of eight patients were included in this study. The clinical presentations were small erythematous macules and papules with centrifugal enlargement. Individual skin lesions persisted more than 24 hours without spontaneous remission. Potassium hydroxide preparation of the scales was negative for fungal hyphae. There were no associated systemic symptoms including fever, headache, muscle, or joint pain. Five patients (patients 1, 3-6) underwent skin biopsy. The histopathology revealed perivascular lymphohistiocytic infiltration in the upper dermis with a coat sleeve like pattern, a characteristic finding of EAC. There was no erythrocyte extravasation, mucin deposition, or neutrophil or plasma cell infiltration. Silver stain was performed to exclude erythema chronicum migrans. Besides, laboratory examination including antinuclear antibody and complete blood cell count were evaluated in patients 2, 7, and 8. EAC of superficial type was diagnosed based on the constellation of clinical and histological findings.

Oral erythromycin stearate at a daily dose of 1000 mg (250 mg four times a day) was prescribed for the eight patients for two weeks. Photographs were taken before and right after the two-week treatment. Follow-up was carried out by phone contact.

All the patients were evaluated by one dermatologist clinically every week until the completion of treatment and by two blinded dermatologists with photographs. The evaluation included improvement in symptoms, appearance of new eruptions or regression of skin lesions, increase or decrease of erythema, scaling, and pigmentation.

Results

Demographic

All the eight patients were adult including seven females and one male. The average age of onset was 41.4 years (ranging from 21 to 54 years old). None had known major systemic diseases nor taken chronic medication before the skin eruptions. There was no previous trauma or history of insect bite. Five of the eight patients had more extensive lesions (more than five lesions). Most patients had a chronic relapsing course with unsatisfactory results to previous treatment. The median duration of disease was one year and three months. Other demographics are shown in Table 1.

Table 1.

Demographics

Treatment response

Rapid response and dramatic improvement with reducing erythema and pruritus was noted in one patient (patient 3) after one week of therapy. At the end of two weeks, all the patients had complete remission with only minimal residual hyperpigmentation. The clinical symptoms before treatment varied from a mild to moderate itch and improvement in the itch was also stated by all the patients. Representative photographs before and after treatment are shown [Figures 1 and 2].

Figure 1.

Photographs taken before (a) and after a two-week treatment (b) with erythromycin for the arm lesion of patient 4

Figure 2.

Photographs taken before (a) and after a two-week treatment (b) with erythromycin for the leg lesion of patient 6

Follow-up

The follow-up period ranged from three to 40 months. Three of the eight patients had recurrence, and the recurrent lesions responded well after the re-administration of erythromycin. All the patients tolerated the treatment well without major side effects.

Discussion

EAC may mimic other figurate erythema such as tinea, annular urticaria, and annular lupus erythematosus. The clinical lesions (scaliness), course of disease (spontaneous remission), location (occurrence in sun exposed areas), associated systemic symptoms, and histological pattern usually aid differential diagnosis. All of our patients had persistent and scaly skin lesions, which were less likely to be urticaria and negative potassium hydroxide preparation was not suggestive of tinea. Three patients who did not have skin biopsy had laboratory evaluation mainly for the screening of autoimmune disease, especially lupus erythematosus. The laboratory result was unremarkable except for mild microcytic anemia in patient 8. Besides, clinical sparing of the head and neck and lack of interface change or mucin deposition on pathology did not favor a diagnosis of lupus erythematosus.

Sometimes, erythema chronicum migrans may also resemble EAC. Erythema chronicum migrans is characterized by a history of tick bites in endemic areas and is associated with systemic symptoms. Microscopically, plasma cells are usually identified in erythema chronicum migrans. Taiwan is not an endemic region of Lyme disease and a few previous cases had a history of travel from endemic regions.[10,11] For our patients, there was no history of tick bites, no plasma cells in microscopy, and result was negative on silver stain for spirochetes. These suggested the diagnosis of EAC rather than erythema chronicum migrans.

The clinical course of EAC is usually self-limited and the treatment is mainly symptomatic.[3] However, some patients suffered from a more protracted course and treatment for chronic and recurrent disease may be challenging.[3,4,12] Several medications had been administered with various responses. Systemic or topical corticosteroids had been used to suppress the inflammation but it did not seem to alter the chronic course of the disease. Rapid relapse after the discontinuation of steroids is common and potential side effects of a long-term steroid limit its use for chronic relapsing EAC. Other agents such as etanercept and metronidazole have also been reported as effective alternatives.[9,13]

In our study, erythromycin showed a promising effect for EAC. All the patients showed complete clearance after the two-week treatment. The treatment response may have been as rapid as one week as observed in patient 2. Among the eight patients, five patients (patients 2, 5-8) had extensive disease and four patients (patients 1, 3, 7, 8) had a chronic course for years. All patients responded poorly to previous treatment including topical steroids, oral antihistamines, and even systemic steroids. Whether erythromycin can prevent recurrence is unclear, but re-administration of erythromycin seemed to be effective. Three of our patients suffered from recurrence of disease and all lesions resolved after re-administration of erythromycin. These three patients with recurrent disease had more widespread lesions. It suggests that increased number of lesions may be a risk factor for a relapsing course.

Macrolide antibiotics were reported as effective treatment for many skin diseases such as rosacea, pityriasis rosea, and pityriasis lichenoides.[14,15,16] Besides antibacterial effects, macrolides also have anti-inflammatory properties similar to metronidazole. The neutrophil chemotactic factors and reactive oxygen species induced by Propionibacterium acnes was significantly inhibited under subminimal inhibition concentration of treatment dose of macrolides.[17] However, the exact mechanism through which macrolides work for EAC is unclear. It may be similar to that of metronidazole, by the anti-inflammatory effect of interfering with the production of free radicals.[13,18]

Erythromycin, first isolated from a metabolite of Streptomyces erythreus in 1952, is one of the oldest macrolides.[19] Although gastrointestinal upset is a common side effect, erythromycin is generally considered safe, even in children.[20] It has been widely used in many diseases but it had no relevant report in the Medline literature for EAC. In our study, most of the patients tolerated erythromycin well without obvious side effects. We suggest erythromycin to be a safe and cost-effective treatment for EAC. Due to the small number of patients in this study, further studies may be required to elucidate this finding and its mechanism of action.

What is new?

Erythromycin is an effective treatment option for erythema annulare centrifugum.