Patients suffering from EAC present with multiple cutaneous lesions that go through characteristic phases: Each single lesion may initially manifest in form of an erythematous, indurated papule that starts to spread at a rate of several millimeters per day. They may turn into a plaque, or the center of the affected area may start to heal, thus leaving only the reddened, hardened margin. This margin is about half a centimeter wide. In most cases, the cleared center immediately adapts the physiological color of skin. However, hyperpigmented spots may remain here in some patients.

While ring-shaped forms may result from the above described process, not all lesions maintain geometrical shapes. Semi-circles, extended arcs, curved lines and even completely irregular patches are also typical. Because several lesions usually develop in close proximity, they may merge with each other.

EAC may comprise large areas of the body. On the one hand, single lesions may grow to measure more than ten centimeters in diameter, and on the other hand, many may appear simultaneously. Most patients show EAC of the trunk; the lower limbs are often affected, too. Arms and face, in contrast, are involved in a smaller share of patients only [8]. Erythema do not develop on palms and soles.

According to the above described forms of erythemas, some patients may suffer from pruritus while EAC may not be associated with additional symptoms in others. Those individuals that claim pruritus often present scales in peripheral regions of the cleared centers of lesions. In some cases, the cleared center may also present vesicles.

Although EAC is a dermatological disorder, it may be triggered by an underlying primary disease. The corresponding symptoms may even dominate the clinical picture. Considering current knowledge about possible etiologic factors, patients may additionally present the following symptoms:

• Malaise, fever, lymphadenopathy and more specific symptoms associated to particular infectious diseases. Dermatomycoses have been related to EAC and may add to cutaneous findings.
• Symptoms associated with cancer, e.g., palpable nodes in the breast, dysuria, lymphadenopathy or recurrent infection. Of note, EAC may precede cancer diagnosis by years or may develop in a delayed manner.
• Enlargement or palpable nodes within the thyroid gland. Signs of hyperthyroidism.
• Symptoms indicating an autoimmune disorder.

A thorough anamnesis should be conducted and may reveal recent initiation of therapy of another condition - and thus intake of antibiotics, analgesics etc. - or diagnosis of any disease that has been associated with EAC before. The following clinical work not only aims at confirming EAC but also at identifying a possible underlying, as of yet undiagnosed primary disease.

With regards to confirmation of EAC, a skin biopsy should be obtained and analyzed histopathologically. Mononuclear infiltrates around dermal blood vessels are characteristic for this disease and may be considered diagnostic in patients presenting typical skin lesions [11]. Usually, specific histopathological findings correlate with the observed symptoms. Pruritus, scales and possibly even vesicles indicate superficial EAC and perivascular infiltrates are mainly detected in the upper dermal layers. While mononuclear cells don't infiltrate the epidermis, epidermal parakeratosis and spongiosis may be noted in these samples. In contrast, the classical, deep type of EAC is not associated with pruritus or scales and does not show any epidermal alterations. Here, mononuclear cell infiltration principally affects the lower dermis.

EAC and dermatomycoses often occur concurrently. In order to rule out fungal infections, tissue samples obtained from lesions' borders should be submitted to potassium hydroxide testing. This readily available technique allows for visualization of hyphae or yeast cells.

A wide variety of diagnostic measures may be taken to rule out the aforementioned, possibly underlying diseases:

• Laboratory analyses of blood samples (hemogram, biochemistry, autoantibodies) may indicate infection, hematopoietic neoplasms, thyroid disorders, pregnancy and autoimmune diseases. Pregnancy may also be confirmed after urine analysis.
• Diagnostic imaging may be of help to diagnose tuberculosis and to detect tumors.
• Stool examination is the method of choice to rule out infestation with intestinal parasites.

EAC is a self-limiting disease and spontaneous remission is usually observed within months or years after symptom onset. If an underlying disease can be identified and treated, this will likely accelerate healing of EAC-associated cutaneous lesions. This also applies for drug-induced EAC. If medication is suspected to be the trigger of EAC, it should be changed or discontinued as long as such a decision is reasonable.

While corticosteroid therapy has shown some effect, to date, no therapeutic approach has been proven to provide long-term relieve. Topical administration of corticosteroids yields topical effects, i.e., the treated lesion resolves, but those distributed over the remaining areas of the skin progress in an unaltered manner. Generalized reduction of dermatological alterations can be induced by systemic corticosteroid therapy, but relapses occur if drug therapy is ceased. The side effects of prolonged corticosteroid application outweigh its possible benefits.

No other compounds can be recommended for treatment, although a number of drugs has successfully been used in isolated cases, e.g, interferon-α, calcipotriol and erythromycin [13] [14] [15].

EAC is a chronic, yet usually self-limiting disorder if not provoked by an underlying, non-curable disease. Duration of EAC in a specific case may vary between a few weeks and several years. While a median duration of less than one year has been reported some time ago [9], a more recent publication states spontaneous remission to occur after an average of 2.8 years [12]. Some patients may suffer from repeated relapses.

In contrast, if EAC results from an underlying, primary disease, prognosis largely depends on progression of the latter. Worst prognosis is associated with EAC due to malignant tumors.

Of note, pregnancy-induced EAC can be expected to resolve within a short period of time after delivery [8].

A variety of conditions, of both physiological and pathological nature, have been associated with EAC. Conclusive evidence supporting the hypotheses that any of the here mentioned states does indeed trigger EAC has not yet been supplied. In detail, the following groups of patients are currently considered to have a higher risk of EAC:

• Patients presenting with infectious diseases triggered by any kind of pathogen, i.e., bacterial, viral, mycotic and parasitic diseases. In this line, Mycobacterium spp., Escherichia coli, herpesviruses such as varicella zoster virus and Epstein-Barr virus [2] [3], human immunodeficiency virus, Trichophyton spp., Candida albicans and intestinal parasites may be mentioned as examples.
• Those treated with antibiotics (particularly with penicillin, although EAC is not a typical manifestation of penicillin allergy), analgesics and anti-inflammatories (acetylsalicylic acid, oxicams), thienodiazepines, tricyclic antidepressants, antimalarials (chloroquine, hydroxychloroquine) and antibodies (ustekinumab, rituximab). This list is most likely not complete, a fact that may be emphasized further by more recent cases of EAC after administration of finasteride or a combination of interferons and ribavirin [4] [5]. Most of these information stems from isolated cases.
• Patients suffering from malignant neoplasms, particularly breast and prostate cancer as well as lymphoma and leukemia [6].
• Individuals showing hormonal imbalances, e.g., Graves disease, other forms of hyperthyroidism and - considering the broader sense of the term - menstruation and pregnancy [7] [8].
• Patients presenting with autoimmune disorders such as systemic lupus erythematosus and Sjogren's syndrome.
• Those who have been exposed to allergens, e.g., to food allergens or insect venoms.
• Familial accumulation has been observed and indicates a genetic background predisposing for EAC. Thus, patients whose relatives have been diagnosed with EAC may have an increased risk of developing the disease themselves.

However, in most cases, no underlying disease can be detected and the disease is deemed idiopathic [9]. Because many of the aforementioned risk factors for EAC have only been related to this dermatological disorder in isolated cases, coincidence cannot be ruled out.

Precise epidemiological data regarding incidence and prevalence of EAC are not available. This may be partially due to the fact that there is no consensus about a definition of EAC, partially because patients generally present with comorbidities that dominate the clinical picture. According to rough estimates, an annual incidence of 1 per 100,000 individuals may be assumed.

EAC has been diagnosed in patients of all races, both genders and all ages. An annually recurring form has been described in one case [10].

The variety of etiologic factors contributing to EAC seems to indicate heterogenous pathogenetic mechanisms. Nevertheless, the most widely accepted hypothesis to date is that of distinct molecules inducing a hypersensitivity reaction. Such molecules may be drugs, antigens introduced by pathogens or expressed by tumor cells, food allergens or insect venoms. Delayed appearance of EAC, the proven involvement of T lymphocytes, histiocytes and locally increased concentrations of tumor necrosis factor-α and other pro-inflammatory cytokines may point at hypersensitivity type IV, but further research is necessary to support that theory [11].

Due to the disease's unknown etiology, no specific measures can be recommended to prevent EAC.

Erythema annulare centrifugum (EAC) is a cutaneous pathology that has first been described by the French dermatologist Ferdinand-Jean Darier. Therefore, it is sometimes also referred to as Erythema annulare centrifugum of Darier. However, this disease is not identical to Darier disease, a designation that describes a condition of keratosis follicularis.

According to its name, EAC is characterized by circular erythemas consisting of an enhanced margin that usually expands gradually while the center of the lesion clears, thus creating the image of a ring. While the original definition of EAC stated that patients suffering from this condition neither present with scaly lesions nor experience pruritus, it has been a matter of debate whether scaly, itchy lesions may also be diagnosed as EAC. Years ago, it has been proposed to discard this term and merely diagnose gyrate erythema [1]. Although these arguments are comprehensible, the term is still in use today.

An explanation for the apparent confusion regarding the presence of scales and pruritus in EAC may possibly be found in histopathological results. Biopsy samples obtained from patients showing the classical clinical picture without scales and pruritus reveal mononuclear cell infiltrates around blood vessels of the dermis. The epidermis does not show such alterations. In contrast, if mononuclear cell infiltration occurs closer to the surface of the skin, i.e., if the patient suffers from a superficial skin lesion rather than from a deep cutaneous alteration as described before, scales and pruritus may occur. In such cases, scales are typically following the erythematous margin of the lesion. Statistics indicate that the scaly, pruritic type of EAC is even more common than the classical one described by Darier a hundred years ago.

This article will consider both deep and superficial gyrate erythema as EAC. The etiology of neither one is completely understood. The pathology has been suggested to be immune-mediated and triggered by infectious diseases, drug administration or neoplasms, but the majority of cases is still deemed idiopathic.

Erythema annulare centrifugum (EAC) is a skin disease characterized by red, ring-shaped lesions that typically expand peripherically.

Causes

The cause of EAC is not yet known. The disease has been related to administration of certain drugs and a plethora of other pathologies, e.g., infection with bacterial, viral, fungal pathogens or parasites, cancer, thyroid disorders, particularly those associated with hyperthyroidism, pregnancy and autoimmune disorders like systemic lupus erythematosus. However, in most cases, no underlying disease can be identified and EAC is deemed idiopathic.

Symptoms

Red papules may appear on distinct areas of the body, mainly on trunk and legs. They spread peripherically, approximately half a centimeter per day, and clear centrally, thus forming circles, arcs and curved lines. The affected skin is generally hardened. Lesions may itch and scales may develop, but this is not characteristic for all forms of EAC.

If EAC is triggered by an underlying disease, the latter may provoke additional symptoms that may indeed dominate the clinical picture.

Diagnosis

EAC is diagnosed based on clinical examination and histopathological analysis of a skin biopsy. However, additional diagnostic measures may be required to rule out any of the above mentioned pathologies that may induce EAC. In this context, further dermatological test, laboratory analyses of blood samples and diagnostic imaging may be realized.

Treatment

EAC is usually self-limiting and spontaneous remission occurs within months or years after symptom onset. If an underlying disease can be identified and treated, this will probably accelerate healing of EAC-associated cutaneous lesions.

Corticosteroids may provide momentary relieve, but are not suitable for long-term therapy. Otherwise, no pharmacological treatment can be recommended.

1. Bressler GS, Jones RE, Jr. Erythema annulare centrifugum. J Am Acad Dermatol. 1981; 4(5):597-602.
2. Ohmori S, Sugita K, Ikenouchi-Sugita A, Nakamura M. Erythema annulare centrifugum associated with herpes zoster. J Uoeh. 2012; 34(3):225-229.
3. Hammar H. Erythema annulare centrifugum coincident with Epstein-Barr virus infection in an infant. Acta Paediatr Scand. 1974; 63(5):788-792.
4. Al Hammadi A, Asai Y, Patt ML, Sasseville D. Erythema annulare centrifugum secondary to treatment with finasteride. J Drugs Dermatol. 2007; 6(4):460-463.
5. Gönül M, Külcü Çakmak S, Ozcan N, Deniz Oguz I, Ozhamam E. Erythema annulare centrifugum due to pegylated interferon-alpha-2a plus ribavirin combination therapy in a patient with chronic hepatitis C virus infection. J Cutan Med Surg. 2014; 18(1):65-68.
6. Carlesimo M, Fidanza L, Mari E, et al. Erythema annulare centrifugum associated with mantle b-cell non-Hodgkin's lymphoma. Acta Derm Venereol. 2009; 89(3):319-320.
7. Braunstein BL. Erythema annulare centrifugum and Graves' disease. Arch Dermatol. 1982; 118(9):623.
8. Senel E, Gulec AT. Erythema annulare centrifugum in pregnancy. Indian J Dermatol. 2010; 55(1):120-121.
9. Mahood JM. Erythema annulare centrifugum: a review of 24 cases with special reference to its association with underlying disease. Clin Exp Dermatol. 1983; 8(4):383-387.
10. Garcia Muret MP, Pujol RM, Gimenez-Arnau AM, Barranco C, Gallardo F, Alomar A. Annually recurring erythema annulare centrifugum: a distinct entity? J Am Acad Dermatol. 2006; 54(6):1091-1095.
11. Chodkiewicz HM, Cohen PR. Paraneoplastic erythema annulare centrifugum eruption: PEACE. Am J Clin Dermatol. 2010; 13(4):239-246.
12. Kim KJ, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J Dermatol. 2002; 29(2):61-67.
13. Guillet MH, Dorval JC, Larregue M, Guillet G. [Darier's erythema annulare centrifugum of neonatal onset with a 15 years' follow-up. Efficacy of interferon and role of cytokines]. Ann Dermatol Venereol. 1995; 122(6-7):422-426.
14. Gniadecki R. Calcipotriol for erythema annulare centrifugum. Br J Dermatol. 2002; 146(2):317-319.
15. Chuang FC, Lin SH, Wu WM. Erythromycin as a Safe and Effective Treatment Option for Erythema Annulare Centrifugum. Indian J Dermatol. 2015; 60(5):519.