Continuing Education Activity

Erythema annulare centrifugum (EAC) is an annular, erythematous lesion that appears as an urticaria-like papule and enlarges centrifugally, then clears centrally. A fine scale is sometimes present inside the advancing edge, known as a trailing scale. Erythema annulare centrifugum is classified as a reactive erythema and has been associated with many different conditions, including malignancy. When erythema annulare centrifugum occurs as part of a paraneoplastic phenomenon, it is called paraneoplastic erythema annulare centrifugum eruption (PEACE). PEACE is more commonly seen in females, typically precedes the clinical diagnosis of malignancy, and may recur with subsequent relapses. This activity describes the pathophysiology, evaluation, and management of erythema annulare centrifugum and highlights the role of the interprofessional team in the diagnosis and management of patients with this condition.

Objectives:

• Identify the etiology of erythema annulare centrifugum.
• Describe the presentation of a patient with erythema annulare centrifugum.
• Review the management options available for erythema annulare centrifugum.
• Explain interprofessional team strategies for improving care coordination and communication to advance the evaluation and management of erythema annulare centrifugum and improve outcomes.

Introduction

Erythema annulare centrifugum (EAC) is an annular, erythematous lesion that appears as urticarial-like papules and enlarges centrifugally, then clears centrally. A fine scale is sometimes present inside the advancing edge, known as a trailing scale. Erythema annulare centrifugum is classified as a reactive erythema and has been associated with various underlying conditions, including malignancies. When erythema annulare centrifugum occurs as a paraneoplastic phenomenon, it has been designated PEACE (paraneoplastic erythema annulare centrifugum eruption). PEACE is more commonly seen in females, typically precedes the clinical diagnosis of malignancy, and may recur with subsequent relapses.[1][2][3]

EAC is one of the three major figurate erythemas, with EAC being the most common. These dermatoses share the common presentation of advancing erythematous, annular lesions, but are each separated by unique clinical and histopathologic characteristics. Once the other major figurate erythemas (erythema marginatum, erythema migrans, and erythema gyratum repens) are excluded, EAC often becomes a diagnosis of exclusion.[4][5]

Etiology

In 1881, Colcott-Fox described “erythema gyratum perstans” as persistent, ring-shaped lesions with pruritus. The term “EAC” was introduced by Darier in 1916 while the name “erythema perstans” is still used by some authors to describe similar annular erythemas. Currently, it is thought that all of these previous terms refer to clinical or pathologic variants of the entity now referred to as EAC. Some dermatologists preferred to divide the two histologically different forms (superficial and deep) of EAC “superficial gyrate erythema” and “deep gyrate erythema,” whereas others thought the superficial and deep forms of EAC were unrelated to one another and should not be referred to by the same name.[6][7][8]

Epidemiology

Although EAC can appear in any age group, the peak incidence is mid-adult life, but neonatal onset has been reported. There is no known gender difference. A rare autosomal dominantly inherited form of EAC referred to as “familial annular erythema,” has also been described.

Pathophysiology

The pathogenesis of EAC is unknown. In most cases, no causative agent can be detected (idiopathic EAC). A hypersensitivity reaction to various external or internal stimuli (especially the superficial form) has been suggested. EAC has been associated with many infectious entities, particularly dermatophytes and other fungal elements such as Candida, Penicillium in blue cheese), but also with viruses (Epstein-Barr virus, poxvirus, HIV, varicella-zoster), parasites, and ectoparasites (Phthirus pubis), and bacteria (Pseudomonas). Some food and drugs (cimetidine, rituximab, salicylate, ustekinumab, diuretics, nonsteroidal anti-inflammatory drugs, antimalarials, amitriptyline, gold sodium thiomalate, amitriptyline, etizolam, hormonal disturbances) have been implicated as additional causative factors. Some other less common entities have been reported in the literature such as Crohn's disease, pregnancy, autoimmune endocrinopathies, hypereosinophilic syndrome.

As mentioned above, when EAC is related to underlying malignancy, it is known as PEACE. The detection of unsuspected paraneoplastic erythema annulare centrifugum is particularly crucial, since it may lead to the discovery of a previously undiagnosed underlying cancer.  In Chodkiewicz et al. review of the world literature, they found a total of 40 patients with malignancies with an association with erythema annulare centrifugum. Of the associated malignancies, 37.5% were solid tumors, and 62.5% were lymphoproliferative disorders. Leukemia and lymphoma were each found in 11 individuals, which comprised the largest association between any malignancy and EAC. Chodkiewicz et al. proposed the underlying malignancy must directly or indirectly elicit cytokines or antigens to stimulate the development of the dermatoses observed in cutaneous paraneoplastic syndromes.

Histopathology

In the superficial variant of EAC, an infiltrate of histiocytes, lymphocytes, and, rarely, eosinophils are present around vessels of the superficial vascular plexus. The infiltrate is well-demarcated, with fairly tight aggregate around vessels, otherwise known as "coat-sleeve" distribution. Cells may reach into the walls of the small vessels. EAC is considered a pseudovasculitis rather than a vasculitis as there is never any fibrin extravasation. The advancing edge, which is slightly raised, may also show edema in the papillary dermis. The central area of clearing may contain dermal melanophages.

In the deep variant of EAC, the epidermis is usually unremarkable, and a mononuclear cell infiltrate with a sharply demarcated perivascular arrangement is present primarily in the mid and lower dermis. Due to the deeper dermal involvement, the lesions are elevated and are more indurated than in the superficial form of EAC, and they do not have a trailing scale. Some dermatopathologists believe that the deep form may be a manifestation of tumid lupus.

History and Physical

The initial lesions of EAC begin as asymptomatic, annular or polycyclic lesions that grow slowly (2 to 3 mm per day), rarely reaching more than 10 cm in diameter, then develop central clearing. An individual lesion can enlarge to greater than 6 cm in diameter over a period of 1 to 2 weeks. Characteristically, there is a trailing scale at the inner border of the annular erythema. If the expansion of the annular plaque is not uniform, incomplete arcs appear, as do polycyclic lesions, or simply festooned bands. In the superficial form, the lesions are minimally elevated, and there is desquamation at the inner margin, i.e., trailing scale. The scale may not be present in all the lesions. The surface of lesions is typically devoid of crusts or vesicles, although atypical cases with telangiectasia and purpura have been described. Occasionally, vesicles develop within the peripheral margin. There may be associated pruritus. Lesions usually occur on the trunk and proximal extremities.

In deep gyrate erythema, the advancing edges are obviously elevated, and there is usually no associated scale or pruritus. Resolving lesions do not have residual scarring, but postinflammatory hyperpigmentation can be seen. Although the lesions of EAC may be localized or generalized, they rarely, if ever, involve the scalp, mucous membranes, palms or soles. Individual lesions can persist for weeks to months, but usually without associated systemic manifestations. The total duration of EAC ranges from days to decades, and an unusual form of EAC has been described that recurs annually.

Evaluation

In addition to a taking a careful history and performing a thorough physical examination, the evaluation of erythema annulare centrifugum consists of ruling out any underlying disorder that could contribute to the cutaneous manifestations. If the dermatologist suspects malignancy, an age-appropriate screening to rule-out cancer would be appropriate. Unfortunately, the majority of cases of EAC are idiopathic. Hence, no causative agent can be detected.

Treatment / Management

The treatment of erythema annulare centrifugum is focused toward relieving any associated symptoms and resolution of the clinical lesions when no underlying disorder can be identified. If EAC is related to an underlying disorder, the cutaneous manifestations will usually resolve once the underlying process has been successfully treated. Topical corticosteroids can be applied to the advancing border of the lesions. Topical antipruritic and sedating antihistamines can be prescribed if there is associated pruritus. Some authors have advocated the empiric use of antibiotics or antifungal in the absence of an identifiable cause due to the associated with many infectious diseases. Although systemic corticosteroids can induce clinical remission, recurrences are common when the medication is discontinued. The following have been reported as beneficial based solely on case reports: topical calcipotriene, topical tacrolimus, NB-UVB, subcutaneous etanercept, oral metronidazole, and subcutaneous interferon-alpha.[9]

Differential Diagnosis

Numerous conditions must be considered in the differential diagnosis of erythema annulare centrifugum. EAC must be differentiated from other annular erythematous lesions, particularly annular psoriasis and tinea corporis when there is associated scale. Additional entities to consider include annular urticarial, annular sarcoidosis, allergic urticarial eruption, cutaneous lymphoid hyperplasia (pseudolymphoma), and mycosis fungoides. Other annular erythemas (such as erythema gyratum repens, erythema chronicum migrans, erythema marginatum, and erythema multiforme) are the most common entities that need to be differentiated from erythema annulare centrifugum. Patients with autoimmune diseases, including Sjögren syndrome, linear IgA bullous dermatosis, and lupus erythematosus (subacute cutaneous lupus erythematosus, tumid lupus erythematosus) can also have erythematous arciform, annular, and polycyclic lesions.

Less commonly, cutaneous metastases from visceral malignancies, such as stomach (inflammatory signet ring or adenocarcinoma), ovary, primary tumors of the breast, or malignancy of unknown primary, can mimic erythema annulare centrifugum.

Enhancing Healthcare Team Outcomes

While there are several benign causes of erythema annulare centrifugum, clinicians need to be aware that this particular skin rash is part of a paraneoplastic process. The detection of unsuspected paraneoplastic erythema annulare centrifugum is particularly crucial, since it may lead to the discovery of a previously undiagnosed underlying cancer. To improve outcomes, if one is not sure about a skin eruption, a dermatology consult should be in order.

If there is no cause identified, the primary care provider, nurse practitioner and dermatology nurse practitioner may treat the symptoms with topical steroids and/or antihistamines to relieve the itch.