Erythema annulare centrifugum

INTRODUCTION — Erythema annulare centrifugum (EAC) is a chronic, reactive phenomenon of the skin presenting with arcuate or annular, erythematous patches or thin plaques that frequently exhibit scale along the inner portion of the advancing edge of lesions ("trailing scale") (picture 1A-D). EAC has been reported to occur in association with a wide variety of conditions, including infections, drug exposures, food exposures, autoimmune disease, and malignancy. EAC also may occur in the absence of an identifiable exposure or disease.

The clinical features, diagnosis, and management of EAC are reviewed here. An overview of cutaneous annular lesions is provided separately. (See "Approach to the patient with annular skin lesions".)

ETIOLOGY — The pathogenesis of EAC is unclear. EAC is thought to be a delayed-type hypersensitivity response (ie, "id reaction") to a wide variety of antigens, with the specific trigger dependent upon an underlying disease process or exposure. In support of this hypothesis, cultured lymphocytes from a woman with progesterone-induced EAC exhibited a marked increase in interferon-gamma release upon in vitro exposure to progesterone [1].

In many patients, a specific trigger for EAC cannot be identified. However, numerous reports have cited conditions such as infectious disease, internal malignancy, medication exposures, food exposures, stress, and vaccination as triggers for EAC (table 1) [2-5]. Data are insufficient to confirm a causative relationship. Case series have yielded the following findings:

●In a retrospective study of 66 patients with EAC, 48 (72 percent) had a concomitant disease [6]. The most common associated disease was cutaneous fungal infection, which accounted for 48 percent of associated diseases. Other associations included other skin diseases (18 percent), internal malignancies (13 percent), and other systemic diseases (21 percent).

●In a retrospective chart review in which 45 of 73 patients with EAC had documentation specifying the presence or absence of associated diseases, 16 patients (36 percent) had documentation of an associated disease, including infections, malignancy, thrombocythemia, rheumatoid arthritis, asthma, and preceding drug reactions [7].

●A retrospective chart review of 39 patients with a histopathologic diagnosis of EAC found that 13 patients (33 percent) developed EAC in association with another disease or medical condition, including cutaneous fungal infection, malignancy, pregnancy, autoimmune disease, and medication use [8].

EPIDEMIOLOGY — EAC appears to be an uncommon disorder; however, the prevalence and incidence are unknown. EAC most often occurs in adults but may also occur in children. A review of 66 patients with EAC found ages of onset ranging from 5 to 71 years, with a mean age of onset of 40 years [6]. EAC in a neonate has been reported [9].

CLINICAL FEATURES — EAC typically begins as urticarial or erythematous papules that expand centrifugally over the course of several weeks. The peripheral extension is followed by central clearing, resulting in annular or arcuate patches or thin plaques (picture 1A-D). Typically, the outer portion of the advancing edge is slightly raised and erythematous, while the trailing edge has a brawny discoloration with scale. When present, the scale can be described as "trailing scale" [10]. The annular and arcuate lesions can coalesce to form gyrate or serpiginous patterns.

EAC can occur anywhere on the body but most commonly develops on the trunk and/or lower extremities. Pruritus is variably present.

The primary lesion in EAC has been a source of debate. Some authors have separated presentations with superficial scale (EAC or superficial gyrate erythema) from presentations without scale (deep gyrate erythema) [11,12]. In general, these presentations are viewed as different morphologic expressions of the same disease process [13].

There are no laboratory abnormalities directly associated with EAC. However, patients may have laboratory abnormalities related to comorbidities. (See 'Etiology' above.)

HISTOPATHOLOGY — The histopathologic findings in EAC vary based upon the clinical presentation. Presentations with superficial scale exhibit a dense, perivascular, lymphocytic, inflammatory infiltrate limited to the superficial dermal vascular plexus (picture 2A-B). The appearance of the perivascular infiltrate is thought to resemble a coat sleeve (picture 3). In addition, there may be alterations in the papillary dermis and epidermis, including edema, spongiosis, parakeratosis, hyperkeratosis, and basal layer vacuolization [6,11].

Presentations without superficial scale most often exhibit a tight, perivascular, lymphocytic infiltrate of the superficial and deep dermal vascular plexuses. Vasculitic changes are not expected but have been reported [10].

DIAGNOSIS — Clinicians experienced in the diagnosis of annular cutaneous eruptions can often make a diagnosis of EAC based upon recognition of the classic clinical presentation, particularly if trailing scale is present. A potassium hydroxide (KOH) preparation is usually performed to rule out tinea corporis. When the diagnosis is uncertain, a skin biopsy should be performed to exclude alternate diagnoses. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation' and 'Histopathology' above.)

Clinical assessment — The clinical assessment typically includes a directed patient history, complete skin examination, and KOH preparation.

The patient history should include a review of the progression and duration of skin disease, associated symptoms, and potential exacerbating factors. Patients with EAC often have a history of the waxing and waning development of annular plaques that expand centrifugally over the course of days to weeks. Pruritus may be present or absent. Findings inconsistent with EAC, such as a history of blistering, erosions, mucosal involvement, or rapidly migrating plaques, should raise suspicion for alternative diagnoses. (See 'Clinical features' above and 'Differential diagnosis' below.)

A complete skin examination is helpful for determining the extent of involvement, recognizing potential triggers for EAC (eg, cutaneous fungal infections), and detecting features that suggest other skin diseases. The characteristic physical findings of EAC are annular, arcuate, gyrate, or serpiginous, erythematous plaques or patches. (See 'Clinical features' above.)

The combination of a careful skin examination and KOH preparation is useful for identifying tinea corporis, one of the most common disorders in the differential diagnosis. In contrast to EAC, scale in tinea corporis is typically found at the leading edge of annular plaques rather than the trailing edge. Performance of a KOH preparation can rapidly confirm a diagnosis of tinea corporis. (See 'Differential diagnosis' below and "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)

Skin biopsy — A skin biopsy is useful when the diagnosis of EAC is not clear following the clinical assessment (eg, clinician uncertainty or atypical clinical presentation). The biopsy should be taken from erythematous skin at the periphery of a skin lesion. A 4 mm punch biopsy is usually sufficient. (See "Skin biopsy techniques", section on 'Punch biopsy'.)

EVALUATION FOR UNDERLYING CAUSE — Although data on inciting diseases or other factors are limited and a cause of EAC often cannot be identified, an evaluation for an underlying trigger is typically performed with the goal of detecting unrecognized underlying disease and improving EAC. (See 'Management' below.)

Our typical assessment for underlying diseases or exposures that may contribute to EAC includes:

●Medication history, including recent vaccinations

●Review of systems

●Physical examination

●Review/completion of age-appropriate cancer screening

Abnormal findings of these investigations guide the selection of additional laboratory studies or other tests. (See 'Etiology' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EAC includes multiple other cutaneous disorders that may present with annular, erythematous skin lesions. (See "Approach to the patient with annular skin lesions".)

Infection-related disorders

●Erythema migrans – Erythema migrans results from Borrelia infection acquired through a tick bite. The disorder presents as a papule at the site of the bite followed by formation of an annular plaque (picture 4). The plaque may range from 5 to more than 68 cm in diameter [14]. Patients may have associated fatigue and lymphadenopathy. Histopathologically, erythema migrans exhibits nonspecific inflammation, but spirochetes may be evident. Serology can aid in the diagnosis and will differentiate erythema migrans from EAC. (See "Clinical manifestations of Lyme disease in adults", section on 'Erythema migrans'.)

●Erythema marginatum – Erythema marginatum develops in a minority of patients with acute rheumatic fever and is highly specific for the syndrome [15,16]. Children with acute carditis are the most likely to develop erythema marginatum. The disorder manifests as annular, erythematous plaques that appear quickly then fade over the course of hours to several days (picture 5). The morphology and association with rheumatic fever aid in differentiating erythema marginatum from EAC. (See "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Erythema marginatum'.)

●Erythema multiforme – Erythema multiforme presents as the abrupt onset of annular, target-like lesions with a predilection for acral sites (picture 6). Vesicles or bullae may arise. Mucosal surfaces also may be involved. Erythema multiforme may be a hypersensitivity reaction to various inciting factors, particularly herpes simplex virus and Mycoplasma pneumoniae infections. Histopathologic differentiation between erythema multiforme and EAC is possible with a skin biopsy. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

●Syphilis – Syphilis may present with a wide variety of cutaneous manifestations. Annular, papulosquamous eruptions may warrant consideration of this diagnosis. Syphilis can easily be ruled out with a rapid plasma reagin (RPR) laboratory test. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV" and "Syphilis: Screening and diagnostic testing".)

●Tinea corporis and tinea imbricata – The annular plaques of tinea corporis, a dermatophyte infection, often have more scale than EAC (picture 7). In addition, pruritus tends to be more pronounced. In contrast to the trailing scale of EAC, scale is often on the leading edge in tinea corporis. Tinea imbricata is a dermatophyte infection characterized by concentric, annular, scaly, erythematous plaques (picture 8). A potassium hydroxide preparation will show branching hyphae in dermatophyte infections. (See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)

Neoplastic and paraneoplastic disorders

●Erythema gyratum repens – Erythema gyratum repens is characterized by the development of concentric rings of migratory, erythematous plaques (picture 9A-B). The appearance of erythema gyratum repens has been described as "wood grain" [17]. Erythema gyratum repens has a strong association with underlying lung, breast, and esophageal cancer and may precede the diagnosis of cancer by several months. Clinically, erythema gyratum repens tends to involve larger areas of the body than EAC and will migrate at a more rapid pace (1 cm per day). Erythema gyratum repens tends to have severe pruritus compared with the variable pruritus seen with EAC. On histopathology, erythema gyratum repens typically does not have the classic tight, perivascular, lymphocytic infiltrate of EAC [17]. (See "Cutaneous manifestations of internal malignancy", section on 'Erythema gyratum repens'.)

●Mycosis fungoides – This type of cutaneous T cell lymphoma can share chronicity and annularity with EAC [18]. Advanced cases of mycosis fungoides may show thicker plaques, nodules, and tumors (picture 10). Lymphadenopathy may be present. A biopsy can differentiate mycosis fungoides from EAC. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●Necrolytic migratory erythema – Necrolytic migratory erythema presents as eczematous or psoriasiform plaques. Annular lesions may occur. Necrolytic migratory erythema tends to be more erosive than EAC. Patients will have associated weight loss, diarrhea, and other metabolic disturbances secondary to an underlying glucagonoma. The distribution of necrolytic migratory erythema tends to be perioral, perianal, and in the inguinal folds [19,20]. (See "Cutaneous manifestations of internal malignancy", section on 'Necrolytic migratory erythema' and "Glucagonoma and the glucagonoma syndrome".)

Other disorders

●Granuloma annulare – Granuloma annulare is an idiopathic disease that most often manifests as annular plaques without scale (picture 11A-B). Granuloma annulare and EAC are easily distinguished on pathology. Granuloma annulare shows an interstitial and/or palisaded, histiocytic infiltrate with or without collagen necrobiosis. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

●Sarcoidosis – This multisystem inflammatory condition can present in the skin with innumerable clinical morphologies, including annular plaques (picture 12). Sarcoidosis is easily distinguished from EAC with a skin biopsy. Patients with sarcoidosis may have additional pulmonary or lymph node involvement. (See "Cutaneous manifestations of sarcoidosis".)

●Urticaria – The plaques of urticaria often are more evanescent than those of EAC (picture 13). Urticarial lesions will present for 8 to 24 hours and then fade, whereas EAC can last weeks to months. The biopsy findings of urticaria are subtle and may show eosinophils or neutrophils scattered around superficial vessels, cells that often are not seen in EAC. (See "New-onset urticaria".)

●Cutaneous lupus erythematosus – Cutaneous lupus erythematosus may show annular lesions with scale; subacute cutaneous lupus erythematosus is the most likely subtype to exhibit this morphology (picture 14). In contrast to EAC, subacute cutaneous lupus erythematosus has a predilection for sun-exposed skin. Definitive differentiation can be made with a biopsy. (See "Overview of cutaneous lupus erythematosus".)

●Erythema papulatum centrifugum – Erythema papulatum centrifugum is a pruritic, sweating-related cutaneous disorder that may be a variant of EAC. Clinically, erythema papulatum centrifugum presents as incomplete annular erythema with numerous peripheral papules on the trunk or proximal extremities. The histologic findings include inflammation around dermal and intraepidermal eccrine ducts, a feature not typically seen in EAC [21].

●Bullous pemphigoid (urticarial phase) – Early- or urticarial-phase bullous pemphigoid may mimic EAC, with annular, erythematous plaques [22]. Unlike EAC, bullous pemphigoid most often affects older adults. A biopsy as well as immunofluorescence studies may easily differentiate these diagnoses. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

MANAGEMENT — The appearance, symptoms, and unpredictable duration of EAC can be distressing, prompting many patients to desire treatment. However, data on treatments for EAC are limited, and there is no clear, effective treatment.

Initial approach — The initial approach to treatment of EAC differs slightly for patients with a suspected trigger for EAC and patients without an identifiable trigger.

Patients with a suspected trigger — Clinical experience suggests that treatment of an associated underlying disease or removal of another cause, such as drug exposure, can lead to resolution of EAC [23,24]. Thus, when a potential underlying cause (eg, cutaneous fungal infection, drug exposure) is identified, it should be treated or removed, if feasible. Patients who desire to accelerate improvement or do not respond to the elimination of the suspected trigger may also be given therapies for EAC without an identifiable trigger. (See 'Etiology' above and 'Patients without an identifiable trigger' below.)

Patients without an identifiable trigger — The treatment of EAC without an identifiable trigger is focused on improvement of the skin lesions and associated symptoms. Local corticosteroids and antipruritic therapies are typically used as initial treatment. Other therapies can be tried for patients who do not respond sufficiently to these treatments. (See 'Refractory disease' below.)

However, data are insufficient to confirm efficacy of any specific treatment for EAC. Given the uncertainty regarding treatment efficacy and the benign nature of EAC, deferring treatment is a reasonable alternative for patients who are not bothered by the signs and symptoms of EAC.

Local corticosteroids — Clinical experience suggests that topical corticosteroids and intralesional corticosteroid injections can reduce clinical signs of inflammation in EAC. The relative safety of these therapies contributes to their use as first-line therapies. However, these treatments do not typically induce complete remission of EAC and have not been evaluated in clinical studies.

We typically use topical corticosteroids first and reserve intralesional corticosteroid injections for limited areas of involved skin with insufficient responses to topical treatment, given the discomfort associated with multiple injections.

Adult patients can apply a medium- to high-potency (eg, group 2 to 4) topical corticosteroid twice daily to affected skin; low- to medium-potency agents (eg, group 4 to 6) are typically used for children (table 2). A typical treatment course is two weeks. If there is no response within four weeks, we discontinue topical corticosteroid treatment.

Intralesional injection is typically performed with injection of triamcinolone acetonide (3 to 5 mg/mL) into affected skin. Individual injections of 0.1 mL are placed approximately 1 cm apart. Improvement is usually evident within one to two weeks after injection. If there is a partial response, injection can be repeated after four to six weeks. If significant improvement is not evident after two injection sessions, a response may be unlikely, and it is reasonable to stop injections. (See 'Refractory disease' below.)

Cutaneous atrophy is a potential side effect of local corticosteroid use. Additional side effects of topical and intralesional corticosteroid therapy are reviewed in detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Intralesional corticosteroid injection".)

Antipruritic agents — Patients with pruritus may achieve symptomatic relief with use of topical antipruritic agents. Common agents include lotions containing menthol, camphor, or pramoxine. (See "Pruritus: Therapies for generalized pruritus", section on 'Elimination of aggravating factors'.)

Refractory disease — The best approach to EAC that persists despite removal of suspected triggers and local corticosteroid therapy is unclear. A variety of treatments have been attempted, including antimicrobial drugs and other therapies. However, data are insufficient for conclusions on the efficacy of these therapies.

Antimicrobial drugs — Several reports describe benefit of antibacterial and antifungal therapies, such as azithromycin, erythromycin, fluconazole, and oral metronidazole. Doxycycline therapy was associated with improvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated EAC with anosmia and ageusia in a case report [25]. Proposed mechanisms for improvement include treatment of subclinical microbial foci that stimulate EAC and the anti-inflammatory properties of some antimicrobial therapies [26,27]:

●Azithromycin – In an uncontrolled study in which 10 patients with idiopathic EAC received azithromycin (250 mg once daily) until clinical resolution or a maximum of three weeks, 8 patients responded to treatment [27]. The mean time to response for superficial and deep EAC were 12 and 34 days, respectively. Responders were followed for 4 to 12 months, and no relapses occurred during this period.

●Erythromycin – In an uncontrolled study in which eight adults received a two-week course of oral erythromycin stearate (1000 mg per day), all patients had a marked reduction in lesion size and erythema within two weeks [28]. Three patients who experienced recurrences responded to a repeat course of erythromycin.

●Fluconazole – In a review of five children treated with oral fluconazole (3 to 6 mg/kg per day) for 2 to 14 weeks (including four children concomitantly treated with topical corticosteroids), all children improved, with complete clearance occurring in three patients [26]. Of note, two children who achieved completed clearance had subsequent relapse of disease.

●Metronidazole – A complete response to oral metronidazole (400 mg per day for six weeks) followed by topical metronidazole is documented in a case report [29].

Other therapies — Other treatments that have appeared beneficial in small numbers of patients include etanercept [30], topical calcipotriol [31], oral apremilast [32], and prolonged exposure to sunlight [33].

PROGNOSIS — EAC may wax and wane over months to years, but most cases eventually resolve spontaneously [6]. Peculiar patterns of recurrence on a yearly basis have been described [34-36]. Treatment or removal of an underlying cause of EAC can accelerate resolution [23,24]. (See 'Management' above.)

There are insufficient data to guide specific recommendations for the reevaluation of patients with persistent, idiopathic EAC for an underlying cause. Periodic reevaluation consisting of a history, review of systems, physical examination, and compliance with age-appropriate cancer screening is reasonable. The need for additional evaluation should be determined on a case-by-case basis. (See 'Evaluation for underlying cause' above.)

SUMMARY AND RECOMMENDATIONS

●Etiology – Erythema annulare centrifugum (EAC) is an uncommon skin disorder that is postulated to represent a delayed-type hypersensitivity response to a variety of antigens. EAC has occurred in association with a variety of conditions, including diseases, drug exposure, and food exposure. In many patients, an associated condition cannot be identified. (See 'Etiology' above and 'Epidemiology' above.)

●Clinical features – EAC can occur on any cutaneous site but most often develops on the trunk and/or lower extremities. The classic clinical findings are annular, erythematous patches or thin plaques that may coalesce to form gyrate or serpiginous patterns (picture 1A-D). There may be overlying trailing scale. EAC may be asymptomatic or pruritic. (See 'Clinical features' above.)

●Diagnosis – Clinicians experienced in the diagnosis of cutaneous annular eruptions often can diagnose EAC based upon the physical findings. A potassium hydroxide preparation is usually performed to rule out cutaneous fungal infections. When the diagnosis is uncertain, a biopsy can be performed to confirm the diagnosis. (See 'Diagnosis' above and "Approach to the patient with annular skin lesions".)

●Evaluation for underlying cause – The underlying trigger for EAC often cannot be identified. A typical evaluation includes a medication history, review of systems, physical examination, and completion of age-appropriate cancer screening. Infection is one of the most common associated conditions. (See 'Evaluation for underlying cause' above and 'Etiology' above.)

●Management – Data on the treatment of EAC are limited, and there is no uniformly effective therapy:

•Removal of suspected cause – Clinical experience suggests that EAC can improve upon treatment of an associated underlying disease or removal of an associated exposure; therefore, we routinely evaluate patients with EAC for underlying disease and other potential triggers. For patients in whom a potential underlying cause is identified, we suggest treatment or removal of the suspected cause, when feasible (Grade 2C). (See 'Evaluation for underlying cause' above and 'Management' above.)

•Pharmacologic treatment – For patients who desire improvement in the appearance of EAC, we suggest topical or intralesional corticosteroids as initial treatment (Grade 2C). Antipruritic agents are useful for managing pruritus. Oral antimicrobial drugs and other agents have been reported to improve EAC in small numbers. (See 'Management' above.)