Erythema annulare centrifugum (EAC) is classified as one of the figurate or gyrate erythemas.[1] First described by Darier in 1916, it is characterized by a scaling or nonscaling, nonpruritic, annular or arcuate, erythematous eruption. It tends to spread peripherally while clearing centrally. Histologically, an intense lymphohistiocytic cuffing occurs about the superficial and deep dermal vessels without epidermal involvement. The etiology has not been defined, but EAC may be due to a hypersensitivity to malignancy, infection, drugs, or chemicals, or it may be idiopathic. EAC-like eruptions have been described with nivolumab.[2]
Classification of the gyrate erythemas has been controversial, and the literature is fraught with ambiguity and contradictions. Since its initial description in 1916, the term erythema annulare centrifugum has grown to include several histologic and clinical variants. Ackerman, and later Bressler and Jones,[3] suggested a classification in which only two types of gyrate erythema are considered: superficial (pruritic, scaling) and deep (nonpruritic, nonscaling). The original description of EAC was of the latter type. However, the superficial type is more commonly seen, with its characteristic trailing scale behind an advancing erythematous border.
In this article, EAC is considered to include all the gyrate erythemas, except for erythema marginatum rheumaticum, erythema chronicum migrans, and erythema gyratum repens. When taken in this broad sense, EAC can be scaly or nonscaly, pruritic or nonpruritic, and rarely vesicular.
Other Medscape erythema articles include the following:
EAC represents a hypersensitivity reaction to a variety of agents, including drugs, arthropod bites, infections (bacterial, mycobacterial, viral, fungal, filarial), ingestion (blue cheese Penicillium), and malignancy.[4] It has been reported in association with eosinophilic granulomatosis with polyangiitis.[5] Injections of Trichophyton, Candida, tuberculin, and tumor extracts have been reported to induce EAC, supporting a type IV hypersensitivity reaction as at least one mechanism for its development.
Another purported mechanism in the pathogenesis of EAC is that of a T helper cell 1 (Th1)-mediated reaction with elevated levels of tumor necrosis factor (TNF)-α and associated proinflammatory cytokines. Minni and Sarro[6] reported response to (and relapse following cessation of) etanercept in a 57-year-old White man as evidence supporting this theory.
Other cases of EAC have been found in association with an underlying systemic or infectious disease (eg, liver disease,[7] Sjögren syndrome, systemic lupus erythematosus, Graves disease,[8] hypereosinophilic syndrome,[9] appendicitis[10] ), herpes zoster,[11] chronic lymphocytic leukemia, and HIV disease). Drugs reported to cause EAC include finasteride, piroxicam, hydroxychloroquine, amitriptyline, and spironolactone. Still other cases have been attributable to a familial form.
In most instances, however, no underlying cause can be found. One study of 24 cases of EAC, with special reference to its association with an underlying disease, found no increased incidence of systemic disease, malignancy, or infection.[12] In another study of 113 cases of gyrate erythemas, seven cases (none of which was erythema gyratum repens) were associated with internal malignancy, compared with six cases in the control group.
Hypotheses about the mechanism of annularity focus on the interaction between mediators of inflammation and ground substance as foreign antigens diffuse through the skin.
Although most commonly, no cause is found for EAC,[13] the literature contains numerous case reports documenting association with other diseases. Often, the eruption of EAC resolves after treatment of the underlying illness.
Bacterial
Associations with EAC include Escherichia coli. One case associated EAC with a urinary tract infection that cleared 3 weeks after treatment of the urinary tract infection.[14] Other associated bacterial infections include streptococcal infections (eg, bacterial meningitis).
Fungal
Dermatophytes (eg, Trichophyton,Epidermophyton, and Pityrosporum orbiculare/Malassezia furfur) are associated, as are Candida albicans and blue cheese Penicillium.
Mycobacterial
Mycobacterium tuberculosis is associated. In one case, treatment with isoniazid, rifampin, and streptomycin cleared the eruption of EAC within 20 day of starting therapy for tuberculosis.
Parasitic
In a case of EAC associated with Ascaris lumbricoides, EAC resolved after treatment with piperazine and thiabendazole.[15] Also, EAC has been reported in association with Phthirus pubis infestation.[16]
Viral
EAC has been reported in association with Epstein-Barr virus (EBV) in an infant[17] and with molluscum contagiosum in an 8-year-old child. In the infant, the appearance and subsequent resolution of the eruption coincided with the patient's anti-EBV antibody titer, supporting EBV as the inciting agent. In addition, the viral genome has been found in the DNA of Reed-Sternberg cells in patients with Hodgkin disease and in patients with nasopharyngeal carcinoma. Both of these neoplasms have been associated with EAC.
Two cases of EAC were reported in a dermatomal distribution within the exact distributions of recent prior herpes zoster infections. These cases were cited as examples of "Wolf's isotopic response."[18] In 2006, EAC was reported in an HIV-positive patient.[19]
In each of the following cases, the eruption of EAC appeared after initiation of the drug and resolved after its cessation. In the cases of the antimalarials chloroquine and hydroxychloroquine, the eruptions took 5 months to 1 year to clear, most likely secondary to their strong DNA-binding properties and affinity for melanin. The following drugs have been associated with EAC:
EAC resolved with successful treatment of the malignancy but relapsed with tumor recurrence in cases of Hodgkin disease, acute myelogenous leukemia (AML), and squamous cell carcinoma in a sebaceous cyst. However, in the latter case, EAC cleared in the terminal stage of the disease. This was purported to be due to immune compromise with tumor progression. The following associations have been noted:
A range of other causes have been reported, including the following:
Defining the incidence and the prevalence of EAC is difficult because the literature consists mostly of case reports and brief reviews. In a review of 24 cases in England, the incidence was reported to be approximately 1 case per 100,000 population per year in a catchment area of 500,000 people.
EAC has been reported in patients from infancy to the ninth decade of life. No predilection for either sex is apparent. Whether any racial predilection exists is not known.
The prognosis for EAC is excellent, except when it is associated with an underlying malignancy or other systemic disease. The mean duration of the condition is 11 months; however, the duration has been reported to range from 4-6 weeks to 34 years (recurrent attacks). Most cases require no treatment and resolve spontaneously. In other cases reported in association with malignancy, the eruptions respond to treatment of the underlying neoplasm, and the prognosis is affected by that of the underlying malignancy. Annually recurring EAC (AR EAC) was reported in 2015.[36] Treatment of the underlying disorder is effective. EAC associated with pregnancy typically resolves after delivery.
Usually, patients with erythema annulare centrifugum (EAC) present with an asymptomatic or pruritic eruption of variable duration. The eruption may be associated with an underlying disease (eg, infection, malignancy, sarcoidosis, other systemic illness) and its accompanying characteristic symptoms (eg, night sweats, fever, and chills for tuberculosis or Hodgkin lymphoma).[37]
EAC may precede malignancy by 2 years or more, but it can also occur concomitantly or after diagnosis.
The temporal relation to other underlying diseases, if any, is also variable. A history of any antecedent infections should be obtained.
A history of recent initiation of a new drug should be ascertained because there have been many reports of EAC associated with medications (most commonly, antimalarials, cimetidine, spironolactone, gold, salicylates, piroxicam, penicillin, and amitriptyline).
One case report described EAC as a manifestation of autoimmune progesterone dermatitis in a female with a recurring annular pruritic eruption.[31] She experienced monthly exacerbations of the eruption a few days prior to onset of menses. A similar hormonal etiology was reported in the case of a woman who developed EAC in week 33 of pregnancy.[38] The eruption resolved 1 month after delivery and had not recurred after 8 months of follow-up.
Pertinent physical findings of EAC are usually limited to the skin, but a full physical examination should nevertheless be conducted to assess for an underlying systemic process.
Primary lesion
The eruption begins as erythematous papules that spread peripherally while clearing centrally. These lesions enlarge at a rate of approximately 2-5 mm/day to produce annular, arcuate, figurate, circinate, or polycyclic plaques. The margin, which is usually indurated, ranges in width from 4 to 6 mm, and a trailing scale is often present on the inner aspect of the advancing edge. The diameter of the polycyclic lesions ranges from a few to several centimeters. Vesiculation may be present. (See the images below.)
![]() View Image | Arcuate lesions of erythema annulare centrifugum demonstrate minimal scale. |
![]() View Image | Superficial erythema annulare centrifugum demonstrates a central clearing and trailing scale behind an advancing, annular, erythematous border. |
Distribution
Lesions demonstrate a predilection for the thighs and the legs, but they may occur on the upper extremities, the trunk, or the face. The palms and the soles are spared.
Color
The lesions are pink to red with central clear areas. Occasionally, residual hyperpigmentation of dull red, brown, or violet is present. A case of EAC associated with hyperbilirubinemia and jaundice secondary to choledocholithiasis has been reported.
Nails
White banding of the toenails has been reported in association with EAC.
Lymph nodes
Lymphadenopathy may be present in cases of EAC associated with Hodgkin or non-Hodgkin lymphoma, tuberculosis, or autoimmune processes.
Neck
The thyroid should be palpated for enlargement or nodules because Graves disease has been associated with EAC.[8]
Lungs
Tuberculosis,[39] lymphoma, sarcoidosis, and malignant bronchial carcinoid have been associated with EAC, warranting examination of the lungs.
Abdomen
Appendicitis,[10] lymphoma (with associated splenomegaly), liver disease (eg, cholelithiasis or hepatitis),[7] and pregnancy have been reported with EAC. The abdomen should be examined for tenderness, masses, or hepatosplenomegaly.
Unless EAC is associated with an underlying disease, there are usually no complications.
Skin scrapings from lesional sites of erythema annulare centrifugum (EAC) should be analyzed after preparation in potassium hydroxide (KOH) to ascertain the presence or absence of hyphae suggestive of tinea or candidiasis.
Lyme antibody titer helps exclude erythema migrans, and serologic studies can exclude syphilis.[41]
An antinuclear antibody (ANA) test should be performed in the appropriate clinical setting. Systemic lupus erythematosus (SLE) is in the differential diagnosis of EAC, and Sjögren syndrome has been reported in association with EAC.
A purified protein derivative (PPD) test and an anergy panel can be used to help determine if an underlying M tuberculosis infection is present.
A complete blood count (CBC) with differential can be used to evaluate a suspected underlying infection (neutrophilia with bacterial infection; eosinophilia with parasitic infection or hypereosinophilic syndrome).
If compatible with the clinical presentation of EAC, liver function tests (LFTs) may be useful because hyperbilirubinemia secondary to cholestasis and elevated transaminase levels secondary to hepatitis have been reported with EAC.
With an appropriate history of gastrointestinal complaints, a stool examination may be useful to search for ova and parasites (ascariasis has been reported with EAC).
For females, serum or urine beta-human chorionic gonadotropin testing may be indicated.
Chest radiography may be performed to exclude pulmonary nodules or hilar adenopathy suggestive of tuberculosis, malignancy (primary or metastatic), sarcoidosis, or lymphoma, all of which have been associated with EAC.
A skin punch biopsy of the lesions can be helpful in confirming a diagnosis of EAC.
Two histologic subtypes of EAC exist: deep and superficial. In the classic or deep type, an intense, superficial and deep lymphocytic or lymphohistiocytic perivascular infiltrate in a coat-sleeve fashion is observed in the middle and lower dermis. No epidermal changes are observed. Clinically, these EAC lesions have indurated borders and are nonscaly and nonpruritic.
In the superficial type of EAC, a less specific perivascular lymphohistiocytic infiltrate about the superficial dermal vessels and edema of the papillary dermis are present. The epidermal changes of parakeratosis and spongiosis may be present. Clinically, these lesions have a scale, may be pruritic, and may have vesiculations.
Erythema annulare centrifugum (EAC) is typically self-limited. Topical steroids (eg, fluocinonide and hydrocortisone) usually cause involution of the treated lesions, but they do not prevent the occurrence of new lesions or recurrence of the eruption. Although systemic or injection steroid therapy (eg, with prednisone) is effective, the eruption returns once these drugs are withdrawn. Response has also been reported with roflumilast and upatacitinib.[42, 43]
As previously mentioned, several cases of EAC have been reported to resolve once the underlying diseases were treated. Accordingly, the primary therapy consists of searching for and treating the underlying disorder. However, an exhaustive workup for occult malignancy is not warranted, because the relation between EAC and cancer is not a consistent one.[44] It must be kept in mind that in most cases, no cause is found.
The patient's medications should be reviewed with particular attention to and discontinuance of the drugs known to be associated with EAC. Recent additions to the patient's drug regimen should be eliminated, and the patient should be observed for signs of resolution.
In a case of EAC associated with hypereosinophilic syndrome, the eruption resolved after treatment with ketoconazole, dapsone, and trimethoprim-sulfamethoxazole.[9]
A case of EAC of infantile onset in the French literature documented dramatic improvement with interferon alfa therapy.[45]
Case reports have documented success in the treatment of EAC with drugs previously not reported to be useful for EAC, including hyaluronic acid, calcipotriol, metronidazole, etanercept, and erythromycin.
A 73-year-old man with an 11-week history of EAC that was associated with the onset of left-knee osteoarthritis received injections of intra-articular hyaluronic acid that effected improvement of his osteoarthritis and resolution of his EAC.[32]
A case of EAC of 3 years' duration in a 73-year-old woman responded to calcipotriol after topical and systemic corticosteroids, antifungals, and psoralen with ultraviolet (UV) A (UVA) therapy were ineffective.[46] The eruption cleared completely after 3 months of treatment with calcipotriol. One report also described EAC responding to combination calcipotriol and narrow-band UVB.[47]
A 38-year-old man with a 2-year history of EAC for which an underlying cause could not be found and for which systemic antibiotics (ie, ciprofloxacin, clarithromycin), antifungal agents (ie, itraconazole, terbinafine), and topical calcipotriol were ineffective did respond to oral metronidazole.[48] The drug had been given to treat papulopustular rosacea. After 1 month of therapy, the EAC was coincidentally found to resolve, as did the rosacea. No recurrence of EAC was noted after 1 year of follow-up. A possible causal relation between rosacea and EAC was postulated.
A 57-year-old man with EAC for which previous treatment with narrow-band UVB, topical steroids, and methotrexate had been unsuccessful responded with complete resolution of his eruption after 4 weeks of therapy with etanercept at 25 mg subcutaneously twice weekly.[6] The EAC eruption recurred upon discontinuance of etanercept and resolved again with resumption of therapy.
In a study from Kaohsiung Chang Gung Memorial Hospital (a tertiary referral medical center in Taiwan), oral erythromycin stearate at a daily dose of 1000 mg (250 mg qid) for 2 weeks was given to eight patients with EAC that had responded poorly to previous treatments, including topical steroids, oral antihistamines, and even systemic steroids.[49] Three of the patients had recurrence of the disease, and all lesions resolved after readministration of erythromycin. These patients had more widespread lesions. The authors suggested that erythromycin can be an effective treatment option for EAC.
A dermatologist should be consulted for diagnosis and evaluation of the underlying cause of EAC. An internal medicine specialist should be consulted for evaluation of the underlying cause of EAC.
Clinical Context:
Clinical Context: