Background
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:
Pathophysiology
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.
Etiology
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.
Infections
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]
Drugs
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:
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Amitriptyline [20]
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Azacitidine [21]
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Chloroquine
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Cimetidine
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Estrogen
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Etizolam [22]
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Finasteride
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Hydrochlorothiazide
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Hydroxychloroquine [23]
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Gold sodium thiomalate
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Pegylated interferon alfa-2a plus ribavirin combination therapy [24]
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Penicillin
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Piroxicam
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Rituximab [25]
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Salicylates
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Ustekinumab [26]
Neoplasms
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:
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Squamous cell carcinoma (in a sebaceous cyst)
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Nasopharyngeal carcinoma
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AML
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Peritoneal carcinomatosis
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Primary bronchial carcinoid [27]
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Chronic lymphocytic leukemia
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Multiple myeloma
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Prostate cancer
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Malignant histiocytosis
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Ovarian carcinoma (mucinous)
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Breast cancer [30]
Other causes
A range of other causes have been reported, including the following:
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Foods - Blue cheese and tomatoes have been reported to cause EAC
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Recurrent acute appendicitis - The lesions of EAC resolved 1 month after appendectomy [10]
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Cholestatic liver disease (secondary to choledocholithiasis) - EAC resolved within 3 days of removal of the stone [7]
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Graves disease - The patient's eruption disappeared 2 weeks after treatment with I-131 for thyroid ablation [8]
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Menstruation - A case has been reported of a woman with EAC whose lesions stopped progressing premenstrually and enlarged again with the onset of menses; another patient experienced exacerbations of EAC premenstrually as a type of autoimmune progesterone dermatitis. [31]
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Hypereosinophilic syndrome - A patient with 31% eosinophilia (with no underlying cause found), pruritus, and EAC was treated with ketoconazole, dapsone, and trimethoprim-sulfamethoxazole with resolution of the eruption occurring after 2 weeks [9]
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Sjögren syndrome
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Sarcoidosis - EAC has been reported in association with underlying systemic sarcoidosis
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Osteoarthritis - 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 resolution of both the osteoarthritis and the EAC [32]
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Stress - One report described stress as an inciting factor in a case of EAC; the patient experienced EAC at the onset of stressful life periods, which abated without treatment upon discontinuance of the stressful periods [33]
Epidemiology
United States and international statistics
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.
Age-, sex-, and race-related demographics
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.
Prognosis
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.
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Arcuate lesions of erythema annulare centrifugum demonstrate minimal scale.
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Superficial erythema annulare centrifugum demonstrates a central clearing and trailing scale behind an advancing, annular, erythematous border.
