Shades of Shelley: Azithromycin therapy for erythema annulare centrifugum

By Warren R. Heymann, MD
April 12, 2018

When I first arrived in Philadelphia in 1984 for my dermatopathology fellowship at the University of Pennsylvania, the most exciting hours of the week were Thursday mornings at the Duhring Conference. Throngs of Delaware Valley dermatologists would attend, listening to the entertaining (and often iconoclastic) pontifications of dermatologic luminaries such as Al Kligman, Jim Leyden, Paul Gross, Margaret Gray Wood, and the new chairman, Jerry Lazarus. Even though he had left just a couple of years before, the influence of Walter Shelley loomed large over the discussions.

No matter the diagnosis, or how preposterous the theory, some dermatologist would say, “I think this is due to an occult infection — I’d prescribe doxycycline.” Quietly, I’d think, “that’s ridiculous.” When I mentioned this to an attending, Bob Rudolf, he warned me that saying so publicly would be pure heresy — akin to telling Pope Francis today that he should swipe Tinder and find himself a mate.
 
Regardless, the Dr. Shelley text Advanced Dermatologic Therapy was (is) a gem. He was a therapeutic genius. Even if I would cringe at some of the ideas, the most important tenet of the text was to always try something new (or old) if the patient is not improving. I have never forgotten that, and it has served my patients well. How did Dr. Shelley come up with such a vast armamentarium? During his residency at the University of Pennsylvania in the mid 1940’s, there were no systemic antibiotics, antifungals, antivirals, nor had cortisone been discovered. He and his colleagues used oral bismuth for warts, Vleminckx solution for acne, tar and 3% ichthammol in zinc oxide paste for eczema, and Fowler’s solution (arsenic!) for lichen planus, among myriad other treatments. (1) Having experienced the advent of isotretinoin, acyclovir, and the biologics in my career, I can imagine his joy at the dawn of the antibiotic and steroid era.

The last time I saw Dr. Shelley was in 2002, literally bumping into him and Dorinda in Ketchikan, Alaska. What a privilege it was to thank him personally for how much I learned from him. He passed away in 2009 at age 92.

Erythema annulare centrifugum (EAC) is an annular, erythematous lesion that appears as urticarial-like papules and enlarges centrifugally, then clearing centrally. A fine, trailing scale is sometimes present inside the advancing edge, in superficial, but not deep forms of EAC.

According to McDaniel and Cook: “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.”
 
When EAC is related to underlying malignancy, it is known as PEACE (Paraneoplastic Erythema Annulare Centrifugum Eruption). Lymphoproliferative disorders are associated more frequently than solid tumors. (2)

Recent literature on EAC has included a unique case demonstrating a dramatic remission during two consecutive pregnancies followed by relapse shortly after delivery. (3) Sorafenib induced EAC in a 71-year-old man with sarcomatoid hepatocellular carcinoma, which resolved after his skin biopsy. (4) And, of course, articles abound about eruptions that can mimic EAC — bullous pemphigoid (5), inflammatory breast carcinoma (6), neutrophilic figurate erythema (7), sarcoidosis, subacute cutaneous lupus erythematosus, and cutaneous T-cell lymphoma.

Managing EAC involves histologic confirmation to rule out other mimickers while searching for any associated conditions. Topical steroids, calcipotriene, tacrolimus may be utilized. Phototherapy may be beneficial. The most interesting approaches though are for cases of idiopathic EAC that are presumed to be due to a subclinical infection causing hypersensitivity. Kruse at al reported 5 children with EAC who were treated empirically with oral fluconazole; improvement was noted in all patients with complete clearing in three.  A limitation of this study was that topical steroids were used concomitantly in 4 of the 5 patients. (8) Ten patients with EAC were treated with oral azithromycin 250 mg daily for up to 3 weeks or clearing of the rash. This dose was believed to be anti-inflammatory rather than antibacterial. Of the 10 patients, 8 responded with no relapse during follow-up. (9).

Although there has been concern for cardiac arrhythmias with the use of macrolides, including azithromycin, my perusal of the literature suggests that the risk is negligible. (10) The bottom line is to help our patients.  While I still roll my eyes at the thought of treating a theoretical hypersensitivity to an unidentified organism, I’ll consider prescribing azithromycin the next time I see patient with idiopathic EAC recalcitrant to topical therapy. Shelley lives on.

Point to remember: The “Shelley approach” of treating a subclinical, occult infection in idiopathic EAC with either fluconazole or azithromycin might be valuable in some patients.

1. Shelley WB. Memoir of a dermatologist’s residency, 1946-9. J Am Acad Dermatol 2004; 51: 674-7.
2. McDaniel B, Cook C. Erythema annulare centrifugum. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018; 2018 Feb 14.
3. Ozkaya E, et al. Erythema annulare centrifugum: Remission during two pregnancies and exacerbation in between. J Dtsch Dermatol Ges 2017; 15: 1136-8.
4. Yao C-A. Sorafenib-induced erythema annulare centrifugum with spontaneous resolution after skin biopsy. Australas J Dermatol 2017; Jul 20 [Epub ahead of print].
5. Yu_yang S. Bullous pemphigoid masquerading as erythema annulare centrifugum. Acta Dermatovenereol Croat 2017; 25: 255-6.
6. Sabater V, et al. Cutaneous metastasis of inflammatory breast carcinoma mimicking an erythema annulare centrifugum: A sign of locally recurrent cancer. Clin Exp Dermatol 2016; 41: 906-10.
7. Wu Y-H, et al. Neutrophilic figurate erythema. Am J Dermatopathol 2017 ; 39 : 344-50.
8. Kruse LL, et al. Pediatric erythema annulare centrifugum treated with oral fluconazole : A retrospective series. Pediatr Dermatol 2016 ; 33 : 501-6.
9. Sardana K, et al. An observational study of the efficacy of azithromycin in erythema annulare centrifugum. Clin Exp Dermatol 2018; 43: 296-99.
10. Gorelik E, et al. The cardiovascular safety of macrolides: A systematic review, meta-analysis, and network meta-analysis. Antimicrob Agents Chemother 2018 Apr 2 [Epub ahead of print]

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