A 22-year-old man presents with an 8-week history of an asymptomatic rash on his face, torso, and groin. He is otherwise healthy, and a review of symptoms finds he is negative for fever, malaise, joint pains, and headaches. He is a student at the local college and reports having had unprotected sex with several partners over the past year. Physical examination reveals several hyperpigmented annular plaques on his face and scalp. Scaly papules are noted over his torso and proximal extremities; two verrucous, flesh-colored plaques are present on the shaft of his penis. Generalized, nontender adenopathy is palpable; no ulcers or mucosal lesions are present.
A 44-year-old woman with a history of intermittent migraines presents with dark spots appearing on her leg over the past year. Initially, there was only one, but over time two others appeared. Her medications include naproxen for her headaches and an oral contraceptive. When the spots first appeared, they were reddish-purple in color and mildly itchy; they subsequently turned black. Review of symptoms is negative for anything obviously contributory. Physical examination reveals three well-demarcated, hyperpigmented patches on her right lower leg. No other lesions are noted, and there is no lymphadenopathy.
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Annular lesions, also known as annular syphilids, are one of many potential cutaneous manifestations of secondary syphilis. Syphilis is caused by the spirochete Treponema pallidum, which is transmitted primarily via sexual contact. Because syphilis has such an extensive variety of clinical manifestations, it has been called “the great imitator.”
Left untreated, the disease naturally progresses through different stages. The primary lesion of syphilis (thus, primary syphilis) is called a chancre and designates the site of inoculation. A chancre is a painless, firm, eroded papule with a raised and indurated margin; although more commonly seen in the genitalia, other inoculation sites have been well-described.
Even without therapy, the chancre involutes spontaneously within 3 to 6 weeks. In untreated individuals, secondary syphilis develops 6 to 12 weeks later and is characterized by systemic manifestations and a large variety of cutaneous findings. Signs and symptoms of secondary syphilis also spontaneously involute but may recur months later in those who still have untreated disease. The timing of the third phase, tertiary syphilis, is highly variable. It may manifest as early as 1 year after the primary infection or decades later. Tertiary syphilis can lead to devastating systemic involvement of the viscera, bones, and cardiovascular and central nervous systems, and it is beyond the scope of this discussion.
Throughout history, the incidence of syphilis has fluctuated markedly. The discovery of penicillin in 1928 allowed some to hope that all bacterial infections, including syphilis, would be eradicated worldwide. Syphilis infection rates did decrease substantially for several decades; however, the human immunodeficiency virus (HIV) epidemic has been associated with resurgence. With the advent of highly active antiretroviral therapy for HIV infection, the incidence of syphilis again declined until the year 2000, at which point it again began to rise. In 2005, there were 2.9 reported cases of syphilis per 100,000 persons, and this figure increased to 5.3 cases per 100,000 persons in 2013.1
The mucocutaneous findings of secondary syphilis are highly variable. Most common is a papulosquamous cutaneous eruption consisting of small, scaly macules and papules that may be reddish-brown or skin-colored; lesions may enlarge, coalesce, and develop various morphologic patterns as they mature. Widespread distribution is customary, and lesions are commonly found on the palms of the hands and soles of the feet. The characteristic reddish-brown, scaly macules on the palms and soles have been dubbed copper penny lesions because their color is similar to that of copper pennies. When present, these lesions are highly suggestive of secondary syphilis. In the groin, secondary syphilis may mimic human papilloma virus-induced condyloma; those lesions due to syphilis are called condyloma lata. Patients may also develop a patchy alopecia and nonspecific mucosal lesions. Pustular lesions are very rare, as are vesicles and bulla; vesicular lesions are seen predominately in newborns and HIV-affected patients.2
An estimated 6% of patients with secondary syphilis develop annular syphilids.3 These lesions develop as annular plaques with slightly raised borders; some lesions may become verrucous. Although any site can be affected, they are common on the head and neck.4
A number of constitutional and systemic signs are common, but not uniformly present, in secondary syphilis, and these include low-grade fever, lymphadenopathy, malaise, headache, myalgias, dysphagia, and mild hepatosplenomegaly.2 A good rule of thumb is to consider syphilis in any patient with a constitutional illness and a generalized eruption.
Diagnosing syphilis serologically is a multistep process. Screening is initiated with more sensitive, but less specific, nontreponemal tests including the rapid plasma reagin and venereal disease research laboratory tests. Specimens with a positive test result should then be tested with the more specific fluorescent treponemal antibody absorption test. Unfortunately, HIV infection and other causes of immunosuppression may lead to false-negative serologic results. Conversely, conditions such as systemic lupus erythematosus, pregnancy, or a concurrent acute febrile illness may lead to a false-positive serologic result.2 If available and performed properly, dark field microscopy allows direct visualization of the spirochetes in aspirated fluid. Unfortunately, this is more of historic interest, because dark field microscopy is no longer readily available to most practitioners.
Results from a skin biopsy may be suggestive, or even diagnostic, of syphilis if the spirochetes can be identified with special staining. Unfortunately, histologic findings are more often nonspecific. Epidermal changes of acanthosis, parakeratosis, and neutrophilic infiltration have been described. Perivascular dermal infiltrates containing lymphocytes and plasma cells can also be seen; the presence of dermal plasma cells in a nonmucosal site may be suggestive of syphilis.4
The differential diagnosis of annular syphilids includes disorders with similarly annular lesions such as tinea corporis, granuloma annulare, discoid lupus, tumid lupus, lichen planus, fixed drug eruption (FDE), and erythema multiforme. Lesional duration and symptoms, epidermal changes, and bedside testing can help to exclude several of these conditions. Lesions of secondary syphilis are typically scaly and short-lived; most lesions self-involute within a few months, although there are reports of more chronic lesions. Scale is not predominant in granuloma annulare or tumid lupus. Although scaly, lichen planus and tinea corporis are typically pruritic. A potassium hydroxide test at bedside can diagnose tinea corporis. Discoid lupus has scarring, not seen in syphilis. Erythema multiforme and FDEs have fairly specific clinical courses that can help confirm the diagnosis clinically. However, if suspected, a biopsy result is helpful, as histology of these conditions is highly specific.
Treatment for syphilis is determined by the stage of the disease. Immune-competent individuals with primary or secondary syphilis can be treated with a one-time intramuscular injection of 2.4 million units of penicillin G benzathine. Penicillin-allergic patients may be treated with a 14-day course of 500 mg of tetracycline four times daily or 100 mg of doxycycline twice daily.2 Longer courses of treatment are required for tertiary syphilis. Pregnant patients with a penicillin allergy require desensitization and treatment with penicillin.
In our case, the amalgamation of clinical findings strongly suggested the diagnosis of secondary syphilis, which was confirmed by serologic testing. Our patient was sent to the Virginia Department of Health and treated with 2.4 million units of intramuscular penicillin G benzathine. The Health Department also communicated with at-risk contacts.
Cutaneous reactions are the most common type of adverse drug event. Among hospitalized patients receiving medications, it is estimated that 2.2% develop a cutaneous drug reaction.5
The morphology, timing, and prognosis of these cutaneous reactions are highly variable and are, in large part, dependent upon the type of immunologic reaction produced. The most common drug eruption is due to a type IV hypersensitivity reaction and presents as the classic morbilliform eruption with generalized pruritic erythematous macules and papules. Less-common reactions include urticaria and angioedema, due to a type I hypersensitivity reaction; these may be mild or life threatening. Other potentially life-threatening reactions include the poorly understood Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis, which represents a disease spectrum that is determined by the percentage of detached body surface area.6 Other cutaneous reactions are typically less serious and include erythema multiforme, drug hypersensitivity reactions, and fixed drug eruption (FDEs).
In the 1980s, 94% of reported cutaneous reactions were morbilliform rashes and 5% were urticarial.5 Historically, FDEs were rarely described, which may have been due to either a lower incidence or lower level of awareness of the condition. Since then, the reported incidence has dramatically increased; FDE is now estimated to be either the second or third highest category of drug-related cutaneous reaction, representing 9% to 22% of total reactions.7 A variety of drugs have been implicated, but more commonly reported culprits include nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics, particularly sulfamethoxazole/trimethoprim and tetracycline.8
A FDE has multiple unique clinical characteristics that can make it a readily diagnosable condition. The original outbreak typically follows the use of the culprit medication, occurring approximately 1 to 2 weeks later. The primary lesion is a mildly symptomatic, erythematous to violaceous, circular plaque that is usually 1 to 3 cm in diameter. Residual hyperpigmentation persists after inflammation of the lesion resolves. With re-exposure to the same medication, the same location will again become inflamed; the inclusion of the word fixed in the term describes this predilection for recurrence in the exact fixed anatomic site.6 Subsequent exposures often lead to recurrence within 24 to 48 hours, and to the development of additional lesions. FDE can affect any part of the body, but frequently affects the lips, genitalia, and extremities. Over time, with multiple exposures, numerous sites can develop; rarely does the outbreak become generalized. The majority of patients do not have associated symptoms, but localized pruritus occurs in 24% of FDE cases and pain occurs in 3.8%.8
The pathogenesis of FDE is hypothetically due to a localized increased concentration of intraepidermal CD8+ T-effector memory (TEM) cells that were primed during the initial outbreak. These cells are quiescent between exposures, but upon reintroduction of the culprit drug, the TEM cells are activated, release large amounts of interferon γ and cytotoxic granules, and cause keratinocyte destruction and the resultant repeat inflammatory reaction.9
Although the classic clinical course makes this diagnosis relatively straightforward, one must be familiar with FDE and distinguish it from other dermatologic conditions to make the correct diagnosis. Recurrent outbreaks of herpes simplex virus infection often result in a postinflammatory hyperpigmented patch, but these outbreaks are typically more symptomatic, associated with blister development, and have a scalloped border. Annular lesions of erythema multiforme and SJS often have a morphologic pattern similar to that of FDE; however, patients with erythema multiforme and SJS typically have innumerable lesions, not just a few, and typically appear ill. Finally, any inflammatory dermatosis may lead to a postinflammatory hyperpigmentation that may be confused with FDE, including lichen planus, contact dermatitis, and annular syphilids.
The diagnosis of FDE is largely clinical; biopsy results will support the diagnosis of FDE but will not identify the etiologic agent. A biopsy may be necessary to exclude other diagnoses. Although a patient’s medication history may be enlightening, it could be difficult to discern the specific culprit in the setting of polypharmacy. An oral rechallenge is usually diagnostic but not always possible or wise. Recently, patch testing has been useful in determining the culprit in certain cases with minimal risk to the patient. Lesional patch testing identified the offending drug in 40% of the patients tested. Unfortunately, this patch testing is only available in certain centers, but this same study demonstrated NSAIDs to be the most likely group of drugs to cause FDE.10
Once the diagnosis of FDE is established and the culprit drug suspected, the key to management is avoidance of the offending agent. Patient education of generic/trade names of the offending drug and the possibility of cross reactivity, especially among NSAIDs, should be stressed. Lesional symptoms such as itching and swelling can be treated with oral antihistamines and topical corticosteroids. In general, no treatment is required because the natural history of this eruption is generally benign and self-limiting. Reassurance should be given that with time, the symptoms and hyperpigmentation will resolve. If necessary, one could try a bleaching agent such as hydroquinone, although the effects may be slow and minimal.
In our case, the patient was diagnosed with FDE due to naproxen use. She was advised to avoid this class of NSAIDs. Fortunately, she could tolerate ibuprofen, and there was no recurrence of the eruption. Over time, the residual hyperpigmentation faded and she was lost to dermatologic follow-up.
Sergey Rekhtman is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.
- Patton ME, Su JR, Nelson R, Weinstock H; Centers for Disease Control and Prevention (CDC). Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63(18):402-406.
- Scaling papules, plaques, and patches. In: Marks JG, Miller JJ, eds. Lookingbill & Marks’ Principles of Dermatology. 5th ed. New York, NY: Elsevier Saunders; 2013:123-125.
- Chapel TA. The signs and symptoms of secondary syphilis. Sex Transm Dis. 1980;7(4):161-164.
- Pournaras CC, Masouye I, Piletta P, et al. Extensive annular verrucous late secondary syphilis. Br J Dermatol. 2005;152(6):1343-1345.
- Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA. 1986;256(24):3358-3363.
- Specialized erythema. In: Marks JG, Miller JJ, eds. Lookingbill & Marks’ Principles of Dermatology. 5th ed. New York, NY: Elsevier Saunders; 2013:208-211.
- Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol. 2000;1(5):277-285.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37(11):833-838.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158(6):1230-1238.
- Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions—a 20-year review. Contact Dermatitis. 2011;65(4):195-201.