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A 60-year-old Black woman presents with a 30-day history of a nonitchy rash. The rash is located on her face, trunk, and extremities. She reports that she has tried topical steroids on the rash, which did not help. The patient has no other medical conditions and takes no medications. She notes that she had unprotected sex with a new partner about 4 months prior to presentation. On physical examination, the patient has many scattered erythematous scaly papules on her face, abdomen, back, and upper and lower extremities including the palms and soles.
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Syphilis is an infection from exposure to the bacterium Treponema pallidum that spreads through sexual transmission or vertically from mother to baby. The only known natural host of T pallidum is humans, affecting 16% to 30% of individuals who have had sexual contact with a syphilis-infected person within the last 30 days.1 The bacterium can inoculate intact mucous membranes or microabrasions leading to anogenital ulcer and then spread to the regional lymph nodes and are carried in the blood to other parts of the body.2
Throughout the centuries, sexually transmitted diseases (STDs) were seen as a single disease. However, Ricord helped differentiate syphilis from gonorrhea in an 1831 study. The discovery of the etiologic agent of syphilis around 1905 by Schaudinn and Hoffman further helped identify syphilis as its own separate disease. The use of dark-field microscopy and serologic tests for the diagnosis of syphilis were introduced in the early 1990s.3
Due to its wide-ranging manifestations, syphilis has been broken down into 3 distinct stages. Primary syphilis presents as a single chancre at the site of inoculation. Chancre appearance begins about 3 weeks after exposure with an incubation period of 10 to 90 days. As the disease progresses, T pallidum spreads to other tissues and manifests as secondary syphilis around 3 months after initial infection. Most commonly, secondary syphilis presents as a disseminated mucocutaneous rash and maculopapular lesions in 50% to 70% of patients. In about 10% of patients, secondary lesions are accompanied by condylomata lata, highly infectious lesions favoring warm and moist areas of the body.1,2 After healing of clinical lesions, patients enter the latency stage, which is characterized by positive serologic tests in the absence of symptoms. Approximately 70% of untreated individuals will remain in latency for the rest of their lives.4 Clinical manifestations of tertiary syphilis may appear 20 to 40 years after initial infection and include gummas (localized bone destruction), cardiovascular syphilis (aortic insufficiency or aneurysm), and neurosyphilis.1,2
Syphilis affected 129,813 individuals in 2019, which represents a 74% increase from 2015. Of the 30,644 cases in 2017, 88% occurred in men with 58% of overall cases occurring in men who have sex with men. Syphilis rates have increased among women every year since 2003 and in every age group. Primary and secondary syphilis disproportionately affects Black men and women and Hispanic men.5 From 2012 to 2016, the rates of congenital syphilis increased by 86.9%, from 8.4 cases in 2012 to 15.7 cases per 100,000 live births in 2016.6
To initiate infection, T pallidum uses proteins such as TP0155 and TP0483 to bind matrix fibronectin and adhere to epithelial cells. The protein TP0751 also strategically uses its zinc-dependent protease domain to degrade laminin and fibrinogen. T pallidum moves through tight junctions between endothelial cells to enter the perivascular space. T pallidum also induces the production of matrix metalloproteinase-1 (MMP-1), which promotes the breakdown of collagen and facilitates systemic spread in secondary syphilis by allowing T pallidum to move to and from the bloodstream and penetrate tissues. Endothelial cells, dendritic cells, and macrophages recognize the lipid moiety by toll-like receptors on the cell surface and promote an immune response.1,7
The clinical presentation of primary syphilis includes an anogenital chancre that is typically indurated and painless and is accompanied by enlarged regional lymph nodes. However, atypical presentations can also occur as soft, multiple, or painful lesions, and lesions may occur in other sites such as the lip or fingers. The primary chancre may not be recognized by the patient.2,4 In terms of exposure site, heterosexual men experience syphilis most commonly on the penis, homosexual men are more likely to experience syphilis on the rectum and anal canal, and women develop syphilis typically on the labia or cervix.1
In secondary syphilis, a generalized rash, generalized lymphadenopathy, and condylomata lata are common clinical findings. Systemic symptoms include sore throat, muscle aches, malaise, low-grade fever, and weight loss. The rash of secondary syphilis consists of scaly, nonpruritic, macules or papules that vary from pink to violaceous to red-brown in color.The exanthem is distributed on the trunk and extremities with the palms and soles involved in 40% to 80% of cases.2,4,5 Less common presentations of secondary syphilis include patchy alopecia, split papules at the oral commissure, granulomatous nodules and plaques, uveitis, retinitis, and hepatosplenomegaly.2,4
The most sensitive and specific test for diagnosis of primary syphilis is dark-field microscopy of fluid from the chancre. Antibodies to cardiolipin can be measured with the rapid plasma regain (RPR) or Venereal Disease Research Laboratory (VDRL) assay, and these antibodies are present in about 80% of patients with clinical symptoms of primary syphilis. Antibodies to T palladium are detected via microhemagglutination T pallidum (MHA-TP) and fluorescent treponemal-antibody absorption (FTA-ABS) assays. These assays are positive in approximately 90% of patients with symptoms of primary syphilis and remain positive for life; therefore, dark-field microscopy is required to differentiate between primary syphilis and an earlier infection. Secondary syphilis is diagnosed via dark-field microscopic examination of serous exudates from lesions of skin and mucous membranes (except those of the oral cavity) and via antibody serologic tests.4
The histopathologic features of secondary syphilis demonstrate extensive variability. The epidermis may be normal, psoriasiform, ulcerated, or necrotic. The dermis contains infiltrates of plasma cells, histiocytes, and lymphocytes; these infiltrates may be perivascular, nodular, lichenoid, or diffuse. Dilated blood vessels and vascular proliferation may also be present.4,8 In a review of 106 cases of secondary syphilis, the most common histologic features were endothelial swelling, interstitial inflammatory pattern, irregular acanthosis, and elongated slender rete ridges.9
The diverse histologic and clinical presentations of secondary syphilis have led to the nickname the great masquerader because symptoms can mimic those of other conditions. As a result, there are many conditions to consider in the differential diagnosis of syphilis such as alopecia areata, bullous pemphigoid, cutaneous lymphoid hyperplasia, granuloma annulare, histiocytoma, mycosis fungoides, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta (PLEVA), eczematous dermatoses, sarcoidosis, vasculitis, leprosy, lichen planus, and lupus erythematosus.8 Differential diagnosis of a truncal rash should include acute HIV infection, viral exanthems, pityriasis rosea, drug eruption, and psoriasis. In addition, clinicians should eliminate erythema multiforme; hand, foot, and mouth disease; and Rocky Mountain spotted fever for a palmoplantar rash. 5
Treatment guidelines from the World Health Organization (WHO), Europe, United States, and United Kingdom recommend penicillin as the drug of choice for syphilis.1,2 For early syphilis (which includes primary, secondary, and early latent syphilis acquired <1 year previously), penicillin should be administered as intramuscular benzathine penicillin 2.4 million units as a single dose.2,4 An alternative treatment for individuals allergic to penicillin includes oral doxycycline, tetracycline, ceftriaxone, or azithromycin.2 However, a rise in the prevalence of macrolide-resistant T pallidum has occurred as a result of increased usage of azithromycin.1,7 Patients with early syphilis who are pregnant require 2 doses of weekly intramuscular benzathine penicillin 2.4 million units. While patients with concurrent HIV infections are at higher risk for neurologic involvement and treatment failure, there is no evidence for alteration of treatment regimens to prevent these outcomes.2,4 All patients diagnosed with syphilis should also be tested for HIV infection. Patients with ocular symptoms should be assessed for uveitis and neuroretinitis.4
The patient in this case had a positive RPR; a punch biopsy of her rash further confirmed a diagnosis of secondary syphilis. She was treated with 1 dose of intramuscular benzathine penicillin 2.4 million units.
Sarah K. Friske, BBA, is a medical student at Baylor College of Medicine in Houston, Texas; Tara L. Braun, MD, is a resident physician at Baylor College of Medicine.
References
1. Lafond RE, Lukehart SA. Biological basis for syphilis. Clin Microbiol Rev. 2006;19(1):29-49. doi:10.1128/CMR.19.1.29-49.2006
2. Goh BT. Syphilis in adults. Sex Transm Infect. 2005;81(6):448-452. doi:10.1136/sti.2005.015875
3. Tampa M, Sarbu I, Matei C, Benea V, Georgescu SR. Brief history of syphilis.J Med Life. 2014;7(1):4-10.
4. Stary G, Stary A. Sexually transmitted infections. In: Dermatology. Bolognia J, ed. Elsevier Limited; 2018:1447-1469.
5. Forrestel AK, Kovarik CL, Katz KA. Sexually acquired syphilis: laboratory diagnosis, management, and prevention. J Am Acad Dermatol. 2020;82(1):17-28. doi:10.1016/j.jaad.2019.02.074
6. Rowe CR, Newberry SM, Jnah AJ. Congenital syphilis: a discussion of epidemiology, diagnosis, management, and nurses’ role in early identification and treatment. Adv Neonatal Care. 2018;18(6):438-445. doi:10.1097/ANC.0000000000000534
7. Ho EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011;121(12):4584-4592. doi:10.1172/JCI57173
8. Carlson JA, Dabiri G, Cribier B, Sell S. The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. Am J Dermatopathol. 2011;33(5):433-460. doi:10.1097/DAD.0b013e3181e8b587
9. Flamm A, Parikh K, Xie Q, Kwon EJ, Elston DM. Histologic features of secondary syphilis: a multicenter retrospective review. J Am Acad Dermatol. 2015;73(6):1025-1030. doi:10.1016/j.jaad.2015.08.062
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