Pathophysiology and Clinical Manifestations of Secondary Syphilis: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Jorge Cervantes.

The subspecies T. pallidum pallidum is the cause of the most infamous sexually and congenitally transmitted disease, syphilis. This disease has an estimated incidence of six million infections every year. Multiple studies have noted that the prevalence of syphilis has been steadily increasing worldwide in recent decades, especially among men who have sex with men (MSMs) and HIV-positive patients. Clinically, syphilis presents in four stages with multiple different clinical manifestations.

  • secondary syphilis
  • inflammation
  • spirochetes

1. Introduction

Clinically, syphilis presents in four stages with multiple different clinical manifestations [14][1]. Each progressive stage of syphilis, apart from its latent stage, brings physiological changes to the human body. The primary and tertiary stages of syphilis have been well defined: the primary stage is generally composed of chancres in the genitals, breasts, or mucocutaneous regions, while the tertiary stage is characterized as systemic dysfunction, particularly in the cardiovascular and neurological systems. The secondary stage of syphilis is commonly mistaken for other diseases due to its clinical presentation and its high rate of coinfection with HIV [15,16][2][3]. The presentation of secondary syphilis (SS) as a maculopapular rash may include differential diagnoses or misdiagnoses, such as Rocky Mountain spotted fever, while oral lesions may be misdiagnosed as herpes; both differential diagnoses are viruses with completely different treatment methodologies [17][4].

2. Pathogenesis of Secondary Syphilis

SS is a stage of the disease with the most exuberant local and systemic clinical manifestations [14,18][1][5]. The basis of the pathogenesis of SS underscores the unique mechanisms by which Treponema pallidum utilizes to escape immune recognition while simultaneously induces inflammation. T. pallidum utilizes adherence mechanisms to bind to epithelia and underlying fibronectin, as well as laminin; after dissemination through the bloodstream, the spirochete invades tissues via inter-junctional penetration [19[6][7],20], which allows it to escape to the skin. In secondary syphilis, spirochetes are found within the epidermis and superficial dermis [21][8].
The clinical manifestations of SS result from the local inflammatory response elicited by syphilis spirochetes replicating within tissues [20][7]. The most common clinical manifestation of secondary syphilis is a disseminated cutaneous eruption [19][6]. As soon as these spirochetes reach a sufficient density in the skin, they trigger a local inflammatory response, making SS skin lesions clinically apparent [22][9]. T. pallidum provokes an intense inflammatory response in the skin, with the presence of various cytokines (IFN-γ and TNF-α), chemokines (CCL2 and CXCL10), macrophage and dendritic cell (DC) activation markers (CD40 and CD86), Fc-mediated phagocytosis receptors (FcγRI and FcγR3), and IFN-β and effector molecules associated with CD8 and NK cell cytotoxic responses [22][9]. A similar intense skin inflammatory process with activation of plasmacytoid DCs and production of type I IFN (IFN-α and IFN-β) is key to starting the development of a psoriatic plaque [23,24][10][11]. This may explain the psoriasiform appearance of SS lesions in some patients [25][12]. Although some other SS lesions present various degrees of inflammation, the vessels around these lesions typically show inflammatory proliferative changes and cellular infiltrates in their walls [25][12].
Less frequent sites of localized inflammation in SS are gastric, renal, and hepatic sites [19][6]. Ocular disease and meningitis are the manifestations of neurosyphilis, which are also infrequent in SS. Such presentations provide evidence that syphilis spirochetes are able to travel to the CSF and to the eyes, possibly through hematogenous dissemination [26][13]. Despite the overt inflammation, immune cells are inefficient in phagocytosing these spirochetes [22][9]. SS lesions take weeks to months to resolve, which is possibly linked to the unusually slow replication rate of T. pallidum. When leukocytes from the skin lesions of patients with SS are examined, there is a predominance of activated dermal plasmacytoid dendritic cells and activated CD4+ with a memory/effector phenotype [18][5].
Syphilis spirochetes not only fail to be cleared rapidly but can replicate and circulate in the midst of a prolific antibody response [20][7]. The basis of this antibody avoidance relies on these spirochetes’ molecular architecture as the antigen availability is limited, given that the outer membrane proteins are mainly attached to the inner leaflet of the outer membrane [20][7], without sufficient surface exposure. These antigens finally become available for immune recognition upon treatment, thereby explaining the development of the Jarisch–Herxheimer reaction, a transient intense inflammatory condition occurring within 24 h of antibiotic therapy [14][1].
The immune evasiveness of T. pallidum is also demonstrated by the fact that its infection does not lead to immunity against reinfection, and repeated episodes of syphilis may occur [14][1].

3. Clinical Features of Secondary Syphilis

Based on clinical features and laboratory tests, syphilis can be divided into four phases: latent, primary, secondary, and tertiary syphilis [27][14]. Among the four phases of syphilis, secondary syphilis is arguably the most crucial. Once syphilis has progressed to the secondary phase, treatment becomes vital to prevent progression into devastating tertiary syphilis.
Primary syphilis usually presents two to three weeks after the inoculation of one or multiple painless genital chancres at the site of inoculation (anal, oral, and genital), with or without local lymphadenopathy [28][15]. Its painless nature allows the genital chancres to go unnoticed and progress to secondary syphilis. In rare cases, the genital chancres may still be present with the appearance of secondary syphilis features [29][16]. SS presents four to eight weeks later and represents hematogenous dissemination of syphilis spirochetes [25][12].
Syphilis has been coined “the great imitator” based on the diverse clinical features of the secondary phase. SS can affect multiple organ systems and become more than just an STD. The most common presentation of secondary syphilis is rash, which manifests as a copper-colored maculopapular lesion on the trunk, palms, and soles. This description might not hold true in dark colored skin where rash is usually violaceous or hyperpigmented [25][12]. In such patients, skin lesions may go unnoticed, but rash in the palms and soles would still be evident. In addition, rash may vary in presentation and can erupt on the back, face, arms, legs, and genitalia. Other morphology of syphilis rash includes papulosquamous, annular, psoriasiform, pustular, and follicular lesions [30][17]. A rupiod presentation, i.e., well-demarcated, cone-shaped plaques with thick, dark, lamellate, and adherent crusts on the skin resembling oyster or limpet shells [31][18], is relatively rare. It usually manifests as skin lesions all over the body [32][19], but when confined, it can be misdiagnosed as verruca vulgaris [33][20]. Physicians are well trained to recognize the most common manifestations of rash in the palms and soles but may not be aware of the deviations from the classic presentation.
Depending on the morphology and the site of the rash, secondary syphilis may be often mistaken for other diseases. A maculopapular rash on the palms and soles can be confused for Rocky Mountain spotted fever, other rickettsioses, viral exanthem, or erythema multiforme [17,34][4][21]. If the rash is pustular and presents on the face, syphilis can masquerade as acne vulgaris [25][12]. SS lesions could also present as prominent scales that resemble psoriasis [27][14]. Other non-infectious conditions to consider are pityriasis rosea, drug eruption, lichen planus, psoriasis, and sarcoidosis [17][4].
The presence of condylomata lata may raise suspicion of secondary syphilis. Condyloma lata is a painless, flat, and well-demarcated grey-to-white plaque or papule that is usually present in the genital, perianal, or other intertriginous areas. Although condyloma lata can be diagnosed with nucleic acid amplification testing, biopsy may be needed to differentiate syphilitic condylomata lata from other lesions, such as human papillomavirus HPV-induced condyloma acuminata, malignant tumors, and genital herpes [35][22]. Biopsy shows numerous spirochetes with plasma cell infiltrate via immunostaining, making condylomata lata the most infectious skin lesions in syphilis based on the concentration of spirochetes in the exudated serum [36][23].
Oral lesions are not uncommon in SS, and the areas most affected are the mucosal surfaces of the upper and lower lips, tongues, and buccal mucosa of the cheeks [37][24]. Lesions usually present as slightly elevated oval plaques associated with a grey or white pseudomembrane. Other lesions are described as “snail track ulcers” characterized by multiple mucous patches that may coalesce to produce serpiginous lesions [38][25].
Other associated symptomatology includes lymphadenopathy, genital and oral mu- cus patches, and, less frequently, fever and alopecia [39][26]. Alopecia in syphilis usually presents as a “moth-eaten” pattern and is considered a pathognomonic manifestation of secondary syphilis. It presents in less than 10% of patients [40][27] and could be the only sign of syphilis infection [41][28]. Some patients present with diffuse alopecia or a combination of diffuse and moth-eaten patterns. Other conditions, such as alopecia areata, alopecia neoplastica, and trichotillomania, can mimic syphilis alopecia [40][27]. The presence of other cutaneous or mucosal findings can help rule out some of the other differential diagnoses.
Rare manifestations include hepatitis, hepatomegaly, splenomegaly, meningitis, peripheral neuropathy, deafness, periostitis, iridocyclitis, and arthritis [39][26]. Misdiagnosis can occur in the manifestations of neurosyphilis in tertiary syphilis and may be underreported given the lack of investigation of syphilis as a cause of uveitis or meningitis.
Ocular syphilis may present in any phase of syphilis, except in primary syphilis, and it accounts for about 5% of the cases in the United States [42][29]. The most common ocular manifestation of syphilis is uveitis, which is more common in patients with neurosyphilis and HIV infection. Panuveitis and posterior uveitis are the most common ocular manifestations [43][30]. Ocular syphilis can easily be misdiagnosed when it is the only disease manifestation, and such misdiagnosis can lead to ocular complications and blindness [44][31]. A suspicion of ocular syphilis (usually in someone with syphilis and eye symptoms) warrants an opthalmologic evaluation, where findings such as posterior placoid lesions, well-circumscribed discrete miliary lesions, and superficial creamy yellow precipitates point toward ocular syphilis [45][32]. According to the Center for Disease Control and Prevention, patients with ocular syphilis should receive a CSF evaluation and lumbar puncture. A diagnosis can be made with ocular findings and a positive treponemal test [45][32].
Syphilis hepatitis is a rare manifestation of SS, which is reported in less than 10% of patients [46][33]. Syphilis hepatitis involves hepatic dysfunction with evidence of treponemal infection. Like many forms of hepatitis, syphilis hepatitis can manifest as fatigue, icterus, abdominal pain, lymphadenopathy, arthralgia, and elevated liver enzymes (including alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyltransferase (GGT), and total bilirubin). Syphilis hepatitis is usually mild and can be asymptomatic, with only slight elevations of liver enzymes and with or without hepatomegaly [47,48][34][35]. The diagnostic criteria for syphilitic hepatitis were proposed in 2004, and they include abnormal liver enzyme levels, serological evidence of syphilis infection, exclusion of other causes of hepatitis, and normalization of liver enzymes after treatment [49][36].
Syphilitic arthritis is another rare but possible presentation of SS. It manifests as the hematogenous spread of spirochetes to the joints. The joints affected include bilateral knees, hips, shoulders, and proximal interphalangeal (PIP) joints [50][37]. Although bone and joint pain can be present in more than 12% of patients with SS [30][17], arthritis and arthralgia are seen in only 2% of patients [39][26]. Patients present with tenderness, swelling, and a restricted range of motion in the affected joints. Joint pain is usually relieved by movement and exacerbated by heat, and most patients report that pain is most severe at night [51][38]. This constellation of symptoms can be mistaken for other forms of arthritis, such as rheumatoid arthritis. Like other presentations of syphilis, evidence of treponemal infection and therapeutic response to syphilis medications support the diagnosis [50][37].
Secondary syphilis excels at disguising as other diseases, so clinicians should always have this great imitator on their radar. The goal is to commence treatment before syphilis progresses to the tertiary phase, where damage can be permanent and mortality is significant.

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