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The initial lesions of EAC begin as firm pink papules that expand centrifugally and then develop central clearing. An individual lesion can enlarge to greater than 6 cm in diameter over a period of 1 to 2 weeks.

If expansion of the annular plaque is not uniform, incomplete arcs appear, as do polycyclic lesions, or simply festooned bands. In the superficial form, the lesions are minimally elevated, and there is desquamation at the inner margin, i.e. trailing scale (Fig. 19.1A,B). The scale may not be present in all the lesions in a particular patient (Fig. 19.2A). There may be associated pruritus, especially in lesions that histologically show spongiosis. Occasionally, vesicles develop within the peripheral margin. In deep gyrate erythema, the advancing edge sare obviously elevated (Fig. 19.1C) and there is usually no associated
scale or pruritus.

As lesions resolve, there is no residual scarring, but postinflammatory hyperpigmentation can be seen and, on occasion, purpura. Although the lesions of EAC may be localized or generalized, they rarely, if ever, involve the palms, soles, scalp or mucous membranes. Individual lesions can persist for weeks to months, but associated systemic manifestations are uncommon. While new lesions can appear just as older ones resolve, there may be prolonged intervals of time between flares. The total duration of the disorder ranges from days to decades2, and
an unusual form of EAC has been described that recurs annually.

When EAC is due to an underlying disorder, flares of the former may correlate with recurrences of the latter. However, most patients with EAC do not have an identifiable underlying disorder, nor can the onset, fluctuations, or duration be related to a specific antigen.
The mechanisms that underlie the appearance of cutaneous lesions of erythema marginatum are unknown. Presumably, there is an abnormal humoral and cellular immune response to one or more antigens associated with group A β-hemolytic streptococci (e.g. M protein). Antigenic mimicry may play a role in that epitopes that cross-react with group A streptococcal antigens have been identified in human myosin, actin, tropomyosin, keratin, laminin, N-acetylglucosamine, and vimentin. Specific characteristics of certain strains of group A β-hemolytic streptococci, such as higher M protein content and mucoid colony formation, may facilitate the development of acute RF. Enhanced expression of genes that encode cysteine proteases (e.g. Streptococcus pyogenes exotoxin B [SpeB], immunoglobulin G degrading enzyme of Str. pyogenes [IdeS]) is also thought to be related to cardiotoxicity and virulence

Clinical Features:
- Following the initial streptococcal pharyngitis, there is usually a latency period of 2-5 weeks before the development of the acute attack of RF. The lesions of erythema marginatum begin as erythematous macules that spread peripherally and become patches or plaques with no scale. Erythema marginatum can also have a polycyclic arrangement. The lesions are usually asymptomatic, and, over a period of 12 hours, they can migrate from 2-12 mm; in areas of previous involvement,
the skin may appear pale or lightly pigmented15. As with other erythemas, exposure to heat can accentuate lesions. The most common locations for erythema marginatum are the trunk, axillae and proximal extremities, with sparing of the face. New
lesions usually last from a few hours to a few days and are often most noticeable during the afternoon. Recurrent crops can occur over a number of weeks. Erythema marginatum is associated primarily with the active phase of RF, and, in general, it is seen in conjunction with the carditis. Of note, children less than 5 years of age appear to have a higher incidence of erythema marginatum as well as carditis and arthritis
- An interstitial and perivascular infiltrate composed predominantly of neutrophils without vasculitis is observed. Occasionally, eosinophils are seen and in later stages, there can be extravasation of erythrocytes. Direct immunofluorescence microscopy for immunoglobulin and complement deposits is negative. These histologic findings are not unique to erythema marginatum, and overlapping features with the neutrophilic variant of annular erythema of infancy (neutrophilic figurate erythema of infancy) may be observed

- The differential diagnosis includes primarily annular urticaria (e.g. urticaria multiforme) and annular erythema of infancy (Fig. 19.4) as well as its variant neutrophilic figurate erythema of infancy21. Less often, Still disease, hereditary periodic fever syndromes (particularly TNF receptor-associated periodic syndrome [TRAPS]; see Table 45.2), EAC, Kawasaki disease, and other entities listed in Table 19.1 need to be considered. There is also an annular erythema with an appearance similar to erythema marginatum that precedes or accompanies episodes of hereditary angioedema22 and is seen only occasionally in patients with cat scratch disease or psittacosis23,24. The angioedema-associated figurate erythema may be related to deposits of bradykinin within the dermis while the latter may reflect an overlap between erythema marginatum and EAC.
In a patient receiving sorafenib, figurate lesions with associated scale-crust and hemorrhage developed and the name "erythema marginatum hemorrhagicum" was proposed, but clinically these lesions can easily be distinguished from erythema marginatum
In mice, B. burgdorferi has been shown to usurp a tick salivary protein, Salp15, as a means of enhancing transmission29. By binding to the outer surface protein C (OspC) of B. burgdorferi, Salp15 provides protection against antibody-mediated killing. In addition, Salp15 inhibits adaptive immune responses against both Borrelia and tick antigens30. Of note, one of the strategies for preventing LD in the future is the development of anti-tick vaccines that utilize tick salivary proteins.

Once the Borrelia organisms have entered the body, spirochetal lipoproteins trigger an innate immune response, with cytokines being produced by macrophages31. In addition, a Th1 response is triggered and B-cell responses facilitate the synthesis of antibodies against different antigens of B. burgdorferi. Spirochetemia is present in approximately 45% of patients at the time of their presentation with erythema migrans32, and these organisms can disseminate widely due to their ability to resist elimination by macrophages, adhere to brain and epithelial cells, penetrate into the cytoplasm via intracellular junctions, and induce TNF-α production33. Even though the lesion expands centrifugally, B. burgdorferi organisms have been found both in the center and at the periphery of lesions of erythema migrans. The persistence of the spirochete in the skin after
the tick bite may be due to an absence of the production of interferon-γ and an ineffective immune response31. Also, different immune responses to the various genospecies of the B. burgdorferi sensu lato complex (B. burgdorferi sensu stricto, B. afzelii, B. garinii) may lead to different clinical presentations34 (e.g. borrelial lymphocytoma in Europe but not the US; see Ch. 74). More recently, an additional genospecies was identified in the upper midwestern US, candidatus B. mayonii, which may lead to a more severe clinical presentation due to an unusually
high spirochetemia
LD is divided into three clinical stages: (1) early localized disease; (2) early disseminated disease; and (3) chronic disease

Erythema migrans is an important clinical feature of early disease. Typically, 7-15 days (range, 3-30 days) after tick detachment, an erythematous, expanding, circular or annular plaque appears that may have a lighter-colored central area or a bull's-eye appearance (Fig. 19.5). The eventual diameter is usually at least 5 cm, and the center may become darker red to violaceous in color, crusted, or even vesicular. Lesions of primary erythema migrans favor the trunk, axilla, groin and popliteal fossa. Untreated, the lesions usually last less than 6 weeks
(median, 4 weeks). In 20-25% of patients, multiple lesions can appear due to multiple tick bites or as a result of disseminated disease secondary to spirochetemia. Disseminated lesions tend to be smaller in size and less pronounced and usually appear days to weeks after the appearance of the primary erythema migrans (Fig. 19.6)35. Erythema migrans is seen in 60-90% of patients diagnosed with LD.

In the US, the systemic manifestations of this initial phase tend to be acute, with influenza-like symptoms, including fatigue, headache, arthralgias, myalgias and fever, as well as lymphadenopathy, conjunctivitis or hepatitis (see Table 19.2)36. In Europe, this initial clinical phase is usually less severe, and the lesions of erythema migrans tend to last longer. If untreated, approximately 60% will go on to have monoarticular
or oligoarticular arthritis (usually the knee) within weeks to months after the initial infection; approximately 10%, a neurologic manifestation (most commonly facial nerve palsy); and approximately 5%, a cardiac complication (usually varying degrees of atrioventricular block)32. For a discussion of borrelial lymphocytoma and acrodermatitis chronica atrophicans.. Depending upon the geographic region, Ixodes ticks can be co-infected with the following microbes (in addition to B. burgdorferi): Babesia microti (babesiosis), Anaplasma phagocytophilum (human [granulocytic] anaplasmosis), Borrelia miyamotoi, or Powassan virus. Co-infections should be considered when patients with LD have prolonged
or severe manifestations of infection, cytopenias, or an unusually high or persistent fever27.
Clinical Features
- Patients usually have multiple, annular or polycyclic, erythematous lesions that develop scale at their edges and advance at a rapid rate (up to 1 cm per day)47. This rate of peripheral spread is significantly faster than that of EAC. Lesions have a wood-grain or zebra-like pattern, due to the development of "rings within rings" (Fig. 19.8). In some patients, the eruption is also pruritic. Additional findings in patients with EGR include acquired ichthyosis, palmoplantar keratoderma, and hypereosinophilia.
In at least 70% of patients, EGR is associated with an underlying neoplasm, most commonly of the lung then breast, esophagus or stomach48. The cutaneous lesions usually develop from 1 year prior to 1 year after the diagnosis of the neoplasm. EGR may coincide with underlying pulmonary tuberculosis, and patients with other disorders (see below) can also have EGR-like lesions. Occasionally, no underlying disorder or malignancy can be identified.

- The histopathologic findings are nonspecific and include hyperkeratosis, focal parakeratosis, moderate patchy spongiosis and a mild, perivascular lymphohistiocytic infiltrate. In some cases, eosinophils and melanophages are seen in the dermis. By immunoelectron microscopy, DIF-detected immune deposits of IgG at the BMZ (see Pathogenesis) were shown in one patient to be beneath the lamina densa45. In addition, anti-EGF receptor, anti-vimentin and anti-α-actin staining was more intense in lesional skin and tumor tissue than in controls. Nevertheless, the meaning of these findings is unknown, given their anecdotal nature, and DIF is not required for confirmation of the diagnosis.