The typical presentation of an erythema migrans (EM) rash manifests after the third day of infection, primarily occurring at the tick bite site and expanding outward as the condition progresses. EM rash typically lacks characteristics such as heat, itching, or elevation and does not typically respond to antihistamines or antifungal creams. The rash may take on circular or oval shapes but can also exhibit a blotchy appearance, varying in coloration from red, blue, and/or purple, with occasional yellowing. (5) A classic manifestation is a "ring-within-a-ring" or a "bull's eye" lesion. The first case described a single classical skin lesion (resembling a "Bull's eye").

When a patient presents with a slowly expanding, annular, erythematous skin lesion during the summer months, along with a potential risk of Lyme borreliosis due to exposure to ixodid ticks, current guidelines advise clinicians to make a clinical diagnosis of EM rather than immediately pursuing Lyme borreliosis diagnostic tests. This approach is preferred due to the lower sensitivity of antibody-based blood tests in the acute phase of the illness. Direct detection through culture or PCR necessitates a skin biopsy and specialized laboratory procedures, typically only available in research settings. Serological testing carries a high risk of producing false-negative results, especially within the first week of infection, while false-positive results are more commonly associated with IgM antibodies, which can also appear in individuals suffering from other bacterial or non-infectious diseases. (6,7)

In diagnosing early Lyme disease, the primary criteria rely on visual identification of EM, associated symptoms, the patient's history of tick exposure, and the epidemiologic risk. The absence of a standardized appearance may lead to misdiagnosis. Distinguishing erythema migrans from conditions like cellulitis, herpes simplex or herpes zoster, mycosis fungoides, granuloma annulare, interstitial granulomatous dermatitis (IGD), tinea corporis (mini-EM), discoid (nummular) eczema, urticaria, erythema multiforme, and erythema necroticans migrants is reliant on the expertise of clinicians. (8)

Numerous erythema migrans lesions are relatively uncommon but suggest infection dissemination. The second case described such a presentation. Multiple erythema migrans lesions are smaller than the original ones and exhibit uniform discoloration. Skin changes associated with erythema migrans can be accompanied by systemic symptoms, including fever, muscle and joint pain, headache, and, occasionally, meningeal signs and lymph node enlargement.

The fields of molecular biology and biochemistry significantly contribute to our understanding of the structure and function of micro and macro-organisms and intracellular regulatory processes. This knowledge of the molecular mechanisms of disease development is crucial for accurate diagnosis and the effective targeting of new therapeutic agents.
The pathogenicity of Borrelia burgdorferi hinges on several factors, including the spirochete's motility, cytotoxicity, antigenic variability, lymphocyte stimulation, and the spirochetes' resistance to complement activation in the absence of specific antibodies. (1) The interaction of spirochetes with glycosaminoglycans, such as heparin, heparan sulfate (facilitating endothelial cell fusion), and dermatan sulfate (enabling fusion with glial cells), plays a pivotal role. Bacterial lipoproteins located on the membrane recognize host skin proteoglycan decorin. The outer membrane contains high-density outer-surface lipoproteins (Osps) and low-density β-barrel outer-membrane-spanning proteins like BamA. The inner membrane consists of integral membrane proteins, many of which function as transporters. Researchers have recently identified tick salivary proteins that contribute to pathogen transmission. This inflammatory response results in the hallmark skin lesion, erythema migrans, during the initial days of infection, characterized by papillary dermal edema and a mixed infiltrate predominantly consisting of T cells, neutrophils, dendritic cells, and monocytes or macrophages. Cytokine expression during this stage is predominantly pro-inflammatory, marked by elevated tumor necrosis factor (TNF), IL-2, IL-6, and type I interferons (IFNs). Chemokines attracting neutrophils (e.g., CXC-chemokine ligand 1, CXCL1), macrophages (e.g., CC-chemokine ligand 3, CCL3, and CCL4), and T cells (e.g., CXCL9, CXCL10, and CXCL11) are also increased in erythema migrans lesions. (9)

Borrelia burgdorferi inhibits phagocytosis, and phagocytosed spirochetes are removed from the host through oxygen-dependent and independent processes. Oxygen-dependent processes involve reactive oxygen and nitrogen species, such as hydrogen peroxide (H2O2), singlet oxygen, and halogenated derivatives. In contrast, oxygen-independent processes rely on hydrolases like proteases and glycosidases located in the lysosomes of phagocytes. (1)