Late and rare skin manifestations of Lyme disease

Lyme disease, caused by certain members of the Borrelia burgdorferi sensu lato complex – mainly B. afzelii and B. garinii in Europe – can be associated with a variety of skin symptoms that indicate different stages of the disease. Although the most well-known manifestation of the early phase is erythema migrans, the late and rarer skin manifestations of Lyme borreliosis, such as borrelia lymphocytoma and acrodermatitis chronica atrophicans, are equally important for the recognition and diagnosis of the disease.

Borreliosis lymphocytoma is a B-cell pseudolymphoma that develops as a skin reaction to the presence of Borrelia burgdorferi sensu lato (Bbsl) antigens. Borrelia is the most common cause of this type of lymphoproliferative reaction in Europe.

Borreliosis lymphocytoma (BL) is a characteristic skin lesion that occurs primarily in children. It may precede or accompany erythema migrans. Clinically, it presents as a painless, sharply edged, bluish-red nodule or plaque, most commonly on the earlobe or scrotum in children, and around the nipple or in the anterior axillary fold in adults. It is 1-5 cm in size and its surface is often slightly indented. It may appear at the site of a previous EM or together with EM, accompanied by regional lymph node enlargement. This lesion appears subacutely and accounts for approximately 5% of skin symptoms in Lyme borreliosis. The history of tick bites is even less frequently positive than in erythema migrans (especially in children), and the incubation period may be longer. The histological picture shows diffuse, perivascular and periadnexal lymphocytic infiltrates, often with germinal centres dominated by CD20-positive B cells, but CD3-positive T cells and plasma cells are also present. The diagnosis of Borrelia lymphocytoma cannot be made on clinical grounds alone; the presence of the pathogen should be confirmed by direct testing methods whenever possible.

Differential diagnoses include insect bite reaction, cutaneous lymphoma, foreign body granuloma, sarcoidosis, skin metastasis, keloid, perichondritis, granuloma faciale, granulomatous contact dermatitis, and Paget’s disease.

Acrodermatitis chronica atrophicans (ACA) is a skin symptom characteristic of the chronic, late stage of Lyme borreliosis, which occurs almost exclusively in Europe, mainly in older women. In less than 10-20% of patients, it occurred in the same area of the body where erythema migrans had occurred months or years earlier. It mainly develops over the large joints and distal parts of the limbs, but can also appear on the face and trunk. The disease develops gradually. In the early stages, it is characterised by oedematous skin swelling accompanied by mild erythema. Thread-like erythema may also develop on the limbs, e.g. ulnar striations on the forearms and tibial striations on the lower legs. As there are usually no subjective symptoms in this phase, early ACA (stage 1 borreliosis) often goes unnoticed. In the later stage 2, the skin becomes thin, atrophied and wrinkled, the bones protrude on the back of the hands and the blood vessels are visible through the skin, and telangiectasia, varicose veins and pigmentation disorders are common.

In the initial stage of ACA, histologically it can be described as a band-like lymphohistiocytic infiltrate, which is found in the superficial dermis and around dilated blood vessels and has a significant plasma cell content. This condition progresses to an atrophic stage, characterised by swelling, homogenisation and then degeneration of collagen and elastic fibres. This stage helps to distinguish ACA from systemic scleroderma, in which the elastic fibres are not damaged. The disease is often associated with peripheral neuropathy, which is mainly observed in the form of allodynia. The presence of high-titre anti-Borrelia IgG may be important information for diagnosis, but positive IgM is only detected in about a quarter of cases, so a definitive diagnosis always requires direct testing, if available.

The diagnosis of ACA is clinically missed in 80% of cases and often goes unrecognised for months or years. The spectrum of differential diagnoses is very broad and depends on the stage of the disease. It is most commonly confused with chronic venous insufficiency (21%). In addition, it can be misdiagnosed as deep vein thrombosis, superficial thrombophlebitis, arterial vascular disease, acrocyanosis, livedo reticularis, lymphoedema, frostbite, ageing skin, erysipelas, erysipeloid, bursitis/arthritis, or morphea. It is important to note that among the co-infections of Lyme disease, Bartonella may also contribute to the destruction of the deeper layers of the skin and damage to elastic fibres, so it is conceivable that the clinical picture may not only show symptoms of Borrelia infection.

Lyme borreliosis can cause skin symptoms at all stages of the disease. In addition to those mentioned above, the skin diseases most commonly associated with Lyme disease are as follows:

At the onset of the disease, a patchy lesion is observed, accompanied by mild, radially spreading inflammatory redness (erythema). This phenomenon may appear in isolation or in groups. The erythema gradually disappears in the central area, replaced by a disc-shaped, ivory-coloured, hardened area surrounded by a bluish-purple, violet-coloured ring. In the late phase, atrophy develops: dirty grey-brown hyperpigmentation can be observed at the edges, while the central part is usually hypopigmented. In this phase, hair loss and sebaceous gland loss may also occur. Morphea most commonly occurs on the trunk, less frequently on the limbs. The lesions may be scattered, but they can merge into patches and even become generalised, in which case they are difficult to distinguish from systemic scleroderma.

At the onset of the disease, small, round or oval atrophic lesions ranging in colour from porcelain to bluish-white are observed, which later merge into irregularly shaped, larger areas. Fine, parchment-like folds develop on the surface of older lesions, with follicular hyperkeratosis and conical papules. The most common sites of LSA in women and men are: the sides of the neck, shoulders, flexor surfaces of the forearms, submammary region, anal and perianal areas, and the genitals.

According to a study published in a scientific article, the Borrelia burgdorferi sensu lato bacterium was detected in 63% of patients with LSA. The frequency of detection was significantly higher in the initial inflammatory phase of LSA (80%) than in the late atrophic phase (33.3%).

Irregularly shaped, sharply defined, disc-like, atrophic plaques appear, covered with telangiectasias. The central part is yellowish-brownish-reddish-yellow in colour, sclerotic and hard. Several foci may merge. In approximately 30% of cases, ulcers develop that are difficult to heal, with a yellowish, greasy, necrotic base and dense edges. During healing, skin atrophy and loss of skin appendages can be observed.

In one study, Borrelia was detected in 75% (42/56) of the NL patients examined with FFM. In cases of more severe inflammation, the pathogen was found in 92.7% (38/41) of cases, while in the atrophic, non-inflammatory phase, it was found in only 26.7% (4/15) of cases.

Small, sharply defined, slightly reddish, slightly shiny papules appear. As they grow, they form arc- or ring-shaped lesions, with a depression in the centre. Secondary lesions, such as erosions and ulcers, may also develop. Common locations: back of the hands and feet, finger joints, elbows, knees, buttocks. We distinguish between erythematosus, subcutaneous, disseminated, perforating and plaque types. The presence of anti-Borrelia antibodies in GA was reported as early as 1987.

It is characterised by reddish-yellow, brownish papules, annular plaques, scars and telangiectasias, mainly around the eyes, but it can also occur on the trunk and proximal limbs. NXG is often associated with paraproteinaemia, other tumours and lymphoproliferative diseases, and has also been described in connection with scleroderma.

In a European study, Borrelia was detected in 6 out of 7 patients (alone, in pairs or in groups). Of the positive cases, 4 were also PCR positive. However, 2 cases were negative.

The association between Lyme disease and erythema multiforme (EM) is rare but documented. EM is an acute, immune-mediated skin reaction most commonly associated with viral infections, particularly herpes simplex virus, but it can also be triggered by certain bacterial infections, including Lyme disease caused by Borrelia burgdorferi.

Several case studies have reported erythema multiforme-like skin lesions in Lyme disease patients. These lesions often appear as targetoid, livid-centred, erythematous maculopapules on the trunk and extremities. The occurrence of EM in Lyme disease is probably not a direct spirochete-induced reaction, but a secondary immunological response to the infection.

For example, in a case study of a 50-year-old man, the appearance of erythema multiforme was preceded by a mild feverish episode and a reported previous tick bite. The Borrelia antibody titre was high (1:8192), the skin biopsy showed perivascular lymphocytic infiltrate, and the symptoms responded well to doxycycline treatment – EM disappeared in the first week of treatment and the antibody level gradually decreased. No spirochetes were detected by Steiner staining, and the histological picture was not specific but could be related to EM.

Although EM is not a classic skin symptom of Lyme disease – unlike erythema migrans, borrelia lymphocytoma or acrodermatitis chronica atrophicans – it can occur in certain cases and should be considered as an important differential diagnosis.

Overall, the skin manifestations of Lyme disease are of significant diagnostic value, especially those that appear in the late stages, such as borrelia lymphocytoma and ACA. To make an accurate diagnosis, it is essential to combine clinical presentation, direct testing where possible, serological tests, histological analysis and, where appropriate, molecular diagnostic methods.

Dr. Klára Esztó, dermatologist, venereologist, clinical immunologist, university lecture on “Lyme borreliosis”

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