Is Localized Scleroderma Caused by Borrelia burgdorferi ?

Introduction

Scleroderma occupies an important place among systemic diseases within connective tissue. In the United States, localized scleroderma morbidity effects 500 per 1,000,000 people under the age of 18. Women suffer 2.6 times more often than men, and children and teenagers constitute 20% of cases (Mayes 1998, Röcken and Ghoreschi 2003, Braun-Falco et al. 2004). In the recent years, two types of scleroderma have been differentiated: systemic and localized (Röcken and Ghoreschi 2003). Systemic scleroderma or systemic sclerosis traditionally refers to autoimmune diseases. In cases when skin changes are patchy and asymmetric, localized scleroderma (“morphea”) should be suggested, which is subdivided into patchy, generalized, and linear types.

Skin sclerosis in localized scleroderma is considered to be caused by three pathogenic mechanisms: vascular disturbances, activation of T cells, and disturbance of connective tissue production from fibroblasts. Pathologically increased collagen production in localized scleroderma is induced by interleukin-4 and tumor necrosis factor α (TNF-α). The peculiarity of localized scleroderma is in the existence of several clinical variants. In the localized form of scleroderma, lesions can be localized on various skin areas in the form of plaque. Lesion foci can have round or oval forms up to several centimeters in diameter, numbering from 1 to 7–10. Skin color in lesion areas is yellowish white, and pink-lilac with lilac rim in the periphery, which shows the progression of the process. Dermatosclerosis of various degrees in the form of dense skin with a wax-like gray or ivory color and a smooth lucid surface is observed in the centre of the plaque. Peripheral growth of the plaque and the appearance of new foci occur slowly. Pigmentation and telangiectasia are sometimes observed in the foci and adjacent areas of the skin. There is no hair growth in these areas (Röcken and Ghoreschi 2003, Braun-Falco et al. 2004).

Despite considerable achievements in the study of localized scleroderma in recent years, and immunological and biochemical investigations, the etiology of the disease has not been completely substantiated. Viruses, hormonal imbalances, toxic compounds, as well as neurological (stress) and genetic factors (antibodies to HLA DR5, HLA DR8, and HLA DR110) are among the possible etiological factors. Also, among possible etiological factors of localized scleroderma are agents of the infectious diseases, most often Borrelia burgdorferi—the agent of Lyme borreliosis. However, research literature shows that this hypothesis is quite controversial.

Since many researchers strongly support the hypothesis about the association of Lyme disease and localized scleroderma, while others reasonably reject this relationship, our aim was to rationally substantiate the role of B. burgdorferi in the occurrence of localized scleroderma.

Materials and Methods

Results

Among the 32 patients with localized scleroderma, lesions in the form of plaques were detected in 25 patients (16 of them at the progressing stage), and a superficial form of the disease (atrophoderma of Pasini-Pierini) was found in 4 patients. Most patients with localized scleroderma sought medical consultation within 2–3 years after the onset of the disease. Late medical consultations were explained by the fact that at early stages of the disease, patients either did not notice skin lesions or tried to treat the problem themselves. According to anamnesis data, factors preceding the disease were excessive insolation—in five patients, exacerbation of focal infection—in four patients, excess exposure to cold—in two patients, and stress reactions—in one patient.

Discussion

Aberer et al. (1987) first suggested the hypothesis about the association of localized scleroderma with B. burgdorferi–microorganism, which is known to cause Lyme disease. According to this research, serum antibodies to B. burgdorferi were detected in 8 patients from 15 with localized scleroderma (53.3%), antibodies of IgG class were found in 6 patients, and IgM and IgG in 2 patients, respectively. The hypothesis of Aberer et al. (1987) is also confirmed by other authors by means of serological investigations. Eisendle et al. (2007) detected antibodies to B. burgdorferi in 68.9% of patients with localized scleroderma (84 out of 122 patients), Svecova and Buchvald (2000) in 34.4% (11 out of 32), Breier et al. (1996) in 33.3% (13 out of 39), Buechner et al. (1995) in 28.9% (13 out of 45), and Wojas-Pelc et al. (2002) in 28% (14 out of 50).

The association of localized scleroderma with B. burgdorferi is confirmed through the examination of damaged parts of the skin by means of PCR. Schempp et al. (1993) detected the genetic material B. burgdorferi in all nine patients with localized scleroderma who were examined. Ozkan et al. (2000) received positive PCR results in 30% of patients (3 out of 10) and Fujiwara et al. (1997) in 26.3% (5 out of 19).

The facts of the association between the agent B. burgdorferi and localized scleroderma are also supported by clinical signs, in particular, an erythematous rim resembling migrating erythema in Lyme disease (Röcken and Ghoreschi 2003, Braun-Falco et al. 2004).

However, a series of investigations have not confirmed the association of localized scleroderma with B. burgdorferi either according to data surrounding serological investigation (Pinazo Canales et al. 1990, Raguin et al. 1992, Alonso-Llamazares et al. 1997, Espinoza-Leyn et al. 2006, Sommer et al. 2006) or data from skin examinations in PCR (Ranki et al. 1994, Dillon et al. 1995, Wienecke et al. 1995, De Vito et al. 1996, Alonso-Llamazares et al. 1997, Weide et al. 2000, Goodlad et al. 2002). Some bacteriological investigations of skin biopsy materials in patients with localized scleroderma do not confirm the etiological role of B. burgdorferi in relation to localized scleroderma either (Raguin et al. 1992, Alonso-Llamazares et al. 1997).

Weide et al. (2000) doubt the etiological role of B. burgdorferi in the appearance of localized scleroderma due to clinical facts and state that late skin lesions in Lyme disease can be accompanied by pseudosclerotic changes. However, these changes cannot be regarded as manifestations of localized scleroderma.

We think that the obtained results of diagnostic levels of anti-Borrelia antibodies in ELISA in 6 out of 32 patients with localized scleroderma prove the borreliosis nature of the disease in seropositive patients. Evidently, localized scleroderma is a polyetiologic disease and B. burgdorferi is one of the etiological factors.

A common method of treatment for localized scleroderma, which has been applied since the 1970's, is penicillin therapy, a theoretical substantiation of which is a property of penicillin metabolite—a penicillamine to inhibit the formation of insoluble collagen (Moynahan 1973, Herbert et al. 1974). Intravenous administration of 5–10 MU of aqueous penicillin G thrice a day for 10–21 consecutive days is recommended in localized scleroderma. In our opinion, the positive effects of benzyl penicillin in some patients with localized scleroderma is associated not only with the inhibition of insoluble collagens with penicillamine but also more with the empiric antimicrobial therapy with a positive effect in case of a borreliosis nature of the disease. We think it is expedient to conduct a laboratory investigation in all patients with localized scleroderma for the confirmation of a possible borreliosis nature of skin lesions. A complete course of antimicrobial therapy with benzyl penicillin in the dose of 10–12 MU per day for 21–28 days should be administered in cases where diagnostic levels of anti-Borrelia antibodies are detected. In such cases, positive results from administrating other antibiotics (doxycycline, ceftriaxone) should be expected.

Lyme disease is a typical spirochetosis and possesses a number of clinical pathogenic peculiarities of this group of infectious diseases, including the property of continuous persistence of the agent in the body, systemic damage of various organs, and susceptibility to chronization. According to existing suggestions, three stages are differentiated in the course of the borreliosis infectious process. The first stage is local infection (a pathological process that develops at the site of the agent's invasion); the second is dissemination (the agent spreads throughout the body from the site of primary invasion); and the third is organ damage (as a result of persistence and continuous pathogenic influence of B. burgdorferi on organs and systems, immunopathologic impairment). Apparently, skin lesions in the form of localized scleroderma are likely in the third stage of the infectious process in patients with Lyme disease.

In summary, our findings established that diagnostic levels of anti-Borrelia antibodies were detected in 18.8% of patients with localized scleroderma, indicating the borreliosis nature of the disease. Localized scleroderma is evidently a polyetiologic disease. It is expedient to conduct investigation in ELISA and PCR for the detection of late Lyme disease in patients with localized scleroderma. In our opinion, it is recommended to carry out a complete course of antimicrobial therapy with benzyl penicillin, dosage 10–12 MU per day for 21–28 days in patients with localized scleroderma in cases where a diagnostic level of anti-Borrelia antibodies is detected or who have positive PCR results.