Lyme disease (Lyme borreliosis)

Best Practice & Research Clinical Rheumatology Vol. 17, No. 2, pp. 241 –264, 2003 doi:10.16/S1521-6942(02)00129-8, www.elsevier.com/locate/jnlabr/yberh

5 Lyme disease (Lyme borreliosis) Juliane K. Franz

MD

Department of Rheumatology and Clinical Immunology, Charite´ University Hospital, Berlin, Germany

Andreas Krause*

MD

Professor of Rheumatology Rheumaklinik Berlin-Wannsee, Berlin, Germany

Lyme borreliosis (Lyme disease) is a systemic infectious disease with a wide spectrum of symptoms affecting the skin, the heart, and the nervous and musculoskeletal systems. Lyme borreliosis is caused by the spirochaete Borrelia burgdorferi and transmitted by ticks. The disease occurs in endemic pockets with an incidence of from 50 to more than 100 cases per 100 000 inhabitants. Despite increasing knowledge about the virulence factors of the spirochaetes and the immune response of the host, many aspects of the pathogenesis, for example of chronic treatment-resistant disease, are still a matter of debate. The diagnosis is based on clinical findings and confirmed by serology. Diagnostic problems arise from patients with non-specific symptoms and a positive IgG serology. In about 80% of the patients, the disease can be cured by adequate antibiotic therapy. Evidence-based guidelines for treatment have been recently published. The only vaccine to prevent Lyme disease, licensed in the USA, has been discontinued due to disappointing sales despite good efficacy and tolerability. Key words: Lyme disease; Lyme borreliosis; epidemiology; pathogenesis; natural outcome; diagnosis; therapy; co-infections; vaccine; prevention; post-Lyme syndrome; web information.

The disease was named after the town of Old Lyme, Connecticut, where, in 1975, there was an accumulation of 12 cases of arthritis in children in a rural community. Originally suspected as juvenile chronic polyarthritis, it soon became obvious through a surveillance study that 25% of the patients had had an erythema migrans and recalled a tick bite prior to the development of arthritis. Since 1910, it has been known that erythema migrans is caused by an infective organism transmitted by ticks.1 Moreover, an association of erythema migrans with neurological symptoms has also been known for decades. Thus, in 1922, Garin-Bujadoux described a sensory radiculitis with meningitis after an erythema migrans.2 In 1941, Bannwarth reported pain, paraesthesias, Bell’s palsy, and lymphocytic pleocytosis of cerebrospinal fluid after having a tick bite and an erythema migrans.3 * Corresponding author. Tel.: þ49-30-80-505-292; Fax: þ49-30-80-505-299. E-mail address: [email protected] (A. Krause). 1521-6942/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.

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In addition to arthritis, skin and neurological symptoms, novel features of the disease, such as cardiac conduction abnormalities, have been observed.4 In 1981, Burgdorfer et al. isolated a spirochaete from ticks in an endemic area. This spirochaete could also be cultured from skin, blood and cerebrospinal fluid from patients with Lyme disease and was named Borrelia burgdorferi.5

EPIDEMIOLOGY Lyme borreliosis is the most common vector-borne disease in USA6 and has become an important infectious disease in Europe and Asia.7 Approximately 15 000 cases of Lyme disease are reported every year in USA.6 Lyme disease occurs in endemic pockets, with over 90% of the cases reported from eight states along the Atlantic Coast and from Wisconsin. In these regions, the annual reported incidence may exceed 100 cases per 100 000 inhabitants. In some areas, such as Old Lyme, the incidence reaches 1000 cases per 100 000 inhabitants. The incidence in children aged 5 –10 years is approximately twice as high as in adults (Table 1).6 In Europe, the disease is most prevalent in forested areas such as Scandinavia and Central Europe. In southern Sweden, a population-based, prospective survey revealed an annual incidence of 69 cases per 100 000 population. In some highly endemic areas, the annual incidence reached 160 per 100 000.8 A similar study in southern Germany found an annual incidence of 111 per 100 000.9 In both European studies, the incidence in children was higher than in adults (Table 1).

AETIOLOGY Lyme disease is caused by B. burgdorferi sensu lato, a Gram-negative spirochaete. B. burgdorferi undergoes enzootic cycles between ixoid ticks — Ixodes ricinus in Europe and I. scapularis and I. pacificus in the USA — and small mammal reservoirs. Ticks may also transmit infectious agents such as the FMSE virus, Babesia microti or the agent of human granulocytic ehrlichiosis in addition to B. burgdorferi. Only recently, Bartonella henselae has been described as a novel co-infecting agent in patients whose central nervous system (CNS) is infected by B. burgdorferi.10

Table 1. Incidence in the USA for the year 2000 (Hayes N., personal communication). Chlamydia Neisseria gonorrhoeae HIV (AIDS) Salmonella Treponema pallidum Varicella Shigella Borrelia burgdorferi sensu lato Mycobacterium tuberculosis Hepatitis A virus

702 385 40 39 31 27 22 17 16 13

093 995 758 574 575 382 922 730 377 397

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Among clinicians, the causative agent of Lyme borreliosis is known as B. burgdorferi. However, B. burgdorferi sensu lato is quite heterogeneous and, so far, 11 different Borrelia species have been isolated from ticks.11 At least three species are pathogenic in humans: B. burgdorferi sensu stricto, B. garinii and B. afzelii (reviewed in Ref. 11). In the USA only B. burgdorferi sensu stricto occurs, whereas all three species can be found in Europe. These different species preferentially invade different organs (organotropism) which may explain at least in part the slightly different clinical picture of Lyme disease in the USA as compared with Europe. Thus, the late dermatological manifestation Acrodermatitis chronica atrophicans (ACA), mostly but not exclusively associated with B. afzelii, can be observed in Europe but rarely, if ever, in the USA. Neuroborreliosis is frequently caused by B. garinii. All three species can cause Lyme arthritis, which occurs more frequently in North America than in Europe.7,12,13

PATHOGENESIS Upon transmission, the spirochaete invades several host tissues. The spirochaetes first encounter cells of the innate immune system (predominantly polymorphonuclear cells and monocytes, but also innate T cells, such as NK T cells and gd T cells) as a first line defence against the spirochaetes.14 The binding of B. burgdorferi lipoproteins to Toll-like receptors induces a variety of pro-inflammatory mediators,15 that account for the inflammatory reaction in the infected host tissue. There is also a strong but delayed adaptive immune response provided by B and T cells. Despite the innate and adaptive immune response of the host, about 80% of infected persons develop a systemic disease. Several properties of the spirochaetes, as well as host factors, are involved in the pathophysiology of the disease. When the B. burgdorferi genome was sequenced,16 no specific virulence factor was detected. One of the most important findings was that B. burgdorferi is not able to produce lipopolysaccharides but possesses a huge number of genes encoding lipoproteins. These proteins are anchored to the outer membrane via their lipid moieties and are called outer surface proteins (Osps). The different expression of these surface antigens as well as the antigenic variation within the vlsE expression cassette17 enables the spirochaetes to evade the host immune response. An important virulence factor facilitating the dissemination of the infective agent is the strong adhesion to various host extracellular-matrix proteins, glycosaminoglycans and integrins. In particular, the high affinity for matrix components may account for the long-term survival of spirochaetes in connective tissue of the joints. Furthermore, spirochaetal lipoproteins are strong inducers of pro-inflammatory cytokines and chemokines.18 Host metalloproteinases are secreted and induced by B. burgdorferi.19,20 Recently, evidence for a spirochaetal carboxyl-terminal processing protease (CtpA) has been reported.21 Specific anti-borrelial antibodies may not be detected in sera from patients with Lyme disease before 3 – 4 weeks after the infection. Lytic antibodies are critical for eradicating the spirochaetes. In a recent study, surface proteins of B. burgdorferi with a high affinity for host complement control proteins (CRASP) have been identified and may reflect one mechanism of survival of the spirochaetes (personal communication). There is only limited cross-reactivity of antibodies among different species of B. burgdorferi. Therefore, the humoral immune response may not be protective and re-infections do occur even in patients with high titres of antibodies. The pathogenesis of chronic persistent Lyme disease, in particular, is still a matter of debate. Most patients with Lyme arthritis recover completely after antibiotic therapy;

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however, in , 10% of patients with Lyme arthritis, the inflammation persists even after repeated courses of antibiotic therapy.7 Both persistent infection and induction of immunopathology by the spirochaetes are currently discussed. The following facts support the concept of a persistent infection. Even at late stages of the disease, spirochaetes can be isolated from involved tissues (e.g. from ACA tissue after 10 years). The B. burgdorferi genome can be detected by polymerase chain reaction (PCR) in synovial tissue.22 Ultrastructural studies of synovial membranes from patients with chronic arthritis, and studies with a three-dimensional in - vitro model of Lyme arthritis, have revealed the presence of spirochaetes not only in tissues with a low turn-over rate, such as within bundles of collagen fibres,23 but also within macrophages and resident synovial fibroblasts. On the other hand, in chronic therapy-resistant Lyme arthritis, the histological lesions of affected synovial tissues resembling those found in rheumatoid arthritis,7 the rare isolation of viable spirochaetes from patients with chronic disease, the unresponsiveness to antibiotic treatment in these patients and the association with HLA DR4 and DR2 point to the pathogenetic role of immunopathological processes induced by the spirochaetes. Cross-reactivity between OspA and a self-antigen has been discussed as a cause of treatment-resistant Lyme arthritis.7,13,24,25 An alternative explanation for the development of treatment-resistant Lyme arthritis would be hypersensitivity that develops to traces of persistent antigen. Cytokines produced by cells of the innate immune system, such as the interleukins IL-1b, IL-6, IL-10, IL-11, IL-12, IL-17 and TNF-a, have been implicated in the regulation of arthritis severity in patients or animal models.13 Altogether, it is likely that non-antigen-specific mechanisms mediate, perhaps in synergy with antigen-specific mechanisms, the immunopathology that finally leads to treatment-resistant Lyme arthritis in susceptible patients.7,25

Research agenda In the pathogenesis of Lyme disease, more information is needed on: † properties of the organism: different expression of Osps, antigenic variation, attachment to extracellular matrix and host-cell-surface molecules, induction of pro-inflammatory cytokines and chemokines, induction of host metalloproteinases † host factors: delayed humoral response, association to HLA DR 4 and 2, hypersensitivity to bacterial fragments † in chronic persistent disease, persistent infection and induction of immunopathology

CLINICAL FEATURES The clinical manifestations of Lyme disease have been reviewed in a recent series of excellent articles.7,26 – 28 For systematic reasons, most textbooks group Lyme disease into three stages. However, the disease may become manifest at any stage, stages might be skipped or may coincide. Therefore, for daily clinical practice, it is more useful to distinguish between early disease or acute phase (erythema migrans, acute neuroborreliosis,

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carditis, early arthritis) and late or chronic (persistent) disease (arthritis, acrodermatitis). The general clinical manifestations of Lyme borreliosis are similar worldwide and will be described in detail below. However, there are some regional variations in frequency and appearance of certain symptoms between Europe/Eurasia and America that are summarized in simplified form in Table 2.

Practice points † for clinical practice, Lyme disease should be staged into early disease, disseminated disease and chronic-persistent disease † pathognomonic features are erythema migrans, lymphadenosis cutis benigna, ACA and the meningoradiculitis Bannwarth † all other symptoms are not restricted to Lyme disease (‘great imitator’) and deserve careful differential diagnosis † general symptoms are similar worldwide, but regional variations occur, partly due to the organotropism of B. burgdorferi

Dermatoborreliosis In most patients, Lyme disease begins with the pathognominic skin lesion, the erythema migrans, and can be accompanied by signs of systemic inflammation such as low-grade fever, chills, arthralgias, myalgias, and malaise (‘flu-like illness’). Headaches and paraesthesias may reflect early neurological dissemination. Erythema migrans starts as a red macule or papule at the site of the tick bite. After an incubation period of a few days up to 8 weeks, the lesions gradually expands (‘migrates’), sometimes reaching a size so large that the margins of an erythema originating on the abdomen may meet at the back of the patient. In Europe, less often in America, lesions lasting for a longer period will clear in the central part leaving a demarcated ring and a small red spot inside which the initial tick bite had taken place (Figure 1). The typical site of the erythema is the belt region, the posterior thigh, popliteal fossa or hairy areas such as the groin, axilla or hair on the head, especially in children. Even without antibiotic treatment, erythema migrans will resolve within 4 –12 weeks; however, in many cases, bacteria will persist at other sites and will cause subsequent Lyme manifestations. Half of the American patients, but not the European patients, develop multiple secondary erythema skin lesions resembling primary lesions, but smaller in size and expansion. An additional dermatological manifestation in the early phase is the lymphocytoma cutis, especially in Europe, usually presenting as a purplish nodule at the ear lobe, the nose (Figure 2), the forehead or the nipple. Chronic borreliosis of the skin is a rare event in the USA, but quite common in untreated European patients. ACA occurs after more than 12 months after the initial infection and is characterized by a unilateral extended distal atrophic skin lesion frequently preceded by an inflammatory, oedematous violaceous stage. A cigarettepaper-like appearance with a wrinkled violet thin skin without hair and with translucent veins (Figure 3) is typical. Frequently it is associated with pain in the joints underneath the skin lesion (usually the PIP joints or toes) and is, therefore, sometimes called ‘arthrodermatitis’. Diagnosis is quite easy owing to the typical skin manifestation and

Organ system

Clinical feature

Europe/Eurasia (Borrelia afzelii, Borrelia garinii, Borrelia burgdorferi sensu stricto)

North America (Borrelia burgdorferi sensu stricto)

Skin Acute phase

Erythema migrans

Slower spreading, less intensely inflamed, and of longer duration; less frequent haematogeneous dissemination, but possible regional or contiguous spread to other sites Rarely and predominantly seen in children and scarcely in adults Caused primarily by Borrelia afzelii

Central clearing , 35%; systemic symptoms common; frequent, possibly widespread haematogeneous dissemination

Reports about the isolation of Borrelia afzelii from lesional skin and improvement after antibiotic therapy in single cases

None reported

Severe radicular pain, meningitis more severe in children, intrathecal pleocytosis and antibody production, caused primarily by Borrelia garinii Subtle sensory neuropathy within areas affected by acrodermatitis. Severe encephalomyelitis, spasticity, cognitive abnormalities, marked intrathecal antibody production

Meningitis, less prominent radiculoneuritis

Borrelial lymphocytoma Chronic phase

Nervous system Acute phase

Chronic phase

Acrodermatitis chronica atrophicans Circumscribed scleroderma and Lichen sclerosus et atrophicus

Meningopolyradiculo-neuritis (Bannwarth), cranial nerve palsy Encephalytis; encephalomyelits; cerebral vasculitis; peripheral neuropathy

None reported Rarely reported

Subtle sensory polyneuropathy without acrodermatitis. Subtle encephalopathy, cognitive disturbance, slight intrathecal antibody production

Heart Acute phase Chronic phase

Carditis Dilated cardiomyopathy

Atrioventricular block and subtle myocarditis Isolation of Borrelia burgdorferi sensu lato from endomyocardial biopsies in only a few cases

Atrioventricular block and subtle myocarditis None reported

Musculoskeletal Acute phase

Arthritis

Chronic phase

Arthritis; myositis; bursitis

Less frequent oligoarticular arthritis, less intense joint inflammation Persistent arthritis less frequent

More frequent oligoarticular arthritis, more intense joint inflammation Treatment-resistant arthritis in about 10% of patients, probably due to immunopathology Expansion of response to many borrelial antigens

Antibody response

Expansion of response to fewer borrelial antigens

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Table 2. Clinical manifestations of Lyme borreliosis in Eurasia and North America.7,29,30

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Figure 1. Erythema migrans. The lesion starts as a red macule or papule (A) at the site of the tick bite and then slowly expands. (B) Central clearance may or may not be present.

usually an extremely marked immune response upon serology. If recognized early, treatment results in a resolution of the skin lesion; however, in prolonged cases, atrophic changes may remain. Moreover, acrodermatitis may lead to severe scarring of affected skin areas. This is of special interest because there is some evidence that a small proportion of morphea cases (localized scleroderma) are also associated with B. burgdorferi infections.31

Figure 2. Borrelial lymphocytoma: typical painless bluish-red nodule of the nose. Kindly provided by Professor W. Sterry, Department of Dermatology, Charite´ University Hospital, Berlin, Germany.

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Figure 3. Acrodermatitis chronica atrophicans. Starting with a bluish-red discoloration, usually on the extensor surface of the extremities, the affected skin slowly becomes atrophic.

Neuroborreliosis In a minority of patients (about 15%), typical neurological symptoms develop within weeks or months after the tick bite: cranial neuropathy (most commonly involving the facial nerve, Bells’s palsy, Figure 4); meningitis, especially in children; and radiculoneuropathy alone or in combination. The radiculoneuropathy accompanied by meningitis is termed Bannwarth’s syndrome. A recent study revealed similarities in the general clinical picture of neuroborreliosis in Sweden, Germany and the USA.32

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Figure 4. Facial nerve palsy in acute neuroborreliosis.

Radiculoneuropathy is usually a very painful acute condition, frequently with a significant increase in pain at night. It may affect any dermatome, or several contiguous dermatomes, and is frequently mixed up with a ‘slipped disk’, even prompting surgery. Further symptoms include paresthesia, sensory deficits and motor weakness. Facial palsy may even be bilateral, especially in children. It may occur when the erythema migrans is still present, or subsequently after a few weeks. In particular, a relationship to Lyme disease in endemic areas should be considered in children and in tick-exposed individuals such as forest workers, house-wives working in the garden, farmers and hunters. Even in these risk groups, however, idiopathic facial palsy is more prevalent than Lyme-associated neuropathy; clinically, however, a distinction is not possible. Other manifestations include the paresis of the abducent nerve (5%). Clinically overt Lyme meningitis may be found in children, only rarely in adults, and is characterized by initial headaches, neck stiffness and additional signs of mild encephalopathy, while meningism is rare. All acute manifestations may eventually remit without treatment; however, in a significant number of patients, mild symptoms may last for years in non-treated patients.36 In all suspected cases of neuroborreliosis, cerebrospinal fluid (CSF) analysis is necessary to establish the diagnosis. The CSF is characterized by a lymphocytic pleocytosis with a cell number up to 1000 ml and elevated protein levels (1– 2 g/l). The ratio of immunoglobulins to albumin might be elevated in the CSF compared with blood levels, and points to an intrathecal production of immunoglobulins. Oligoclonal electrophoretic bands within the CSF reflect an immunological process. However, in early cases of neuroborreliosis, spinal fluid findings may still be negative, and in cases of chronic disease, only mild elevations of protein may persist. Especially in these circumstances, detection of B. burgdorferi DNA by PCR may be important to establish the diagnosis.

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The rare manifestations of chronic neurological Lyme disease occurring months to years after infection include distal symmetric polyneuropathy (often associated with acrodermatitis), mononeuritis multiplex, stroke-like disorders (caused by a cerebral vasculitis), chronic encephalitis, encephalomyelitis or meningoencephalomyelitis. The latter are characterized by slowly progressive courses with increasing spastic para-, tetra- or hemiparesis. Some rare cases of demyelinating encephalopathy resembling multiple sclerosis have been described.33 Other manifestations include cognitive defects, memory loss and concentration deficits. The diagnosis has to be made with great caution and under strict criteria because the latter symptoms are particularly difficult to discriminate from neuropsychiatric or neurotic diseases. Ocular manifestations of Lyme disease Ophthalmological changes are relatively rare and may include conjunctivitis and all varieties of uveitis (anterior, intermedia and posterior and panuveitis). Meningitis may lead to a papillar oedema. In the chronic stage, uveitis, keratitis and episcleritis may evolve. The recognition of Lyme borreliosis as a cause of ocular conditions is important because treatment with antibiotics usually results in resolution of the disease. Lyme carditis Lyme carditis is a rather rare entity occurring in about 5% of patients. It frequently develops after a preceding erythema migrans. Many patients also have concomitant neurological symptoms and arthralgias. Typical manifestations are conduction abnormalities with varying degrees of atrioventricular block, right or left bundle block, atrial fibrillations or tachycardias. In Particluar, Lyme carditis should be suspected in younger individuals showing conduction abnormalities without other apparent risk factors. In Europe, rare instances of a chronic Lyme carditis have been described that result only in cardiomyopathy, even with a fatal course. However, cardiac involvement usually subsides spontaneously within a few weeks and does not recur. Spirochaetes have been successfully cultured from cardiac biopsies. Therapy is symptomatic together with antibiotic treatment — which usually results in prompt resolution. In cases of conduction abnormalities, steroids have been added. Articular manifestations In the USA, arthritis is the predominant manifestation of disseminated B. burgdorferi infection, with about 60% of untreated patients developing joint manifestations usually weeks to years after the initial infection. In Europe, a smaller proportion of patients experience arthritis — which may either occur in early disseminated disease or, more typically, in late stages of disease. The clinical course is usually intermittent with acute attacks and transient-seeming ‘remissions’. left untreated, it may go on for months or years. In most cases, there is a mono- or oligoarticular course predominantly affecting the knees, ankles and sometimes elbows, usually with massive effusions (Figure 5). In our experience, only a minority of patients will remember a tick bite or an erythema migrans, and arthritis may be the only presentation of Lyme disease. Therefore, the diagnosis of Lyme arthritis is one of the greatest the challenges in rheumatology.

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Figure 5. Lyme arthritis of the right knee.

Popliteal (Baker’s) cysts are common, and — if present — dactylitis and achilles tendon involvement can be helpful as diagnostic signs if reactive arthritis, psoriatic arthritis and spondyloarthropathies have been ruled out. Involvement of the sacroiliac joints or the spine does not occur in Lyme borreliosis and is therefore most valuable for differentiating Lyme arthritis from the latter arthritides. Otherwise, Lyme arthritis cannot be distinguished from reactive arthritis or other acutely presenting oligoarticular diseases on clinical grounds alone. Joint fluid analysis usually shows non-specific inflammatory changes, with a cell count of about 25 000 cells/mm3, predominantly granulocytes. Histological investigations of the synovial membrane have concentrated on chronic cases and have documented changes similar to those in rheumatoid arthritis, with a hyperplasia of the lining and lymphocytic infiltration. While it is generally difficult to culture B. burgdorferi from intra-articular sites, PCR analysis of the joint fluid and synovial biopsies have shown the presence of spirochaetes. Therefore, PCR investigations may be helpful in unclear cases (see below). In some cases, there is no overt arthritis, and the disease is characterized by nonspecific arthralgias, myalgias and periarticular pain, making the differential diagnosis difficult with regard to functional syndromes and fibromyalgia, especially in seropositive individuals living in endemic areas. The prognosis of the disease is usually good. Joint destruction, even in long-standing cases, is rare. After adequate therapy, more than 80% of patients are cured, even after a single course of antibiotic therapy. In some patients, repeated therapy is necessary. The success of antibiotic treatment often cannot be evaluated before several weeks after completion of treatment because symptoms usually fade slowly and complete recovery may take several months. A small proportion of patients with Lyme arthritis do not respond even to repeated courses of antibiotic treatment. In our (European) experience, these therapy-resistant patients are rare, while in the USA a proportion of 10% has been described.

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Practice points Characteristics of Lyme arthritis: † often in North America, less frequent in Europe † occurs usually in later stages of Lyme disease † huge effusion possible † frequent recurrence † no systemic inflammation † no involvement of the sacroiliac joints Problem: arthritis is the only manifestation, tick bite and/or erythema migrans are not recalled The incidence is lower in children than in adults. Treatment with steroids, especially given intra-articularly, before adequate antibiotic treatment significantly increases the risk of developing treatment-resistant Lyme arthritis. While some of these cases may be driven by intra-articular persistence of B. burgdorferi, there is some evidence that others are maintained by infection-induced immunopathology, including autoimmune mechanisms. Extra-articular manifestations in the musculoskeletal system Compared with arthritis, other rheumatological manifestations are much rarer. These consist of tenosynovitis and bursitis. Despite frequent myalgias, overt myositis or dermatomyositis has only been described in rare cases — which could, however, be confirmed by a positive culture from a muscle biopsy. Also, three cases of a polymyalgia-like disease have been reported after an erythema migrans with a good response to antibiotic therapy. Post-Lyme syndrome Clinical problems arise in a small percentage of patients who have been appropriately treated for Lyme disease but who still complain about multiple, mostly non-specific, symptoms, including fatigue, myalgias, arthralgias and cognitive impairment. This so-called ‘post-Lyme disease syndrome’ may be severely disabling, with a substantially reduced health-related quality of life, and it has many features in common with chronic fatigue syndrome and fibromyalgia. The frequency, pathogenesis, diagnosis and treatment of this syndrome have been a highly contentious issue for more than a decade. Two recently published studies34,35 tested the effect of long-term therapy in patients with well-documented Lyme disease and who had various persisting symptoms despite an average of three previous courses of antibiotics. Patients received either 2 g ceftriaxone daily for 30 days followed by 200 mg doxycycline daily for another 60 days, or placebo. The study was stopped prematurely because there was no difference between the treatment group and the placebo group, and therefore it was highly unlikely that even this massive antibiotic therapy was of any benefit. Taken together, especially in patients with late stages of Lyme disease, it may be necessary to give two or sometimes even three courses of antibiotics with the antibiotics, dosages and durations recommended above.34 Despite this therapy, there is a small group of patients with

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ongoing, so-called treatment-resistant arthritis or various, sometimes disabling symptoms of post-Lyme syndrome. While we do not know the optimum treatment for these patients yet, it is obvious that prolonged antibiotic treatment should be avoided because it is not only ineffective but also expensive, and is burdened with a number of severe and sometimes lethal side-effects.

NATURAL HISTORY AND LONG-TERM OUTCOME The long-term outcome of Lyme borreliosis has been addressed by several studies. Shadick et al.,35 reported more joint pain, memory impairment and poorer functional status in 186 patients who had Lyme disease (6 years after infection) compared with 167 controls. However, no significant examination differences could be found between the groups. In 2001, Kalish et al. published a follow-up study of 84 randomly selected patients 10 –20 years after infection and 30 controls.36 The groups did not differ in current symptoms or neuropsychological tests. However, in patients with neuroborreliosis who had not received antibiotic treatment, more residual neurological deficits, more joint pain and sleeping disturbances occurred. Reviewing the current data on the long-term outcome, the prognosis of Lyme disease is excellent.

Practice points Long-term outcome of Lyme disease: † patients report more joint pain, memory impairment and poorer functional status, but tests did not unreveal significant differences compared with normal controls † patients not receiving antibiotic therapy exhibit more residual symptoms

CO-INFECTIONS Ticks may serve as vectors for additional pathogens, such as Babesia microti and Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis (HGE). Human co-infection may occur from a single tick bite that transmits multiple pathogens or from multiple tick bites. The first co-infection with B. burgdorferi and B. microti was reported in 1983,37 and the first co-infection of B. burgdorferi and A. phagocytophila in 1997.38 Several prospective studies analysed the clinical symptoms of co-infections. A total of 671 persons in an endemic region of New York revealed no seroconversion to two or more infective agents during the 1-year follow-up39, although five patients had initial signs of co-infection. Co-infections (any combination of borreliosis, babesiosis, HGE) were found in 75/192 (39%) patients with either erythema migrans or flu-like symptoms in Connecticut and Block Island over a 6-month period.40 The most frequent co-infection was B. burgdorferi and B. microti. Co-infection was associated with a higher percentage of flu-like illness. Another prospective study conducted from 1996 to 1997 found only 4%

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of patients with evidence for a co-infection.41 Therefore, the risk of acquiring coinfections appears to be rather low in endemic areas. Although either of the co-infecting organisms may cause severe disease, they most commonly result in asymptomatic infection. A retrospective study on the long-term outcome of Lyme borreliosis and babesiosis co-infection on Nantucket Island revealed no increased disease severity or persistent symptoms,42 the same was found for co-infection with B. burgdorferi and A. phygocytophila.43 In daily clinical practice, a complete blood smear should be performed in patients suspected to have co-infections, especially in patients with erythema migrans and flu-like symptoms. Leucocytopenia (HGE), anaemia (babesiosis) and thrombocytopenia (both) support the diagnosis of co-infection (Belongia E, personal communication). Recently, Bartonella henselae has been described as a novel co-infecting agent in patients whose CNS is infected with B. burgdorferi.10 For further reading, we recommend an excellent review on tick-borne co-infections by Thompson et al.44 Practice points Co-infections may occur with: † FMSE virus (Europe) † Babesia microti † Anaplasma phygocytophila † Bartonella henselea Frequency is rather low (, 5%), and infections are mostly asymptomatic † for clinical practice, complete blood smear (anaemia, leucopenia, thrombopenia) is recommended in patients with erythema migrans combined with flu-like symptoms

LYME DISEASE IN CHILDREN Originally described in children, arthritis remains the most common manifestation of Lyme disease in the USA. In endemic regions, the incidence of Lyme arthritis is twice as high in children compared with adults. In general, Lyme arthritis appears to be less painful in children. The long-term outcome in children is excellent; there are no reports of chronic persistent Lyme arthritis in children. In European children, erythema migrans and lymphocytic meningitis (facial palsy) are the major clinical manifestations.45 Recently, involvement of the optical nerve has been described in children.46 This might be due to inflammation or increased intracranial pressure;47 it caused bilateral blindness in one case.46

DIFFERENTIAL DIAGNOSIS The characteristic appearance of the erythema migrans can hardly be misdiagnosed. However, the differential diagnosis of atypical cases includes all other erythematous skin

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diseases such as erythema gyratum repens, erythema anulare and the erythema necrolyticum migrans. There are usually no laboratory abnormalities in early Lyme disease except for rare elevations of the ESR, mild anaemia, leukocytosis and slight elevations of liver enzymes. At this stage of the disease, only 50% of patients develop serological signs of a B. burgdorferi infection (see below). If fever and flu-like symptoms are the predominant findings, Lyme borreliosis can hardly be distinguished from viral infections. However, rhinitis, sore throat or cough do not belong to the clinical spectrum of Lyme disease. In later stages, Lyme disease can manifest with a variety of cardiac, neurological and arthritic symptoms which are not specific for Lyme disease. Lyme carditis can be confused with viral carditis or with rheumatic fever. Neurological symptoms may simultaneously or sequentially involve multiple levels of the central and peripheral nervous system with a wide array of possible differential diagnoses. However, CSF analysis usually permits diagnosis of Lyme disease or rules it out. Although most cases remain ‘idiopathic’, Lyme disease is the most common recognized cause of Bell’s palsy, especially if it occurs bilaterally. Lyme arthritis may resemble reactive arthritis. A remarkable finding in Lyme arthritis is the frequent absence of systemic inflammatory signs. Thus, despite massive effusions, ESR and CRP values are often normal or only slightly elevated. Therefore, if, for example, a knee swelling is the initial symptom — especially in a younger athletic person — acute meniscopathy may be a wrong diagnosis if Lyme arthritis is not considered. On the other hand, reactive arthritis is normally characterized by significant elevations of the ESR and CRP. In contrast to spondyloarthropathies, Lyme arthritis is not associated with HLA-B27 and axial involvement is missing. In severe cases of Lyme arthritis, rheumatoid factor and antinuclear antibodies may be positive, making the differential diagnosis of Lyme disease difficult — especially in rare cases of a polyarticular or erosive course of disease. An important disease to consider is Lo¨fgren’s syndrome which frequently presents with acute arthritis of the lower extremities. The erythema nodosum and bihilar lymphadenopathy will help to distinguish this condition from Lyme arthritis. Practice points Differential diagnosis: † skin: erythema gyratum repens, erythema anulare, erythema necrolyticum migrans † heart: viral myocarditis, rheumatic fever † musculoskeletal system: fibromyalgia, polymyalgia rheumatica † arthritis: reactive arthritis, gout, atypical rheumatoid arthritis, Lo¨fgren’s syndrome † peripheral and central nervous system: cranial neuropathy, meningitis, radiculoneuropathy; rarely: symmetric polyneuropathy, mononeuritis multiplex, strokelike disorders (vasculitis), meningoencephalitis

DIAGNOSIS Diagnosis depends largely on recognition of a characteristic clinical picture, while serological tests confirm the diagnosis. A typical erythema migrans can be diagnosed only by appearance. In all other cases, the diagnosis of Lyme borreliosis is based on clinical grounds and supported by

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laboratory analyses, especially Lyme serology. A history of exposure to ticks, or a tick bite in an area that is endemic for Lyme disease, symptoms characteristic for, or at least compatible with, Lyme disease, and the detection of specific antibodies against B. burgdorferi are the most important diagnostic hallmarks. In Lyme neuroborreliosis, the diagnosis may be confirmed by the detection of CSF pleocytosis and intrathecal antibody production against borrelial antigens. In contrast, the diagnosis of Lyme arthritis is difficult to establish. Patients usually present with non-specific symptoms and often do not remember having had specific early Lyme manifestations. The direct detection of the spirochaete is still difficult, and positive serology does not necessarily differentiate between previous or ongoing infection. Therefore, it is often possible to give only a probable diagnosis of Lyme arthritis after having ruled out other forms of arthritis. The European Concerted Action Against Lyme Borreliosis (EUCALB) and the Centers for Disease Control (CDC) have published case definitions for Lyme disease which combine clinical and laboratory data (URL http://www.dis.strath.ac.uk/vie/ LymeEU/).48,49 These may be used for public health surveillance and studies on Lyme disease. Practice points Diagnosis of Lyme disease: † based on clinical and geographical data † confirmed by serology: two-step approach – screening: ELISA (IgG and IgM) – confirmation: immunoblot † Borrelia PCR (urine, cerebrospinal fluid, synovial fluid) in special cases

Serology Serology is usually performed when Lyme disease is suspected. Specific IgM antibodies against B. burgdorferi first become detectable 3 –4 weeks after the infection, peak after 6 –8 weeks and usually decline subsequently. IgG antibodies appear 6 – 8 weeks after the infection and remain detectable for many years.7 For diagnostic purposes, it is important to keep in mind that both IgG and IgM responses can persist for over 10 years, even after successful antibiotic treatment.7 Two-tiered testing is currently recommended. The most commonly used screening tests are ELISAs. Western blotting procedures are applied for the confirmation of positive ELISA results.7,27,48 Falsepositive ELISA results can be caused by other bacteria (e.g. Treponema denticulata) or by a polyclonal B cell stimulation. The sensitivity, specificity and reproducibility of the currently available commercial tests vary greatly. Guidelines for the appropriate use of serodiagnostic tests for Lyme disease in the USA have been developed by the American College of Physicians.50 According to these guidelines, serological testing is useful only when the pre-test probability of Lyme disease is 0.20 –0.80. In clinical practice, Lyme serology should be performed only in patients with signs and symptoms compatible with Lyme disease. As positive serology alone is not sufficient to make the diagnosis, differential diagnoses need to be ruled out in parallel. Usually, highly positive serology in an ELISA does not need to be confirmed by an immunoblot. Cross-reactivities with syphilis tests do occur

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but they are only rarely of clinical relevance. If so, it is much more likely that positive Lyme serology leads to false-positive syphilis serology than vice versa. A significant advance in serology appears to be the development of an IgG ELISA using a conserved vlsE peptide of the spirochaete.51 This test has a high specificity and sensitivity, becomes positive prior to the IgG response detected by Western blot and might also be of value in European Lyme borreliosis caused by B. afzelii and B. garinii. Direct detection methods The culture of B. burgdorferi from patient specimens would prove the diagnosis of Lyme disease. Unfortunately, it is difficult to perform, insensitive and slow, and therefore rarely attempted for diagnostic purposes, except for unclear skin manifestations of Lyme borreliosis.7 PCR-based assays detecting B. burgdorferi DNA have shown increasing significance on the basis of their high sensitivity, specificity and capability for typing and quantification of spirochaetes in specimens; however, they are currently not considered a routine method — partly because there is considerable interlaboratory variation in the results.7 B. burgdorferi DNA can be detected in synovial fluid22,52 or synovial tissue22 from patients with Lyme arthritis, and in the CSF from patients with early CNS manifestations of Lyme disease.53 Positive serology in asymptomatic patients In areas endemic for Lyme disease, many inhabitants are seropositive yet lack any history or symptoms of Lyme disease.7 The frequency of asymptomatic infection may be considerable and further complicates the interpretation of serological data. During the 2-year observation period of the clinical trial of the Lyme vaccine, 137 of the placebo recipients seroconverted on Western blotting. Twenty-eight of those (20%) did not show any clinical symptoms of Lyme disease.54 A retrospective Swedish study even found that more than half of the people who were seropositive by ELISA could not recall any symptoms suggestive of Lyme disease.55

TREATMENT Antibiotic treatment There is no need to treat persons with positive Lyme serology but without any symptoms of Lyme disease. Treatment decisions should always be based on clinical signs. All manifestations of Lyme borreliosis should be treated with antibiotics as early as possibly to shorten the clinical course and prevent the progression of the disease. Detailed, essentially comparable and evidence-based recommendations have been issued by EUCALB (URL http://www.dis.strath.ac.uk/vie/LymeEU/) and by the Infectious Disease Society of America.56 Therapeutic decisions depend on duration, stage and symptoms of the disease. Amoxicillin, doxycycline and third-generation cephalosporins are the drugs of choice.7,26 – 28 Doxycycline has the advantage of being also effective against the agent of human granulocytic ehrlichiosis which may be cotransmitted by ticks. In early infections, azithromycin and oral cephalosporines are also effective and may serve as alternatives if the first-line drugs are contraindicated. However, their efficacy has not been proven in later stages of disease. Penicillin G is

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also recommended for disseminated infections but has the disadvantage of short dosage intervals. Erythromycin is less effective than the recommended compounds and therefore regarded as the last choice. Doxycyline must not be prescribed for children or for pregnant or nursing mothers because of the discoloration of the child’s teeth. Patients taking doxycycline have to be told that the therapy causes photosensibility. The duration of treatment ranges from 2 to 4 weeks. Details are given in Table 3. Uncomplicated Lyme arthritis, i.e. without neurological or any other organ manifestations, may be treated orally with amoxicillin or doxycycline. However, one study found the subsequent development of neuroborreliosis in patients treated with

Table 3. Treatment of Lyme borreliosis. Condition

Drug

Dose/day (dosages for childrena)

Duration

Early infection

Doxycycline

1 £ 200 mg or 2 £ 100 mg orally 3 £ 500–750 mg or 2 £ 1000 mg orally (50 mg/kg) 2 £ 500 mg orally 500 mg 2 £ 500 mg orally

14– 21 days

1st day 2nd to 5th day 14– 21 days

1 £ 2 g i.v. (50 mg/kg)

14– 21 days

3 £ 2 g i.v. (100 mg/kg) 4 £ 5 MioU i. v. (500 000 U/kg) 1 £ 200 mg or 2 £ 100 mg orally 1 £ 2 g i.v. 3 £ 2 g i.v. 4 £ 5 MioU i.v. 1 £ 200 mg or 2 £ 100 mg orally 3 £ 500–750 mg or 2 £ 1000 mg orally 1 £ 2 g i.v. 3 £ 2 g i.v. 3 £ 500–750 mg or 2 £ 1000 mg orally 4 £ 5 MioU i. v. 1 £ 2 g i.v. 3 £ 2 g i.v.

14– 21 days 14– 21 days

Amoxicillin

Azithromycinb

Acute neuroborreliosisc

Cefuroxime acetylb Ceftriaxone Cefotaxime Penicillin G Doxycyclined

Carditise

Arthritis, acrodermatitis

Ceftriaxone Cefotaxime Penicillin G Doxycycline Amoxicillin

Lyme borreliosis during pregnancy

Ceftriaxone Cefotaxime Amoxicillin Penicillin G Ceftriaxonef Cefotaximef

a b c d e f

14– 21 days

14– 21 days 14 days 14 days 14 days 30– 40 days 30– 40 days 14– 21 days 14– 21 days 14– 21 days 14– 21 days 14 days 14 days

Dosages for adults are the maximum dosages. Only in cases of doxycyclin and amoxicillin allergy or contraindications. In chronic neuroborreliosis, intravenous therapy only for 14–28 days. Only in cases with facial palsy alone. In patients with first-degree atrioventricular block, oral therapy for 14–21 days may be sufficient. Should be used with caution in the first trimester because of lack of data on safety.

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doxycycline but not in those primarily treated with ceftriaxone. If the oral regimen was not effective, which may occur in some 20% of patients, or in cases with symptoms of neurological or other organ involvement, parenteral therapy with ceftriaxone or cefotaxime should be given. In patients with persistent symptoms, a second parenteral antibiotic therapy should be given, again following the evaluated approaches for parenteral treatment. There is no need to change the drug because borreliae do not become resistant to any of the recommended antibiotics. Similarly, other therapeutic regimens such as high-dose pulse therapy or long-term antibiotic treatment are neither necessary nor evaluated and may be associated with a substantial risk of serious side-effects. The important treatment study of post-Lyme syndrome34 is discussed in the section above. Using the recommended therapeutic approach, the prognosis of Lyme disease is excellent. Almost all early infections are rapidly cured without sequelae. In later stages of disease, especially in Lyme arthritis, symptoms often wane slowly and clinical improvement is observed only several weeks after therapy. It should be kept in mind that there are several potential reasons for treatment failures or incomplete responses to therapy, including misdiagnosis and irreversible tissue damage caused by the infection. However, about 10% of patients with Lyme arthritis in the USA and probably a smaller percentage of European patients do not respond sufficiently even to repeated courses of antibiotic treatment. The pathogenesis of this so-called treatment-resistant Lyme arthritis has not been fully elucidated yet but there is some evidence that infection-induced immunopathology plays a major role in most of these cases (see above). Additional therapy As no controlled therapeutic studies, for example with disease-modifying antirheumatic drugs, have yet been performed, symptomatic treatment with anti-inflammatory agents should be given. In patients with persistent monoarthritis, especially with proliferative synovialitis, synovectomy can be beneficial. A recent study reported the successful symptomatic treatment of neuropathic pain in late-stage Lyme borreliosis by gabapentin (Weissbacher S, personal communication). C vaccine Immunization with several different B. burgdorferi proteins, including OspA, can induce specific neutralizing antibodies. OspA is expressed on B. burgdorferi in the mid-gut of the tick and is down-regulated after migration to the salivary gland of the tick and injection into the human host. During the blood meal, the anti-OspA antibodies kill the spirochaetes within the mid-gut of the tick prior to transmission of the spirochaetes.57 A vaccine consisting of recombinant lipidated OspA (LYMErixw) was found to be safe and effective in a large clinical trial involving more than 10 000 participants aged 15– 70 years who lived in areas of the USA where Lyme disease is endemic.54 In 1998, this vaccine was approved by the Food and Drug Administration for use in persons older than 16 years. The OspA vaccine was not tested in Europe, based on the heterogeneity of OspA sequences found in European Borrelia isolates and the expected limited efficacy. Since vaccine licensure, about 1.49 million doses have been distributed. Besides hypersensitivity reactions, no severe side-effects have been described in the post-marketing reports.58 The induction of arthritis was a major concern owing to

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reports on cross-reactivity between OspA and human antigens, but no anti-OspAinduced synovitis has been reported. However, in February 2002, GlaxoSmithKline discontinued manufacturing the LYMErix vaccine due to disappointing demands and sales. Prophylaxis Exposure prophylaxis Prophylactic measures for avoiding tick bites include simple physical measures such as wearing long sleeves and long pants that are tucked into the socks, the complete avoidance of wooded areas, and drastic measures such as area application of insecticides. One popular recommendation is the use of tick and insect repellents. However, to maintain effectiveness, DEET (N,N-diethylmetatoluamide)-containing repellents need to be applied every 1 –2 h. Moreover, their use may result in severe complications, including encephalopathy, seizures, coma and death in children.13 Permethrin kills ticks and can be sprayed on to clothing, but skin exposure should be avoided due to its possible carcinogenicity. In infested areas, daily careful screening for tick bites and the rapid removal of ticks appears to be the most realistic and useful prophylactic measure.7 Experimental and observational data indicate that transmission of B. burgdorferi occurs only after ticks have been attached to the host for at least 24 to over 50 h.13 Persons who have been bitten by a tick should be informed about early Lyme disease manifestations and advised to seek immediate treatment in case of the development of respective symptoms. Secondary prevention The risk of acquiring B. burgdorferi infection through a tick bite is low and varies between 1.2 and 3.2%. It increases, however, to greater than 25% when someone has been bitten by an infected tick.59 Transmissions rarely occur within the first 24 h of the tick bite and can take place only when the tick has become at least partially engorged with blood. Weighing the low risk and the possible side-effects of doxycycline treatment, the Infectious Diseases Society of America has published a recommendation that antibiotic treatment should not be administered routinely to persons who have been bitten by a tick.56 In a study performed in Westchester County NY, where the incidence of Lyme disease is probably the highest in the world, one dose of 200 mg doxycycline p.o. administered within 72 h after a tick bite was 87% effective in preventing Lyme disease.60 However, the observation period in that study was only 6 weeks and the first symptoms of Lyme disease may occur much later. Only 3% of those who received placebo in this study developed Lyme disease. Thus, 40 doses of doxycycline had to be administered to prevent one case of Lyme disease. This number would be higher in areas with a lower incidence of Lyme disease. The efficacy of prophylactic doxycycline administration is further reduced by the fact that most cases of Lyme disease result from unrecognized tick bites. Conversely, for many people, including physicians, it may be difficult to distinguish a tick bite from an insect bite so that some patients would be treated unnecessarily. Taken together, routine antibiotic prophylaxis is not recommended. Individuals with tick bites should be stratified according to their risk of infection by borreliae. Only in those rare patients who have really been bitten by a tick and not, for example, by an insect, and who have a high risk of infection (i.e. nymphal tick from an endemic area, long duration of tick attachment, ticks at least partially engorged) may antibiotic prophylaxis be considered.

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LYME DISEASE INFORMATION ON THE WEB The web sites listed in Table 3 provide profound information on Lyme disease.61 † Clinical features and diagnosis: home page of the center of Disease Control (CDC on Lyme disease: http://www. cdc.gov/ncidod/dvbid/lyme/index.htm † Pictoral diagnosis aid: http://www.journals.uchicago.edu/CID/journal/issues/v35n4/020270/020270. text.html † EUCALB (European Concerted Action on Lyme Borreliosis) http://www.dis.strath.ac.uk/vie/LymeEU/index.htm † On-line seminar from The Lancet: http://www.thelancet.com † Education source for patients: The American Lyme Disease Foundation, http://www.aldf.com

SUMMARY Lyme disease (syn.: Lyme borreliosis) is a complex, multisystem infectious disease with a wide and still expanding spectrum of clinical symptoms. Lyme borreliosis is caused by the spirochaete B. burgdorferi and transmitted by infected ticks. Currently, three species of B. burgdorferi sensu lato are known to cause the disease in humans: B. burgdorferi sensu stricto (USA and Europe), B. garinii (Europe) and B. afzelii (Europe). The disease occurs in endemic pockets in large parts of Europe, North America and Asia, with an annual incidence of 50– 100 (in some endemic areas, even . 300) cases per 100 000 inhabitants. Co-infections with B. microti and A. phagocytophila (human granulocytic ehrlichiosis) may occur, but the frequency is rather low and they most commonly result in asymptomatic infections. Host factors (late and insufficient immune response, hypersensitivity reaction) as well as several properties of the organism (antigenic variation, evasion of host immune response, induction of pro-inflammatory cytokines and metalloproteinases of the host) are involved in the pathophysiology of the disease. However, the mechanisms leading to chronic treatment-resistant Lyme arthritis are still a matter of debate. Novel insights are expected from gene transfer experiments. The diagnosis is based on clinical symptoms and endemic data, and confirmed by serology. Pathognomonic features are the erythema migrans, the lymphadenosis cutis benigna, the ACA and the meningoradiculitis Bannwarth. All other symptoms of Lyme borreliosis may also occur in other diseases and require careful differential diagnosis. The general clinical picture of Lyme borreliosis is similar in the USA and Europe. However, at least in part due to the organotropism of the Borrelia species, there are some differences concerning the frequency and appearance of leading symptoms. Problems in daily clinical practice arise from patients with positive serology but lacking typical clinical signs of Lyme borreliosis and from patients with so-called post-Lyme syndrome. Lyme disease is usually cured by antibiotic treatment at any stage of the disease. Therapy is easier and more successful the earlier it is started. Recently, evidence-based guidelines for antibiotic therapy have been provided by the Infectious Disease Society of America.

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The first and only vaccine to prevent Lyme disease was licensed in the USA in 1998. However, despite the good efficacy and tolerability in the post-marketing period, manufacturing was discontinued in February 2002, owing to disappointing demand for the product and poor sales. The overall prognosis of the disease is excellent. Despite the common concerns of some physicians, and of the general population, about Lyme disease as a dangerous illness with the risk of chronic sequelae, one should keep in mind that the disease is treatable (90%), non-fatal and non-contagious. From a scientific point of view, Lyme arthritis may serve as a model system for rheumatic diseases with a known aetiology.

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264 J. K. Franz and A. Krause * 56. Wormser GP et al. Practice guidelines for the treatment of Lyme disease. Clinical Infectious Diseases 2000; 31: 1–14. 57. Fikrig E et al. Elimination of Borrelia burgdorferi from vector ticks feeding on OspA-immunized mice. Proceedings of the National Academy of Sciences U.S.A. 1992; 89: 5418–5421. 58. Lathrop SL et al. Adverse event reports following vaccination for Lyme disease-December 1998– July 2000. Vaccine 2002; 20: 1603–1608. 59. Maiwald M et al. Transmission risk of Borrelia burgdorferi sensu lato from Ixodes ricinus ticks to humans in southwest Germany. Epidemiology and Infection 1998; 121: 103 –108. 60. Nadelman RB et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. New England Journal of Medicine 2001; 345: 79–84. 61. Sood SK. Effective retrieval for Lyme disease information on the Web. Clinical Infectious Diseases 2002; 35: 451–464.