Robert T. Schoen

The Clinical Evolution of Lyme Arthritis

To determine the clinical evolution of Lyme arthritis, 55 patients who did not receive antibiotic therapy for erythema chronicum migrans were followed longitudinally for a mean duration of 6 years. Of the 55 patients, 11 (20%) had no subsequent manifestations of Lyme disease. From 1 day to 8 weeks after disease onset, 10 of the patients (18%) began to have brief episodes of joint, periarticular, or musculoskeletal pain for as long as 6 years, but they never developed objective joint abnormalities. From 4 days to 2 years after disease onset, 28 (51%) had one episode or began to have intermittent attacks of frank arthritis, primarily in large joints; a few had polyarticular movement. The total number of these patients who continued to have recurrences decreased by 10% to 20% each year. The remaining 6 patients (11%) developed chronic synovitis later in the illness; of these, 2 (4%) had erosions, and 1 (2%), permanent joint disability. The spectrum of Lyme arthritis ranges from subjective joint pain, to intermittent attacks of arthritis, to chronic erosive disease.

Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant

BACKGROUND The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important. METHODS We conducted a multicenter, double-blind, randomized trial involving 10,936 subjects who lived in areas of the United States in which Lyme disease is endemic. Participants received an injection of either recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant or placebo at enrollment and 1 and 12 months later. In cases of suspected Lyme disease, culture of skin lesions, polymerase-chain-reaction testing, or serologic testing was done. Serologic testing was performed 12 and 20 months after study entry to detect asymptomatic infections. RESULTS In the first year, after two injections, 22 subjects in the vaccine group and 43 in the placebo group contracted definite Lyme disease (P=0.009); vaccine efficacy was 49 percent (95 percent confidence interval, 15 to 69 percent). In the second year, after the third injection, 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease (P<0.001); vaccine efficacy was 76 percent (95 percent confidence interval, 58 to 86 percent). The efficacy of the vaccine in preventing asymptomatic infection was 83 percent in the first year and 100 percent in the second year. Injection of the vaccine was associated with mild-to-moderate local or systemic reactions lasting a median of three days. CONCLUSIONS Three injections of vaccine prevented most definite cases of Lyme disease or asymptomatic B. burgdorferi infection.

Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice.

The Lyme disease vaccine is based on the outer-surface lipoprotein (OspA) of the pathogen Borrelia burgdorferi, and 95% of vaccine recipients develop substantial titers of antibodies against OspA. Here, we identified seven individuals with very low antibody titers after vaccination (low responders). The macrophages of low responders produced less tumor necrosis factor-α and interleukin-6 after OspA stimulation and had lower cell-surface expression of Toll-like receptor (TLR) 1 as compared to normal cells, but normal expression of TLR2. TLRs activate innate responses to pathogens, and TLR2 recognizes lipoproteins and peptidoglycan (PGN). After OspA immunization, mice genetically deficient in either TLR2 (TLR2−/−) or TLR1 (TLR1−/−) produced low titers of antibodies against OspA. Notably, macrophages from TLR2−/− mice were unresponsive to OspA and PGN, whereas those from TLR1−/− mice responded normally to PGN but not to OspA. These data indicate that TLR1 and TLR2 are required for lipoprotein recognition and that defects in the TLR1/2 signaling pathway may account for human hyporesponsiveness to OspA vaccination.

Successful Parenteral Penicillin Therapy of Established Lyme Arthritis

In a double-blind placebo-controlled trial carried out from 1980 to 1982, 20 patients with established Lyme arthritis were assigned treatment with 2.4 million U of intramuscular benzathine penicillin weekly for three weeks (total, 7.2 million U) and 20 patients received saline. Seven of the 20 penicillin-treated patients (35 per cent) had complete resolution of arthritis soon after the injections and have remained well during a mean follow-up period of 33 months. In contrast, all 20 patients given placebo continued to have attacks of arthritis (P less than 0.02). In 1983, of 20 patients treated with intravenous penicillin G, 20 million U a day for 10 days, 11 (55 per cent) had complete resolution of arthritis and have remained well since. As compared with nonresponders, penicillin-responsive patients in both studies were more likely to have previously received antibiotics for erythema chronicum migrans (P less than 0.02) and less likely to have been given intraarticular corticosteroids during or at the conclusion of parenteral therapy (P less than 0.1). The Lyme spirochete was not cultured from synovium or joint fluid. We conclude that established Lyme arthritis can often be treated successfully with parenteral penicillin. However, neither of the regimens that we tested is uniformly effective, and further experience will be needed to determine the optimal course of therapy.

Clinical Characteristics and Treatment Outcome of Early Lyme Disease in Patients with Microbiologically Confirmed Erythema Migrans

Context Lyme disease is the most common vector-borne disease in the United States. The traditional clinical presentation, an expanding erythematous rash with partial central clearing, sometimes accompanied by systemic symptoms, was described in patients who usually had clinically manifest Lyme disease for several days. Contribution This study describes 118 patients who acquired Lyme disease while under surveillance in a vaccine trial. Fifty-nine percent of rashes were homogeneous lesions, 32% had dense central erythema, and only 9% had classic central clearing. Signs and symptoms usually resolved within 3 weeks of antibiotic treatment. Implications Early Lyme disease may present with homogeneous or dense central erythematous lesions rather than classic erythema migrans. With antibiotic treatment, the prognosis is excellent. Early Lyme disease may present with homogeneous or dense central erythematous lesions rather than classic erythema migrans. With antibiotic treatment, the prognosis is excellent. The Editors Lyme disease in the United States is caused by the tick-transmitted spirochete Borrelia burgdorferi sensu stricto (1). This infection is the most common vector-borne disease in the country (2). The illness usually presents with localized infection of the skin, erythema migrans, which is often followed days to a few weeks later by dissemination of the spirochete to multiple sites, particularly to other skin sites, the nervous system, the heart, or the joints (3). Borrelia burgdorferi has been cultured readily from skin biopsy samples of erythema migrans early in the illness (4, 5), but later culture from other sites has been difficult. As a substitute for culture, B. burgdorferi DNA may be detected by polymerase chain reaction (PCR) in most patients with erythema migrans (6, 7) and in the joint fluid of patients with Lyme arthritis (8, 9). However, PCR has had low sensitivity in samples from other sites, including cerebrospinal fluid and blood. Serodiagnosis is not sensitive during the first several weeks of infection, but patients often seroconvert during convalescence (10). The initial clinical series of patients with early Lyme disease (11) was described before identification of the causative agent. Researchers used clinical criteria for study entry, particularly the classic appearance of erythema migrans, a slowly expanding erythema with partial central clearing. In that series of 314 patients, most had systemic symptoms and nearly half also had multiple annular erythemas, suggesting dissemination of the spirochete to multiple sites. In a subsequent study, 79 patients from Westchester County, New York, with early Lyme disease had erythema migrans from which B. burgdorferi was cultured (12). Most of the patients in this series, who were often seen earlier than those in the original study, had systemic symptoms, but only 18% had multiple erythemas. In Europe, where erythema migrans more often results from infection with B. afzelii or B. garinii rather than B. burgdorferi sensu stricto, inflammation of erythema migrans is less intense and migration is slower; in addition, patients generally have fewer systemic symptoms (13). In the southeastern United States, patients have been reported to have erythema migranslike skin lesions, but laboratory evidence of B. burgdorferi infection has been lacking. This suggests that another agent, perhaps even from the Borrelia genus, may cause the infection in this geographic area (14-16). Moreover, the same tick that transmits the Lyme disease agent may transmit other infectious agents, including the agent of human granulocytic ehrlichiosis and Babesia microti, and co-infection may influence the clinical presentation of Lyme disease (17, 18). Thus, microbiological confirmation is beneficial in describing the clinical features of Lyme disease in endemic areas in the United States. The recent phase III study of SmithKline Beechams Lyme disease vaccine provided an exceptional opportunity to assess the clinical picture of early Lyme disease in a large cohort of patients who acquired the infection in major endemic locations throughout the United States (19). As part of the protocol, patients who had symptoms of Lyme disease were extensively evaluated for that infection. We describe the clinical presentation, serologic results, and treatment outcome of early Lyme disease in 118 patients with microbiologically confirmed cases of erythema migrans. Methods Patients A total of 10 936 participants 15 to 70 years of age were enrolled in a double-blind, placebo-controlled study of the efficacy and safety of an outer surface protein A Lyme disease vaccine (LYMErix, recombinant outer surface protein A, SmithKline Beecham [now GlaxoSmithKline], Collegeville, Pennsylvania) at 31 sites in 10 endemic states. The Human Investigations Review Committees at all participating centers approved the study protocol. The complete protocol, as well as all members of the Lyme Disease Vaccine Study Group, have been reported elsewhere (19). Briefly, study participants received a packet with information about Lyme disease. Participants were requested to report promptly to their clinician-investigator any symptoms that suggested infection, including onset of a new rash or flu-like illness (without predominant respiratory or gastrointestinal symptoms), arthralgias or arthritis, facial palsy, radiculopathy, or syncope. All participants who were thought to have possible Lyme disease underwent a focused history, physical examination, and laboratory testing. All clinical data were entered on an electronic data form for central analysis. Antibiotic treatment was prescribed according to recommended guidelines (20), but the actual antibiotic and the duration of treatment were at the discretion of the investigator or the patients personal physician. Of the 10 936 participants, 146 met study criteria for definite Lyme disease and 118 had an acute illness with culture-proven or PCR-confirmed erythema migrans. Two clinicians independently reviewed photographs of erythema migrans from case-patients. Laboratory Methods Serologic testing was done at the New England Medical Center exclusively by Western blot (MarDx, San Diego, California), since the standard enzyme-linked immunosorbent assay would be expected to yield positive results in patients vaccinated with outer surface protein A (21). A baseline sample was obtained at study entry, and acute and convalescent samples were obtained when the patient had symptoms suggestive of Lyme disease. The diagnosis of Lyme disease was serologically supported by IgM or IgG seroconversion, or both, between baseline and the acute phase of the illness or between the acute and convalescent phases of the illness. Samples from the same participant were always tested together in the same assay. Western blot results were interpreted according to the criteria of the Centers for Disease Control and Prevention and of the Association of State and Territorial Public Health Laboratory Directors (22). On Western blot, outer surface protein A antibodies bind to a 31-kilodalton band; this is not included in the Centers for Disease Control and Prevention criteria. Following local anesthesia, skin biopsy specimens from erythema migrans were obtained by using 2-mm punch biopsy. Half of each sample was placed directly into a 15-mL tube of BarbourStoennerKelly medium (BSK-H medium, Sigma-Aldrich, St. Louis, Missouri) with ciprofloxacin (0.4 g/mL) and rifampin (40 g/mL); the other half was placed in a 2-mL polypropylene plastic tube for PCR testing. Specimens were shipped the same day by Federal Express to New England Medical Center. On arrival at the laboratory, half of the medium was replaced with fresh medium. Skin samples for culture were placed in an incubator at 33 C and were examined weekly for 1 month by darkfield microscopy for motile spirochetes. Polymerase chain reaction assays of skin biopsy samples were performed as described elsewhere (8). Role of the Funding Source SmithKline Beecham provided data and gave the authors permission to review them, compile them, and independently present results. Dr. Parenti was employed as a research physician with SmithKline Beecham during the early phases of the study. Results During the 20-month study period, which covered two summers of Lyme disease transmission, 1917 of the 10 936 study participants were evaluated for possible Lyme disease (19). Of the 1917 patients, 146 (7.6%) met study criteria for definite Lyme disease, and 118 (6.2%) had microbiological confirmation of this infection by culture or PCR testing of erythema migrans. The mean age of these 118 patients was 51 years (range, 17 to 71 years); 53% were men, and 47% were women. Forty-seven percent were from New England, 51% were from mid-Atlantic states, and 2% were from Wisconsin, reflecting the locations of the study sites. June and July were the peak months of disease onset, which correlated with the expected peak questing period of nymphal Ixodes scapularis ticks. However, cases occurred from March through October, suggesting that adult ticks may also transmit the disease. Vaccine and placebo recipients did not differ in the size of erythema migrans, persistence of symptoms after treatment, and morphologic characteristics of the lesions. In addition, no clinical differences were noted in different geographic areas. Therefore, we present data from vaccine and placebo recipients and from different geographic areas together. Characteristics of Erythema Migrans One hundred eighteen patients had erythema migrans in which B. burgdorferi was detected by culture (88%); by PCR testing (72%); or, in most instances, by both methods (60%). Rashes, which were evaluated a median of 3 days after onset (range, 1 to 30 days), were a median of 10 cm in diameter (range, 5 to 37 cm) at the time of diagnosis. In this adult population, nearly half of the lesions were located on the groin, buttocks, or lo

Asymptomatic Infection with Borrelia burgdorferi

The natural history of asymptomatic seroconversion to Borrelia burgdorferi has been unclear. We report here, on the basis of a post hoc assessment, the frequency and outcome of asymptomatic seroconversion to B. burgdorferi in participants of a large Lyme disease vaccine trial. We show that infection with B. burgdorferi may be asymptomatic but that asymptomatic infection is unusual in the United States.

Borrelia burgdorferi basic membrane proteins A and B participate in the genesis of Lyme arthritis

Lyme arthritis results from colonization of joints by Borrelia burgdorferi and the ensuing host response. Using gene array–based differential analysis of B. burgdorferi gene expression and quantitative reverse trancription-polymerase chain reaction, we identified two paralogous spirochete genes, bmpA and bmpB, that are preferentially up-regulated in mouse joints compared with other organs. Transfer of affinity-purified antibodies against either BmpA or BmpB into B. burgdorferi–infected mice selectively reduced spirochete numbers and inflammation in the joints. B. burgdorferi lacking bmpA/B were therefore generated to further explore the role of these proteins in the pathogenesis of Lyme disease. B. burgdorferi lacking bmpA/B were infectious in mice, but unable to persist in the joints, and they failed to induce severe arthritis. Complementation of the mutant spirochetes with a wild-type copy of the bmpA and bmpB genes partially restored the original phenotype. These data delineate a role for differentially produced B. burgdorferi antigens in spirochete colonization of mouse joints, and suggest new strategies for the treatment of Lyme arthritis.

Decision tool to improve the quality of care in rheumatoid arthritis.

Despite the importance of achieving tight control, many patients with rheumatoid arthritis (RA) are not effectively treated with disease‐modifying antirheumatic drugs. The objective of this study was to develop a decision support tool to inform RA patients with ongoing active disease about the risks and benefits related to biologic therapy.

The Lyme Disease Vaccine: Conception, Development, and Implementation

A form of Lyme disease may have existed for centuries. The characteristic rash of Lyme disease, erythema migrans, was first described in Sweden in 1909 and was properly attributed to bites from the tick Ixodes ricinus (1) . However, the syndrome now known as Lyme disease was not described until 1975, when a cluster of cases of juvenile oligoarthritis occurred in Lyme, Connecticut (2). The causative agent was isolated in 1981 and was subsequently identified as Borrelia burgdorferi, a previously unknown species of Borrelia (3). In 1996, B. burgdorferi was isolated from European ticks that were more than a century old, which suggests that Europeans may have been exposed to Lyme disease spirochetes as early as 1884 (4). Today, Lyme disease is the most common vector-borne illness in the United States and Europe and has been found in Russia, Japan, China, and Australia (5, 6). A 1998 pharmacoeconomic analysis sponsored by SmithKline Beecham (Philadelphia, Pennsylvania) estimated the direct and indirect costs of Lyme disease in the United States alone, including costs of therapeutic interventions, to be

Differential Expression of Borrelia burgdorferi Genes during Erythema Migrans and Lyme Arthritis

2.5 billion over 5 years (7). Studies of nucleic acid hybridization have delineated eight Borrelia genospecies, four of which have been identified as causal agents of Lyme disease. Borrelia burgdorferi sensu stricto is dominant in North America. In Europe, where mixed infections have been reported, B. burgdorferi sensu stricto, B. garinii, and B. afzelii coexist (8). Newly described strainsB. valaisiana, B. lusitaniae, and B. japonicahave been isolated only in Europe and Japan. Borrelia garinii is thought to be the ancestor of the whole group and is believed to be largely responsible for the neurologic symptoms so common in Europe. In 1996, a syndrome similar to Lyme disease was described in Georgia and Missouri; an uncultivable spirochete, B. lonestari, is thought to be the etiologic agent (9). The approved vaccine is directed against B. burgdorferi sensu stricto only, and cross-protection against other strains is unlikely. In North America, 90% of cases of Lyme disease occur in 10 states in the coastal northeastern and Great Lake regions. In some hyperendemic regions of New York and Connecticut, Lyme borreliosis is such a threat that it has depreciated real estate values (10). From 1980 through 1988, a total of 13 795 cases were reported in the United States (11). Official reports to the Centers for Disease Control and Prevention (CDC) place the number of cases in 1998 alone at 16 801; however, because underreporting has been a serious problem, the true number may have been six to nine times greater (Figure 1) (12). Figure 1. Number of reported cases of Lyme disease in the United States, 1982-1997. The rationale for development of a safe, effective vaccine centered on the documented increase in the incidence of Lyme disease; the progressive geographic spread of the illness; the failure of infection to confer lasting immunity; and the association of Lyme disease with chronic rheumatologic and neurologic sequelae as well as transient, severe cardiac conduction disturbances. Lyme Disease Lyme disease is a multisystem inflammatory disease that occurs in similar frequencies in men and women and affects persons of all ages. Lyme disease occurs when the ixodid tick vector injects the causative spirochete B. burgdorferi into humans. The most characteristic clinical finding is a skin lesion, erythema migrans, which usually appears 3 to 30 days after inoculation; however, it appears in only 65% to 80% of infected persons. In early disseminated disease, erythema migrans may occur in isolation or may be associated with flu-like illness; multiple episodes of erythema migrans; or neurologic (Bell palsy or meningitis), cardiac (arrhythmia), or rheumatologic (arthritic) features that suggest hematogenous dissemination of the spirochete. Dissemination from the site of the tick bite is now thought to occur in part through attachment of the causative agent to host plasmin and subsequent degradation of glycoproteins (13). Late-stage Lyme disease usually affects the joints (Lyme arthritis). Approximately 70% of untreated persons develop arthralgia, arthritis, or synovitis. Chronic Lyme arthritis typically occurs in the knees (14). In the United States, an estimated 10% of patients with Lyme arthritis have persistent arthritis for months or even years after antibiotic therapy (14, 15). This chronic arthritis, which is usually monoarticular, can be severe and disabling. Kalish and colleagues (16) report that in persons with HLA-DR4 haplotype, antibody reactivity to two outer surface proteins of Borrelia species (OspA and OspB) is seen in association with chronic arthritis and a lack of response to antibiotic therapy in some patients (16). It is theorized that this relative antibiotic resistance could be caused by a persistent immunologic response, which might continue even in the absence of the antigen (15, 17). Extra-articular manifestations of Lyme disease include cardiac disease, which typically develops weeks to months after infection and is usually manifested by a fluctuating degree of atrioventricular block. Pericarditis, left ventricular dysfunction, and cardiomegaly are rare. Neurologic Lyme borreliosis accounts for no more than 10% of cases, according to 1990-1995 data from the State of Connecticut (18). Early in the illness, Bell palsy is a common manifestation of disseminated disease and may take weeks to months to resolve (19). Other peripheral neuropathies and Lyme meningitis are also seen at this stage. In late-stage disease, the central nervous system may be involved. A new diagnostic test measuring glial fibrillary acidic protein in cerebrospinal fluid may prove to be a useful tool for measuring such involvement (20). In Europe, untreated Lyme disease can manifest as acrodermatitis chronica atrophicans, a condition in which the skin becomes reddened, wrinkled, and paper-thin. One third of patients have an associated polyneuropathy. This is extremely uncommon in the United States because of the absence of B. afzelii. Antibiotic treatment is at least 90% curative in active early Lyme disease (21-24) but is less successful in late-stage disease. The antibiotic therapy of choice for early Lyme disease is a 21- to 28-day course of doxycycline, 100 mg twice per day, or amoxicillin, 500 mg three times per day. For arthritis, a 30-day course is preferable. Optimal treatment for Lyme carditis or neurologic disease is ceftriaxone, 2 g intravenously for 14 to 28 days. Environment of the Tick The ixodid tick is virtually restricted to forested areas in which its hosts are plentiful. Human disease is thought to be caused largely by nymphal ticks, whose peak activity is in spring and summer. The adult female transmits disease in the fall. In endemic areas, 25% to 35% of nymphal ticks and 50% to 70% of adult ticks are infected with B. burgdorferi. Other species of pathogens, such as Babesia and Ehrlichia, are perpetuated in the same vector ticks and the same reservoir mice as B. burgdorferi (25). Mixed infections in humans are not uncommon. In the western United States, the low rate of B. burgdorferi infection seems to have two causes. The western fence lizard, a principal blood source for the nymphal tick, contains a thermolabile borreliacidal factor (isolated but not yet identified) that has been shown to destroy almost all spirochetes in vitro in less than 1 hour (26). This factor travels to the ticks mid-gut and kills the spirochetes in a fashion similar to that of the newly developed recombinant vaccine. In addition, the I. neotomae tick, which is common in the western United States, does not feed on humans. Fortunately, it takes 24 to 72 hours for spirochetes to be transmitted into humans after the ticks initial attachment. This allows time for persons to safely remove the tiny (< 3 mm) ixodid ticks. After much review, experts have decided that postexposure prophylactic antibiotics should not be used, even in high-risk areas (27, 28). Prevention on a regional level has proven to be cumbersome and ineffective. Communities have attempted to reduce the prevalence of ixodid ticks by burning vegetation, spraying acaricide, locally distributing acaricide, and reducing the deer population. These measures, however, are expensive, inefficient, and harmful to the environment. Avoidance of tick bites remains the mainstay of prevention. Early Vaccine Research: Whole-Cell Studies Research for a vaccine against Lyme disease progressed in earnest when, in 1986, Johnson and coworkers (29) reported passive immunization studies in which Syrian hamsters were successfully protected against live spirochete challenge. In addition, hamsters actively immunized with a single dose of a formalin-inactivated whole-cell lysate vaccine were protected after intraperitoneal inoculation of B. burgdorferi (30). These studies indicated the feasibility of vaccination as a method for the prevention of borreliosis in other species. Canine borreliosis was first reported in 1984 (31). The recognized seroprevalence in dogs increased rapidly. The canine form of the disease produced lameness, fever, and anorexia. In 1992 and 1994, two inactivated whole-cell vaccines were developed and licensed for use in dogs. An inactivated whole-cell vaccine with adjuvant (Borrelia burgdorferi bacterin, Fort Dodge Laboratories, Fort Dodge, Iowa) and a bivalent whole-cell killed vaccine (Solvay Animal Health, Mendota Heights, Minnesota). Studies done under experimental conditions showed that the bacterin was immunogenic and efficacious in protecting vaccinated dogs from developing spirochetemia (32). Protection seemed to be antibody-mediated because the inoculation of serum from immunized animals protected recipient animals (30). Concern was later raised that this immune response may mediate some of the adverse effects of Lyme disease, particularly large-joint arthritis. Furthermore, i