48. | Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)

Chapter 41 Lyme Disease

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 41 Lyme Disease

Steven K. Magid

History
Microbiology
Vectors
Epidemiology
Clinical presentation
Diagnosis
Treatment
Vaccines

Lyme disease has become an increasingly common cause of arthritis and disability. Although it is most prevalent on the East Coast, the disease is also common in Wisconsin and Minnesota, and in fact may be found throughout the continental United States.

I. History. Lyme disease was first described in the United States by Steere et al. (1977) when clusters of an illness first thought to be juvenile rheumatoid arthritis were noted in three small Connecticut communities. These cases were associated with a rash, already known in Europe as erythema chronicum migrans and now referred to as erythema migrans (EM). In Europe, EM was thought to be transmitted by the sheep tick. Spirochetes were noted in the skin lesions, and antibiotics were successfully used to treat the rash. It was soon appreciated that a proportion of the Connecticut patients remembered a tick bite at the site of their rash. In addition, there was a 30-fold higher incidence of EM and Lyme disease in areas inhabited by the Ixodes dammini tick (later renamed Ixodes scapularis ). Eventually, spirochetes were isolated from blood, cerebrospinal fluid, and EM lesions of patients with what was soon appreciated to be a systemic disorder Lyme disease.

II. Microbiology. In 1982, I. dammini ( scapularis ) ticks collected in the locale of EM patients were found to contain spirochetes in their midgut. These organisms were eventually grown on selective media. They led to the development of the EM rash and an antibody response in exposed laboratory animals. These spirochetes were of the genus Borrelia, belonging (along with genera Leptospira and Treponema ) to the order Spirochaetales; they were named Borrelia burgdorferi ( Bb ). Genetic differences have been reported between the Bb genospecies seen in the United States and those seen in Europe and elsewhere. The strain that infects humans in the United States is called Bb sensu stricto. The two most important genospecies in Europe are Bb garinii and Bb afzelii. The differences in genospecies may account for some of the differences between the clinical presentation of Lyme disease in Europe and in the United States. Bb isolated from ticks will grow easily in culture medium. This is not the case with clinical specimens, from which the organism is difficult to isolate and grow.

More than 30 Bb proteins have been identified by immunoblot techniques. There are three major outer surface proteins (Osp): Osp A (30 kd), Osp B (34 kd), and Osp C (23 kd). There is also a 41-kd flagellar antigen that is shared by other spirochetes. In addition, the 18-, 28-, 35-, 37-, 39-, 45-, 58-, 66-, and 93-kd antigens evoke important immune responses.

III. Vectors. Bb is transmitted from the tick by inoculation of saliva and the regurgitation of midgut contents into the bite site. Lyme disease is not thought to be transmitted by sexual contact or by breast milk. Although Bb may survive in banked blood, as of 1994, transfusion-associated Lyme disease had not been reported. The life cycle of I. dammini spans 2 years and includes three stages of development: larva, nymph, and adult. If infected, ticks may spread Lyme disease during each stage. However, ticks at the nymphal stage are the most important vector. Nymphs are most active during the spring and summer, when many people are outdoors in shorts and short sleeves. And nymphs are so small, they are easily overlooked. This probably accounts for the peak onset of Lyme disease during these months. The preferred host of the I. dammini tick is the white-footed mouse. Adult ticks feed on deer and other rodents, but it is the deer that most often serves as the mating ground of the adult tick (hence the name deer tick). Humans, birds, and many other animals also serve as vectors. In the endemic areas of the northeast, 30% to 50% of nymphal and adult ticks may be infected with Bb (in some areas, the rate of infection may be even higher). In the north central United States, rates of 10% to 20% are reported, in contrast to the Pacific Coast, where the rate of tick infection is approximately 1% to 2%.

A number of different members of the I. ricinus complex of ticks are involved in the dissemination of Lyme disease. On the East Coast, I. scapularis is the most important vector. In the Western United States, I. pacificus, the Western black-legged tick, is responsible. I. ricinus is the main vector in western and central Europe; and I. persulcatus is found in eastern Russia, China, and Japan.

IV. Epidemiology. According to the Centers for Disease Control and Prevention, Lyme disease is the most common vector- borne disease in the United States. Since 1982, more than 95,000 cases have been reported in the United States. This is almost certainly a vast underestimate, as many cases are thought not to be reported. In the United States, Lyme disease causes 95% of all vector-borne diseases. The overall incidence in the United States is about 5 in 100,000. However, in endemic areas, it may be as high as 1 to 3 in 100 per year! Through 1995, cases have been reported in all states except Montana. In 1995, the eight states (Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, Maryland, Wisconsin, and Minnesota) with the highest reported rate of Lyme disease accounted for 91% (10,613) of the 11,700 cases reported. New York State reported 38% (4,438) of all cases. Cases have been reported from most European countries , the (former) U.S.S.R., China, Japan, and Australia. Lyme disease may occur in all age groups. There is a peak in children and in persons ages 30 through 49. The earliest cases of Lyme disease were thought to have occurred 25 years ago on Cape Cod and in Connecticut. However, the spirochete has been identified in ticks collected more than 50 years ago! There has obviously been a rapid spread of Lyme disease since that time.

V. Clinical presentation. Steere has outlined a useful clinical classification for Lyme disease. In this scheme, Lyme disease is divided into early localized (stage 1), early disseminated (stage 2), and late disseminated (stage 3) infection (Table 41-1).

Table 41-1. Manifestations of Lyme disease by stage ^a

Early localized (stage 1). Lyme disease is initiated by the injection of the Bb spirochete into the skin by an infected tick. After local spread, the characteristic rash of EM develops 3 to 32 days later (mean, 7 days) in approximately 70% of patients. Only one-third of patients may remember the actual tick bite. EM may be seen anywhere , but it frequently occurs on the thigh, groin, and axilla. In children, the earlobe crease is a common site. The size may be from 3 cm to 70 cm (mean, 15 cm). A hallmark of the rash is its gradual expansion in size up to 1 to 2 cm a day. As it expands, bright red outer borders develop. Typically, there is a central clearing, and the rash takes on a ringlike appearance. However, the rash may also be vesicular, necrotic, or targetlike. The skin may be burning, painful, and pruritic. If antibiotics are not given, the lesions usually clear within a month (range, 1 day to 14 months). If antibiotics are used, the lesions clear in several days. During the early localized stage, there may be minor constitutional symptoms and regional lymphadenopathy.
Early disseminated (stage 2). Within days to weeks of the tick bite, the spirochete spreads systemically via blood or lymph. At this time, blood culture results may be positive. There are many possible manifestations of Lyme disease, but often a characteristic syndrome develops. Early on, there may be excruciating headaches and a stiff neck. These episodes typically occur in short, hour -long attacks. There are frequently migrating, intense pains in joints, bursae, tendons, muscles , and bones. The patient may appear ill and complain of debilitating malaise and fatigue. These symptoms appear during the phase of hematogenous spread. Later, in stage 2, the spirochetes seem to establish themselves preferentially in certain sites, including the nervous system, heart, and musculoskeletal system. The spirochete may be found in pathologic specimens from the heart, retina , muscle, bone, synovium, spleen, liver, meninges, and brain. Secondary EM occurs in approximately 50% of patients who note primary EM. These lesions resemble primary EM but are smaller and tend to migrate less. They are frequently multiple and annular, with merging borders.
1. Neurologic manifestations
  1. Cranial nerves. Weeks to months after the onset of Lyme disease, neurologic symptoms develop in 15% to 20% of patients. Bell's palsy is particularly common. It is usually unilateral but may be sequential or bilateral. Other cranial neuropathies are less common and may occur with or without Bell's palsy. Involvement of cranial nerves III, IV, and VI may cause extraocular palsy. If the fifth cranial nerve is involved, facial dysesthesia may occur. Dizziness, otalgia, sore throat, and deafness may occur with cranial nerve VIII involvement. Optic atrophy and Argyll-Robertson pupils may occur if the optic nerve is involved.
  2. Peripheral nerves. Neuropathies are sometimes seen and frequently involve the median nerve.
  3. Radiculopathy may be unilateral, often in the dermatome of the tick bite. It commonly involves T-5 and T-8 through T-12. The radiculopathy may be sequential and bilateral.
  4. Aseptic meningitis. Recurrent attacks of prostrating headaches may occur and are often associated with stiff neck, photophobia, nausea, and vomiting. Patients are frequently afebrile. Such severe attacks may last weeks and alternate with periods of milder headache . Spinal fluid shows a lymphocytic pleocytosis with increased production of immunoglobulin G (IgG). Evidence of local antibody to Bb may be found. Oligoclonal banding may also be seen.
  5. Encephalitis may begin in stage 2. It is manifested by lethargy, fatigue, dementia, poor concentration and memory, and emotional lability.
    It has not been established whether peripheral and cranial neuropathies are always associated with central nervous system infection. It is also not known whether resolution of neurologic signs and symptoms without treatment are indicative of resolution of infection, or if infection persists in a latent state.
2. Cardiac manifestations. Several weeks after the EM rash, cardiac involvement may develop in 4% to 8% of patients. Atrioventricular block in fluctuating degrees is the most common finding. The duration is usually brief (3 days to 6 weeks). Complete heart block rarely occurs and, when present, usually does not last more than a week. A permanent pacemaker is usually not needed. Ventricular tachycardia has been reported. Other manifestations may include acute myopericarditis, mild left ventricular dysfunction, cardiographic abnormalities, and rarely pancarditis. The latter may be fatal. Valvular lesions are not seen.
3. Joint manifestations. Arthritis is usually considered a late manifestation of disease, but acute attacks may begin in the early disseminated phase. They may appear as early as a few weeks after disease onset. At a mean of 6 months after the onset of Lyme disease (range, 2 weeks to 2 years), attacks of arthritis will develop in 60% of patients. It is usually asymmetric and oligoarticular (involving four or fewer joints). Large joints are preferentially involved, especially the knee. Initially, these attacks are brief and may last days or weeks and then remit without antibiotic therapy . Although some patients have continuous inflammation , most do not. The leukocyte counts in specimens of Lyme disease effusions obtained by arthrocentesis range from 500 to 110,000/mm ³ ; polymorphonuclear leukocytes predominate. As demonstrated by polymerase chain reaction (PCR), culture, and staining, the involved joints are usually directly infected with Bb.
Late persistent infection (stage 3)
1. Arthritis
  1. Clinical presentation. In one study, 55 patients with untreated EM were followed. Eleven patients had EM as the only manifestation of Lyme disease, with no joint involvement at all. Ten patients had EM with arthralgias, 28 had EM with intermittent arthritis, and only 6 had EM with chronic arthritis. The most common pattern was an asymmetric oligoarthritis or monarthritis of large joints. Most patients had knee involvement at some point in their illness. Characteristically, the knees became very swollen (sometimes massively). They appeared warm but not hot. Pain was moderate but not severe. In three patients, Baker's cysts developed with early rupture . Arthritis of the ankle, wrist, and occasionally elbow and hand has also been seen. Temporomandibular joint involvement is also frequent. It is rare for more than five joints to be involved. Although it is unusual for small joints to be involved, a rheumatoid arthritis-like picture has been reported. Nodules are unusual but have been described in atypical locations.
  2. Chronic arthritis. Arthritis dominates stage 3. With time, the above-mentioned episodic attacks may last for months rather than weeks. Eventually, chronic arthritis (defined as arthritis lasting more than a year), may develop. This occurs in fewer than 10% of Lyme disease patients, and it has been suggested that the presence of the HLA-DR4 haplotype, in addition to a lack of response to antibiotics, places a person at greater risk for the development of chronic arthritis. The transition from episodic attacks to chronic arthritis has been associated with the development of antibodies to Osp A. To explain the fact that in some patients with chronic arthritis the PCR does not show Bb sequences, many theories have been advanced. It appears that some cases of chronic Lyme arthritis may not be caused by persistent Bb infection, but rather by a reactive or immune process. It is interesting to note that chronic arthritis may spontaneously resolve, even after years.
2. Neurologic manifestations. Chronic or late Lyme neuroborreliosis may have manifestations in both the peripheral and central nervous systems.
  1. Chronic radiculoneuropathy presents mainly with sensory symptoms, especially radicular pain or distal paresthesias. They usually affect the limbs , rather than the trunk, in a stocking-glove distribution.
  2. Patients with encephalopathy usually complain of difficulty with memory and concentration. Hypersomnolence, depression, irritability, and marked memory loss are noted.
  3. Leukencephalitis and encephalomyelitis are rare in the United States. Optic neuropathy, spastic paraparesis, bladder dysfunction, ataxia, dysarthria, and encephalopathy may also be seen.

VI. Diagnosis. The diagnosis of Lyme disease is a clinical one. Laboratory data are used solely as a means of confirmation. Supporting clinical evidence includes epidemiologic data, characteristic clinical presentations, and the exclusion of other disorders in which joint, cardiac, and neurologic phenomena occur. Serologic testing remains the best way to confirm a clinical diagnosis in a patient with suspected Lyme disease.

The immunofluorescence assay (IFA) was the first to be developed. An indirect immunofluorescence technique involving the whole Bb organism is used. Antibodies detected by this technique are seen within weeks of the onset of the disease.
Enzyme -linked immunosorbent assay (ELISA) is usually considered to be the preferred screening method. The sensitivity, specificity, and reproducibility are considered better than those of the IFA. Sonicated, whole- Bb extracts are used as the antigens. IgM antibodies appear 2 to 4 weeks after the EM rash. They peak after 8 weeks and usually normalize by 4 to 6 months. Continued or late appearance of IgM antibodies may be indicative of ongoing or recurrent infection. IgG antibodies occur within 6 to 8 weeks after the EM rash, peak after 4 to 6 months, and may remain elevated indefinitely.
Western blot. This technique separates the major Bb proteins on an agar gel by molecular weight. By overlaying a patient's sera, it is possible to determine which Bb proteins (if any) are the targets of an antibody response. Some of the more important Borrelia antigens identified by Western blot include 31-kd Osp A; 34-kd Osp B; 21- to 24-kd Osp C (varies with the strain of Bb used); Bmp A (p39), which appears to be highly specific for Lyme disease; 41-kd flagellin (a motility component with strong cross-reactivity to flagellins of other organisms); and 58-, 60-, 66-, and 72-kd heat shock proteins (which are widely conserved in all cells and have strong homology with other organisms).
Characteristic patterns of antibody formation after infection with Bb have been used by the Centers for Disease Control and Prevention to develop criteria for a positive Western blot. IgM2 of three positive bands: 24 (Osp:C), 39 (Bmp A), and 41 (Fla) kd. IgG5 of 10 bands: 18, 21 (= 24), 28, 30, 39, 41, 45, 58 (not GroEL), 66, and 93 kd.
The polymerase chain reaction is a technique that amplifies a single copy of Bb DNA into many millions of copies, allowing the detection of even a single Bb genome. It is most useful in testing inflammatory fluids such as cerebrospinal and joint fluid rather than blood. The PCR technique is limited by the fact it cannot distinguish between the DNA from living Borrelia and the DNA from nonviable organisms. In addition, special laboratory techniques are required to avoid false-positive results in this highly sensitive test.
Cellular immunity testing. T cells reactive against Bb have been found in the blood, synovial fluid, and cerebrospinal fluid of Lyme disease patients. The interest in this test stems from the occasional Lyme disease patient with a positive T-cell proliferation test result in the absence of a positive serologic test result. However, this circumstance is decidedly rare. The utility of the T- cell proliferation test is limited by the fact that it is difficult to perform and interpret. Fresh T cells are required, the results depend on the way the Bb organisms are prepared, and there are many interlaboratory variations in reported results. Although considerable discussion and debate about the utility of clinical T-cell testing are ongoing, at present it cannot be routinely recommended.
Urinary antigen testing is based on the ability to detect Osp that has been shed and filtered by the glomerulus. It currently has no clinical role.
False-negative results of immunofluorescence assay or enzyme-linked immunosorbent assay may be caused by the following:
1. Testing during the first weeks of infection, before antibody development. It is important to recognize that in tertiary neuroborreliosis and in Lyme arthritis, results of serologic testing are almost universally positive.
2. Laboratory variation or error. Studies have demonstrated marked interlaboratory variations in test results.
3. Early use of antibiotics, which may abort a humoral immune response.
4. T-cell suppression of antibody production early in the course of the disease.
5. Immune complex sequestration of antibodies.
  Lyme disease patients with negative IFA or ELISA serologies may occasionally be positive for cerebrospinal fluid antibodies or, as mentioned above, demonstrate a T-cell proliferation response to Bb .
False-positive results of immunofluorescence assay or enzyme-linked immunosorbent assay are common. They may be caused by the following:
1. Cross-reactivity with other spirochetes
  1. Nonpathogenic oral spirochetes and those that cause gingivitis.
  2. Treponema pallidum (and Treponema organisms that cause yaws and pinta).
  3. Cross-reactivity with homologous non- Bb proteins (heat shock proteins or flagellin).
2. Polyclonal B-cell activation, particularly in patients whose serum contains rheumatoid factor, antinuclear antibodies, or anti- thyroid antibodies, and in patients with malaria, Epstein-Barr virus infection, and Rocky Mountain spotted fever .
3. Prior, possibly asymptomatic Bb infection. If another type of illness occurs in these patients, it may be wrongly attributed to Lyme disease. This is exemplified by a report of four patients who were initially thought to have Lyme disease but were shown to have endocarditis. This highlights the care with which a diagnosis of Lyme disease must be made.

VII. Treatment

Protection from ticks may be the most important method of combating Lyme disease. This is accomplished by the following:
1. Wearing protective, light-colored clothing tucked in at the ankles and wrists.
2. Using insect repellent on clothing.
3. Inspecting for ticks. It probably takes more than 24 hours for transmission of Bb after tick attachment.
4. Proper tick removal.
5. Modifying residential landscapes (clear leaf litter, brush, tall grass; remove stone walls, wood piles; erect deer barriers).
6. Area application of acaricides. This is effective but raises safety concerns.
Facts about tick bites
1. Tick removal. Proper removal minimizes the risk for inoculation of tick gut contents. Use tweezers to grasp the tick behind its head, pull slowly and gently.
2. The risk for acquiring Lyme disease varies and depends on the local Bb infection rate of ticks (which may range from 1% to 50%). It is likely that most tick bites (cited as <95%) do not result in the transmission of Lyme disease. Transmission rates also vary with the duration of tick attachment; it is thought that transmission of Lyme disease rarely occurs earlier than 48 hours after attachment.
3. Use of prophylactic antibiotics. Studies have not been able to prove the efficacy of prophylactic antibiotic treatment after a tick bite. In addition, it has been stated that the risk for acquiring Lyme disease after an observed tick bite is equal to the risk for an adverse drug effect, including anaphylaxis and photosensitivity (especially with doxycycline).
Recommended strategy for possible infection. After a tick bite has been sustained, one approach is to observe the area of the bite to see if EM develops. If it does, antibiotics should be given. Similarly, if a flulike illness or fever develops, antibiotics should also be given. More controversial is whether antibiotics should be given for a worried patient or a worried doctor! Much of this depends on an evaluation of the risk for Lyme disease, the prevalence of Bb -infected ticks in the area, and whether or not the tick was engorged. An exception to this would be a pregnant patient, to whom a 10-day course of oral amoxicillin might be offered .
Recommended approach to seropositive patients
1. Without signs or symptoms. Most experts do not advocate treatment in this group of patients, especially if the Western blot does not confirm the diagnosis. However, patients with a positive Western blot result and no symptoms may be offered a lumbar puncture, with treatment based on the results. Alternatively, an empiric course of oral antibiotics may be given. In clinical practice, the latter may be the easiest route to follow.
2. With nonspecific symptoms. This is the most difficult group to evaluate. In general, most patients with Lyme disease will have objective evidence of the disease on history, physical examination, and laboratory testing. The pitfalls of treating ELISA-positive patients with nonspecific symptoms but without Western blot confirmation of Lyme disease should be appreciated.
Treatment of confirmed Lyme disease. The treatment protocols currently recommended are summarized in Table 41-2.

Table 41-2. Recommendations for antibiotic treatment ^a
1. Early localized (stage 1). Antibiotic treatment of EM is felt to shorten the course of the rash and decrease the chance of disease progression. Bb is sensitive, in animal studies and in vitro, to tetracycline, ampicillin, ceftriaxone, imipenem, and erythromycin. The advantages of doxycycline over tetracycline are better gastrointestinal absorption and central nervous system penetration and twice-daily dosing. However, neither should be used in pregnant women or in children. It is important to be aware of the possibility of photosensitivity reactions . Cefuroxime axetil (Ceftin) seems to be as effective as doxycycline. Azithromycin may be less effective than amoxicillin. The greater the number of extra-cutaneous manifestations, the slower the antibiotic response and the greater the risk for late disease. A higher dose and longer duration of antibiotic treatment may be required in this setting. If treatment is given early in Lyme disease, the antibody response may disappear. In this setting, recurrent infections have been reported.
2. Early disseminated (stage 2). Oral antibiotics are generally effective during early stage 2 disease. They are effective for secondary EM, migratory musculoskeletal pain, severe malaise, isolated Bell's palsy, and possibly acute arthritis. Longer courses may be required for persistent symptoms. However, IV antibiotics are generally needed for any neurologic sign other than Bell's palsy and for abnormal lumbar puncture findings. Some specialists advocate a lumbar puncture for all patients with neurologic signs or symptoms, including Bell's palsy, because abnormal findings would suggest that IV therapy should be given. The antibiotics standard for high-degree atrioventricular block or cardiomegaly are ceftriaxone and penicillin G. A temporary pacer and an intensive care unit setting are also indicated.
3. Arthritis. The optimal treatment regimen for arthritis has still not been completely defined. Early on in the course of the disease, bouts of arthritis may be self-limited and resolve without antibiotics. Although arthritis has been treated with both oral and parenteral antibiotics, some patients prefer initial oral treatment. It may take many months for a clinical response to occur. Those who fail an initial oral antibiotic course should be treated with IV antibiotics. Some physicians may opt to treat IV from the start, particularly if neuroborreliosis has not been ruled out. A fibromyalgia picture with nonspecific complaints has been described. Antibiotics are not effective in treating this malady. Intraarticular steroids should be avoided before the institution of antibiotic therapy because they have been associated with an increased risk for antibiotic failure. Arthroscopic synovectomy of the knee has also been reported to be beneficial in treating chronic Lyme arthritis refractory to other modalities.
4. Pregnancy. There have been case reports of Bb causing prematurity, stillbirth, central nervous system infection, and cardiac malformations in the fetus. However, follow-up studies do not directly implicate Lyme disease as a cause of the congenital malformations. Seropositivity in an otherwise asymptomatic pregnant patient or a prior history of Lyme disease in a patient who is currently pregnant does not confer an increased risk to the fetus. Nonetheless, most physicians believe that active Lyme disease in a pregnant patient warrants aggressive and usually IV treatment.

VIII. Vaccines. Recombinant Osp A vaccine has been shown to protect against Lyme disease in a mouse model. A chemically inactivated whole-cell vaccine has been approved for use in dogs. In humans, recombinant Osp A vaccination is being studied. A phase II randomized, double-blind, placebo-controlled study of 350 residents of an island highly endemic for Lyme disease showed high efficacy and no significant side effects ( participants had no prior infection). Another study done in subjects with prior Lyme disease showed good tolerance. Two double-blind phase III trials of recombinant Osp A have been completed. Both studies demonstrate safety and efficacy. It has been postulated that the vaccine may work by causing antibody-mediated death of spirochetes in the tick midgut, before the spirochetes can be transmitted to the vaccinated host.

Bibliography

Abramowicz M, ed. Treatment of lyme disease. Med Lett Drugs Ther 1997;39:47.

Burgdorfer W, et al. Lyme disease: a tick-borne spirochetosis? Science 1982;216:1317.

Centers for Disease Control and Prevention. Lyme diseaseUnited States, 1987 and 1988. JAMA 1989;262:2209.

Dattwyler RJ, et al. Seronegative Lyme disease: dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 1988;319:1441.

Kaell AT, et al. Positive Lyme serology in subacute bacterial endocarditis: a study of four patients. JAMA 1990;264:2916.

Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438.

Rahn DW, Evans J, eds. Lyme disease. American College of Physicians, Philadelphia, 1998.

Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis and treatment. Ann Intern Med 1991;114:472.

Sigal LH, et al. A vaccine consisting of recombinant Borrelia burgdorferi outer surface protein A to prevent Lyme disease. N Engl J Med 1998;339:216.

Steere AC. Lyme disease. N Engl J Med 1989;321:586.

Steere AC, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 1977;20:7.

Steere AC, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209.

Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 1987;107:725.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

-->