Background Borrelia burgdorferi is difficult to detect in synovialfluid, which limits our understanding of the pathogenesis ofLyme arthritis, particularly when arthritis persists despiteantibiotic therapy.
Methods Using the polymerase chain reaction (PCR), we attemptedto detect B. burgdorferi DNA in joint-fluid samples obtainedover a 17-year period. The samples were tested in two separatelaboratories with four sets of primers and probes, three ofwhich target plasmid DNA that encodes outer-surface proteinA (OspA).
Results B. burgdorferi DNA was detected in 75 of 88 patientswith Lyme arthritis (85 percent) and in none of 64 control patients.Each of the three OspA primer-probe sets was sensitive, andthe results were moderately concordant in the two laboratories(kappa = 0.54 to 0.73). Of 73 patients with Lyme arthritis thatwas untreated or treated with only short courses of oral antibiotics,70 (96 percent) had positive PCR results. In contrast, of 19patients who received either parenteral antibiotics or longcourses of oral antibiotics ( 1 month), only 7 (37 percent)had positive tests (P<0.001). None of these seven patientshad received more than two months of oral antibiotic treatmentor more than three weeks of intravenous antibiotic treatment.Of 10 patients with chronic arthritis (continuous joint inflammationfor one year or more) despite multiple courses of antibiotics,7 had consistently negative tests in samples obtained threemonths to two years after treatment.
Conclusions PCR testing can detect B. burgdorferi DNA in synovialfluid. This test may be able to show whether Lyme arthritisthat persists after antibiotic treatment is due to persistenceof the spirochete.
Source Information
From the Divisions of Rheumatology/Immunology (J.J.N., F.D., A.C.S.) and Pediatric Rheumatology (J.J.N., F.D.), New England Medical Center and Tufts University School of Medicine, Boston; and the Sections of Clinical Microbiology, Infectious Diseases, and Experimental Pathology, Mayo Foundation, Rochester, Minn. (B.J.R., P.N.R., D.H.P.).
Address reprint requests to Dr. Nocton at the Division of Rheumatology/Immunology, New England Medical Center, 750 Washington St., Boston, MA 02111.
Castano, M. J., Solera, J.
(2009). Chronic Brucellosis and Persistence of Brucella melitensis DNA. J. Clin. Microbiol.
47: 2084-2089
[Abstract][Full Text]
Thompson, A., Mannix, R., Bachur, R.
(2009). Acute Pediatric Monoarticular Arthritis: Distinguishing Lyme Arthritis From Other Etiologies. Pediatrics
123: 959-965
[Abstract][Full Text]
Hodzic, E., Feng, S., Holden, K., Freet, K. J., Barthold, S. W.
(2008). Persistence of Borrelia burgdorferi following Antibiotic Treatment in Mice. Antimicrob. Agents Chemother.
52: 1728-1736
[Abstract][Full Text]
Nardelli, D. T., Callister, S. M., Schell, R. F.
(2008). Lyme Arthritis: Current Concepts and a Change in Paradigm. CVI
15: 21-34
[Full Text]
Iliopoulou, B. P., Alroy, J., Huber, B. T.
(2007). CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis. J. Immunol.
179: 8076-8082
[Abstract][Full Text]
Hsieh, Y.-F., Liu, H.-W., Hsu, T.-C., Wei, J. C.-C., Shih, C.-M., Krause, P. J., Tsay, G. J.
(2007). Serum Reactivity against Borrelia burgdorferi OspA in Patients with Rheumatoid Arthritis. CVI
14: 1437-1441
[Abstract][Full Text]
Kannian, P., Drouin, E. E., Glickstein, L., Kwok, W. W., Nepom, G. T., Steere, A. C.
(2007). Decline in the Frequencies of Borrelia burgdorferi OspA161 175-Specific T Cells after Antibiotic Therapy in HLA-DRB1*0401-Positive Patients with Antibiotic-Responsive or Antibiotic-Refractory Lyme Arthritis. J. Immunol.
179: 6336-6342
[Abstract][Full Text]
Crandall, H., Dunn, D. M., Ma, Y., Wooten, R. M., Zachary, J. F., Weis, J. H., Weiss, R. B., Weis, J. J.
(2006). Gene Expression Profiling Reveals Unique Pathways Associated with Differential Severity of Lyme Arthritis. J. Immunol.
177: 7930-7942
[Abstract][Full Text]
Lazarus, J. J., Meadows, M. J., Lintner, R. E., Wooten, R. M.
(2006). IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses. J. Immunol.
177: 7076-7085
[Abstract][Full Text]
Dennis, V. A., Jefferson, A., Singh, S. R., Ganapamo, F., Philipp, M. T.
(2006). Interleukin-10 Anti-Inflammatory Response to Borrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3.. Infect. Immun.
74: 5780-5789
[Abstract][Full Text]
Sartin, J. S., Oettel, K. R.
(2006). A Morphealike Skin Condition Caused by Borrelia burgdorferi in an Immunocompromised Patient. Mayo Clin Proc.
81: 1259-1263
[Full Text]
Steere, A. C., Klitz, W., Drouin, E. E., Falk, B. A., Kwok, W. W., Nepom, G. T., Baxter-Lowe, L. A.
(2006). Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. JEM
203: 961-971
[Abstract][Full Text]
Crandall, H., Ma, Y., Dunn, D. M., Sundsbak, R. S., Zachary, J. F., Olofsson, P., Holmdahl, R., Weis, J. H., Weiss, R. B., Teuscher, C., Weis, J. J.
(2005). Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase. Am. J. Pathol.
167: 775-785
[Abstract][Full Text]
Aguero-Rosenfeld, M. E., Wang, G., Schwartz, I., Wormser, G. P.
(2005). Diagnosis of Lyme Borreliosis. Clin. Microbiol. Rev.
18: 484-509
[Abstract][Full Text]
Dinser, R, Jendro, M C, Schnarr, S, Zeidler, H
(2005). Antibiotic treatment of Lyme borreliosis: what is the evidence?. Ann Rheum Dis
64: 519-523
[Abstract][Full Text]
Behera, A. K., Hildebrand, E., Scagliotti, J., Steere, A. C., Hu, L. T.
(2005). Induction of Host Matrix Metalloproteinases by Borrelia burgdorferi Differs in Human and Murine Lyme Arthritis. Infect. Immun.
73: 126-134
[Abstract][Full Text]
Wang, X., Ma, Y., Weis, J. H., Zachary, J. F., Kirschning, C. J., Weis, J. J.
(2005). Relative Contributions of Innate and Acquired Host Responses to Bacterial Control and Arthritis Development in Lyme Disease. Infect. Immun.
73: 657-660
[Abstract][Full Text]
Bolz, D. D., Sundsbak, R. S., Ma, Y., Akira, S., Kirschning, C. J., Zachary, J. F., Weis, J. H., Weis, J. J.
(2004). MyD88 Plays a Unique Role in Host Defense but Not Arthritis Development in Lyme Disease. J. Immunol.
173: 2003-2010
[Abstract][Full Text]
Salazar, J. C., Pope, C. D., Sellati, T. J., Feder, H. M. Jr, Kiely, T. G., Dardick, K. R., Buckman, R. L., Moore, M. W., Caimano, M. J., Pope, J. G., Krause, P. J., Radolf, J. D.
(2003). Coevolution of Markers of Innate and Adaptive Immunity in Skin and Peripheral Blood of Patients with Erythema Migrans. J. Immunol.
171: 2660-2670
[Abstract][Full Text]
Bergmann, A. R., Schmidt, B. L., Derler, A.-M., Aberer, E.
(2002). Importance of Sample Preparation for Molecular Diagnosis of Lyme Borreliosis from Urine. J. Clin. Microbiol.
40: 4581-4584
[Abstract][Full Text]
Steere, A. C.
(2002). A 58-Year-Old Man With a Diagnosis of Chronic Lyme Disease. JAMA
288: 1002-1010
[Full Text]
Sibilia, J, Limbach, F-X
(2002). Reactive arthritis or chronic infectious arthritis?. Ann Rheum Dis
61: 580-587
[Abstract][Full Text]
Hajjar, R. J., Kradin, R. L.
(2002). Case 17-2002 - A 55-Year-Old Man with Second-Degree Atrioventricular Block and Chest Pain. NEJM
346: 1732-1738
[Full Text]
Giambartolomei, G. H., Dennis, V. A., Lasater, B. L., Murthy, P. K., Philipp, M. T.
(2002). Autocrine and Exocrine Regulation of Interleukin-10 Production in THP-1 Cells Stimulated with Borrelia burgdorferi Lipoproteins. Infect. Immun.
70: 1881-1888
[Abstract][Full Text]
Hosoi, M., Sato, T., Yamagami, K., Hasegawa, T., Yamakita, T., Miyamoto, M., Yoshioka, K., Yamamoto, T., Ishii, T., Tanaka, S., Itoh, A., Haze, K., Fujii, S.
(2002). Impact of Diabetes on Coronary Stenosis and Coronary Artery Calcification Detected by Electron-Beam Computed Tomography in Symptomatic Patients. Diabetes Care
25: 696-701
[Abstract][Full Text]
Smith, R. P., Schoen, R. T., Rahn, D. W., Sikand, V. K., Nowakowski, J., Parenti, D. L., Holman, M. S., Persing, D. H., Steere, A. C.
(2002). Clinical Characteristics and Treatment Outcome of Early Lyme Disease in Patients with Microbiologically Confirmed Erythema Migrans. ANN INTERN MED
136: 421-428
[Abstract][Full Text]
Potter, M. R., Rittling, S. R., Denhardt, D. T., Roper, R. J., Weis, J. H., Teuscher, C., Weis, J. J.
(2002). Role of Osteopontin in Murine Lyme Arthritis and Host Defense against Borrelia burgdorferi. Infect. Immun.
70: 1372-1381
[Abstract][Full Text]
Liang, F. T., Jacobs, M. B., Bowers, L. C., Philipp, M. T.
(2002). An Immune Evasion Mechanism for Spirochetal Persistence in Lyme Borreliosis. JEM
195: 415-422
[Abstract][Full Text]
Reed, K. D.
(2002). Laboratory Testing for Lyme Disease: Possibilities and Practicalities. J. Clin. Microbiol.
40: 319-324
[Full Text]
Pacheco-Tena, C., Alvarado de la Barrera, C., Lopez-Vidal, Y., Vazquez-Mellado, J., Richaud-Patin, Y., Amieva, R. I., Llorente, L., Martinez, A., Zuniga, J., Cifuentes-Alvarado, M., Burgos-Vargas, R.
(2001). Bacterial DNA in synovial fluid cells of patients with juvenile onset spondyloarthropathies. Rheumatology (Oxford)
40: 920-927
[Abstract][Full Text]
Steere, A. C.
(2001). Lyme Disease. NEJM
345: 115-125
[Full Text]
Moro, M. H., Bjornsson, J., Marietta, E. V., Hofmeister, E. K., Germer, J. J., Bruinsma, E., David, C. S., Persing, D. H.
(2001). Gestational Attenuation of Lyme Arthritis Is Mediated by Progesterone and IL-4. J. Immunol.
166: 7404-7409
[Abstract][Full Text]
Trollmo, C., Meyer, A. L., Steere, A. C., Hafler, D. A., Huber, B. T.
(2001). Molecular Mimicry in Lyme Arthritis Demonstrated at the Single Cell Level: LFA-1{{alpha}}L Is a Partial Agonist for Outer Surface Protein A-Reactive T Cells. J. Immunol.
166: 5286-5291
[Abstract][Full Text]
Lünemann, J. D., Zarmas, S., Priem, S., Franz, J., Zschenderlein, R., Aberer, E., Klein, R., Schouls, L., Burmester, G. R., Krause, A.
(2001). Rapid Typing of Borrelia burgdorferi Sensu Lato Species in Specimens from Patients with Different Manifestations of Lyme Borreliosis. J. Clin. Microbiol.
39: 1130-1133
[Abstract][Full Text]
Taylor-Robinson, D, Keat, A
(2001). How can a causal role for small bacteria in chronic inflammatory arthritides be established or refuted?. Ann Rheum Dis
60: 177-185
[Full Text]
Marques, A. R., Stock, F., Gill, V.
(2000). Evaluation of a New Culture Medium for Borrelia burgdorferi. J. Clin. Microbiol.
38: 4239-4241
[Abstract][Full Text]
Potter, M. R., Noben-Trauth, N., Weis, J. H., Teuscher, C., Weis, J. J.
(2000). Interleukin-4 (IL-4) and IL-13 Signaling Pathways Do Not Regulate Borrelia burgdorferi-Induced Arthritis in Mice: IgG1 Is Not Required for Host Control of Tissue Spirochetes. Infect. Immun.
68: 5603-5609
[Abstract][Full Text]
Brown, C. R., Reiner, S. L.
(2000). Bone-Marrow Chimeras Reveal Hemopoietic and Nonhemopoietic Control of Resistance to Experimental Lyme Arthritis. J. Immunol.
165: 1446-1452
[Abstract][Full Text]
Homer, M. J., Aguilar-Delfin, I., Telford, S. R. III, Krause, P. J., Persing, D. H.
(2000). Babesiosis. Clin. Microbiol. Rev.
13: 451-469
[Abstract][Full Text]
Liang, F. T., Nowling, J. M., Philipp, M. T.
(2000). Cryptic and Exposed Invariable Regions of VlsE, the Variable Surface Antigen of Borrelia burgdorferi sl. J. Bacteriol.
182: 3597-3601
[Abstract][Full Text]
Malawista, S. E., Montgomery, R. R., Wang, X.-M., Fu, L. L., Giles, S. S.
(2000). Geographic clustering of an outer surface protein A mutant of Borrelia burgdorferi. Possible implications of multiple variants for Lyme disease persistence. Rheumatology (Oxford)
39: 537-541
[Abstract][Full Text]
Sung, S. Y., McDowell, J. V., Carlyon, J. A., Marconi, R. T.
(2000). Mutation and Recombination in the Upstream Homology Box-Flanked ospE-Related Genes of the Lyme Disease Spirochetes Result in the Development of New Antigenic Variants during Infection. Infect. Immun.
68: 1319-1327
[Abstract][Full Text]
Toivanen, P., Toivanen, A.
(1999). Two forms of reactive arthritis?. Ann Rheum Dis
58: 737-741
[Abstract][Full Text]
Axford, J. S, Rees, D. H E, Mageed, R. A, Wordsworth, P., Alavi, A., Steere, A. C
(1999). Increased IgA rheumatoid factor and VH1 associated cross reactive idiotype expression in patients with Lyme arthritis and neuroborreliosis. Ann Rheum Dis
58: 757-761
[Abstract][Full Text]
Wang, G., van Dam, A. P., Schwartz, I., Dankert, J.
(1999). Molecular Typing of Borrelia burgdorferi Sensu Lato: Taxonomic, Epidemiological, and Clinical Implications. Clin. Microbiol. Rev.
12: 633-653
[Abstract][Full Text]
Brown, J. P., Zachary, J. F., Teuscher, C., Weis, J. J., Wooten, R. M.
(1999). Dual Role of Interleukin-10 in Murine Lyme Disease: Regulation of Arthritis Severity and Host Defense. Infect. Immun.
67: 5142-5150
[Abstract][Full Text]
Hirschfeld, M., Kirschning, C. J., Schwandner, R., Wesche, H., Weis, J. H., Wooten, R. M., Weis, J. J.
(1999). Cutting Edge: Inflammatory Signaling by Borrelia burgdorferi Lipoproteins Is Mediated by Toll-Like Receptor 2. J. Immunol.
163: 2382-2386
[Abstract][Full Text]
Tham, J. M., Lee, S. H., Tan, T. M. C., Ting, R. C. Y., Kara, U. A. K.
(1999). Detection and Species Determination of Malaria Parasites by PCR: Comparison with Microscopy and with ParaSight-F and ICT Malaria Pf Tests in a Clinical Environment. J. Clin. Microbiol.
37: 1269-1273
[Abstract][Full Text]
Morrison, T. B., Ma, Y., Weis, J. H., Weis, J. J.
(1999). Rapid and Sensitive Quantification of Borrelia burgdorferi-Infected Mouse Tissues by Continuous Fluorescent Monitoring of PCR. J. Clin. Microbiol.
37: 987-992
[Abstract][Full Text]
Weis, J. J., McCracken, B. A., Ma, Y., Fairbairn, D., Roper, R. J., Morrison, T. B., Weis, J. H., Zachary, J. F., Doerge, R. W., Teuscher, C.
(1999). Identification of Quantitative Trait Loci Governing Arthritis Severity and Humoral Responses in the Murine Model of Lyme Disease. J. Immunol.
162: 948-956
[Abstract][Full Text]
Akin, E., McHugh, G. L., Flavell, R. A., Fikrig, E., Steere, A. C.
(1999). The Immunoglobulin (IgG) Antibody Response to OspA and OspB Correlates with Severe and Prolonged Lyme Arthritis and the IgG Response to P35 Correlates with Mild and Brief Arthritis. Infect. Immun.
67: 173-181
[Abstract][Full Text]
Brettschneider, S., Bruckbauer, H., Klugbauer, N., Hofmann, H.
(1998). Diagnostic Value of PCR for Detection of Borrelia burgdorferi in Skin Biopsy and Urine Samples from Patients with Skin Borreliosis. J. Clin. Microbiol.
36: 2658-2665
[Abstract][Full Text]
Steere, A. C., Sikand, V. K., Meurice, F., Parenti, D. L., Fikrig, E., Schoen, R. T., Nowakowski, J., Schmid, C. H., Laukamp, S., Buscarino, C., Krause, D. S., The Lyme Disease Vaccine Study Group,
(1998). Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant. NEJM
339: 209-215
[Abstract][Full Text]
Krause, P. J., Spielman, A., Telford, S. R., Sikand, V. K., McKay, K., Christianson, D., Pollack, R. J., Brassard, P., Magera, J., Ryan, R., Persing, D. H.
(1998). Persistent Parasitemia after Acute Babesiosis. NEJM
339: 160-165
[Abstract][Full Text]
Giambartolomei, G. H., Dennis, V. A., Philipp, M. T.
(1998). Borrelia burgdorferi Stimulates the Production of Interleukin-10 in Peripheral Blood Mononuclear Cells from Uninfected Humans and Rhesus Monkeys. Infect. Immun.
66: 2691-2697
[Abstract][Full Text]
Linn, M. L., Mateo, L., Gardner, J., Suhrbier, A.
(1998). Alphavirus-Specific Cytotoxic T Lymphocytes Recognize a Cross-Reactive Epitope from the Capsid Protein and Can Eliminate Virus from Persistently Infected Macrophages. J. Virol.
72: 5146-5153
[Abstract][Full Text]
Wooten, R. M., Morrison, T. B., Weis, J. H., Wright, S. D., Thieringer, R., Weis, J. J.
(1998). The Role of CD14 in Signaling Mediated by Outer Membrane Lipoproteins of Borrelia burgdorferi. J. Immunol.
160: 5485-5492
[Abstract][Full Text]
Leong, J. M., Wang, H., Magoun, L., Field, J. A., Morrissey, P. E., Robbins, D., Tatro, J. B., Coburn, J., Parveen, N.
(1998). Different Classes of Proteoglycans Contribute to the Attachment of Borrelia burgdorferi to Cultured Endothelial and Brain Cells. Infect. Immun.
66: 994-999
[Abstract][Full Text]
Roessner, K., Trivedi, H., Gaur, L., Howard, D., Aversa, J., Cooper, S. M., Sigal, L. H., Budd, R. C.
(1998). Biased T-Cell Antigen Receptor Repertoire in Lyme Arthritis. Infect. Immun.
66: 1092-1099
[Abstract][Full Text]
Pohl-Koppe, A., Balashov, K. E., Steere, A. C., Logigian, E. L., Hafler, D. A.
(1998). Identification of a T Cell Subset Capable of both IFN-{gamma} and IL-10 Secretion in Patients with Chronic Borrelia burgdorferi Infection. J. Immunol.
160: 1804-1810
[Abstract][Full Text]
Priem, S., Burmester, G. R, Kamradt, T., Wolbart, K., Rittig, M. G, Krause, A.
(1998). Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis
57: 118-121
[Abstract][Full Text]
Gross, D. M., Steere, A. C., Huber, B. T.
(1998). T Helper 1 Response Is Dominant and Localized to the Synovial Fluid in Patients with Lyme Arthritis. J. Immunol.
160: 1022-1028
[Abstract][Full Text]
Ma, Y., Seiler, K. P., Eichwald, E. J., Weis, J. H., Teuscher, C., Weis, J. J.
(1998). Distinct Characteristics of Resistance to Borrelia burgdorferi-Induced Arthritis in C57BL/6N Mice. Infect. Immun.
66: 161-168
[Abstract][Full Text]
Tang, Y.-W., Procop, G. W., Persing, D. H.
(1997). Molecular diagnostics of infectious diseases. Clin. Chem.
43: 2021-2038
[Abstract][Full Text]
Ellenbogen, C.
(1997). Lyme Disease: Shift the Paradigm!. Arch Fam Med
6: 191-195
[Abstract]
Granter, S. R., Barnhill, R. L., Hewins, M. E., Duray, P. H.
(1994). Identification of Borrelia burgdorferi in Diffuse Fasciitis With Peripheral Eosinophilia: Borrelial Fasciitis. JAMA
272: 1283-1285
[Abstract]
(1994). Lyme Arthritis:B. burgdorferi DNA in Synovial Fluid. Journal Watch Dermatology
1994: 10-10
[Full Text]
(1994). A NEW DIAGNOSTIC TEST FOR LYME ARTHRITIS. JWatch General
1994: 6-6
[Full Text]
Rahn, D. W.
(1994). Lyme Disease -- Where's the Bug?. NEJM
330: 282-283
[Full Text]