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.
Lyme disease is caused by the tick-borne spirochete Borreliaburgdorferi1. Weeks to months after the onset of disease, approximately60 percent of untreated patients begin to have brief, intermittentattacks of arthritis that may recur for several years2. A smallpercentage of these patients have continuous arthritis for oneyear or longer, a condition we have termed "chronic Lyme arthritis"2,3.Eventually, both intermittent and chronic Lyme arthritis resolve,even in untreated patients2,4.
Lyme arthritis can usually be treated successfully with eithera one-month course of doxycycline or amoxicillin or a two-weekcourse of intravenous ceftriaxone or penicillin5,6,7. However,a small percentage of patients have persistent arthritis despitemultiple courses of oral and intravenous antibiotic therapy5,6,7.In these patients there is an increased frequency of HLA-DR4or, secondarily, HLA-DR2 in association with antibody reactivityto outer-surface proteins A and B (OspA and OspB) of the spirochete8,9.It has been unclear whether this treatment-resistant courseresults from persistent infection or from postinfective immune-mediatedphenomena. The ability to demonstrate the presence or absenceof B. burgdorferi in the joint would improve our understandingof the pathogenesis of Lyme arthritis.
B. burgdorferi can be cultured readily from the skin lesionsof erythema migrans,10 but it has been difficult to detect thespirochete in joints; it has been recovered from the synovialfluid of only two patients with Lyme arthritis11,12. With immunohistologictechniques, spirochetal forms have been seen in synovial tissue,13but this method of detection has been inconclusive. The polymerasechain reaction (PCR) has recently been used to amplify and detectB. burgdorferi DNA in cultured spirochetes,14,15 Ixodes damminiticks,16,17 infected animals,18,19 and patients with Lyme disease20,21,22,23,24,25,26,27,28,29,30,31,32,33.In these studies, DNA sequences have been successfully detectedin blood,20,21,30,32 cerebrospinal fluid,22,23,24,25,32,33 urine,21,25,28,32skin,29,30,31 and (in eight cases) synovial fluid21,26,27,32.Thus, the PCR assay is capable of amplifying and detecting B.burgdorferi DNA, but its value as a reliable diagnostic test,particularly in synovial fluid, is not yet clear.
We report here on our evaluation of PCR testing as a diagnostictest for the presence of B. burgdorferi DNA in synovial fluid.If the test can reliably identify the presence of spirochetes,it may help to determine whether persistent arthritis aftertreatment is due to active infection or to an immune reactionthat persists after the eradication of viable spirochetes.
Methods
Patients
During a 17-year period, samples of synovial fluid were collectedfrom 127 patients with Lyme arthritis who were seen in the Lymedisease clinics at Yale-New Haven Hospital (1975 to 1987) orNew England Medical Center (1987 to 1992). The following criteriawere used to define Lyme arthritis: brief, intermittent attacksof oligoarticular arthritis, exposure in an area of endemicdisease, an elevated antibody response to B. burgdorferi onenzyme-linked immunosorbent assay, and the exclusion of otherknown forms of arthritis. The synovial-fluid samples were dividedinto multiple aliquots and frozen at -70 °C; in most instances,the aliquot used for PCR testing was not opened before thisstudy. Samples from 37 of the patients were collected in heparin,a known inhibitor of PCR amplification34; these samples wereexcluded from the study. Single samples were tested in 61 ofthe remaining 90 patients, and two to five serial samples weretested in 29. Clinical data collected from the charts of patientswith Lyme arthritis were analyzed without knowledge of the resultsof PCR assays. During the same 17-year period, synovial fluidwas also obtained from 69 control patients with other formsof arthritis. Seventeen of these samples were collected, processed,and stored in the same way as those from the patients with Lymearthritis. Among the control patients, 20 had rheumatoid arthritis;7 each had gout, osteoarthritis, and degenerative joint disease;5 had juvenile rheumatoid arthritis; 2 each had pseudogout,psoriatic arthritis, scleroderma, spondyloarthropathy, and Reiter'ssyndrome; and 13 had other forms of arthritis.
PCR Assay
Synovial-fluid samples from case and control patients were processedin a blinded manner in two separate laboratories according tothe following protocol. DNA was isolated from 100 to 200 microlof synovial fluid with a commercially available kit (Isoquick,Microprobe, Bothell, Wash.) according to the manufacturer'sspecifications, modified by the addition of 20 µg of glycogento each sample as a carrier during isopropanol precipitation.With each DNA extraction, synovial-fluid samples from case andcontrol patients were processed simultaneously. Filter-barrierpipette tips and a dedicated set of pipettors were used to prepareall samples.
Three separate regions of the B. burgdorferi genome were targetedfor PCR amplification by four sets of primers and probes (Table 1).Sets 1, 2, and 3 targeted portions of the B. burgdorferiplasmid gene encoding OspA, and set 4 targeted a portion ofthe chromosomal DNA encoding 16S ribosomal RNA35. Sets 2 and3 targeted the same sequence of the OspA gene for amplification,but used different internal probes for detection.
Table 1. Oligonucleotide Primer and Probe Sequences.
Primers and probes were synthesized on an oligonucleotide synthesizer(Applied Biosystems, Foster City, Calif.), desalted on an oligonucleotide-purificationcartridge (Glen Research, Sterling, Va.), and used without furtherpurification. Total DNA was dissolved in 30 microl of water;5 microl of this solution was added to a PCR mixture containing50 pM of each primer (final concentration, 1.0 micro M), 200micro M of each deoxynucleoside triphosphate, 10 mM TRIS-hydrochloride(pH 8.3), 50 mM potassium chloride, 17.5 mM magnesium chloride,0.01 µg of bovine serum albumin per microl, 10 percentglycerol, 0.5 percent Tween-20, and 1.25 units of Taq polymerase(Amplitaq, Perkin-Elmer Cetus, Norwalk, Conn.). Five microgsof isopsoralen was added to the PCR mixture to inactivate productsafter amplification,36 and the total volume was adjusted to50 microl with water. The mixture was overlaid with one dropof mineral oil. Amplification reactions, which were performedin a thermal cycler (Perkin-Elmer Cetus) stored in a separatelaboratory, consisted of 45 cycles of denaturation at 94 °Cfor 45 seconds, annealing at 50 °C for 45 seconds, and extensionat 72 °C for 1 minute. The cycles were preceded by a four-minutephase at 94 °C and followed by a final seven-minute extensionphase at 72 °C. After amplification, samples were immediatelyexposed to 20 mW of 300-to-400-nm light per square centimeterfor 20 minutes to inactivate the products and were stored at-20 °C.
Control samples included with each amplification assay includedsamples with DNA extracted from control patients, three blankcontrol samples with 5 microl of water substituted for DNA,and a positive control sample with 60 pg of total B. burgdorferiDNA (strain 297). Amplification products were stored and analyzedin a separate area, and positive-displacement pipettes withdisposable pistons were used to prepare all PCR reagents.
Amplified products (5 microl) were resolved by 4 percent agarosegel electrophoresis (3 percent NuSieve and 1 percent SeaKem,FMC Corporation, Rockland, Me.) at 35 to 100 V for one to threehours. The gel was then stained with ethidium bromide and visualized,washed with water, washed in denaturation solution (1.5 M sodiumchloride and 0.5 M sodium hydroxide) for 45 minutes, rinsedagain with water, washed in neutralization solution (1.5 M sodiumchloride and 0.5 M TRIS [pH 7.5]), and blotted. Blotting wasperformed overnight on a nylon membrane (Hybond-N, Amersham,Arlington Heights, Ill.) with 0.15 M sodium chloride and 0.015M sodium citrate (SSC). The membrane was cross-linked with 0.12J of ultraviolet light.
Membranes were washed in hybridization fluid (5x Denhardt'ssolution [1x Denhardt's solution is 0.02 percent Ficoll, 0.02percent polyvinylpyrrolidone, and 0.02 percent bovine serumalbumin], 0.75 M sodium chloride, 0.025 M sodium phosphate,0.005 M ethylenediamine tetraacetate, 0.5 percent sodium dodecylsulfate, and 100 µg of denatured salmon-sperm DNA permicrol) for four hours at 55 °C. An oligonucleotide probeend-labeled with phosphorus-32 was then added for 15 to 17 hoursat 55 °C. After hybridization, the membranes were washedin 2x SSC and 0.1 percent sodium dodecyl sulfate for 10 minutes,1x SSC and 0.1 percent sodium dodecyl sulfate for 20 minutes,and 0.2x SSC and 0.1 percent sodium dodecyl sulfate for 30 minutes.Finally, the membranes were exposed to Kodak XAR-5 film for4 to 72 hours at -70 °C. Alternatively, the amplificationproducts were detected by means of a chemiluminescent probeas described elsewhere37. DNA bands were rarely seen on ethidium-stainedgels; samples were therefore considered positive on the basisof signal detection after hybridization.
Inhibition Assays
The initial samples from each patient with Lyme arthritis inwhich B. burgdorferi DNA was not detected and 62 of the 69 samplesfrom the controls were tested for the presence of PCR inhibitors.One thousand copies (as determined by serial dilution) of theOspA2-OspA4 amplification product made without isopsoralen cross-linkingwere added to each sample and then amplified with primers OspA2and OspA4. Samples that yielded no amplification signal wereconsidered inhibitory and were excluded from the study.
Statistical Analysis
The similarity of groups was compared by Fisher's exact test,the distribution of values among the groups was compared byWilcoxon rank-sum test, and concordance among test results wascalculated with values according to the following formula: = (observed agreement - expected agreement) divided by (1 -expected agreement). All P values are two-tailed.
Results
In tests performed independently in two laboratories, B. burgdorferiDNA was detected with at least one primer-probe set in the initialsamples of synovial fluid from 75 of the 90 patients with Lymearthritis. In contrast, B. burgdorferi DNA was not found inany of the 69 control patients or in the blank control samples.In inhibition assays, 2 of the 15 negative samples from thepatients with Lyme arthritis and 5 samples from control patientsstill produced negative results, indicating that inhibitorsof PCR amplification were present. With these samples excluded,B. burgdorferi DNA was detected in the initial sample from 75of 88 patients with Lyme arthritis but none of 64 control patients(Table 2).
Table 2. PCR Results in Synovial Fluid from Case and Control Patients.
Of the four primer-probe sets used in the two laboratories,the three OspA sets each detected B. burgdorferi DNA in 75 to89 percent of the 75 patients with positive test results (Table 2).Forty-eight patients (64 percent) had positive results withall three OspA sets, whereas 18 patients (24 percent) had positiveresults with only one of the sets. Set 4, which detected chromosomalDNA encoding 16S ribosomal RNA, was less sensitive than theOspA primer-probe sets; 56 percent of the 75 patients had positiveresults with this set, and all of them also had positive resultswith OspA set 3. In laboratory 1, 88 percent of the patientshad concordant results with the two OspA primer-probe sets usedin that laboratory (kappa = 0.73). Between laboratories 1 and2, 78 percent had concordant results with the OspA primer-probesets that targeted the same gene segment (sets 2 and 3) (kappa= 0.54).
Clinical data from the 88 patients with Lyme arthritis werecorrelated with the PCR results from their initial samples ofsynovial fluid (Table 3). As compared with the 13 patients withnegative results, the 75 patients in whom B. burgdorferi DNAwas detected in joint fluid had significantly higher white-cellcounts in synovial fluid (P<0.003), shorter durations ofillness (P<0.02) and arthritis (P<0.03), and a longerduration of arthritis after aspiration (P = 0.03). Almost allof those with positive results were untreated or had only receivedshort courses of oral antibiotic therapy (<1 month) beforejoint aspiration (P<0.001).
Table 3. Clinical Data and PCR Results in Patients with Lyme Arthritis.
Of the 88 patients in this study, 45 never received antibiotictherapy. B. burgdorferi DNA was detected in the synovial fluidof 43 of these patients (Table 4). All 12 patients from whomserial samples were available for testing had detectable B.burgdorferi DNA in their first sample (Figure 1). In 9 of the12 patients, including the 3 who had chronic arthritis (oneyear or more of continuous joint inflammation), all additionalsamples were also positive months to years later during subsequentepisodes of arthritis. In the remaining three patients, B. burgdorferiDNA was not detected in the last synovial-fluid sample, andtheir arthritis resolved within the next few months.
Figure 1. Natural History of Lyme Arthritis and PCR Results in 12 Untreated Patients.
The horizontal lines indicate periods of arthritis. Patients 10, 11, and 12 had chronic Lyme arthritis, defined as one year or more of continuous joint inflammation. The results of PCR testing are indicated above the horizontal lines, with plus and minus signs denoting positive and negative results, respectively. Syn denotes synovectomy.
Forty-three of the 88 patients received antibiotic therapy sometimeduring the course of Lyme disease. Of the 16 patients with pretreatmentsynovial-fluid samples available for testing, 15 had positivetest results (Table 4). In another 12 patients with synovialfluid obtained two months to four years after short coursesof oral antibiotic therapy, all samples were also positive.In 19 patients, 4 of whom also had pretreatment samples availablefor testing, synovial fluid was obtained after either long coursesof oral antibiotics (doxycycline or amoxicillin for one monthor more) or parenteral antibiotics (intravenous or intramuscularpenicillin or intravenous ceftriaxone), regimens recommendedfor the treatment of Lyme arthritis38,39. In 7 of the 19 patients,B. burgdorferi DNA was detected in samples obtained 1 day to17 months after the completion of antibiotic therapy. Threeof these patients were treated with both oral and intravenousantibiotics, two received three weekly doses of intramuscularpenicillin G benzathine, and two were given only oral antibiotics.The median duration of their oral treatment was 37 days (range,20 to 58), and the median duration of intravenous therapy was14 days (range, 14 to 20). In the remaining 12 patients, samplesobtained one day to four years after antibiotic treatment wereall negative. Seven of these patients were treated with intravenousantibiotics, two received intramuscular penicillin, and threewere given only oral antibiotics. Their median duration of oraltreatment was 48 days (range, 21 to 120), and the median durationof intravenous therapy was 30 days (range, 7 to 44). Althoughthe patients with negative PCR results tended to have been treatedlonger than those with positive PCR results, the differenceswere not statistically significant. Of 10 patients who had chronicLyme arthritis despite multiple courses of antibiotic therapy,7 had negative test results in all post-treatment samples.
Altogether, of 73 patients with Lyme arthritis who were untreatedor treated with short courses of oral antibiotics before testing,70 (96 percent) had positive PCR results. In contrast, of 19patients who received either parenteral antibiotics or longcourses of oral antibiotics, only 7 (37 percent) had positivetest results after treatment (P<0.001). In the 29 patientsfor whom serial samples were available, all pretreatment sampleswere positive. Once post-treatment samples became negative,all subsequent samples remained negative.
Discussion
We present evidence that PCR is a useful method for detectingB. burgdorferi DNA in synovial fluid from patients with Lymearthritis. The main concern about this technique is that minutecontamination may produce false positive results. To ensurethat contamination did not influence our results, control samplesof joint fluid were collected and stored like case samples,DNA extraction and PCR preparation were performed in a dedicatedroom, all PCR products were inactivated with isopsoralen afteramplification, multiple blank control samples were includedwith each group of samples tested, and the samples were testedin a blinded manner in two separate laboratories. In both laboratories,nearly all joint-fluid samples from untreated patients withLyme arthritis contained detectable B. burgdorferi DNA, mostpost-treatment samples did not, and all control samples werenegative. This distribution would be extremely unlikely hadthe samples been contaminated.
In both laboratories, the sensitivity of each of the three OspAprimer-probe sets was high (75 to 89 percent), and the resultsamong these sets were moderately concordant. In contrast, theprimer-probe set that detected chromosomal DNA was less sensitive.This discrepancy has been observed consistently in all our studiesof B. burgdorferi detection in synovial fluid35. Multiple copiesof OspA DNA segments may be contained within spirochetes, andthese targets may therefore be more easily detected. Alternatively,spirochetes may not always be present in synovial fluid butmay be capable of shedding OspA segments into the fluid fromthe surrounding synovium. Membrane vesicles containing extrachromosomalDNA are shed from the surface of the spirochete,40,41 and theyhave been postulated to be mediators of DNA transfer betweenorganisms42. A third possibility is that plasmid DNA may persistin synovial fluid after the death of the spirochete. In ourstudy and others,21,24 however, OspA DNA was detected primarilyin untreated patients with clinically active disease. Afterantibiotic treatment, the PCR results were usually negative,which would not be expected if OspA DNA persisted after thespirochete had been killed. Likewise, in studies of experimentalB. burgdorferi infection in mice, PCR results were almost alwaysnegative within two to four weeks after treatment with ceftriaxone(unpublished data). Another example of this phenomenon is theclearance of viral DNA from cerebrospinal fluid within one tofour weeks after acyclovir treatment in patients with herpessimplex encephalitis43. Thus, it seems likely that the detectionof OspA DNA in joint fluid indicates the presence of viablespirochetes. Further studies aimed at detecting potentiallymore labile spirochetal RNA molecules44 may help to confirmthis hypothesis.
Since joint effusions resolved in most patients during the courseof antibiotic therapy, it was usually not possible to obtainsamples of synovial fluid after treatment. Of the patients withpersistent effusions after one month of oral antibiotics ortwo weeks of intravenous antibiotics, approximately one thirdstill had positive PCR results, suggesting that the spirochetemay not have been eradicated. However, none of the patientswith positive PCR results after treatment had received morethan two months of oral antibiotics or three weeks of intravenousantibiotics. Most of the patients who had chronic arthritisdespite multiple courses of antibiotic therapy had negativePCR results in all post-treatment samples. In these patients,the lack of response to antibiotics, the negative PCR results,and the association of this syndrome with immunogenetic andimmune markers8,9 suggest that genetically susceptible personsmay continue to have arthritis for months or even several yearsafter the eradication of viable spirochetes from synovial fluid.
Despite the identification of B. burgdorferi as the cause ofLyme disease in 1982, it has been practically impossible todemonstrate the presence of the spirochete in synovial fluid.The PCR test of synovial fluid in Lyme arthritis now shows promiseand may fill the role that culture serves in detecting commonbacterial pathogens in septic arthritis. In addition, PCR resultsmay prove useful when therapeutic decisions are made for patientswith persistent Lyme arthritis despite multiple courses of antibiotictherapy.
Supported in part by grants (AR-20358, AR-40576, and AR-07570to Dr. Steere; and AR-41497, AI-32403, and AI-30548 to Dr. Persing)from the National Institutes of Health and by the Eshe Fund.
We are indebted to Brenda Fung for many helpful suggestions,Michael Berne for synthesizing oligonucleotide primers and probes,Chris Schmid for statistical assistance, Tim Rotman for assistancein preparing the figures, and April Chang-Miller, Joseph Duffy,Paul Dellaripa, Robert Kalish, James Logan, and other membersof the Mayo Section of Rheumatology and the New England MedicalCenter Division of Rheumatology/Immunology for providing synovial-fluidsamples from control patients.
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.
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1 month), only 7 (37 percent) had positive tests (P<0.001). None of these seven patients had received more than two months of oral antibiotic treatment or more than three weeks of intravenous antibiotic treatment. Of 10 patients with chronic arthritis (continuous joint inflammation for one year or more) despite multiple courses of antibiotics, 7 had consistently negative tests in samples obtained three months to two years after treatment. 
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