The influence of polygenic risk scores on heritability of anti-CCP level in RA.

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.

Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study.

BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Antibodies to T- and L-isoforms of the cytoskeletal protein, fimbrin, in patients with systemic lupus erythematosus.

The cytoskeleton is a complex network of proteins that maintain cell shape, mobility, and organelle function. Its components can be divided into three distinct classes: microfilaments, microtubules, and intermediate filaments. Fimbrins are microfilament proteins, a family of cytoplasmic phosphoproteins. Expression of the L-fimbrin isoform is restricted to replicating blood cells and expression of the T-fimbrin isoform to replicating cells of solid tissues. Sera from normals and from patients with systemic lupus erythematosus (SLE), juvenile arthritis, rheumatoid arthritis, Sjögren's syndrome, osteoarthritis, vasculitis, scleroderma, and mixed connective tissue disease were tested for the presence of antibodies to T- and L-fimbrin by ELISA, using purified recombinant fimbrin. The mean OD of sera from SLE patients was significantly higher than in normals (T-fimbrin, P less than 0.0001; L-fimbrin, P less than 0.001). 48 of 98 SLE sera had antibodies to T-fimbrin; 32 had antibodies to L-fimbrin; 20 had antibodies to both; 28 had only anti-T, and 12 had only anti-L-fimbrin. The mean OD for sera of the other rheumatic diseases was not significantly different from normals. The presence of either L- or T-fimbrin antibody was associated with pleuropericarditis (P = 0.015), photosensitivity (P = 0.011), and anti-Sm antibody (P = 0.010). Central nervous system SLE was associated with the presence of the L-fimbrin antibody alone (P = 0.016). There was a strong association between DR7 (but not other MHC alleles) and anti-L-fimbrin antibodies in SLE patients (chi square = 18; P less than 0.00002). No MHC association was observed with anti-T-fimbrin antibodies.

The cost-effectiveness of vaccination against Lyme disease.

BACKGROUND: Vaccination against Lyme disease appears to be safe and effective; however, the cost per quality-adjusted life-year (QALY) gained with vaccination is unknown. METHODS: We developed a decision-analytic model to evaluate the cost-effectiveness of vaccination compared with no vaccination in individuals living in endemic areas of Lyme disease. Our analysis encompassed a 10-year time horizon including a 2-year vaccination schedule with an additional year of vaccine effectiveness. The costs and probabilities of vaccination risk, compliance and efficacy, and Lyme disease clinical sequelae and treatment were estimated from the literature. Health-related quality-of-life weights of the various clinical sequelae of Lyme disease infection were obtained from a sample of 105 residents from Nantucket Island, Massachusetts. RESULTS: Vaccinating 10 000 residents living in endemic areas with a probability of Lyme disease per season of 0.01 averted 202 cases of Lyme disease during a 10-year period. The additional cost per QALY gained compared with no vaccination was $62 300. Vaccination cost $12 600/QALY gained for endemic areas with an attack rate of 2.5% per season, and $145 200/QALY gained for an attack rate of 0.5%. Vaccinating individuals over an accelerated 2-month vaccination schedule improved the cost-effectiveness to $53 700/QALY gained. If a yearly booster shot is required for persisting efficacy, the marginal cost-effectiveness ratio increases to $72 700/QALY. The cost-effectiveness of vaccination was most sensitive to the Lyme disease treatment efficacy and assumptions about the persistence of vaccination effect. CONCLUSION: Vaccination against Lyme disease appears only to be economically attractive for individuals who have a seasonal probability of Borrelia burgdorferi infection of greater than 1%.

Bronchiectasis. A late feature of severe rheumatoid arthritis.

Bronchiectasis as a feature of rheumatoid arthritis is considered rare and, in most series, has preceded rheumatoid arthritis. We identified 23 patients with rheumatoid arthritis and bronchiectasis at the Brigham and Women's Hospital followed between 1984 and 1991, 18 of whom had arthritis preceding lung disease. The 18 patients with rheumatoid arthritis and subsequent bronchiectasis had a mean age of 63.8 years. Fourteen were women and 4 were men, with a mean arthritis duration of 24.7 years before bronchiectasis developed. Most patients had seropositive and nodular disease. All but 1 had advanced radiographic changes of rheumatoid arthritis, and many had received joint replacement surgery. In addition to standard treatment regimens, 17 patients had received corticosteroids. Productive cough, hemoptysis, and dyspnea were the most common respiratory symptoms and were present for an average of 4.3 years prior to bronchiectasis diagnosis. The most common radiographic abnormalities were bibasilar diffusely increased interstitial markings and focal infiltrates, although nodules, bullae, cysts, and air-fluid levels were found. Common pulmonary-function abnormalities were obstructive and/or restrictive abnormalities. Three patients died of complications relating to bronchiectasis. Five patients with rheumatoid arthritis had antecedent bronchiectasis. Compared with patients with rheumatoid arthritis and subsequent bronchiectasis, those with antecedent lung disease had milder arthritis (stage I or II radiographic changes, p < 0.001), a lower frequency of rheumatoid nodules (p < 0.05) and a lower comorbidity score (5.8 versus 9.4, p < 0.01). They also had received fewer disease-modifying agents for the treatment of their rheumatoid arthritis. Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe, long-standing nodular disease. Recurrent pulmonary infections and respiratory failure occur and may be fatal.

Determinants of tick-avoidance behaviors in an endemic area for Lyme disease.

BACKGROUND: Tick bite control is an important initiative to prevent Lyme disease and other tickborne infections. While several studies have demonstrated that knowledge and awareness of Lyme disease in endemic areas are good, none has evaluated the relative importance of knowledge with other attitudinal and health belief variables to determine motivators of preventive behavior. METHODS: We conducted a cross-sectional analysis of 304 commuter ferry passengers departing Martha's Vineyard Island, Massachusetts, in August 1992, to ascertain the prevalence of tick-avoidance behaviors among individuals from an endemic area of Lyme disease and to identify the knowledge, behavioral, and demographic variables that best determine precautionary behavior. RESULTS: Overall, survey respondents (n = 304) had very good knowledge of Lyme disease (73% items correct on a knowledge test), but only 59% of respondents reported limiting time in tick areas, 58% usually wore protective clothing, 40% wore tick repellent, and 66% usually performed tick checks. By stepwise linear regression analysis, determinants of tick-avoidance behaviors included perceiving the behavior's benefits as outweighing its inconvenience (P < .0001), having confidence in recognizing Lyme disease symptoms (P < .0004), believing that Lyme disease is a serious illness (P < .0009), and believing that the avoidance behavior is effective in reducing the risk of Lyme disease (P < .01). Younger respondents (P < .05) performed fewer avoidance behaviors. Visitors (P < .0001) performed fewer tick checks than residents. Having confidence that one could find a tick on oneself with a tick check also predicted performance (P < .008). Increased general knowledge about Lyme disease did not predict any protective behaviors. CONCLUSIONS: Precautionary behaviors were underperformed in an at-risk population despite good knowledge of Lyme disease symptoms and transmission. Instead, performance was related to confidence in finding a tick on oneself and a perception that a precaution's benefit outweighed its inconvenience and would adequately reduce risk for Lyme disease. These data have implications for Lyme disease prevention programs, which typically focus on enhancing general knowledge as a means toward disease reduction.

Lyme disease and preventive behaviors in residents of Nantucket Island, Massachusetts.

BACKGROUND: To determine the age-specific prevalence of Lyme disease and whether preventive behaviors on Nantucket Island correlate with Lyme disease, we surveyed island residents. METHODS: A survey with questions on Lyme disease symptoms, history, and preventive behaviors was mailed to all residents. Respondents were stratified by likelihood of having had Lyme disease. A subsample was selected for examination, and then classified according to the Lyme disease national surveillance case definition. RESULTS: The overall lifetime prevalence of Lyme disease for Nantucket residents was 15% (CI, 10%-19.8%): 19% among females, and 11% among males. The prevalence was highest among age groups 0-16 and 30-49 years. Overall, 86% of the population practiced at least one behavior. The most frequently reported preventive behavior was checking oneself for ticks (80%), followed by wearing protective clothing (53%), avoiding tick areas (34%), and using tick repellent (11%). Younger individuals practiced fewer preventive behaviors than older individuals (p=0.001). Although males reported greater tick exposure than females, females uniformly practiced preventive behaviors more frequently (p=0.001). The practice of preventive behaviors was not associated with a history of Lyme disease, but finding more than 5 ticks per year on oneself was (p=0.001). CONCLUSION: Lyme disease is highly prevalent on Nantucket Island. Young people are particularly at risk and health education should emphasize preventive behaviors less frequently practiced: using tick repellent, avoiding tick areas, and wearing protective clothing.

Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity and certain disease phenotypes in rheumatoid arthritis.

BACKGROUND: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. METHODS: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. RESULTS: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. CONCLUSION: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Relationship of serum IgE concentration to level and rate of decline of pulmonary function: the Normative Aging Study.

BACKGROUND: Previous reports on the relationship between serum immunoglobulin E (IgE) concentration and the level and rate of decline of pulmonary function in the general population have produced conflicting results. The relationship between total serum IgE concentration and pulmonary function was therefore examined in 1078 men aged 41-86 years followed in the Normative Aging Study. METHODS: The serum IgE concentration determined at the start of the three year follow up period was examined in relation to both the level and longitudinal rate of decline of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: In a cross sectional analysis restricted to subjects who had ever smoked cigarettes, multiple linear regression models indicated an inverse association between total serum IgE concentration and both FEV1 (beta = -0.090 1/log10 IU/ml; SE = 0.030; p < 0.005) and FVC (beta = -0.110 1/log10 IU/ml; SE = 0.034; p < 0.005) but not FEV1/FVC, after adjustment for age and height. This relationship persisted when individuals with diagnosed asthma or methacholine hyperresponsiveness were excluded. In subjects who had never smoked cigarettes the total serum IgE concentration was unrelated to spirometric indices. No association was observed in smokers or non-smokers between the serum IgE concentration measured at the beginning of the period of follow up and the decline in FEV1, FVC, or FEV1/FVC. CONCLUSION: Increased levels of serum IgE measured at the beginning of the follow up period are associated with lower levels of pulmonary function but are not predictive of an accelerated rate in the decline of pulmonary function among middle aged and older men.

Effect of low level lead exposure on hyperuricemia and gout among middle aged and elderly men: the normative aging study.

OBJECTIVE: To determine whether longterm lead accumulation is associated with hyperuricemia and gouty arthritis among middle aged and elderly men. METHODS: In a retrospective cohort study, 777 male participants were evaluated between August 1991 and October 1996 in the Department of Veterans Affairs Normative Aging Study, a 35 year longitudinal study of aging. We examined the development of gout and an increased uric acid level in relation to lead, adjusting for other known risk factors. Lead levels were measured in blood and by K x-ray fluorescence (K-XRF) technique in tibial (cortical) and patellar (trabecular) bone. RESULTS: Blood lead levels in this mostly Caucasian (97%) population were low (mean 5.9 microg/dl, SD 3.5). Bone lead levels were comparable to those described in other general populations. In a multivariate analysis adjusting for the risk factors, age, body mass index, diastolic blood pressure, alcohol intake, and serum creatinine level, there was a positive association between patellar bone lead and uric acid levels (p = 0.02). Of 777 participants, 52 (6.7%) had developed gouty arthritis. In logistic regression of similar covariates, body mass index (p < 0.0001) and serum creatinine level (p = 0.005) were the strongest determinants of gout; neither bone nor blood lead levels predicted gout in this cohort. CONCLUSION: The longterm accumulation of lead is associated with an increased uric acid level in middle aged and elderly men. However, this study shows no association between lead and gouty arthritis at the levels arising from community exposure.

Coexposure to Borrelia burgdorferi and Babesia microti does not worsen the long-term outcome of lyme disease.

Previous studies suggest that concurrent Lyme disease and babesiosis produce a more sever illness than either disease alone. The majority of babesiosis infections, however, are subclinical. Our objective was to characterize on the basis of a total-population survey of Nantucket Island, Massachusetts, whether coexposure to Lyme disease and babesiosis causes more severe illness or poorer long-term outcomes than Lyme disease alone. In this retrospective cohort study, residents indicating a history of Lyme disease were compared with randomly selected population controls on a standardized medical history, blinded physical examination, and serological studies for Borrelia burgdorferi and Babesia microti. Serological evidence of exposure to babesiosis was not associated with increased severity of acute Lyme disease. The groups did not differ with regard to the prevalence of constitutional, musculoskeletal, or neurological symptoms a mean of 6 years after acute Lyme disease. Prior Lyme disease and serological exposure to B. microti are not associated with poorer long-term outcomes or more persistent symptoms Lyme disease alone.

Lack of cardiac manifestations among patients with previously treated Lyme disease.

BACKGROUND: Cardiac involvement is common in acute Lyme disease, and case reports suggest that cardiac abnormalities might also occur years after the primary infection. OBJECTIVE: To determine the prevalence of cardiac abnormalities in persons with previously treated Lyme disease. DESIGN: Population-based, retrospective cohort study with controls. SETTING: Nantucket Island, Massachusetts. PARTICIPANTS: From among 3703 adult respondents to a total-population (n = 6046) mail survey, 336 (176 case-patients and 160 controls) were randomly selected for clinical evaluation. MEASUREMENTS: Current cardiac symptoms and major or minor abnormal electrocardiographic features, including heart rate; rhythm; axis; PR, QRS, and QT intervals; QRS structure; atrioventricular blocks; and ST-segment and T-wave changes. RESULTS: Persons with Lyme disease (case-patients, n = 176) (mean duration from disease onset to study evaluation, 5.2 years) and persons without evidence of previous Lyme disease (controls, n = 160) did not differ significantly in their patterns of current cardiac symptoms and electrocardiographic findings, including heart rate (P > 0.2), PR interval (P = 0.15), QRS interval (P > 0.2), QT interval (P > 0.2), axis (P > 0.2), presence of arrhythmias (P > 0.2), first-degree heart block (P = 0.12), bundle-branch block (P > 0.2), and ST-segment abnormalities (P > 0.2). In multivariate analyses that adjusted for age, sex, and previous heart disease, a history of previously treated Lyme disease was not associated with either major (odds ratio, 0.78; P > 0.2) or minor (odds ratio, 1.09; P > 0.2) electrocardiographic abnormalities. CONCLUSION: Persons with a history of previously treated Lyme disease do not have a higher prevalence of cardiac abnormalities than persons without a history of Lyme disease.

The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study.

BACKGROUND: Exercise-induced anaphylaxis (EIA) is a unique physical allergy that is triggered by exertion, the clinical spectrum and modifying factors of which have been previously studied. At the time of initial description, it was postulated that other factors contributed to this disorder. OBJECTIVE: We sought to determine the clinical course and potential modifying factors in EIA. METHODS: In 1993, we conducted a cross-sectional analysis of 671 individuals with exercise-associated symptoms for more than a decade using a validated 75-item questionnaire. Subjects met criteria for EIA if they had anaphylactic symptoms, including hypotension or upper airway obstruction, urticaria, or angioedema with physical exertion but without a passive increase in core body temperature. RESULTS: Of 365 (54%) questionnaire respondents, 279 (87%) met criteria for EIA (199 females and 80 males). At the time of study entry, subjects with EIA (mean age, 37.5 years; range, 13 to 77 years) had an average of 10.6 years of symptoms, which were most frequently triggered by aerobic activities such as jogging or brisk walking (78% and 42%, respectively). On average, subjects reported that the frequency of attacks had decreased (47% of subjects) or stabilized (46% of subjects) since onset. One hundred (41%) subjects reported being completely free of attacks in the past year. Subjects reduced their attacks by avoiding exercise during extremely hot or cold weather (44%), avoiding ingestion of certain foods before exercise (37%), and restricting exercise during their allergy season (36%) or humid weather (33%). The most common pharmacologic agents used to manage symptoms were H1 antagonists (56%) and/or epinephrine (31%). However, 28% used no treatment at all. CONCLUSION: EIA is an episodic condition in which the frequency of attacks tends to stabilize or decrease over time. Improvement appears to result from individual modification of exercise and avoidance of known environmental and ingestible precipitants.

Outcomes of children treated for Lyme disease.

OBJECTIVE: To study the outcome of Lyme disease (LD) in children identified in a total population survey of an endemic island. METHODS: We conducted a population-based retrospective cohort study off the coast of Massachusetts. Twenty-five children who met the Centers for Disease Control case definition for prior LD were compared with 26 children without LD from the same community. All children with LD received antibiotics during the acute phase of their disease. All 51 children were invited for a clinical evaluation, including 12-lead electrocardiogram (EKG), and measurement of antibodies to Borrelia burgdorferi by antibody-capture ELISA and Western blot. RESULTS: At a mean of 3.2 years from the initial manifestation of LD, children with prior LD did not have a higher prevalence of musculoskeletal or neurological symptoms, examination abnormalities, abnormal EKG, or behavioral difficulties, compared to children with no history of LD. CONCLUSION: Children who receive appropriate antimicrobial therapy for LD appear to have no demonstrable longterm morbidity.

The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study.

OBJECTIVE: To ascertain the prevalence of and risk factors for long-term sequelae from acute Lyme disease. DESIGN: Population-based, retrospective cohort study. SETTING: A coastal region endemic for Lyme disease. PARTICIPANTS: Patients with a history of Lyme disease who were previously treated with antibiotics were compared with randomly selected controls. MEASUREMENTS: A standardized physical examination, health status measure (Short Form 36), psychometric test battery, and serologic analysis. RESULTS: Compared with the control group (n = 43), the Lyme group (n = 38; mean duration from disease onset to study evaluation, 6.2 years) had more arthralgias (61% compared with 16%; P < 0.0001); distal paresthesias (16% compared with 2%; P = 0.03); concentration difficulties (16% compared with 2%; P = 0.03); and fatigue (26% compared with 9%; P = 0.04), and they had poorer global health status scores (P = 0.04). The Lyme group also had more abnormal joints (P = 0.02) and more verbal memory deficits (P = 0.01) than did the control group. Overall, 13 patients (34%; 95% CI, 19% to 49%) had long-term sequelae from Lyme disease (arthritis or recurrent arthralgias [n = 6], neurocognitive impairment [n = 4], and neuropathy or myelopathy [n = 3]). Compared with controls, patients who had long-term sequelae had higher IgG antibody titers to the spirochete (P = 0.03) and received treatment later (34.5 months compared with 2.7 months; P < 0.0001). CONCLUSIONS: Persons with a history of Lyme disease have more musculoskeletal impairment and a higher prevalence of verbal memory impairment when compared with those without a history of Lyme disease. Our findings suggest that disseminated Lyme disease may be associated with long-term morbidity.

Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease.

BACKGROUND: Previous follow-up studies of patients with Lyme disease suggest that disseminated infection may be associated with long-term neurologic and musculoskeletal morbidity. OBJECTIVE: To determine clinical and functional outcomes in persons who were treated for Lyme disease in the late 1980s. DESIGN: Population-based, retrospective cohort study. SETTING: Nantucket Island, Massachusetts. PARTICIPANTS: 186 persons who had a history of Lyme disease (case-patients) and 167 persons who did not (controls). MEASUREMENTS: Standardized medical history, physical examination, functional status measure (Medical Outcomes Study 36-item Short Form Health Survey [SF-36]), mood state assessment (Profile of Mood States), neurocognitive tests, and serologic examination. RESULTS: The prevalence of Lyme disease among adults on Nantucket Island was estimated to be 14.3% (95% CI, 9.3% to 19.1%). In multivariate analyses, persons with previous Lyme disease (mean time from infection to study evaluation, 6.0 years) had more joint pain (odds ratio for having joint pain in any joint, 2.1 [CI, 1.2 to 3.5]; P = 0.007), more symptoms of memory impairment (odds ratio for having any memory problem, 1.9 [CI, 1.1 to 3.5]; P = 0.003), and poorer functional status due to pain (odds ratio for 1 point on the SF-36 scale, 1.02 [CI, 1.01 to 1.03]; P < 0.001) than persons without previous Lyme disease. However, on physical examination, case-patients and controls did not differ in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance. Persons with previous Lyme disease who had persistent symptoms after receiving treatment (n = 67) were more likely than those who had completely recovered to have had fever, headache, photosensitivity, or neck stiffness during their acute illness (87% compared with 13%; odds ratio, 2.4 [CI, 1.0 to 5.5]; P = 0.045); however, the performance of the two groups on neurocognitive tests did not significantly differ. CONCLUSIONS: Because persons with previous Lyme disease exhibited no sequelae on physical examination and neurocognitive tests a mean of 6.0 years after infection, musculoskeletal and neurocognitive outcomes seem to be favorable. However, long-term impairment of functional status can occur.