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An epidemic of oligoarticular arthritis in children and adults in three connecticut communities.

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7
LYME ARTHRITIS
AN EPIDEMIC OF OLIGOARTICULAR ARTHRITIS IN CHILDREN
AND ADULTS IN THREE CONNECTICUT COMMUNITIES
ALLEN C. STEERE, STEPHEN E. MALAWISTA, DAVID R. SNYDMAN, ROBERT E. SHOPE,
WARREN A. ANDIMAN, MARTIN R. ROSS, and FRANCIS M. STEELE
An epidemic form of arthritis has been occurring in
eastern Connecticut at least since 1972, with the peak
incidence of new cases in the summer and early fall. Its
identification has been possible because of tight geographic clustering in some areas, and because of a characteristic preceding skin lesion in some patients. The authors
studied 51 residents of three contiguous Connecticut communities-39 children and 12 adults-who developed an
From the Departments of Internal Medicine. Pediatrics, and
Epidemiology and Public Health, Yale University School of Medicine,
New Haven, Connecticut; the Field Services Division, Bureau of
Epidemiology, Center for Disease Control, USPHS, Atlanta, Georgia;
and the Preventable Disease Division and Laboratory Division, State
Health Department, Hartford, Connecticut.
Presented in part at the 40th Annual Meeting of the American Rheumatism Association, Chicago, Illinois, June 30, 1976 ( I ) .
Supported in part by USPHS grants AM-10493. AM-5639,
AI-10984, BRSG-RR-05443, and RR-00125, by the Connecticut
Chapter and National Office o f The Arthritis Foundation, and by the
Kroc Foundation.
Allen C. Steere, M.D.: Postdoctoral Fellow in Rheumatology, Department of Internal Medicine, Yale University: Stephen E.
Malawista, M.D.: Head. Rheumatology Section, Departmentbf Internal Medicine, Yale University: David R. Snydman, M.D.: Acting
Director, Preventable Disease Division, State Department of Health,
and Bureau of Epidemiology, Center for Disease Control; Robert E.
Shope, M.D.: Department of Epidemiology and Public Health, Yale
University; Warren A. Andiman, M.D.: Department of Pediatrics,
Yale University; Martin R. Ross, Ph.D.: Laboratory Division, State
Department of Health; Frances M. Steele, Ph.D.: Laboratory Division, State Department of Health.
Address reprint requests to Allen C . Steere. M.D., Section of
Rheumatology, Department of Internal Medicine. Yale University
School of Medicine, New Haven, Connecticut 06510.
Submitted for publication September 16, 1976 accepted September 18, 1976.
Arthritis and Rheumatism, Vol. 20, No. I (January-February 1977)
illness characterized by recurrent attacks of asymmetric
swelling and pain in a few large joints, especially the knee.
Attacks were usually short (median: 1 week) with much
longer intervening periods of complete remission (median :
2.5 months), but some attacks lasted for months. To date
the typical patient has had three recurrences, but 16
patients have had none. A median of 4 weeks (range:
1-24) before the onset of arthritis, 13patients (25%)noted
an erythematouspapule that developed into an expanding,
red, annular lesion, as much as 50 cm in diameter. Only 2
of 159 family members of patients had such a lesion and
did not develop arthritis (P < 0.000001). The overall
prevalence of the arthritis was 4.3 cases per 1,000 residents, but the prevalence among children living on four
roads was 1 in 10. Six families had more than 1 affected
member. Nine of 20 symptomatic patients had low serum C3 levels, compared to none of 31 asymptomatic
patients ( P < 0.005); no patient had iridocyclitis or a
positive test for antinuclear antibodies. Neither cultures
of synovium and synovial fluid nor serologic tests were
positive for agents known to cause arthritis. “Lyme
arthritis” is thought to be a previously unrecognized
clinical entity, the epidemiology of which suggests transmission by an arthropod vector.
I n November 1975 a mother from Old Lyme,
Connecticut, informed the State Health Department
that 12 children from that small community of 5,000, 4
of whom lived ciose together on the same road, had a
disease diagnosed as juvenile rheumatoid arthritis
(JRA). During the same month another mother from
STEERE ET AL
8
the same community reported at the Yale Rheumatology Clinic and to the Health Department that she,
her husband, 2 of their children, a n d several neighbors
all had arthritis. Again most of the children were
thought t o have JRA. Subsequent studies of children
and adults in that geographic region suggest that “Lyme
arthritis” is a previously unrecognized clinical entity.
MATERIALS AND METHODS
A system of surveillance was organized in the three
contiguous communities of Old Lyme, Lyme, and East Haddam (total population: 12,000) through contacts with healthcare personnel-area physicians, school nurses, and local
health officers. In addition, several patients identified other
affected individuals. In these small communities, such methods
are likely to have identified at least those patients severely
enough affected to have sought medical assistance, and
through the patient “grapevine,” to have emphasized the presence of family, geographic, or social clustering.
in an effort to exclude children with diverse forms of
arthritis who may have clustered by chance alone, affected
residents were invited to participate in a study at the Yale
University School of Medicine, in which an attempt would be
made to determine the cause of their arthritis.* From December 1975 through May 1976, the same physician evaluated all
patients by means of an extensive history, a physical examination, blood tests, and if possible a synovial biopsy. In
addition, the authors contacted the patients’ physicians (many
patients had several-general practitioner, internist, pediatrician, rheumatologist, orthopedic surgeon, or opthalmologist),
to study their office records and available hospital records.
The study included only patients with both joint pain and
swelling, documented by a physician and diagnosed as J R A or
arthritis of unknown etiology. Of the 51 resulting patients,
2 0 had active disease at the time of the author’s examination.
Laboratory tests performed on all patients in the study
(except as noted) included peripheral blood and synovial fluid
cell and differential counts, erythrocyte sedimentation rates
(Westergren), and synovial fluid protein and glucose determinations. Both blood and joint fluid specimens were tested for
rheumatoid factor by latex fixation, for antinuclear antibodies
by immunofluorescence, and for the third component of complement (C3) by radial immunodiffusion. In addition, serum
antibodies against various agents were sought in all patients as
follows: adenoviruses, cytomegalovirus, herpes simplex, influenza, and mumps viruses, by complement fixation; rickettsiae by complement fixation and immunofluorescence (the
latter, in 10 sera); M pneumoniae, by complement fixation and
cold agglutination; groups A, B, and other arboviruses, by
complement fixation and hemagglutination inhibition (2,3);
leptospira by microscopic agglutination (in 11 sera) (4); rubella by hemagglutination inhibition (also rubella-specific IgM
antibodies were sought in 16 sera in which IgG had been
adsorbed to Staphylococcus aureus (5,6); and coxsackie viruses
* Protocol No.
1125, approved by the Human Investigations Committee, Yale University School of Medicine.
BI-5 and A-9, by neutralization tests done in rhesus monkey
kidney tissue cultures (7). Hepatitis B surface antigen was
sought both by radioimmunoassay and by reversed passive
hemagglutination; antibody (in 16 sera) was sought by passive
hemagglutination (Abbott Laboratories, North Chicago, IL).
Twenty patients (I6 children and 4 adults) were tested for the
histocompatibility antigen HL-A B27 (8).
Synovial fluid specimens were inoculated in thioglycolate broth and on blood, deoxycholate, chocolate, and pleuropneumonia-like organism (PPLO) agar (Difco Laboratories,
Detroit, M I ) supplemented with dextrose, yeast extract, and
horse serum. The PPLO plates were incubated in a C02-rich
environment at 37°C for 3 weeks. Specimens of synovium and
joint fluid were each placed in tubes containing a monolayer of
human placental fibroblasts and Eagle’s basal medium supplemented with 10% fetal calf serum. After transport to the laboratory, each specimen was inoculated into four tissue culture
systems: human placental fibroblast, Vero, Hep-2, and rhesus
monkey kidney. Each specimen was examined for cytopathic
effect twice weekly for 4 weeks. Throat and rectal swab specimens were taken from the 7 patients who had the onset of
arthritis during the study, and these specimens were cultured
for viruses in the same manner.
RESULTS
Clinical Characteristics
Fifty-one residents (39 children and 12 adults)
were identified who had an apparently similar type of
arthritis. It usually began with the sudden onset of swelling, and often pain, in a knee, another large joint, or the
temporomandibular joint (Table 1). Five patients also
described pain in unspecified joints of the hands or feet.
The onset was monoarticular in 35 patients (69%), oligoarticular in 15 (29%), and polyarticular in only 1 (2%).
T h e first attack lasted a median of 1 week, but sometimes persisted for as long as 6 months (Table 2).
To date, 35 patients (69%) have had recurrent
attacks, and t h e typical patient has h a d three recurrences (range: 2-10). Large joints, particularly the knee,
were again most commonly affected, and a median of
three joints, usually one a t a time, were affected in all
attacks (Table 1). Recurrences were usually short (median: 1 week) and separated by much longer periods of
complete remission (median: 2.5 months) (Table 2).
However, even in an individual patient, both the duration of recurrent attacks (up to 4 months) a n d t h e interval between them ( u p t o 23 months) were highly variable
and therefore unpredictable. During remissions some
patients remembered short periods of joint pain, sometimes lasting only hours, without swelling (and therefore
not included as attacks). Children and adults did not
differ significantly in joint symptoms.
Although nearly half the patients reported only
LYME ARTHRITIS
9
Table 1. Joints Affected
Number of Patients
First Attack
Children
(39)
Adults
(12)
35
3
3
2
2
3
2
8
2
2
3
2
I
Recurrent Attacks
Total
(51)
Children
(25)
Adults
22
5
7
2
4
4
8
3
(10)
Total
(35)
~
Knee
Ankle
Wrist
Temporomandibular
Shoulder
Hip
Elbow
* Percentage
43
5
5
5
4
4
3
I
(84)*
(10)
(10)
(10)
(8)
(8)
(6)
10
1
3
3
0
6
30 (86)*
8 (23)
8 (23)
5 (14)
7 (20)
4 (11)
16 (46)
o f patients with either or both joints affected
articular symptoms, 28 had concomitant fever (100103"F), 14 malaise and fatigue, 8 headache, 8 myalgia, and 3 a maculopapular rash. Several adults described episodic symptoms not necessarily associated
with documented arthritis, such as severe headache, periorbital edema, malar or photosensitive maculopapular
rash, or swelling of the hands or feet. In addition, 7
adults noted profound fatigue and hyperesthesias, sometimes persisting for months after the arthritis had gone.
During the study period from December 1975
through May 1976,20 of the 51 patients were symptomatic, usually with recurrent attacks, at the time of examination. In these patients the typical physical finding was
marked swelling and sometimes warmth of a single
joint, with mild to moderate pain on motion. N o one
was found t o have evidence of permanent joint damage.
None of the 22 children who had had ophthalmologic
examinations was found to have iridocyclitis.
Preceding Symptoms
A median of 4 weeks (range: 1-24) before the
onset of arthritis, 13 patients (25%; 8 adults and 5 children) described an erythematous papule that developed
into an expanding, red annular lesion, usually with partial central clearing. The lesion, often on an extremity,
became 20-50 cm in diameter in some patients. Three
patients had multiple concurrent lesions, but none had
recurrent lesions. Associated symptoms included burning of the lesion in 10 patients, fever in 7, severe headache in 5 , stiff neck in 3, nausea and vomiting in 2, and
Bell's palsy in 1 . The skin lesion lasted a median of 1.5
weeks (range: 0.5-4). Although physicians and patients
thought it to be an insect bite, only 1 patient remembered having been bitten at the site of the lesion, in that
instance by a tick. Adults had the skin lesion significantly more often than children (P < 0.01). Only 2 of
Table 2. Clinical Characteristics
First attack
Type o f onset
Monoarticular
Oligoarticular (1-4 joints)
Polyarticular (5 or morejoints)
Duration of first attack (weeks)
Recurrent attacks
Number of patients
Number of
recurrent attacks
joints affected in all attacks
Duration of
recurrent attacks (weeks)
complete remissions (months)
*
Median (range).
Children
(39)
Adults
(12)
Total
28 (72%)
10 (26%)
I ( 2%)
1 (.3-12)*
7 (58%)
5 (42%)
0
I .5 (1-24)
35 (69%)
15 (29%)
I ( 2%)
I (.3-24)
25 (64%)
10 (83%)
35 (69%)
3 (1-6)
3 (1-7)
2.5 (1-10)
4 (1-8)
3 (1-10)
3 (1-8)
I (.l5-12)
2 (.25-23)
I (1-16)
3 (.5-ll)
(51)
1 (.15-16)
2.5 (.25-23)
STEERE ET AL
10
the 159 family members of patients noted such a lesion
and did not develop arthritis (P< 0.000001). No patient
described a sore throat or diarrhea before the onset of
arthritis.
Epidemiology
The three communities studied are all small (population 5,400 or less) and relatively sparsely settled (each
area 29 square miles or more). Old Lyme borders Long
Island Sound, all three communities border the Connecticut River, and the interiors are laced with streams
and lakes (Figure 1). Except for the town centers of Old
Lyme and East Haddam, most residents live on large
wooded lots or on farms. Each household has its own
well water. The residents of Old Lyme and Lyme share a
school system; those of East Haddam have a separate
one.
The onset of arthritis in the 51 patients occurred
from July 1972 through May 1976 (the cut-off time for
Long
I s l a n d Sound
Fig 1. The three communities studied are shown. Two state forests and major lakes are indicated. bur the
enrire region is laced wirh smaller lakes and streams. Geographic clustering occurred in rhe more sparsely
settled. heavily wooded areas, and not in the town cenrers or along Long Island Sound.
LYME ARTHRITIS
11
this study), except for 1 patient whose arthritis began in
March 1967.* The 44 patients whose arthritis began
from 1972 through 1975 are represented in Figure 2.
Twenty-eight patients (55%) had their onset from June
through September. All patients with the expanding skin
lesions developed them during these months. The onset
of arthritis in 6 additional patients was in the first 5
months of 1976 (1 each in January, March, April, and
May; 2 in February). At the onset the patients had a
median age of 1 1 (ra.nge: 2-45), and the sex ratio was
1.3: 1 in favor of males (Figure 3).
The overall period prevalence rate was 4.3 per
1,000 residents (Table 3). However marked geographic
clustering was observed. Six families had more than 1
affected member. Half the affected residents in Old
Lyme lived on two adjoining country roads, as did half
of those affected in East Haddam. One in 10 children
living on those four roads had the illness (Table 4). In
contrast, no affected resident was identified who lived in
the town centers or on Long Island Sound.
Residents who lived close together usually did
not have the onset of illness at the same time. In all but 1
of the families with more than 1 affected member, those
affected had the onset of symptoms in different years.
Similarly, patients living on the same roads often had
1972
'1
'1
0 Old
HLyme
0 East Haddom
I
1973
'
m
0
5
1974
I
JAN
SEPT
JULY
MAY
MAR
NOV
MONTH OF ONSET
Fig 2. The months of onset of arthritis and towns of origin are shown for
the complete years 1972 through 1975 (44 of the J I patients). Twentyeight patients (55%) had their onset from June through September. and
all I 3 patients (25%) with preceding, expanding skin lesions (see text)
had them during that 4-month period. Only 2 of the IS9 nonarthritic
family members of patients had similar skin lesions ( P < 0.000001 I.
the onset of the illness in different years, as did friends
and classmates who might have had contact with one
another. Fifteen patients did not know others with the
illness. No common exposure, such as an immunization,
* This patient seems to belong to the group because she had symptoms
similar to those of her husband and 2 of their 4 children, who
currently have arthritis. She is mentioned to indicate the possibility
that the disease has been endemic in the area for some time.
NO. OF
CASES
10
c
0
n
H
Male
Female
Expanding
skin lesion
n
Idl
I2
56
910
13-
17-
14
18
Lyme
2122
I.1
25-
29-
26
30
3334
3738
4142
4546
AGE OF ONSET
Fig 3. The age of onset of arthritis, sex, and age distribution of the preceding. expanding skin lesion are
shown. The median age of onset was I I . arthritis below age S was rare, I2 patients were adults, and the
sex ratio was I .3: I in favor of males.
STEERE ET AL
12
Table 3. Prevalence Rates in Three Communities
Number of
Patients
Town
Children Adults
~~
Total
Children
Adults
Total
3,942
1,246
3,518
5,400
1,600
4,900
9.6
22.6
12.3
0.5
6.4
0.5
3.0
10.0
3.9
8,706
11,900
12.2
1.4
4.3
14
8
17
2
8
2
16
16
19
1,458
354
1,382
Total
39
12
51
3, I94
a swimming place, or a particular food, could be identified. All but 3 families had either a dog or a cat.
Laboratory Findings
None of the 51 patients was found t o be anemic
or to have an elevated white blood cell count. Twenty
patients with joint effusions at the time of the study
(symptomatic patients) had a median erythrocyte sedimentation rate of 15 mm/hour (range: 4-55) compared
to 8 mm/hour (range: 4-22) in 31 asymptomatic
patients. Joint fluid cell counts on 9 patients showed a
median white blood cell count of 26,000 cells/mm3
(range: 500-98,000), with a median of 87% polymorphonuclear leukocytes, 9% lymphocytes, and 4% tissue cells. The joint fluid had a median protein of 5 g%
(range: 3.5-5.6), and the joint fluid glucose concentrations were not less than two-thirds those of the serum.
In serum, none of the patients had a positive test
for antinuclear antibodies, and only 1 had a positive test
for rheumatoid factor (titer: 1 :20). In joint fluid, none
of the 9 patients tested had antinuclear antibodies, but 4
had a positive test for rheumatoid factor (titer: 1 : 32 in
all). The 20 symptomatic patients had a median C3 in
serum of 78 mg% (range: 42-1 10 mg%) compared to 31
Table 4. Prevalence Rates on Four Roads
~
Number ofchildren
Affected
Total
Old Lyme
Road A
Road B
4
4
51
East Haddam
Road C
Road D
Total
Children Adults
Total
~
Old Lyme
Lyme
East Haddam
Town and
Road
Prevalence per
I ,OOO Residents
Population
Prevalence per
100 Children
asymptomatic patients who had a median C3 of 90 mg%
(range: 70-100 mg%). (These distributions were not significantly different by the median test.) However 9 of 20
symptomatic patients had serum C3 levels below 70
mg% (the lower limits of normal in this laboratory), but
none of 3 1 asymptomatic patients did (P< 0.005). Joint
fluid C3 values on 9 patients were not less than twothirds of the serum C3 values. Only 2 of 20 patients
(10%) were positive for the antigen HL-A B27, and both
were adult women.
Roentgenograms of affected joints in 18 patients
showed only soft tissue changes. Five patients had synovial biopsies, and these specimens, stained with hematoxylin and eosin, showed synovial hypertrophy, vascular proliferation, and marked infiltration by lymphocytes, monocytes, and plasma cells.
The results of serologic tests for various bacteria,
mycoplasma, rickettsia, leptospira, and viruses are
shown in Table 5. Although serum was taken from each
patient only once, sometimes years after the onset of
arthritis, and although a few patients had elevated titers
against a particular organism, the serologies did not
suggest that any of the agents tested caused arthritis in
the 51 patients. Synovium and joint fluid from 5 patients
were cultured for bacteria, mycoplasma, and viruses,
and throat and rectal swab specimens from 7 patientsthose with the onset of arthritis during the study-were
cultured for viruses. None of the specimens showed any
evidence of infection.
DISCUSSION
65
7.8
7.7
5
26
33
15.4
12.1
17
I75
9.7
4
Thirty-nine children and 12 adults in three contiguous Connecticut communities were found to have an
apparently similar type of arthritis. It was characterized
by usually short but recurrent attacks of pain and swelling in a few large joints, often the knee, with longer
intervening periods of complete remission and with, as
yet, no permanent joint deformity. Most of the 39 chil-
LYME ARTHRITIS
13
Table 5. Antibody Titers* in 51 Patients
~~
~~
Agent
Adenoviruses
Arboviruses
Group A
Aura
Ch ikungunya
Eastern eq enceph
Getah
Highlands J
Mayaro
Mucambo
Ndumu
O'nyong-nyong
Pixuna
Ross River
Semliki Forest
Sindbis
Una
Western eq enceph
Y-62-33
Group B
Powasson
St. Louis enceph
Group other
Bunyamwera
Mermet
Flanders
Calif enceph
~~
Median (range)
N t (N-64)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Agent
Coxsackie viruses
Group A
9
Group B
I
2
3
4
5
Cytomegalovirus
Hepatitis B (Ab$ and Ag)
Herpes simplex
Influenza
Type A
B
Mumps
Rubella
Hemagglut inhibition
IgM antibodies$
Leptospira (22 antigens)§
Gr A streptococci (ASLO)
M pneumoniae
Comp fixation
Cold agglutination
Rickettsia11
R akari
R rickettsia
R mooseri
Coxiella burnetii
Median (range)
N
N
N
N
8
N
N
N
N
(N-512)
(N-8)
(N-128)
(N-32)
(N-128)
(N-32)
(N-32)
(N-64)
8 (4-32)
8 (4-32)
16 (N-32)
16 (N-256)
N
N
60 (60-120)
8 (N-256)
N (N-32)
N
N
N
N
* Reciprocal
t N-negative
of serum dilutions.
undiluted.
$ Tested in 16 patients instead of in all 51.
9 Tested in I I patients instead of in all 51.
1) Tested in all patients by complement fixation and in 10 patients by immunofluorescence.
dren studied had been thought initially to have juvenile
rheumatoid arthritis. However many problems with that
diagnosis emerged for both clinical and epidemiologic
reasons. First, all but 1 patient had a monoarticular or
an oligoarticular onset of their arthritis. In series from
university hospitals, only 3 0 4 0 % of patients with JRA
have had this type of onset, although such series are
probably biased toward patients with more severe presentations (9-1 1). Second, oligoarticular JRA has an
overall female-to-male ratio of 3 t o 1, and two peak ages
of onset, 1-3 and 11-13 (9,ll-13). In this study there is
no clear sex preponderance a t any age (Figure 3). Although the peak onset was at age l l , only l patient had
the onset between ages 1 and 3, and 12 patients were
adults. Third, 20-25% of children with the oligoarticular
form of JRA develop antinuclear antibodies and/or iridocyclitis (10-13); none of the present patients has done
so as yet. There is a subgroup of oligoarticular J R A
consisting primarily of older children with negative tests
for antinuclear antibodies, many of whom eventually
turn out to have ankylosing spondylitis (14). However,
unlike the present patients, they are mostly males, sometimes develop acute iritis, and usually are HL-A B27
positive.
The usual duration of joint pain and swelling in
any one attack in the patients reported in this study was
characteristically short, only 1 week, with much longer
intervening periods of complete remission. This pattern
has been described in JRA (15,16), but less frequently
than one of exacerbations followed by partial remissions
( 16). The American Rheumatism Association defines
JRA as a) 6 weeks of monoarticular or polyarticular
arthritis if other symptoms such as intermittent fever,
maculopapular rash, or morning stiffness are present, or
b) 3 months of arthritis if they are not present (17). Only
23 of the patients reported here (48%) meet that definition. By the more rigorous definition of JRA of Ansell
and Bywaters (18), which requires arthritis in 4 or more
STEERE ET AL
joints for 3 months in a child under age 16, only 15 of
the patients reported here (31%) would qualify.
But the major argument against the diagnosis of
juvenile rheumatoid arthritis in these patients is their
geographic, familial, and seasonal clustering. The prevalence of oligoarticular arthritis in the three communities
is about 100 times the reported prevalence of JRA (19).
Approximately 1 in 10 children living on four roads had
the illness, and 6 families had more than 1 affected
member. In addition, most patients had their onset in
the summer or early fall.
In summary, the diagnosis of juvenile rheumatoid arthritis in these patients is unlikely because of
a) mono-oligoarticular onset of arthritis in almost all
patients, b) the usual short duration ofjoint effusions, c)
the lack of iridocyclitis or positive tests for antinuclear
antibodies, d) the occurrence in 12 adults, e) the seasonal onset, and f) the prevalence of the disease in the
three communities and within 6 families.
Could some of these patients have had traumatic
arthritis? Fifteen of them had only monoarticular arthritis for less than 3 months, and 2 of those had only one
attack. However none gave a history of trauma, none
appeared to have a structural abnormality of the affected joint, and some had associated symptoms such as
fever, myalgia, or fatigue. All five synovial biopsies revealed marked infiltration with inflammatory cells, including three from patients with monoarticular involvement.
The clustering of cases observed in this study
suggests an infectious etiology. An outbreak of arthritis
occurred in Haverhill, Massachusetts, in January 1926,
which was transmitted by raw milk contaminated with
Haverhillia multiformis (later called Streptobacillus moniliformis) (20,21). The onset of this illness was unusually
abrupt, with severe chills, fever, vomiting, and headache, and the arthritis, which followed in many patients
within days, was not recurrent and caused joint destruction in some. Thus the clinical characteristics of that
illness are different from those in the patients reported
here. Clustering of cases with Reiter’s syndrome has
been observed following outbreaks of dysentery caused
by Shigella (22,23). Arthritis following infection with
this and other intestinal pathogens, Salmonella and Yersinia enterocolitica, has been linked to the histocompatibility antigen HL-A B27 (24-26). However none of these
patients had diarrheal illnesses before the onset of arthritis, other clinical components of Reiter’s syndrome
were absent, and only 2 of 20 tested were HL-A B27
positive; both were adult women. Although patients
with rheumatic fever could conceivably cluster as observed
here, the arthritis in that entity is typically migratory,
none of the patients met the Jones criteria for rheumatic
fever (27), and none had an elevated antistreptolysin 0
(ASLO) titer.
Arthritis may be associated with certain viral
infections including rubella, rubeola, hepatitis B,
mumps, smallpox, influenza, and some ECHO and adenoviruses (28.29). However arthritis is rarely the only or
even the major symptom in these entities. The same is
true for erythema infectiosum, an epidemic exantham of
presumed viral etiology, which often causes arthritis in
adults (30). The arthritis following vaccination for rubella usually affects large joints, often the knee, and
short exacerbations and remissions may occur for years,
much as observed here (31,32). However this type of
arthritis follows 2 to 4 weeks after vaccination, and none
of these patients was vaccinated within 1 year of the
onset of arthritis. Three group A arboviruses-chikungunya, o’nyong-nyong, and Ross River-all transmitted through mosquito vectors, have been reported to
cause primarily arthritis, in epidemic proportions
(33-37). However chikungunya and o’nyong-nyong arthritides are dengue-like illnesses that typically affect
large joints symmetrically, epidemic polyarthritis in
Australia caused by the Ross River virus usually affects
small joints in the hands, and none of the three has been
reported to recur. Finally, the results of serologic tests
and cultures in the present patients d o not suggest infection with rubella, group A arboviruses, or any other
agent currently known to cause arthritis.
The geographic clustering of the patients in more
sparsely settled, heavily wooded areas rather than in
town centers or along the shore, the peak occurrence in
summer months, and the usual lack of close temporal
onset in those living close together, are best explained by
transmission of an agent by an arthropod vector or
possibly by a continuing common source such as water.
I n contrast, had the spread been from person to person
or airborne, patients in close proximity such as those in
the same family or the same classroom would have been
expected to have had the onset of symptoms in the same
year. The peak occurrence in the summer and early fall
is compatible with an enterovirus infection originating
possibly i n a contaminated lake or in contaminated
drinking water. But the patients did not swim in a common place, all residents had their own wells, and throat
and rectal swabs from those with the onset of arthritis
during the study showed no evidence of viral infection.
Thus the authors believe that the epidemiology fits best
with an illness transmitted by an arthropod vector.
I n this regard the occurrence of an unusual ex-
LY M E ARTHRITIS
panding skin lesion 1 to 24 weeks before the onset of
arthritis in one-quarter of the patients is particularly
intriguing. This lesion fits the description of an entity
called erythema chronicum migrans, which was described
by Lipschutz in 1913 (38). It has been reported in Europe, particularly in Scandinavia (38-44), but only recently in the United States, interestingly in eastern Connecticut (45,46). The disease is thought to be transmitted
by the sheep tick, Ixodes ricinus (39), but this vector has
been disputed because the disease has been reported in
areas that do not have ticks (44). Although allergic and
toxic reactions to the bite have been postulated as a
cause of the lesion, the most widely held view is that an
infectious agent is involved. Binder et al were able to
reproduce the disease serially in volunteers by inoculation of material from the edge of the lesion (47);
these results were reproduced by Sonck, who induced a
ring on his own forearm (43). In 1962 two French
groups reported that some patients with the illness have
positive microagglutination titers against Rickettsia conori, R mooseri, and R prowazeki (42), but others have
not been able to confirm this finding.
The lesion, which may not become apparent for
weeks or months after the bite, may last from a few days
to many months (38-44). Associated symptoms include
fever, malaise, fatigue, and headache. Several authors
have noted that neurologic symptoms such as meningeal
and encephalitic signs, hyperesthesias, and peripheral
neuropathy may occur (40), but others think that these
symptoms may have resulted from other diseases that
occurred coincidentally (48).
Arthritis, however, has not been associated with
erythema chronicum migrans, and-if this is indeed the
lesion that the present 13 patients experienced-there
can be no certainty that it is related. However only 2 of
159 family members of these 51 patients had the skin
lesion without developing arthritis. Although the prevalence of erythema chronicum migrans in the three communities reported here is not known, it is doubtful that
it is so common that one-quarter of the patients with
arthritis would have the skin lesion just weeks before the
arthritis by chance alone. Thus the authors think that
both symptoms may be manifestations of the same illness.
The best treatment for this illness is not clear.
Some physicians have reported that penicillin or tetracycline results in disappearance of the skin lesion (41,42),
but others find antibiotics ineffective. Four of the
patients with expanding skin lesions received penicillin
but still developed arthritis. Because most of the patients
with arthritis were thought to have JRA, most were
15
treated with aspirin. But regardless of aspirin, other
antiinflammatory agents, immobilization, aspiration of
the effusion, or no therapy, joint attacks were usually
short. However 2 patients with persistent effusions underwent aspiration and injection of corticosteroid esters,
only to have the effusions return within days; after six
months 1 of them had a synovectomy. Salicylates do not
seem either to suppress the more prolonged attacks or to
prevent recurrences. At present, we usually prescribe
aspirin only during symptomatic periods.
The authors believe that the arthritis described
here is a previously unrecognized clinical entity and
have named it “Lyme arthritis,” after the community
where it was first studied. Can it be distinguished from
oligoarticular juvenile rheumatoid arthritis-another
disease(s) of unknown etiology-in
the individual
patient? Perhaps, if the characteristic skin lesion has
been present. Otherwise the usual short duration of joint
effusions, the typically complete remissions, the lack of
antinuclear antibodies .and iridocyclitis, and possibly
low serum C3 levels during symptomatic periods are
somewhat suggestive, but certainly not diagnostic, of
Lyme arthritis. Because other patients from eastern
Connecticut who fit the clinical description have been
seen, it is believed that Lyme arthritis extends beyond
the three communities studied here; but how far beyond
is not known.
ADDENDUM
I n the 1976 summer season-after this article
was completed-the authors saw 38 new patients with
Lyme arthritis. In this group we have a) confirmed prospectively the importance of erythema chronicum migrans as a marker for subsequent Lyme arthritis, and
b) found serum cryoprecipitates associated with clinical activity of skin and joints (49,50).
ACKNOWLEDGMENTS
The authors thank the numerous primary and consulting physicians who supplied information about their patients,
and local health and school officials in Old Lyme and East
Haddam who supplied census data and follow-up support for
the study. We gratefully acknowledge the laboratory assistance of Dr. Dorothy M. Horstmann and Ms. Jean Emmons
for rubella serologies, Ms. Catherine R. Sulzer for leptospira
serologies, Dr. George L. LeBouvier for hepatitis testing, Dr.
Edward S. Murray for rickettsia1 testing by immunofluorescence. Ms. Grace Tucker for viral cultures, Ms. Johanna
Shansky for tissue typing, Dr. Alexander Baumgarten for
STEERE ET AL
16
rheumatic disease serologies, Dr. John Redys for ASLO titers,
and Dr. Philip W. Askenase for microscopy reports. We also
thank Mr. Daniel Freeman for statistical consultation, Mrs.
Stella Cretella for technical assistance, and Mrs. Wanda D.
Prinz for preparation of the manuscript.
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