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Reactive arthritis associated with shigella sonnei infection.

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Several studies have failed to show an association
between Shigella sonnei dysentery and reactive arthritis.
We describe 3 patients who had reactive arthritis and a
recent or concurrent S sonnei infection. To our knowledge, this is only the second study to suggest this
association. We propose that S sonnei should be considered as a triggering agent for reactive arthritis.
It is well established that reactive arthritis,
sterile joint inflammation triggered by infection elsewhere in the body, can follow enteritis due to Shigella
flexneri (1-3). In 1947, Young and McEven (4) described 14 patients with bacillary dysentery who developed Reiter’s syndrome, a form of reactive arthritis
associated with urethritis and conjunctivitis. Stool
cultures from 1 patient yielded Shigella sonnei, and in
2 others, antibodies against S sonnei were found.
However, an association between S sonnei enteritis
and reactive arthritis was not evident in recent studies
of 3 outbreaks of S sonnei dysentery (2,5,6). These
epidemiologic findings suggested that, unlike SfIexneri
serotypes 1, 2, and 2a, S sonnei is not arthritogenic
We recently treated a patient with Reiter’s
syndrome that developed after S sonnei dysentery.
This prompted us to retrospectively investigate
From the Departments of Medicine and Microbiology,
Aurora Hospital, and the Second Department of Medicine, Helsinki
University Central Hospital, Helsinki, Finland.
Anneli Lauhio, MD; Juhani Lahdevirta, MD; Rita Janes,
MD; Sirkka Kontiainen, MD; Heikki Repo, MD.
Address reprint requests to Anneli Lauhio, MD, Department of Medicine, Aurora Hospital, Nordenskioldinkatu 20, Helsinki SF-00250, Finland.
Submitted for publication December 31, 1987; accepted in
revised form March 22, 1988.
Arthritis and Rheumatism, Vol. 31, No. 9 (September 1988)
whether any of the patients who had been treated in
our hospital during the past 10 years because of S
sonnei infection had developed clinical symptoms of
reactive arthritis: 2 additional patients were found.
Patient 1. The patient, a 31-year-old man who
had previously been in good health, presented with
bloody diarrhea and fever. A stool culture yielded S
sonnei. Eleven days after the onset of diarrhea, the
patient developed a urethral discharge. Two days
later, he had fever and pain in the right knee, and he
was admitted to Aurora Hospital.
The patient had effusions in both knees and
conjunctivitis in the left eye. The Westergren erythrocyte sedimentation rate (ESR) was 87 mdhour, the
C-reactive protein (CRP) level was 21 0 mg/liter
(normal <lo), and the white blood cell (WBC) count
was 14.5 x 109/liter (normal 4.0-10.0 x 109/liter).
Because septicemia was suspected, the patient was
treated for 11 days with oral ciprofloxacin hydrochloride, 750 mg twice a day. Results of urinalyses performed before and after the ciprofloxacin therapy
repeatedly showed a leukocyte count of >200 x lo6/
liter (normal < I 3 X 106/liter), although urine cultures
for bacteria were negative, as were urethral cultures
for Neisseria gonorrhoeae and isolations of Chlamydia trachomatis. Repeated stool cultures for salmonellae, yersiniae, and campylobacteriae, and results of
examinations for parasites were negative. Blood cultures were performed twice and both times the findings
were negative. Test results for antistreptolysin 0
(ASO) and anti-chlamydia antibodies in serum were
repeatedly negative. Results of tests for rheumatoid
factor (RF; by Rose-Waaler and latex fixation tests)
and antinuclear antibodies (ANA; by immunofluorescence) were negative. Radiographic findings on examination of the chest were normal. The patient was
HLA-B27 positive.
The patient was febrile (38-39°C) for 3 weeks.
He developed pain in his right shoulder and an ulceration in the cornea of his left eye. Two months after
admission, the CRP value was 25 mglliter and the ESR
was 55 mmhour, and the patient was discharged.
Twelve months later he still had pain in his right
shoulder. His ESR was 15 mm/hour and the CRP level
was <lo mg/liter.
Retrospective study method. The Department of
Microbiology of Aurora Hospital receives stool samples from the Helsinki area, which has approximately
one-half million inhabitants. Stool samples for culturing shigellae were transported to the Department of
Microbiology in Stuart transport tubes (Difco, Detroit,
MI). Procedures for the culture and identification of
shigellae were performed as previously described (6).
For biochemical identification, API20E profiles (API
System, Montalieu-Vercieu, France) were used. Antisera used in serologic identification of the Shigella
isolates were obtained from Wellcome (Dartford,
UK). The antisera used allowed confirmation of biochemical identification, as well as serologic grouping
for S jlexneri and Shigella hoydii, which may be
identical on biochemical tests.
Review of the laboratory files revealed that
during the past 10 years, stool or urine cultures from
371 patients grew shigellae: 183 (49%) grew S sonnei,
162 (44%) grew SfEexneri, 19 (5%) grew S boydii, and
7 (2%) grew Shigella dysenteriae. Of the 183 subjects
with positive cultures for S sonnei, 48 had been treated
at Aurora hospital. Medical records revealed that 2 of
the patients had had a clinical picture that denoted
reactive arthritis. These 2 patients are described below.
Patient 2. Patient 2, a 35-year-old man with a
history of bronchial asthma, had diarrhea for 1 week
during a visit to Ethiopia in 1986. Two weeks later, he
developed a urethral discharge, and 5 days after this,
pain in the right knee and fever up to 38.4"C.
On admission, his right knee was warm and
swollen. His ESR was 79 mdhour, the CRP value was
168 mghter, the peripheral blood WBC count was 12.0
X 109/liter,and the hemoglobin level was 13.9 gmfliter.
Synovial fluid samples contained 39,000 leukocytes/
mm3 (84% polymorphonuclear granulocytes). Lactic
acid concentration was 3.99 mmoles/liter, which suggested inflammation rather than infection. Results of
Gram stain and bacterial cultures of synovial fluid
were negative. Repeated stool cultures for shigellae,
campylobacteriae, yersiniae, or Clostridium dificile,
as well as examinations for parasites, were negative.
Urethral cultures for N gonovrhoeae and isolations of
C trachomatis were negative. No serologic evidence
of streptococcal (streptolysin 0, deoxyribonuclease
B), staphylococcal (staphylolysin, teichoic acid),
Carnpylohacter, Salmonella, or Yersinia infection was
obtained. Results of tests for ANA and RF were
negative. Urine cultures for bacteria, including Salmonella, were negative. Results of radiologic examination of the knees and the sacroiliac joints were normal.
The patient was HLA-B27 positive.
The patient was treated with nonsteroidal antiinflammatory drugs and physiotherapy. He also took
oral doxycycline, 100 mg once a day, for a 12-day
period; urinalysis before and after therapy revealed
100-200 x 106/literleukocytes.
The patient became afebrile over a 2-week
period. He developed pain in the left ankle and the first
metatarsophalangeal joint of the right foot. After 3
weeks, he left the hospital. Two weeks later, in tests
performed at the outpatient department, urinalysis
showed 100 X 106/liter leukocytes and, unexpectedly,
urine culture yielded S sonnei. The patient was then
treated with oral amoxicillin, 375 mg 3 times a day, for
10 days, after which the subsequent 4 urine cultures
failed to grow shigellae, and the urinalysis results were
repeatedly normal. Eight months later the patient had
recovered completely.
Patient 3. The patient, a 25-year-old, previously healthy man, developed diarrhea and fever in
1981 during ajourney to Mexico. Four weeks later he
developed severe pains in his wrists, knees, ankles,
and neck. Results of a stool culture were positive for S
sonnei and negative for Salmonella. His ESR was 3
mm/hour, WBC count 5.6 X 109/liter,and hemoglobin
level 14.3 gm/liter. A urethral culture for N gonorrhoeae was negative. Findings of urinalysis and radiographic examination of the chest were normal.
The patient was treated with a 2-week course of
oral trimethoprim/sulfamethoxazole and indomethacin. Stool cultures for S sonnei became negative.
However, he continued to have pain in his knees,
ankles, and wrists. Results of ESR, CRP, WBC, ASO,
Rose-Waaler, and latex fixation tests were repeatedly
within the normal range during a 12-month followup
In 1987, we contacted this patient for reexamination. During the past 6 years he had had, particularly
early in the morning, pain and stiffness in the lower
back, and arthralgias following respiratory infections.
There was tenderness in the left sacroiliac joint. His
scores on a chest expansion test, Schober’s test, and
fingertips-to-floor test were 8 cm, 3 cm, and 30 cm,
respectively. The ESR, CRP level, WBC count, hemoglobin level, and results of urinalysis, Rose-Waaler
test, latex fixation test, and tests for ANA were normal
or negative. Findings of radiologic examination of the
sacroiliac joint were normal. He was not HLA-B27
positive but had HLA-Bw22.
All 3 patients described in the present study had
clinical pictures that denoted reactive arthritis. Two of
the patients were HLA-B27 positive and the third had
HLA-Bw22, an antigen also belonging to the crossreactive group of HLA antigens centered on B7 (the
B7 CREG). There was no evidence of enteric or
urogenital infections known to trigger reactive arthritis. However, each patient had a recent or concurrent
S sonnei infection.
Previous failure to demonstrate an association
between S sonnei dysentery and the development of
reactive arthritis in epidemiologic studies could have
been attributed to a sampling error, as has been
suggested earlier (7). Furthermore, the frequency of
HLA-B27, and thereby the genetic susceptibility to
reactive arthritis, varies. In Finland, the frequency is
14%; therefore, the number of subjects susceptible to
reactive arthritis is high (8).
The etiology of the triggering episode remains
unclear in about 26% of patients with typical reactive
arthritis (9). This may be due to eradication of the
microbe before the development of reactive symptoms, intermittent microbial excretion, fastidious
growth characteristics of the microbe, or lack of
appropriate serologic testing. Serologic testing is unreliable in the detection of Shigella infections because
cross-reactions between Shigella and other enteric
bacteria are common (10). Furthermore, repeated cultures of stool and urine may be needed, as shown in
the case of our patient 2.
The mechanism by which arthritogenic strains
cause reactive arthritis is not known, although it has
been suggested that structural similarities between
patient cells and SJEexnrri or other microbes trigger
reactive arthritis (1 1). HLA-B27-like antigenic epitopes have been detected on SJlexneri serotype 2a, but
not on S sonnei (12). The presence of these epitopes
did not, however, correlate with the occurrence of
reactive arthritis. Furthermore, Welsh et a1 (13) have
reported evidence of cross-reacting antigenic determinants between HLA-B27 positive cells and S sonnei.
In a recent study, 53% of patients with Reiter’s syndrome were found to have serum antibodies against a
6-amino acid peptide shared by HLA-B27 antigen and
Klebsiella pneumoniae nitrogenase (14); it remains to
be seen whether such peptide structures are also
components of the shigellae. Unfortunately, the
strains of S sonnei isolated from the 3 patients described in the present study are no longer available for
further evaluation.
Although we cannot exclude with certainty the
possibility that the reactive arthritis was triggered by a
microorganism that we did not recognize, the findings
in this report and those in an earlier one (4) support the
view that S sonnei infection should be taken into
account as a possible triggering episode of reactive
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2. Simon D, Kaslow R, Calin A, Kaye R: Studies of
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3. Good AE, Schultz JS: Reiter’s syndrome following
Shigella flexneri 2a: a sequel to traveller’s diarrhea:
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Manual of Clinical Microbiology. Fourth edition. Edited
by EH Lennette, A Balows, WJ Hausler Jr, HJ Shadomy. Washington, DC, American Society for Microbiology, 1985
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8. Aho K , Leirisalo-Rep0 M, Rep0 H: Reactive arthritis.
Clin Rheum Dis 11:25-39, 1985
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Seppala I, Larinkari U, Ranki M, Koskimies S, Malkamaki M, Makela PH: Triggering infections in reactive
arthritis. Ann Rheum Dis 44:39905, 1985
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JE, Dinant HJ, Zanen HC: Lack of correlation between
HLA B27 like antigenic epitopes on Shigella flexneri and
the occurrence of reactive arthritis. Clin Exp Immunol
65:679-682, 1986
13. Welsh J , Avakian H , Cowling P, Ebringer A, Wooley P,
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ankylosing spondylitis and Reiter’s syndrome: molecular mimicry with Klebsiella pneumoniae as potential
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