Campylobacter-triggered reactive arthritis: a population-based study

T. Hannu, L. Mattila1,2, H. Rautelin3, P. Pelkonen4, P. Lahdenne4, A. Siitonen2 and M. Leirisalo-Repo

Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital,
1 Department of Medicine, Division of Infectious Diseases, Helsinki University Central Hospital,
2 Laboratory of Enteric Pathogens, National Public Health Institute, Helsinki,
3 Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, and Helsinki University Central Hospital Laboratory Diagnostics and
4 Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To study the incidence and clinical picture of Campylobacter-associated reactive arthritis (ReA) and other reactive musculoskeletal symptoms in the population.

Methods. A questionnaire on enteric and extraintestinal, including specifically musculoskeletal, symptoms was sent to 870 consecutive patients with Campylobacter-positive stool culture and 1440 matched controls. Analysis of self-reported musculoskeletal symptoms with clinical examination was performed.

Results. Forty-five of the patients (7%) had ReA and eight (1%) had reactive tendinitis, enthesopathy or bursitis. No child had ReA. The arthritis was oligo- or polyarticular, and, in most cases, mild. HLA-B27 was positive in 14% of ReA patients. Of the 45 ReA patients, 37 had C. jejuni and 8 had C. coli infection. No controls had ReA.

Conclusion. ReA is common following Campylobacter infection, with an annual incidence of 4.3 per 100000. At the population level, acute ReA is mild, more frequent in adults, and not associated with HLA-B27. Besides C. jejuni, C. coli can trigger ReA.

KEY WORDS: Reactive arthritis, Campylobacter jejuni, Campylobacter coli, Population-based study.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Reactive arthritis (ReA) is a non-purulent joint inflammation which can be triggered by infections in the gut or in the urogenital tract. Among these triggering agents are different serotypes of Salmonella, Yersinia enterocolitica, Shigella flexneri, Chlamydia trachomatis and Campylobacter jejuni [1].

Campylobacter jejuni is the most common cause of human bacterial enteritis in developed countries. Most cases of Campylobacter infection are sporadic, but small outbreaks occur. Human cases of Campylobacter infection have increased during recent years in many countries. In the USA, an estimated 2.1–2.4 million cases of human campylobacteriosis occur each year [2]. In Finland, with a population of 5.1 million, the annual number of bacteriologically verified cases of Campylobacter reported, according to the National Infectious Disease Registry (National Public Health Institute), exceeded the number for Salmonella for the first time in 1998, and a similar trend has been reported both in the USA [2] and in England and Wales (Laboratory Reports, Communicable Disease Surveillance Centre, England). In 2000, the number of laboratory-confirmed cases of Campylobacter infection reported in Finland was 3527. The most common species involved was C. jejuni, which accounted for 90–95% of Campylobacter-positive stool cultures; C. coli accounted for 5–10% (National Infectious Disease Registry).

Patients with Campylobacter infection may have extraintestinal complications such as meningitis, septic arthritis, carditis, pancreatitis, urinary tract infection, Guillain–Barré syndrome and ReA. Reports of about 40 Campylobacter-triggered cases of ReA have appeared in the English medical literature [322]; these were mainly reports of sporadic cases. Two outbreaks followed by a rheumatological survey have been described, with occurrences of ReA between 0.7 and 1.8% [15, 20]. However, no large population-based study of the incidence of Campylobacter-triggered ReA has yet been performed. All ReA cases in which the triggering Campylobacter species has been specified have been due to C. jejuni, except one case triggered by C. lari [22].

The aims of our study were (i) to assess the incidence and the clinical picture of Campylobacter-associated ReA and other reactive musculoskeletal symptoms in the population, and (ii) because musculoskeletal complaints are frequent in the community, to analyse the frequency of such symptoms in age- and sex-matched controls.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
This study was carried out between April 1997 and September 1998, and was approved by the Ethics Committee of Helsinki University Central Hospital (HUCH) and of the National Public Health Institute, Helsinki. Campylobacter infection was diagnosed at HUCH Laboratory Diagnostics, which serves a population of about 1 000 000 people in southern Finland, where about 40% of all bacteriologically verified cases of Campylobacter infection in Finland are detected. In addition to Campylobacter, most stool specimens were also cultured for Salmonella, Shigella, Yersinia, Aeromonas and Plesiomonas. The presence of parasites in the stool specimens was sought in a few cases. A questionnaire on enteric and extraintestinal symptoms (see below) was sent to consecutive subjects with a Campylobacter-positive stool culture (Fig. 1Go). The same questionnaire was also sent to controls recruited from the Finnish Population Registry. If no response was obtained from the controls within 2 weeks, the questionnaire was sent to another control subject. Altogether, the questionnaire went to a total of 870 subjects with Campylobacter infection and to 1440 controls. Of these patients and control subjects, 609 (70%) and 771 (54%) respectively returned the questionnaire. On this basis, we were able to form 405 (one control for one patient) pairs matched for age-, sex- and municipality for comparison of musculoskeletal symptoms of Campylobacter-positive patients with those of controls.



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FIG. 1.  Study profile. MS, musculoskeletal.

 

Analysis of Campylobacter stool specimens
Stool samples submitted in Stuart tubes to HUCH Laboratory Diagnostics were inoculated on Campylobacter blood-free selective agar (Oxoid, Basingstoke, UK or LAB M, Bury, UK). All isolates were Gram-negative and oxidase- and catalase-positive and grew at 42°C in a microaerobic atmosphere. Hippurate hydrolysis was determined with diagnostic tablets containing sodium hippurate (Rosco Diagnostica, Taastrup, Denmark) according to the manufacturer's instructions. Hippurate-positive isolates were regarded as C. jejuni. In some cases, the polymerase chain reaction, with C. jejuni- and coli-specific primers for the ceuE gene, served for the identification of hippurate-negative isolates [23].

Questionnaire
The questionnaire covered the presence, severity and duration of diarrhoea, the presence of concomitant symptoms of infection, such as abdominal pain, fever, eye symptoms, skin and urinary symptoms, painful or swollen joints, limitation of joint movement, pain in tendon insertions, low back or neck pain, onset and duration of these symptoms, eventual visits to a physician or hospital and drug therapy for these symptoms during the preceding 6 months, and previous joint or other musculoskeletal complaints or diagnoses. The questionnaire included a graphic representation of the body, on which the subject was asked to mark swollen or painful joints and tendons. The patients and the controls received similar questionnaires. The questionnaire was slightly modified from that used in our earlier studies dealing with ReA after Salmonella outbreaks [24, 25].

Diagnostic criteria
The gastrointestinal infection was defined as imported if the diarrhoea developed during a visit abroad or within 2 weeks after returning home. ReA was defined as the development of synovitis (either swelling or limitation of joint movement, and pain) in a previously asymptomatic joint, or as inflammatory low back pain (low back pain that was worse at night) within the first 2 months after a gastrointestinal infection. For synovitis, we accepted either the findings of the clinical examination or the description given in the questionnaire. Each affected joint in the fingers and toes was counted individually. Tendinitis, enthesopathy and bursitis were regarded as reactive if they occurred within the first 2 months after the infection. Any other forms of joint or back pain during or after the acute infection were also recorded. An appropriate musculoskeletal diagnosis, given to all patients and control subjects, was based on information from the questionnaire, completed with data from a clinical examination if available.

Clinical examination
Two hundred and twenty subjects in the Campylobacter-positive group and 185 in the control group had reported joint complaints recently. On the basis of the information in the questionnaire, subjects with acute joint symptoms were invited to a clinical examination performed by study rheumatologists (adults, TH, ML-R; children, PP, PL). The clinical examination was performed within a median of 11 weeks (range 3–37) after the onset of infection on Campylobacter patients and within a median of 11 weeks (range 3–33) after the return of the questionnaire by controls. A detailed study of affected joints and tendons was an essential part of the clinical examination. In addition, blood was collected for measurement of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) and for HLA-B27 antigen analysis.

Statistical analysis
Data were analysed with the SPSS statistical software system, version 10.05 (SPSS, Chicago, IL, USA). Proportional data were compared with the {chi}2 test or with Fisher's exact test. The Mann–Whitney U-test or Student's t-test was used in comparisons of continuous variables. Differences at the 5% level were considered statistically significant.

As all subjects did not answer all the items on the questionnaire, the data in the Results section are, if necessary, given as the proportion of positive answers to the number of responders.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Campylobacter-positive patients
The mean age of the 609 Campylobacter-positive patients was 37.1 yr (range 1–91). Of these, 10% were younger than 16 and 59% were females. As symptoms of Campylobacter infection, 98% (598 of 608) of patients reported diarrhoea, 88% (524 of 592) abdominal pain and 81% (481 of 592) fever (>=37.5°C). A total of 74% of Campylobacter cases were imported.

Of the 609 Campylobacter-positive stool cultures, 88% were positive for C. jejuni and 10% for C. coli; the remaining 13 Campylobacter isolates were not identified to species level by the routine methods used and were thus designated Campylobacter sp. No statistically significant differences existed between patients with C. jejuni or C. coli in respect to their self-reported symptoms of acute enteritis. Mixed infection was found in 30 patients (5%): Salmonella enterica (11 cases), Aeromonas sp. (9), Yersinia enterocolitica (7), Giardia lamblia (2) and Plesiomonas shigelloides (1).

Reactive musculoskeletal symptoms
Recent joint or other musculoskeletal symptoms were reported by 38% (220 of 582) of the Campylobacter-positive patients and by 24% (185 of 758) of the controls (P<0.001). Of these 220 Campylobacter-positive patients and 185 controls, 113 (51%) and 31 (17%), respectively, with acute musculoskeletal symptoms were examined clinically. Of the 609 patients with Campylobacter infection, 45 (7%) fulfilled the criteria for ReA and another eight (1%) for reactive tendinitis, enthesopathy or bursitis (ReTEB). Thus, in total, of the patients examined clinically, 53 (9%), all adults (10% of adults vs 0% of children; P=0.001), showed reactive musculoskeletal symptoms. (In addition, seven patients described symptoms suggestive of ReA on the questionnaire but did not participate in the clinical examination; adding these patients to the calculations would have increased the frequency of ReA to 8.5%.) On the basis of the clinical examination and/or questionnaire, no subject in the control group (n=771) had acute reactive symptoms.

Among the Campylobacter-positive patients, the 53 with reactive musculoskeletal symptoms had significantly higher frequencies of urinary (38 vs 21%, P=0.01) or skin (25 vs 11%, P=0.009) symptoms than patients without reactive symptoms (n=556). The former were also older (mean±S.D.; 45.5±15.1 vs 36.3±18.0 yr, P=0.001), and more often female (74 vs 58%, P=0.022). Patients with reactive symptoms also had a longer median duration of diarrhoea [10.0 (interquartile range 5.5–17.0) vs 7.0 (5.0–12.0) days, P=0.027], fever [3.0 (2.0–4.0) vs 2.0 (2.0–4.0) days, P=0.035] and abdominal pain [5.0 (3.0–8.2) vs 4.0 (3.0–7.0) days, P=0.038] than patients without reactive symptoms.

Besides Campylobacter, some other concurrent enteric pathogen (Salmonella or Yersinia enterocolitica) was isolated from stool cultures in three out of 53 patients with reactive musculoskeletal symptoms (Table 1Go). There were no statistical differences related to the occurrence of ReA between patients with or without mixed infection (data not shown).


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TABLE 1.  Campylobacter species and mixed infection among patients with ReA and ReTEB

 

Patients with Campylobacter-triggered ReA
Of the 45 ReA patients (Table 2Go), 37 had a positive stool culture for C. jejuni and eight for C. coli. The occurrence of ReA did not differ statistically significantly between the C. jejuni (7%) or C. coli (13%) groups.


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TABLE 2.  Clinical characteristics of patients with ReA and ReTEB

 
Nine of the ReA patients had inflammatory low back pain without peripheral arthritis. The peripheral arthritis was monoarticular in four, oligoarticular (two to four affected joints) in 14 and polyarticular in 18 patients. The most frequently affected joints were the knees and proximal interphalangeal joints of the hands (36% for each), followed by the metacarpophalangeal joints (33%), ankles (29%), shoulders (27%), metatarsophalangeal joints and distal interphalangeal joints of the hands (24% for each), and wrists (22%). The size of the affected joints was large in four and small in 13 patients; 19 (53%) had both large and small joints affected. Both upper and lower extremities were affected in 21 patients (58%), only the upper extremities in seven, and only the lower in eight.

The arthritis was mild in most cases. Nine of the 45 ReA patients (20%) had visited a physician because of arthritis, but only one suffered arthritis severe enough to lead to admission to hospital. The number of patients visiting a physician was higher among those with ReA of the large joints than among those with only small joints affected (8 of 23 vs 0 of 13 patients, P=0.032). The duration of acute ReA could be determined in 20 of 45 patients (44%) who had recovered fully from the arthritis by the clinical examination: <=1 month in 10 patients, 1–2 months in three patients, 2–3 months in one patient, 3–4 months in five patients and 4–6 months in one patient.

Patients with Campylobacter-triggered ReTEB
Of the eight ReTEB patients (Table 2Go), seven had a positive stool culture for C. jejuni, and in one Campylobacter was not identified to species level (Campylobacter sp.). None of these ReTEB patients had visited a physician for their musculoskeletal complaints.

Laboratory findings for patients with ReA and ReTEB at the clinical examination
The frequency of HLA-B27 was 14% (six of 44) in the ReA and 13% (one of eight) in the ReTEB subgroup. In the ReA patients, the presence of the HLA-B27 antigen had no statistically significant effect on the duration of ReA or on the size of the affected joints (data not shown). Five of the ReA patients (11%) were positive for RF, but the clinical characteristics of these patients was not suggestive of rheumatoid arthritis; none of the ReTEB patients were RF-positive. The ReA and ReTEB patients did not differ significantly in ESR (mean±S.D.; 12±9 and 10±8 mm/h respectively) and CRP (5±6 and 5±6 mg/l).

Comparison of musculoskeletal symptoms of Campylobacter-positive patients and of controls
Because joint symptoms are frequent in the community, we compared musculoskeletal symptoms in the Campylobacter-positive patients and controls matched for age, sex and municipality (Table 3Go). The mean age of these 405 pairs was 37.2 yr (range 1.1–86.5). Of these pairs, 10% were aged under 16 yr and 60% were female. A recent (during the previous 6 months) visit abroad, an extended visit (over 7 days) and a high number of countries visited were risk factors for Campylobacter infection (data not shown).


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TABLE 3.  Comparison of musculoskeletal diagnoses of the 405 matched pairs based on questionnaire or clinical examinationa

 
Joint or other musculoskeletal symptoms during the last 6 months were reported by 38% (149 of 387) of patients and by 26% (102 of 398) of control subjects (P<0.001). ReA and other reactive symptoms occurred only in the Campylobacter patient group; no control subject had such symptoms. Conversely, however, chronic joint complaints or previous musculoskeletal disease (especially degenerative symptoms or chronic joint pain) were more frequent in the controls than in the Campylobacter group (Table 3Go).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is the first large population-based study of the frequency of joint symptoms in patients with positive stool culture for Campylobacter. On the basis of calculations at the clinical examination, the occurrence of Campylobacter-triggered ReA was 7%. When the other reactive musculoskeletal symptoms (tendinitis, enthesopathy or bursitis) were included with ReA, the total increased to 9%. If questionnaire data without a clinical examination were also included, the occurrence of ReA was 8.5% and that of all the musculoskeletal symptoms was 10%. In Finland, with about 3000 identified Campylobacter infections per year, this makes the actual minimum incidence of reactive musculoskeletal symptoms after campylobacteriosis 5.1/100 000 population/yr and of ReA 4.3/100 000. In two previous reports on Campylobacter outbreaks, the occurrence of ReA ranged from 0.7% in Sweden [20] to 1.8% in England [15]. On the other hand, in a small population-based study with only 52 subjects from Norway, the incidence of ReA was 8% [17]. Our results confirm the finding of this last study, and show that a higher frequency of ReA following Campylobacter infection is observed in the general population than in earlier reports of outbreaks.

The clinical picture of Campylobacter-triggered ReA was polyarticular in half the cases, with frequent arthritis in the proximal interphalangeal and metacarpophalangeal joints of the hands. The polyarticular form has been observed previously in association with Campylobacter [5, 6, 8, 10] and also with other triggering agents, such as Salmonella [26, 27] and Yersinia [28, 29]. In the classic study of Ahvonen et al. [29], the involvement of the small joints of the hands and feet as part of the clinical characteristics of ReA is well documented. Since then, arthritis of these small joints has also been reported following infections with Campylobacter [46, 812]. This finding contradicts the prevailing concept of ReA as being mono- or oligoarthritis, predominantly in the large joints of the lower extremities. Our results at population level in this series show that the oligo- or polyarticular form of small-joint affection is often benign and only infrequently leads to a visit to a doctor, whereas involvement of the larger, weight-bearing joints is a less common but a more severe form. This fact can cause bias in the description of the clinical picture of ReA in population- vs hospital-based series. Furthermore, enthesopathy has not been reported previously in association with Campylobacter-triggered ReA, although tenosynovitis of the finger has been observed [10]. On the basis of the present series and the previous studies with Salmonella-triggered ReA [30, 31], ReTEB can be accepted as a reactive entity either alone or in association with ReA.

The durations of diarrhoea and abdominal pain were statistically longer in our Campylobacter patients with reactive musculoskeletal complications than in those with an uncomplicated course. Previously, a longer duration of enteritis has been reported to occur in patients with ReA triggered by Salmonella than in patients without complications [32], while the reverse has been reported for yersiniosis [33].

According to our findings, C. coli is a new triggering factor in ReA, appearing in eight of 45 ReA patients. In those published ReA cases for which the triggering Campylobacter species is mentioned, it has been C. jejuni, except for one case report, in which the preceding infection was caused by C. lari [22]. There is also one case report of Reiter's syndrome in association with C. fetus infection [34]. Because this patient had a negative stool but multiple blood cultures positive for C. fetus, this was not, however, the classic form of ReA.

The literature reports four cases of Campylobacter-triggered ReA in children [5, 11, 17, 21], although the present study observed no children with ReA. Therefore, in agreement with previous findings [9], ReA seems to be a rare complication of Campylobacter enteritis in children, as observed also in association with Salmonella [24] and Yersinia [35] infections.

In our study population, antigen HLA-B27 occurred in 14% of patients with ReA, a figure equal to that of the general population in Finland [35] but considerably lower than the figures (80–90%) usually reported in patients with ReA [1]. However, studies reporting a high frequency of HLA-B27 usually involve hospital-based series of patients with more severe and complicated disease. This suggests that, at community level, where most cases of ReA are mild, the presence of HLA-B27 is less important as a marker of ReA. In our earlier studies involving two food-borne outbreaks caused by Salmonella enterica serotypes, the frequencies of HLA-B27 in ReA patients were 31% [24] and 45% [25]. In studies of Campylobacter-triggered ReA, HLA-B27 has been positive in 53% (18 of 34) of patients tested [320]. However, if the analysis is limited to hospital-based case reports [38, 1014, 18, 19], the frequency of HLA-B27 positivity in tested patients is higher: 70% (16 of 23). Interestingly, in the earlier small population-based study [17], all three ReA patients with Campylobacter were HLA-B27-negative. Along with these observations, our results may indicate a continuum in the effect of HLA-B27 in ReA: from the community, where the effect is smallest, through outbreaks, where the effect is average, to hospital-based series, which show the most dramatic effect. It is possible, however, that the presence of HLA-B27 antigen may contribute to the late prognosis of patients with acute Campylobacter-triggered ReA, as is the case in the follow-up series with Yersinia- and Salmonella-triggered ReA [35, 36]. To investigate this question in the current patients, a follow-up study is warranted.

The high frequency of reactive complications and the low frequency of HLA-B27 may raise questions about diagnostic accuracy. However, because our series was based on patients with a positive stool culture for Campylobacter, the confirmation of the triggering infection was certain. Furthermore, we based our diagnosis of ReA on a questionnaire we had used previously [24, 25]. Although a small number (11%) of our ReA patients were positive for RF, the clinical picture and the short duration of arthritis in these patients did not favour the diagnosis of rheumatoid arthritis, and a positive RF test does not exclude the diagnosis of ReA. Though the frequency of ReA was higher in our study than in previous reports for Campylobacter outbreaks [15, 20], it was of the same magnitude as in our earlier studies [24, 25] for Salmonella and in a study by Johnsen et al. [17] for Campylobacter. In comparison with some other epidemiological studies of the incidence of ReA, we had a high response rate. In addition, our results were based not only on information from the questionnaire but also on clinical study of patients with reactive musculoskeletal symptoms, which increases the reliability of the data. To validate the diagnoses of patients with reactive symptoms, and because joint complaints are frequent in the community, we also used the questionnaire to analyse musculoskeletal symptoms in controls. Contrary to the situation for patients with Campylobacter, the survey did not observe any ReA among matched controls, indicating that the questionnaire performed well and identified the patients with ReA.

In summary, ReA occurred in 7% of patients with Campylobacter infection; other reactive musculoskeletal symptoms (tendinitis, enthesopathy, bursitis) were also observed. In most cases, the acute reactive disease was mild and its association with HLA-B27 was low. C. coli should be included among the triggering factors in the aetiology of reactive arthritides. Finally, on the basis of the increasing frequency of Campylobacter in the community, we recommend that, in patients with acute joint symptoms, a history of diarrhoea should always be asked about, and in cases with a history of diarrhoea and recent arthritis, Campylobacter infection should be considered as one of the possible triggering agents.


    Acknowledgments
 
We thank the nurses of the participating departments of the Helsinki University Central Hospital, Kirsi Mäkisalo, Anja Laine and Ritva Marizu of National Public Health Institute, Helsinki, for their assistance, and Hannu Kautiainen for statistical advice. This work was supported by grants from Helsinki University Central Hospital Research Funds, the Clinical Research Institute of Helsinki University Central Hospital and the Academy of Finland.


    Notes
 
Correspondence to: T. Hannu, Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, PO Box 263, FIN-00029 HUCH, Finland. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 8 May 2001; revised version accepted 10 October 2001.