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Rheumatology 2001; 40: 262-266
© 2001 British Society for Rheumatology

A case–control study examining the role of physical trauma in the onset of rheumatoid arthritis

A. W. Al-Allaf, P. A. Sanders, S. A. Ogston1 and J. S. Marks

Department of Rheumatology, Devonshire Royal Hospital, Buxton, Derbyshire SK17 6RX and
1 Department of Public Health, Dundee Teaching Hospital NHS Trust, Dundee DD1 9SY, UK


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Statistical analysis
 Results
 Discussion
 References
 
Objective. To investigate whether physical trauma may precipitate the onset of rheumatoid arthritis (RA).

Method. In a case–control study comparing RA out-patients with controls attending non-rheumatology out-patient clinics, 262 patients and 262 age- and sex-matched controls completed a postal questionnaire or were interviewed about any physical trauma in the 6 months before the onset of their symptoms.

Results. Fifty-five (21%) of the RA patients reported significant physical trauma in the 6 months before the onset of their disease, compared with only 17 (6.5%) of the controls (P<0.00001). A preceding history of physical trauma was significantly more common in RA patients who were seronegative for rheumatoid factor (P=0.03), but was not significantly associated with sex (P=0.78), age (P=0.64), a family history of RA (P=0.07) or type of occupation, defined as manual or sedentary (P=0.6).

Conclusion. Physical trauma in the preceding 6 months is significantly associated with the onset of RA.

KEY WORDS: Rheumatoid arthritis, Physical trauma, Occupation.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Statistical analysis
 Results
 Discussion
 References
 
The role of physical trauma in precipitating rheumatoid arthritis (RA) is uncertain, but rheumatologists are frequently asked by their patients or their legal representatives whether trauma could have caused or aggravated their disease.

Some earlier studies on the link between trauma and arthritis were based on retrospective case-note reviews [1, 2] or did not include a matched control group [1, 3–5]. Some studies did not define the nature of the arthritis [1, 3, 4, 6]. In other studies, the latent period between a history of trauma and the onset of arthritis may have been too short to show any risk [7, 8].

We therefore carried out a multicentre hospital-based retrospective case–control study into the link between clearly defined trauma and RA in hospital out-patients using age- and sex-matched controls recruited from other out-patient clinics in the same hospitals.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Statistical analysis
 Results
 Discussion
 References
 
Two hundred and sixty-two patients with RA were recruited from rheumatology out-patient clinics in Greater Manchester (Stepping Hill Hospital, Hope Hospital and Withington Hospital), Buxton (the Devonshire Royal Hospital) and Dundee (Ninewells Hospital). Their hospital case notes were reviewed to confirm that all patients fulfilled the 1987 revised American College of Rheumatology criteria for RA [9], and we tried to avoid recall bias by only including patients whose symptoms has been present for less than 5 yr. One hundred and eighty-five patients were interviewed and all completed a questionnaire about life events and trauma in the 6 months before the onset of their symptoms. Controls with non-rheumatological diseases attending an out-patient clinic in the same hospital were deliberately recruited from many different departments to avoid any bias that might have resulted from using a control group with a specific disease (Table 1Go).


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  		TABLE 1. Classification of controls according to speciality and diagnosis

 
All controls were matched for age and sex with a RA patient. Each control was given a specific date coinciding with the onset of arthritis in their matched RA patient and was asked to complete questionnaire about life events and trauma in the 6 months before the onset of their own disease and in the 6 months before the onset of joint symptoms in their matched RA patient.

Hospital records were reviewed to confirm the data about the onset of disease in the RA patients and their controls, and we interviewed 140 of the controls to confirm that the information provided by the questionnaire was valid.


   Statistical analysis
Top
 Abstract
 Introduction
 Materials and methods
 Statistical analysis
Results
 Discussion
 References
 
The number needed in the study was calculated according to a standard method based on detecting at least a twofold difference between the two groups in their histories of physical trauma with a significance level of 0.05 and a power of 0.90 [10]. We made an assumption that if the percentage of controls with positive history of physical trauma was 10%, a value of 20% or more for patients with RA would be considered significant. Accordingly, the number calculated was 260 in each group or 520 in total.

The SPSS statistical programme was used to analyse the data. Paired t-tests were performed for comparison of normally distributed data. Data that were not normally distributed were analysed using the {chi}2 test. For both tests, statistical significance was taken as P<0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Statistical analysis
 Results
Discussion
 References
 
The 262 RA patients were matched with their controls for sex (77 men and 185 women in each group) and age (mean age 56 yr in each group). The mean duration of disease in the patients was 3.1 yr compared with 5.41 yr in the controls. Rheumatoid factor status was recorded in 256 patients; 226 (88.3%) were seropositive. The patients were more likely to be doing manual work than the controls (Table 2Go).


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  		TABLE 2. Type of job at the onset of disease

 
Physical trauma within 6 months before the onset of their arthritis was reported in 55 (21%) of RA patients compared with only 17 (6.5%) of the controls before the onset of their disease (P<0.00001) and only 16 (6.1%) of the controls before the onset of the joint symptoms in their matched RA patients (P<0.00001).

The type of physical trauma in RA patients and their controls is shown in Table 3Go. When trivial trauma, joint sprains, childbirth and abortion were excluded, then significant physical traumas, such as severe falls, road traffic accidents, fracture and surgery (all of which needed medical attention) were still significantly more common before disease onset in the RA patients (31 patients, 11.8%) than in the controls (12 patients, 4.6%) ({chi}2=9.4, P<0.002)


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  		TABLE 3. Classification of the physical trauma in RA patients and their controls

 
Thirteen RA patients had surgical operations (some had more than one) in the 6 months before the onset of RA compared with seven in the control group. The types of surgery in both groups are shown in Table 4Go. No lymphoid surgery was reported in either group apart from one operation for lymphoma in an RA patient.


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  		TABLE 4. Type of surgery

 
The characteristics of RA patients with and without trauma are shown in Table 5Go. Seventeen out of 77 (22.1%) men had a history of physical trauma before the onset of RA compared with 38 out of 185 (20.1%) women; the difference was not statistically significant. Forty-two out of 53 (79.2%) RA patients with trauma were seropositive for rheumatoid factor compared with 184 out of 203 (90.6%) without trauma, and this difference was statistically significant (P=0.04). Eleven out of 30 (36.7%) patients seronegative for rheumatoid factor reported physical trauma compared with 42 out of 226 (18.6%) seropositive patients (P=0.03).


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  		TABLE 5. Characteristics of RA patients with and without physical trauma 6 months before disease onset

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Statistical analysis
 Results
 Discussion
References
 
These results suggest that physical trauma was significantly associated with the onset of RA. The choice of a 6-month cut-off for reported trauma was arbitrary but in keeping with previous studies, which have used periods varying from days to 2 yr. We felt that 6 months was a realistic period for accurate recall and, as the mechanism for trauma acting as a trigger for RA is unknown and may not be immediate, we chose a longer period than a few weeks. If trauma does act more quickly as a trigger, then it is likely that taking a 6-month cut-off would tend to mask any association.

Twenty-one per cent of the RA patients had a history of physical trauma in the preceding 6 months compared with only 6.5 or 6.1% of the controls (before the onset of their own disease and the matched onset with the RA patients respectively). The second comparison was done in an attempt to limit the possibility of recall bias. Either way, the difference was highly significant (P<0.00001). Similar significant results were found when we excluded trivial traumas and joint sprains (as they were considered to be minor) and childbirth and abortion (because of the possible role of hormonal changes) (P=0.002). The type of job, classified as manual or sedentary, could not explain this difference, and although we found that significantly more patients with RA were in manual jobs at the onset of their disease, there was no significant difference in the history of preceding trauma between RA patients in manual or sedentary jobs.

The RA patients had age and sex distributions similar to those in other published studies [11]. Rheumatoid factor was positive in 88.3% of our patients, which was slightly higher than the 75–80% reported in other studies [12].

Our result of 21% of RA patients reporting trauma before the onset of RA was a higher figure than in other published studies. However, including only patients with major trauma, our figure (11.8%) was more in line with some previous results. It is difficult to interpret the results of older studies carried out before the ARA/ACR diagnostic criteria came into use, but comparison of our results with more recent studies is of interest.

Jacoby et al. [5] found that 14% of RA patients had recognized precipitating factors (six followed trauma, five followed surgery, one followed pregnancy, one followed infection and one followed inoculation). This study can be criticized for not assessing the frequency of similar precipitating factors in the previous year in a matched control population.

Julkunen et al. [13] found that only 2.9% of 270 patients admitted to an intensive therapy trauma unit developed RA over 1–2 yr of follow-up compared with no individuals in a control population. This was not a statistically significant difference, but there was a possibility of selection bias as the patients were recruited from hospitals whereas the controls were taken from the community and neither group was matched for age (the trauma group being significantly younger).

Others have reported from France that about 3% of all RA subjects had a history of physical trauma before the onset of their arthritis [14, 15], but this may be a falsely low figure as only serious physical trauma within days or weeks of the onset was considered.

Scarpa et al. [2], from Italy, found the only two out of 138 RA patients (1%) had precipitating events (one trauma, one viral infection) compared with 9% of a psoriatic arthritis group. No non-disease controls were included, so the 1% figure for RA is of uncertain significance. This study may be criticized for being a retrospective case-note review and the information may not have been recorded completely, explaining the low rate of trauma.

Contradictory results have been reported about the relationship between surgery (another type of physical trauma) and the subsequent development of RA [16–19]. A reassessment of the facts suggested that there was indeed a relationship [20]. All these studies had only considered the influence of antecedent lymphoid surgery and patients undergoing other types of surgical procedures were not included. This might explain why their studies showed only weak evidence that surgery was a trigger for RA. Although our study was not designed to answer the question of what type of surgery is important, it showed no hint that lymphoid surgery is an important factor in precipitating RA.

In our study there was a statistically significant difference between the number of seronegative patients and the number of seropositive patients reporting physical trauma (36.7 vs 18.8%) (P=0.04). This has not been reported in previous studies and might show that there is a different form of reactive inflammatory polyarthritis precipitated by physical trauma in those with seronegative disease. All our patients satisfied the ACR criteria for RA, and we are confident this group did not include patients with a reflex dystrophy syndrome or occupational upper limb disorder that might have been misdiagnosed as RA. It would be of interest in future to look for genetic heterogeneity in RA in the presence and absence of preceding trauma.

Our own results are, of course, retrospective and may still be influenced by recall bias, but if they are confirmed in a further prospective study this would lead us to speculate on the possible mechanisms by which trauma might precipitate RA.

It has been suggested that trauma may alter and/or release antigen(s) from connective tissues. Although the nature of such antigens remains speculative, type II collagen may be an important source of endogenous antigen. Trentham et al. [21, 22] has demonstrated the antigenicity and arthritogenic potential of type II collagen in rats. Alternatively, neuropeptide substance P, which may be released from peripheral nerve terminals after trauma, may contribute to the development of inflammation and destruction of the joints as it stimulates the proliferation of synoviocytes and triggers the release of prostaglandin E2 and collagenase [23, 24].

It is still not clear why major trauma in most individuals is not associated with any sequelae while others develop or experience exacerbated autoimmunity leading to RA. It must be speculative whether patients who are genetically predisposed to autoimmune disease have a different response from normal subjects exposed to the same trauma.

In conclusion, our study suggested that physical trauma in the 6 months before onset was significantly associated with the onset of RA in patients attending a rheumatology out-patient clinic.


   Acknowledgments
 
We would like to thank Dr D. P. M. Symmons for her helpful comments on the design of the questionnaire. We acknowledge the help of Professor M. I. V. Jayson, Drs A. Jones, A. L. Herrick and R. C. Hilton of Hope Hospital and Drs T. Pullar and K. D. Morley of Ninewells Hospital for helping to recruit patients for the study. Special thanks to Maureen Bevens for her help in recruiting patients.


   Notes
 
Correspondence to: A. W. Al-Allaf, University Department of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Statistical analysis
 Results
 Discussion
 References
 

  1. Short CL, Bauer W, Reynolds WE. Rheumatoid arthritis. Cambridge, MA: Harvard University Press, 1957:180.
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Submitted 24 February 2000; Accepted 18 September 2000


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