Early inflammatory polyarthritis: results from the Norfolk Arthritis Register with a review of the literature. I. Risk factors for the development of inflammatory polyarthritis and rheumatoid arthritis

D. Symmons and B. Harrison1

ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester and East Cheshire NHS Trust, Macclesfield and
1 Withington Hospital, Manchester, UK


    Introduction
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
Soon after people develop a chronic disease such as rheumatoid arthritis (RA), they ask their physicians two searching questions: the first is ‘Why me?’ and the second is ‘What will happen to me now?’ In 1989 the ARC Epidemiology Unit set up the Norfolk Arthritis Register (NOAR) with the aim of providing answers to these two questions. This paper is the first in a series of two reviews which focus on the work of NOAR, a register of a primary care-based inception cohort of patients with inflammatory polyarthritis (IP). The present paper examines genetic and environmental risk factors for the development of IP and of its subset, RA. The second paper summarizes the natural history and predictors of prognosis [87]. In both papers the NOAR data are presented in the context of a detailed review of the literature which summarizes current knowledge in this challenging area.


    Background
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
The cause and prognosis of any disease are best studied by identifying incident cases from the general population. The study of prevalent cases makes it difficult to distinguish factors which lead to the development of disease from those which influence disease outcome. Hospital-based studies may be subject to selection bias. A major problem in studying rheumatoid arthritis (RA) lies in the definition of the disease. The earlier in the course we try to identify patients, the harder it is to distinguish different forms of inflammatory polyarthritis (IP). Many of the criteria currently used to classify RA [1] [e.g. radiological erosions, rheumatoid nodules and rheumatoid factor (RF)] are features of chronic or severe disease, and may not appear until months or years after disease onset.


    The Norfolk Arthritis Register
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
The Norfolk Arthritis Register (NOAR) is a population-based register which aims to recruit all patients who potentially have RA by using deliberately broad inclusion criteria. Details of the register have been published elsewhere [2]. General practitioners (GPs) working in the former Norwich Health Authority, which covers a population of almost 0.5 million, predominantly (99%) of European Caucasoid origin, notify NOAR of adults (age 16 yr or older) who have swelling of at least two peripheral joints which has persisted for a minimum of 4 weeks. A parallel notification system operates from the local hospitals. Patients who do not satisfy the 1987 American College of Rheumatology (ACR) criteria for RA are later excluded if they are referred to hospital and are given a diagnosis other than RA, psoriatic arthritis, viral arthritis or undifferentiated IP.


    Assessment of patients referred to NOAR
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
Within 2 weeks of notification, patients are visited at home by a research nurse, who takes a history using a structured questionnaire and examines the following joints for tenderness, soft-tissue swelling and deformity: distal interphalangeal joints, proximal interphalangeal joints (PIP), metacarpophalangeal joints (MCP), wrists, elbows, shoulders, knees, ankles and metatarsophalangeal joints (MTP). Patients are asked to provide a blood sample, which is frozen as serum and EDTA-anticoagulated specimens. Patients are assessed annually for a minimum of 5 yr. At each visit patients are asked to complete the Stanford Health Assessment Questionnaire [3], which is scored from 0 to 3. The 1987 ACR criteria are applied at each assessment.

At the 1-yr assessment, those who satisfy at least two of the 1987 ACR classification criteria for RA are asked to have X-rays taken of the hands and feet. The X-rays are read independently by two observers, and the following joints are graded from 0 to 5 using the grading system of Larsen et al. [4]: PIPs, MCPs, wrists and MTPs II–V. A third observer acts as arbiter if there is disagreement about whether a patient has erosions. At the 2-yr assessment visit, patients who satisfy at least two of the ACR criteria and who were non-erosive at the 1-yr visit are asked to have further X-rays.


    The NOAR case–control study
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
During 1994–95 a case–control study was conducted, the results of which form the basis of much of this review paper. The cases were consecutive patients recruited by NOAR between May 1994 and April 1995 who were aged 18–70 yr and who had a symptom duration of less than 12 months at the time of registration with NOAR. The control subjects were selected from the combined registers of all GPs in the Norwich Health Authority. The controls were matched to the case by sex and by date of birth (± 1 day) [5]. If the first control subject approached declined then another was approached until one agreed to participate or until 6 months had elapsed from the time of notification of the case. We tried to recruit two controls for each male case aged less than 45 yr in order to increase the power of the investigation. Cases and controls were mailed identical questionnaires, which asked about marital status, occupation, educational qualifications, current height and weight, previous medical history, current medication, smoking habits and reproductive factors.

Controls were assigned a dummy date of disease onset corresponding to that of their matched cases. Odds ratios (OR) were calculated using a conditional logistic regression model which maintained the matching. In total 177 cases were recruited. Controls were found for 165 of the cases, including 13 young males for whom two controls were identified. The analyses are therefore based on 165 cases and 178 controls. Of the cases, 90 (55%) satisfied the 1987 ACR criteria for RA at the baseline assessment, and are referred to in this review as ‘RA’.

This paper reviews our current understanding of the range of genetic and environmental factors which may predispose to or protect against the development of RA. The majority of previous studies of the aetiology of inflammatory arthritis have focused specifically on RA. We have therefore examined risk factors in the whole NOAR cohort (‘IP’) and those who satisfied classification criteria for RA (‘RA’).


    Genetic risk factors
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
The importance of genetic factors in the aetiology of RA has been recognized for many years. Concordance rates for RA are higher in monozygotic (12–15%) than in dizygotic twins (3–4%), and higher in dizygotic twins than one would expect by chance from population prevalence estimates [6, 7]. These observations support the hypothesis that there is a genetic component to RA. However there is an ongoing debate as to the relative contribution of genetic factors to disease susceptibility as opposed to disease severity. For example, the occurrence of RA in the first-degree relatives of NOAR RA patients was not increased compared with that of matched controls [8]. Around 2–3% of NOAR RA cases have at least one first-degree relative with RA compared with around 11% of hospital clinic RA patients [9, 10]. This suggests that genetic factors may be more important in determining disease severity (and thus hospital referral).

The association between RA and HLA-DR4 was first demonstrated more than 20 yr ago [11]. It has since been estimated that up to 50% of the genetic component of RA susceptibility may be accounted for by genes in the HLA region [12]. As more advanced molecular biology techniques have been developed, it has become clear that RA is primarily associated with a specific amino acid sequence on the ß1 chain of a number of class II alleles. Studies of clinic-derived RA patients from a wide range of populations [13] led to the formulation of the ‘shared epitope’ (SE) hypothesis [14]. Variation in the frequency of SE-positive alleles (DRB1*0101, *0102, *0401, *0404, *0405, *0408, *1001 and *1402) in different populations may account for some of the variation in RA prevalence around the globe. It is unclear how the SE is involved in the causation of RA, but there are a number of possibilities. For example the SE may act as a receptor for an arthritogenic peptide; the SE may model the T-cell repertoire to favour an arthritogenic response; or there may be molecular mimicry between SE and a pathogen such as the Epstein–Barr virus [15].

As mentioned above, these genes may be more important in determining the clinical course of RA than in determining susceptibility to the disease. It appears, from a number of reports, that the DR4-positive RA-associated alleles are more frequent in patients with severe, erosive disease [16], whereas a study of cases ascertained from a population survey did not demonstrate an important association between HLA and RA [17]. We investigated this relationship in the NOAR cohort. Six hundred and eighty consecutive patients with IP, registered between 1991 and 1995, were typed for HLA-DRB1 alleles. The controls were taken from the case–control study described above or from another population-based prospective study in Norfolk which is investigating the relationship between diet and the subsequent development of cancer (the EPIC study). We found only a modest association between IP and the presence of any SE [OR 1.8; 95% confidence interval (CI) 1.4, 2.4]. The effect of being homozygous for the SE was only moderately greater (OR 2.1; 95% 1.5, 3.0) than the effect of being heterozygous (OR 1.3; 95% CI 1.1, 1.6) [18]. However the risk of being RF-positive was substantially higher in those who were homozygous for the SE (OR 3.3; 95% CI 2.1, 5.3) than in those who were heterozygous (OR 1.5; 95% CI 1.0, 2.0). We examined the associations of certain alleles that include the SE. All showed a pattern similar to that described above, with the exception of *0404 (OR 3.5; 95% CI 1.8, 6.8). There was a strong association with IP, RA and seropositivity in cases who were homozygous for *04 and in whom one of the alleles was *0404. For example, individuals who had the genotype *0404/*0404 had a markedly increased risk of having IP (OR 17.9; 95% CI 4.2, 77.8). Similar results were obtained by restricting analysis to the subset of patients with RA. Therefore the ACR criteria did not define a subgroup of patients with a stronger association with HLA.

It is important to be aware that, although the majority of patients with IP and RA possess at least one copy of the shared epitope, so do a large proportion of the normal population. According to the NOAR data, in a Caucasian population about 44% of people are SE-positive but only one in 43 of these individuals will develop RA. The highest risk is conferred by possession of two *0404 genes. This combination occurs in only 0.1% of the Caucasian population, but one in six will develop RA. Among new cases of RA, approximately 5% will be homozygous for *04 and approximately 0.5% will be homozygous for *0404.

Until recently, most studies of RA susceptibility have focused on genes in the HLA region. However, it now appears that HLA genes may be more important in determining the clinical course of RA than in conferring susceptibility to the disease. The availability of rapid gene sequencing techniques and highly polymorphic microsatellite markers means that it is now possible to search for other susceptibility genes using both whole-genome screening and the candidate gene approach. Some preliminary results have been published, and this is likely to be an area of intensive investigation in the next few years.


    Hormonal and reproductive risk factors
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
A number of observations point to a role for hormonal and reproductive factors in the development of RA. RA is more common in women than men, especially in the pre-menopausal age groups [2]. RA is rare before the menarche. Women have a reduced susceptibility to RA during pregnancy. This is followed by a period of increased susceptibility in the immediate post-partum period [19]. This increased susceptibility does not simply represent a ‘catch-up’ phase in which those women who might otherwise have developed RA during the 9 months of pregnancy all develop it in the 3 or 4 months post-partum. Rather, the risk seems to be related to breast-feeding. A case–control study of 88 women who developed RA within 12 months of delivery of their first child showed that they had a five-fold increased frequency of breast-feeding compared with 129 control women [20]. It seems that if a woman ‘survives’ her first exposure to breast-feeding without developing RA, then her risk after each subsequent pregnancy will be less. Prolactin, the hormone which maintains lactation and which is known to be proinflammatory, may play a role in the onset of post-partum RA.

It is not clear whether pregnancy itself is a risk factor or protective against RA. An early study by Kay and Bach suggested that nulliparous women may have an increased risk of developing RA [21]. However, recent studies (Table 1Go), including a large community study [28] and the NOAR case–control study [5], have failed to confirm this. Nulliparity might be a result of fetal loss in the early weeks of pregnancy. In the NOAR case–control study, women with RA reported more miscarriages (OR 2.2; 95% CI 0.9, 5.5) than age-matched controls [5]. Nelson et al. [27] found a non-significantly increased rate of nulliparity amongst their RA patients. They also found that 14% of their cases were gravid but not parous, compared with 9% of controls. The difference was attributed to a higher rate of induced abortion amongst the RA patients. In a more recent study from NOAR, women with RA also reported a higher frequency of prior termination of pregnancy than age-matched controls (OR 3.7; 95% CI 1.6, 8.6) (29). A number of studies have also reported an increased frequency of stillbirth (Table 1Go). It therefore appears that an adverse pregnancy outcome (either spontaneous or iatrogenic) may be a risk factor for developing RA, often many years later.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Pregnancy history and the development of RA

 
A number of studies suggest that exposure to the oral contraceptive pill (OC) may either reduce the risk of developing severe RA or may delay the onset of RA (Table 2Go). A protective effect of OC use against the development of RA was first suggested in 1978 as an unexpected finding from the Royal College of General Practitioners’ study of the effect of the OC pill on various aspects of women's health [36]. Current OC use among 23 000 women halved the risk of developing RA. Since 1978 a number of studies have been published which examine this issue (Table 2Go). Their results are conflicting. The most plausible explanation for this came from a meta-analysis published in 1990 which divided the studies into those which were hospital-based and those which were population-based [42]. The pooled OR for the hospital-based studies published up to that time was 0.49 (95% CI 0.39, 0.63) and for the population-based studies it was 0.95 (95% CI 0.78, 1.16). As indicated in Table 2Go, it appears that this difference between hospital- and community-derived cases has been maintained in studies published since 1990. It suggests that OC use does not protect against the development of RA, but does prevent it from becoming severe enough to warrant hospital referral.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Oral contraceptive use and the development of RA

 
We explored the link between OC use and the development of IP in the context of the NOAR case–control study [5]. We found a protective effect for current use of an OC (OR 0.2; 95% CI 0.1, 0.9) but not for having ever taken an OC (OR 0.9; 95% CI 0.5, 1.6) [41]. The effect was similar for those who satisfied the criteria for RA (currently use OC: OR 0.2; 95% CI 0.1, 2.3) (have ever used OC: OR 1.1; 95% CI 0.5, 2.5). It does, therefore, appear that, even in the 1990s, there is still a protective effect from the current use of the OC, even in a community setting. However, there are difficulties in interpreting these studies because the women have chosen whether or not to take an OC and this decision is likely to be influenced by their lifestyle and health status. It is possible that OC use is a surrogate for another variable which is the true modifier of RA. This explanation is made more likely by the fact that no dose or duration effect has been documented convincingly. Further studies will be difficult because the majority of women now take an OC at some point in their lives. This may explain why the NOAR study found no protective effect for ever having used an OC [40]. Another possible explanation is that OC use is delaying the onset of RA rather than preventing it altogether. The peak age of onset of RA appears to be getting higher in women but not in men, which is consistent with the theory that the use of the OC delays the onset of RA [43].

If hormonal factors are so important in the pre-menopausal woman, questions obviously arise as to the effect of the menopause and the use of hormone replacement therapy (HRT) on the onset of RA. In the NOAR case–control study there was no link between menopausal status and the onset of RA, although women with RA did report a higher frequency of prior hysterectomy (OR 2.4; 95% CI 0.9, 6.2). Only 23% of cases and 21% of controls reported having ever used HRT. The first study to address this issue found a protective effect in women exposed to HRT [32], but three subsequent studies have failed to confirm this [4446].

Finally, what about hormonal factors in men with RA? A number of case–control studies have suggested that RA is associated with low testosterone levels in men and women, but it is impossible to know whether this is a cause or the effect of the disease [4750]. Masi et al. [51] reported low androgen levels in females before the onset of RA and suggested that this may be involved in the causation of RA rather than an effect of the disease. However, a more recent population-based study from Finland found similar levels of testosterone and dehydroepiandrosterone sulphate in both men and women who subsequently developed RA, compared with the general population [52].

There is also some evidence to support the hypothesis that some people who develop RA have a genetically determined [53] defect of the hypothalamic–pituitary–adrenal axis [54] which prevents them from developing an adequate anti-inflammatory response to immune stimulation. While this may account for the persistence of some cases of IP, it is probably of no aetiological significance.


    Environmental risk factors
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
Medical risk factors
Infectious agents have been suspected as potential triggers of RA for a long time. However, no organisms have been recovered consistently from synovial tissue or fluid, and serological studies for a wide variety of bacteria, mycobacteria, viruses and parasites have been negative when applied to cohorts of patients with recent-onset RA. In the NOAR patients there was no evidence of clustering of RA in space or time [55]. In the NOAR case–control study the cases did not report an increased frequency of infections before the development of their arthritis [5]. This suggests that RA is not caused by a single organism. It does not, however, rule out the possibility that infection may trigger RA in individual cases. It has been suggested that Epstein–Barr virus [56] and Proteus infection [57] may play an aetiological role in some individuals, although results of different studies are conflicting. There are certainly well-documented cases of typical RA developing after proven infection with, for example, parvovirus and rubella [58, 59]. Such cases do not make up a large proportion of all cases of RA but do, nevertheless, exist. In the NOAR cohort, only four out of 147 (2.7%) newly ascertained patients with a history of IP of less than 16 weeks tested positive for parvovirus. Three of the four patients satisfied the ACR criteria for RA [60].

The same arguments can be applied to the evidence that immunization may trigger RA [61]. There is clear evidence that rubella immunization may trigger an arthritis in susceptible women [59]. In many, the arthritis is short-lived but in those in whom it persists it looks and behaves like typical RA. Similarly, there is evidence that tetanus and influenza immunization may trigger RA in susceptible hosts [62]. In the NOAR case–control study there was an association between immunization in the 6 weeks preceding symptom onset and the development of RA (OR 2.4; 95% CI 0.2, 23.2) [5]. Nevertheless, such individuals constitute only a small proportion of all those with RA.

Another intriguing finding from the NOAR case–control study was that previous blood transfusion may be a risk factor for RA (OR 4.8; 95% CI 1.3, 18.1) [5]. This did not appear to be due to possible confounding factors, such as pregnancy, appendectomy and tonsillectomy. In the IP group the association with prior blood transfusion was higher for women than for men, and the association was stronger with seropositive than seronegative arthritis. Most transfusions were performed more than 10 yr before symptom onset. Blood transfusion is known to have a number of effects on the immune system, including the induction of RF production [63] and overall immune suppression [64]. In addition, differences between HLA antigens on the donor and host white blood cells may lead to the development of alloantibodies and the down-regulation of specific T-cell clones [65]. These effects have been exploited for patients with active RA [66]. It is also possible that there may be a transmissible agent in transfused blood, perhaps with a long latent period. Changes in the way that donor blood is processed may account for the fact that there have been no cases of RA following blood transfusion in recent years.

Other medical risk factors for RA include other autoimmune disorders, in particular thyroid disease, Sjögren's syndrome and insulin-dependent diabetes. Psoriasis is also a risk factor for the development of IP [67].

‘Lifestyle’ risk factors
There is no convincing evidence from NOAR that the incidence of RA is influenced by either socioeconomic factors or occupation [68], although both of these may be important in the prognosis of established RA. In the NOAR case–control study, RA was found to be associated with having ever smoked cigarettes (OR 1.7; 95% CI 1.0, 3.1) and with obesity [body mass index (BMI) 30] (OR 3.7; 95% CI 1.1, 12.3) [5]. Other studies have demonstrated a link between smoking and the development of RA, in particular seropositive RA, especially in men [38, 6973]. The situation is less clear in women, one study even suggesting a protective effect [74], but a number of large studies have shown an association between smoking and RA in women [38, 69, 71]. Cigarette smoking is associated with RF production in individuals without RA [74]. The exact role of RF in pathogenesis is unknown, although it is clear that RF production may precede the development of RA, often by many years [76]. Smoking may be associated with changes in the levels of oestrogens and androgens, which could influence immunity [71, 74]. Another possible explanation is that factors commonly associated with smoking, such as a poor diet, may actually be responsible for the development of RA. For example, a recent study of blood donors found lower levels of antioxidants in those who later developed RA [77]. Finally, smoking is associated with other co-morbidities including infections which could be involved in the causation of RA. Of interest, moderate alcohol consumption was found to protect against the development of RA in two studies which recruited only women [71, 74].

Two previous studies found an increased incidence of RA in women who were significantly overweight [38, 71] but the US Nurses' Health study found no association between BMI and RA [69]. The NOAR case–control study was the first to demonstrate an association between obesity and RA in men. It also demonstrated that the association in both sexes was with obesity, since being overweight (BMI 25.0–29.9) did not confer an increased risk.

There is a widespread lay belief that the occurrence of RA is related to diet. There are no reliable studies which address this issue. The NOAR case–control study suggested that many patients modify their diet soon after the onset of arthritis in an attempt to improve their symptoms. Thus any study of prevalent cases of RA will be confounded by changes in eating habits since disease onset. The EPIC study in Norfolk, which is recording the diet of a large number of healthy adults, offers the opportunity to address the issue of pre-morbid diet in patients who subsequently develop IP and are notified to NOAR.

Psychological and physical trauma as risk factors
Many patients believe that their RA was triggered either by stress or by physical trauma. The most commonly alleged triggers are road traffic accidents, physical trauma associated with occupation, and psychologically stressful life events The association between life events, psychological stress, physical trauma and the onset of RA has been examined in a number of studies, most of which have been small (fewer than 50 patients) or had a poor design (for example, they have not included a control group or have questioned patients long after the onset of their RA). Although, in an uncontrolled study, Rimon reported that 55 of 100 patients with RA with a duration of less than 7 yr had experienced at least one emotionally traumatic life event in the year before onset [78], the only two controlled studies of recent-onset RA (less than 5 yr) involving more than 50 patients have both reported no association between the occurrence of life events and the subsequent development of RA [79, 80]. A recent case–control study linked to NOAR found no evidence that stressful life events or adverse childhood experiences played a causative role in patients who developed RA after the age of 45 yr [29]. There is even less evidence about the postulated link between physical trauma and RA. In an uncontrolled study, Jacoby et al. [81] found that, of 100 patients with RA of less than 1 yr duration, six attributed their disease to physical trauma and five attributed it to surgery. In a prospective cohort study of 204 patients with multiple fractures (mean age 31 yr), 2.9% developed RA in the next 2 yr compared with none of 103 controls (mean age 41 yr) [82]. Two studies reported an association between prior tonsillectomy and appendectomy and the subsequent development of RA [83, 84], but another two studies failed to confirm this [85, 86]. However, in this situation the underlying hypothesis related to the effect of removing lymphoid tissue rather than to the trauma associated with surgery many years before. In the NOAR case–control study there was a non-significant association between RA and prior appendectomy (OR 2.5; 95% CI 0.8, 7.5) and no association with prior tonsillectomy (OR 1.0; 95% CI 0.4, 2.1) [5].


    Conclusion
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 
This review may appear to have confused the aetiology of IP and RA. However, the results from NOAR failed to find any difference in the aetiological associations of these two entities. The explanation as to why some patients have self-limiting disease and others go on to have RA lasting a lifetime does not appear to lie with the trigger which initiated the process. It seems more likely that the patient's genetic or psychological make-up and treatment and other events which occur after the onset of disease are more important in determining the long-term outcome. The available evidence does not support a simple view of the cause of IP or RA. It seems that a series of events, or triggers, may be necessary before the disease develops. No single essential factor, either genetic or environmental, has been identified to date. More work is needed on the mechanisms by which some of the risk factors outlined above may actually permit the development of IP, often many years later. When more is known about these mechanisms it may be possible to put forward a single coherent theory of how IP starts. When this question had been answered, the next issue will be why, in some people, IP is self-limiting and why, in others, it lasts a lifetime.


    Acknowledgments
 
This study was funded by the Arthritis Research Campaign, UK. We are grateful to the GPs and hospital doctors in the Norwich Health Authority for their dedication in referring patients for study. In particular, we thank Professor D. G. I. Scott, consultant rheumatologist, Norfolk & Norwich Hospital. We also thank the current and previous NOAR staff and research nurses for their hard work: J. Barnard, B. Barrett, D. Bunn, J. Chipping, L. Galpin, S. Ivins, A. Langrish-Smith, L. Massingham, P. van Poortvliet, M. Sommerville and S. Whiting. We thank members of the ARC Epidemiology Unit: R. Bradbury, P. Brennan, C. Burt, A. Silman and N. Wiles.


    Notes
 
Correspondence to: D. Symmons, ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester M13 9PT, UK. Back


    References
 Top
 Introduction
 Background
 The Norfolk Arthritis Register
 Assessment of patients referred...
 The NOAR case-control study
 Genetic risk factors
 Hormonal and reproductive risk...
 Environmental risk factors
 Conclusion
 References
 

  1. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  2. Symmons DPM, Barrett EM, Bankhead CR, Scott DGI, Silman AJ. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol1994;33:735–9.[ISI][Medline]
  3. Fries JF, Spitz PW, Kraines RG. Measurement of patient outcome in arthritis. Arthritis Rheum1980;23:137–45.[ISI][Medline]
  4. Larsen A, Dale K, Eek M. Radiographic assessment of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn1977;18:481–91.[ISI]
  5. Symmons DPM, Bankhead CR, Harrison BJ et al. Blood transfusion, smoking and obesity as risk factors for the development of rheumatoid arthritis. Arthritis Rheum1997;40:1955–61.[ISI][Medline]
  6. Aho K, Markku K, Tuiminen J, Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol1986;13:899–902.[ISI][Medline]
  7. Silman A, MacGregor A, Thomson W, Hooligan S, Carty D, Farhan A. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol1993;32:903–7.[ISI][Medline]
  8. Jones MA, Silman AJ, Whiting S, Barrett EM, Symmons DPM. Occurrence of rheumatoid arthritis is not increased in the first degree relatives of a population-based inception cohort of inflammatory polyarthritis. Ann Rheum Dis1996;55:89–93.[Abstract]
  9. Wolfe F, Kleinheksel SM, Khan MA. Prevalence of familial occurrence in patients with rheumatoid arthritis. Br J Rheumatol1988;27(suppl. II):150–52.[ISI][Medline]
  10. Deighton GM, Wentzel J, Cavanagh G, Roberts DF, Walker DK. Contribution of inherited factors to rheumatoid arthritis. Ann Rheum Dis1992;51:182–5.[Abstract]
  11. Statsny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med1978;298:869–71.[Abstract]
  12. Deighton CM, Walker DJ, Griffiths ID, Roberts DF. The contribution of HLA to rheumatoid arthritis. Clin Gen1989;36:178–82.[ISI]
  13. Ollier W, Thomson W. Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am1992;18:741–9.[ISI][Medline]
  14. Gregerson PK, Silver J, Winchester RJ. The shared epitope hypothesis—an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum1987;30:1205–13.[ISI][Medline]
  15. Ollier WER, MacGregor A. Genetic epidemiology of rheumatoid disease. Br Med Bull1995;51:267–85.[Abstract]
  16. Nepom NT, Nepom B. Genetics of the major histocompatibility complex in rheumatoid arthritis. In: Klippel J, Dieppe P, eds. Rheumatology. London: Mosby-Wolfe, 19985.7.1.
  17. de Jongh BM, van Romunde LKJ, Valkenberg HA, de Lange GG. Epidemiological study of HLA and GM in rheumatoid arthritis and related symptoms in an open Dutch population. Ann Rheum Dis1984;43:613–9.[Abstract]
  18. Thomson W, Harrison B, Ollier B et al. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis. Arthritis Rheum1999;42:757–62.[ISI][Medline]
  19. Silman AJ, Kay A, Brennan P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum1992:35;152–5.[ISI][Medline]
  20. Brennan P, Silman A. Breast-feeding and the onset of rheumatoid arthritis. Arthritis Rheum1994;37:808–13.[ISI][Medline]
  21. Kay A, Bach F. Subfertility before and after the development of rheumatoid arthritis. Ann Rheum Dis1965;24:169–73.[ISI]
  22. Kaplan D. Fetal wastage in patients with rheumatoid arthritis. J Rheumatol1986;13:875–77.[ISI][Medline]
  23. Silman AJ, Roman E, Beral V, Brown A. Adverse reproductive outcome in women who subsequently develop rheumatoid arthritis. Ann Rheum Dis1988;47:979–81.[Abstract]
  24. Spector TD, Roman E, Silman AJ. The pill, parity, and rheumatoid arthritis. Arthritis Rheum1990;33:782–9.[ISI][Medline]
  25. Silman AJ, Spector T. Is poor pregnancy outcome a risk factor in rheumatoid arthritis? Ann Rheum Dis1990;49:12–4.[Abstract]
  26. Hazes JHM, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A. Pregnancy and the risk of rheumatoid arthritis. Arthritis Rheum1990;33:1770–5.[ISI][Medline]
  27. Nelson JL, Voigt LF, Koepsell TD, Dugowson CE, Daling JR. Pregnancy outcome in women with rheumatoid arthritis before disease onset. J Rheumatol1992;19:18–21.[ISI][Medline]
  28. Heliovaara M, Aho K, Reunanen A, Knekt P, Aromaa A. Parity and risk of rheumatoid arthritis in Finnish women. Br J Rheumatol1995;34:625–8.[ISI][Medline]
  29. Carrette S. A study of the psychosocial risk factors for rheumatoid arthritis [MPhil thesis]. Cambridge: University of Cambridge, 1998.
  30. Vandenbroucke JP, Valkenburg HA, Boersma JW et al. Oral contraceptives and rheumatoid arthritis: further evidence for a protective effect. Lancet1982;ii:839–42.
  31. Allebeck P. Ahlbom A, Ljungstrom K, Allander E. Do oral contraceptives reduce the incidence of rheumatoid arthritis? Scand J Rheumatol1984;13:140–6.[ISI][Medline]
  32. Vandenbroucke JP, Witteman JCM, Valkenburg HA et al. Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women. J Am Med Assoc1986;255:1299–303.[Abstract]
  33. Darwish MJ, Armenian HK. A case–control study of rheumatoid arthritis in Lebanon. Int J Epidemiol1987;16:420–4.[Abstract]
  34. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A. Reduction of the risk of rheumatoid arthritis among women who take oral contraceptives. Arthritis Rheum1990;33:173–9.[ISI][Medline]
  35. Jorgensen C, Picot MC, Bologna C, Sany J. Oral contraception, parity, breast feeding, and severity of rheumatoid arthritis. Ann Rheum Dis1996;55:94–8.[Abstract]
  36. Wingrave SJ, Kay CR. Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet1978;i:569–71.
  37. Del Junco DJ, Annegers JF, Luthra HS, Coulam CB, Kurland LT. Do oral contraceptives prevent rheumatoid arthritis? J Am Med Assoc1985;254:1938–41.[Abstract]
  38. Vessey MP, Villard-Mackintosh L, Yeates D. Oral contraception, cigarette smoking and other factors in relation to arthritis. Contraception1987;35:457–65.[ISI][Medline]
  39. Hernandez-Avila M, Liang M, Willett WC et al. Exogenous sex hormones and the risk of rheumatoid arthritis. Arthritis Rheum1990;33:937–53.
  40. Moskowitz MA, Jick SS, Burnside S et al. The relationship of oral contraceptive use to rheumatoid arthritis. Epidemiology1990;1:153–6.[Medline]
  41. Brennan P, Bankhead C, Silman A, Symmons D. Oral contraceptives and rheumatoid arthritis: results from a primary care based incident case–control study. Semin Arthritis Rheum1997;26:817–23.[ISI][Medline]
  42. Spector T, Hochberg M. The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytic epidemiological studies using meta-analysis. J Clin Epidemiol1990;43:1221–30.[ISI][Medline]
  43. Kaipiainen-Seppanen O, Aho K, Isomaki H, Laakso M. Shift in the incidence of rheumatoid arthritis toward elderly patients in Finland during 1975–1990. Clin Exp Rheum1996;14:537–42.[ISI][Medline]
  44. Carette S, Marcoux S, Gingras S. Postmenopausal hormones and the incidence of rheumatoid arthritis. J Rheumatol1989;16:911–13.[ISI][Medline]
  45. Spector TD, Brennan P, Harris P, Studd JW, Silman AJ. Does estrogen replacement therapy protect against rheumatoid arthritis? J Rheumatol1991;18:1437–46.
  46. Koepsell TD, Dugowson CE, Nelson JL, Voigt LF, Daling JR. Non-contraceptive hormones and the risk of rheumatoid arthritis in menopausal women. Int J Epidemiol1994;23:1248–55.[Abstract]
  47. Gordon D, Beastall GH, Thomson JA, Sturrock RD. Androgenic status and sexual function in males with rheumatoid arthritis and ankylosing spondylitis. Q J Med1986;60:671–9.[ISI][Medline]
  48. Cutulo M, Balleari E, Giusti M, Monachesi M, Accardo S. Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotrophin stimulation. Arthritis Rheum1988;31:1314–7.[ISI][Medline]
  49. Spector TD, Perry LA, Tubb G, Silman AJ, Huskisson EC. Low testosterone levels in males with rheumatoid arthritis. Ann Rheum Dis1988;47:65–8.[Abstract]
  50. Sambrook PN, Eisman JA, Champion GD, Pocock NA. Sex hormones and osteoporosis in post-menopausal women with rheumatoid arthritis. Arthritis Rheum1988;31:973–8.[ISI][Medline]
  51. Masi AT, Chatterton RT, Comstock GW, Malamet RL, Hochberg MC. Decreased serum dehydroepiandrosterone sulphate levels before onset of rheumatoid arthritis in younger, premenopausal women: a controlled, prospective study. Arthritis Rheum1994;37:S315.
  52. Heikalla R, Aho K, Heliovaara M et al. Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann Rheum Dis1998;57:281–5.[Abstract/Free Full Text]
  53. John S, Myerscough A, Eyre S et al. Confirmation of linkage to corticotropin releasing hormone and oestrogen sulphate (CYP 19) to rheumatoid arthritis in a second cohort of families. Ann Rheum Dis1999;58(suppl.):10–11.
  54. Chikanza ID, Petrou P, Kingsley G, Chrousos G, Panayi G. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum1992;35:1281–8.[ISI][Medline]
  55. Silman A, Bankhead C, Rowlinson B, Brennan P, Symmons D, Gattrell A. Do new cases of rheumatoid arthritis cluster in time or space? Int J Epidemiol1997;26:628–34.[Abstract]
  56. Kouri T, Peterson J, Rhodes G et al. Antibodies to synthetic peptides from Epstein–Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera. J Rheumatol1990;17:1442–9.[ISI][Medline]
  57. Ebringer A, Ptaszynska T, Corbett M et al. Antibodies to Proteus mirabilis in rheumatoid arthritis. Lancet1985;ii:305–7.
  58. Cohen BJ, Buckley MM, Clewley JP, Jones VE, Puttick AH, Jacoby RK. Human parvo-virus infection in early rheumatoid arthritis and inflammatory arthritis. Ann Rheum Dis1986;45:832–8.[Abstract]
  59. Tingle AJ, Allen M, Petty R, Kettyls GD, Chantler JK. Rubella-associated arthritis: I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunisation. Ann Rheum Dis1986;45:110–4.[Abstract]
  60. Harrison B, Silman A, Barrett E, Symmons D. Low frequency of recent parvovirus infection in a population-based cohort of patients with early inflammatory polyarthritis. Ann Rheum Dis1998;75:375–7.
  61. Symmons D, Chakravarty K. Can immunisation trigger rheumatoid arthritis? Ann Rheum Dis1993;52;843–4.[ISI][Medline]
  62. Harrison BJ, Thomson W, Pepper L et al. Patients who develop inflammatory polyarthritis (IP) after immunisation are clinically indistinguishable from other patients with IP. Br J Rheumatol1997;36:366–9.[ISI][Medline]
  63. Celada A, Aguado MT, Ortega F, Magallon M, Martin-Villar J, Lambert PH. Frequency and clinical and transfusional significance of rheumatoid factor in patients with haemophilia and von Willebrand's disease. Vox Sang1984;47:271–5.[ISI][Medline]
  64. Bordon JO, Blajchman MA. Immunosuppressive effects of allogenic blood transfusions: implications for patients with a malignancy. Hematol Oncol Clin North Am1995;9:205–18.[ISI][Medline]
  65. van der Mast BJ, Hornstra N, Ruigrok MB, Claas FHJ, van Rood JJ, Lagaay EL. Transfusion-associated graft-versus-host disease in immunocompetent patients: a self-protective mechanism. Lancet1994;343:753–7.[ISI][Medline]
  66. van der Horst-Bruinsma IE, Huizinga TWJ, Lagaay EM et al. The influence of partially HLA-matched blood transfusion on the disease activity of rheumatoid arthritis. Rheumatology1999;38:53–8.[Free Full Text]
  67. Harrison BJ, Silman AJ, Barrett EM, Scott DGI, Symmons DPM. Presence of psoriasis does not influence the presentation or short term outcome of patients with early inflammatory polyarthritis. J Rheumatol1997;24:1744–9.[ISI][Medline]
  68. Bankhead C, Silman AJ, Barrett B, Scott D, Symmons D. The incidence of rheumatoid arthritis is not related to indicators of socioeconomic deprivation. J Rheumatol1996;23:2039–42.[ISI][Medline]
  69. Hernandez-Avila M, Liang MH, Willett WC et al. Reproductive factors, smoking and the risk for rheumatoid arthritis. Epidemiology1990;1:285–9.[Medline]
  70. Heliovaara M, Aho K, Aromaa K, Knekt P, Reunanen A. Smoking and the risk of rheumatoid arthritis. J Rheumatol1993;20:1830–35.[ISI][Medline]
  71. Voigt LF, Koepsell TD, Nelson JL, Dugowson CE, Daling JR. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiology1994;5:525–32.[ISI][Medline]
  72. Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum1996;39:732–5.[ISI][Medline]
  73. Uhlig T, Hagen KB, Kvein TK. Current tobacco smoking, formal education and the risk of rheumatoid arthritis. J Rheumatol1999;26:47–54.[ISI][Medline]
  74. Hazes JM, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A. Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption. Ann Rheum Dis1990;49:980–2.[Abstract]
  75. Tuomi T, Heliövaara M, Palusuo T, Aho K. Smoking, lung function, and rheumatoid factors. Ann Rheum Dis1990;49:753–6.[Abstract]
  76. Aho K, Heliövaara M, Maatela J, Tuomi T, Palusuo T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol1991;18:1282–4.[ISI][Medline]
  77. Comstock GW, Burke AE, Hoffman SC et al. Serum concentrations of tocopherol, carotene, and retinal preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis1997;56:457–64.
  78. Rimon R. A psychosomatic approach to rheumatoid arthritis: a clinical study of 100 patients. Acta Rheum Scand1969;13(suppl. 1):1–154.
  79. Empire Rheumatism Council. A controlled investigation into the aetiology and clinical manifestation of rheumatoid arthritis. Br Med J1950;1:799–805.
  80. Conway S, Creed F, Symmons D. Life events and the onset of rheumatoid arthritis. J Psychosom Res1994;38:837–47.[ISI][Medline]
  81. Jacoby RK, Jayson MIV, Cosh JA. Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study of 100 patients with 11 year follow-up. Br Med J1973;2:96–100.[ISI][Medline]
  82. Julkunen H, Rasanen JA, Kataja J. Severe trauma as an aetiological factor in rheumatoid arthritis. Scand J Rheumatol1974;3:97–102.[ISI][Medline]
  83. Gottlieb NL, Page WF, Applerouth DJ et al. Antecedent tonsillectomy and appendectomy in rheumatoid arthritis. J Rheumatol1979;6:316–23.[ISI][Medline]
  84. Fernandez-Madrid F, Reed AH, Karvonen RL and Granda JL. Influence of antecedent lymphoid surgery on the odds of acquiring rheumatoid arthritis. J Rheumatol1985;12:43–8.[ISI][Medline]
  85. Wolfe F, Young DY. Rheumatoid arthritis and antecedent tonsillectomy. J Rheumatol1983;10:309–12.[ISI][Medline]
  86. Patel SB, Eastmond CJ. Preceding tonsillectomy and appendectomy in rheumatoid arthritis and degenerative arthritis. J Rheumatol1983:10:313–5.[ISI][Medline]
  87. Harrison B, Symmons D. Early inflammatory polyarthritis: results from the Norfolk Arthritis Register with a review of the literature. II. Outcome at three years. Rheumatology2000;39:939–949.[Free Full Text]
Submitted 26 August 1999; revised version accepted 3 March 2000.