rheumatoid arthritis: are pets implicated in its etiology?

Rheumatoid Arthritis: Are Pets Implicated in Its Etiology?

Colin Bond and Leslie Glen Cleland

Rheumatoid arthritis (RA) is thought to be triggered by an environmental agent or agents in immunogenetically predisposed persons. To investigate if animals or animal products might be the disease reservoir for a putative environmental trigger for RA that acts in childhood, a case-control study was undertaken. Included were 122 cases of RA and 114 control subjects of similar age. A specifically trained assistant, blinded to the diagnosis, used a standard inter- view proforma to gather information on ages of exposure to agents before onset of symptoms. Univariate analysis showed that cases were significantly more likely to have had a close association with a cat in the prepubertal period (65%) than were controls (27%); odds ratio (OR), 4.9 (confidence interval [CI] 2.7 to 9.0). In addition, there was a dose-response relationship between extent of prior exposure to cats and RA. There was a weaker association between recalled prior exposure to birds, budgerigars (parakeets) in particular, and RA. These data suggest that certain pets may be the reservoirs for environmental agents that trigger RA after a period of latency. Semin Arthritis Rheum 25:308-317. Copyright © 1996 by W.B. Saunders Com- pany

INDEX WORDS: Rheumatoid arthritis; epidemiology; etiology; pets.

R HEUMATOID ARTHRITIS (RA) is a chronic inflammatory disease of unknown

etiology. It is widely believed that an infectious agent or another foreign immunologic stimulus triggers the disease, which is characterized by self-damaging inflammation and immunologic autoreactivity. Numerous studies have sought associations between RA and immunologic re- sponsiveness to particular candidate organisms, with little tangible success.

Gottlieb et al 1 have shown that, during the 5-year period before disease onset, RA patients had greater exposure to dogs, cats, or birds (combined), dogs alone, and sick animals than

From the Department of Community Medicine, The Univer- sity of Adelaide, and the Rheumatology Unit, The Royal Adelaide Hospital, Adelaide, South Australia, Australia.

Colin Bond, BEc, BSc, MPH: Research scholar, Department of Medicine, The University of Adelaide, Adelaide, South Australia, Australia; Leslie Glen Cleland, MD, FRACP: Direc- tor of Rheumatology, The Royal Adelaide Hospital, Adelaide, and The University of Adelaide, Adelaide, South Australia, Australia.

Address reprint requests to Leslie Cleland, MD, FRACP, The Rheumatology Unit, The Royal Adelaide Hospital, North Terrace, Adelaide, 5000, South Australia, Australia.

Copyright © 1996 by WB. Saunders Company 0049-0172 / 96/2505-000355. O0/0

did control patients. They reported more cats and birds in the homes of patients who developed RA than in controls, but the differences were not statistically significant.

Rothman 2 advances the need for consideration of induction and latent periods for epidemiological study design and interpretation when cause and effect are not close in time. The latent period for chronic diseases generally has received little attention until recently. Wolfson and Wolfson 3 summarize the three periods considered important in the pre-onset natural history of chronic diseases: the induction period, the latent period, and the empirical induction period. Because RA is of unknown etiology, so is the timing of the effect of putative environmental factors and the time of initiation. Epidemiological studies seeking causal associations should include the possibility that RA is a disease with a latency period. Observations outside the time span of the true induction period would record exposures irrelevant to disease causation and dilute real causal associations with the disease, thereby making their detection difficult.

RA and multiple sclerosis (MS), as well as their respective animal models, 4,5 share many pathological features. The early pathogenesis of

308 Seminars in Arthritis and Rheumatism, Vo125, No 5 (April), 1996: pp 308-317

RA: ARE PETS IMPLICATED IN ITS ETIOLOGY 309

RA may be similar to that of MS, for which it is accepted that environmental factors have an important etiologic role. Migration studies 6 have shown MS to have a long latency period that is preceded by heightened susceptibility before adolescence. An important question is, "When does rheumatoid disease start? ''7 Silman 8 and Heath and Fortin 9 deem RA to be a disease with a long latency, which is a barrier to identifi- cation of etiologic agents. Studies by Aho's group in Finland, 7,1° Del Puente et al, 11 with Pima Indians, and Silman et a112 in the United Kingdom showed that, in some healthy individuals, rheumatoid factor occurred several years before clinical RA. If RA has a long and variable latency period, strategies for the identi- fication of environmental etiologic agents must be tailored accordingly.

Possible associations between reservoirs of potentially pathogenic organisms and the occurrence of RA have received little attention. To address this issue, a case-control epidemiological investigation was undertaken to determine if patients with RA have a significantly greater exposure to some animals or animal products than do controls before the onset of disease. Because RA might have a long latency, exposures that occurred long before the onset of symptoms of RA were documented on a yearly basis.

PATIENTS AND METHODS

RA Cases and Controls

The RA cases comprised 82 women and 40 men who fulfilled the American Rheumatism Association 1987 revised criteria 13 for the diagnosis of RA. The control group included 74 women and 40 men who were attending the same clinics as the RA subjects and had a rheumatic diagnosis other than RA (osteoarthri- tis, 102; osteonecrosis of the hip, 6; gout, 4; polymyalgia rheumatica, 1; and back pain, 1).

Cases and controls were selected from patients' files from four private rheumatology practices, a general practice, and from Outpa- tient Clinics at the Royal Adelaide Hospital and the Queen Elizabeth Hospital. Both groups resided in Adelaide, South Australia, and patients with onset of symptoms before 16 years of age or older than 80 years of age were excluded. The proportion of public clinic patients was

47% for cases and 54% for controls. Research Ethics Committees of the participating hospi- tals and the University of Adelaide sanctioned the study.

Method of Data Collection

Subjects were interviewed in person except for a small minority of subjects who were interviewed by telephone because of access problems. A lengthy questionnaire was adminis- tered to the patients by a specifically trained assistant, who was blinded to the purpose of the study and the subjects' diagnosis.

Exposure to Animals and Animal Products

The duration of exposure to animals and animal products was sought by years, with each participant providing his or her age at the beginning of exposure and his or her age when exposure ceased. Criteria were developed to describe the extent of exposure to each animal according to an ordinate scale of 1 to 5, as below. The grade of exposure allocated was the maximum exposure that had been continued for at least 6 months. Grade 1 indicated the subject had nothing to do with the animals or they were kept outside the house; grade 2 subjects would pat occasionally, walk or feed the animals inside the house; grade 3 activities included playing with, sitting on lap, nursing, and cleaning up messes; in grade 4, the animals were allowed to sleep on the bed in the bedroom; and in grade 5, the subject allowed licks, kisses, and sleeping in the same bed.

Contextual Data

Demographic and socioeconomic data gath- ered included age, place of birth, family particu- lars, residential history, occupational history of the subjects' parents and spouse/partner, and stressful life events in the 2 years before the onset of symptoms. Age of onset was defined as age at the first unambiguous symptom of the disease in both cases and controls. Details of the personal medical history obtained included drug therapy, use of oral contraceptives and hormone replacement therapy, and age at puberty.

Statistical Analyses

Statistical anaIyses were performed using com- puter programs Epi Info, 14 Systat, 15 and SAS. t6

310 BOND AND CLELAND

Odds ratios (OR) were used extensively in analysis of the data. Confidence intervals (CIs) were determined by using Cornfield's approxi- mation 17 or, when these were not reasonably close to exact values as determined by Klein- baum e t al, a8 exact CIs were determined by using the algorithm of Mehta et aI. 19 Logistic regression 2° was used to control concurrently for a number of potential confounders.

RESULTS

Contextual Data

Place of birth was similar in cases and con- trois (Table 1). The ratio of women to men among the cases was 2:1, and among the controls 1.9:1. The mean age of cases was 59 years (range, 21 to 80) and of controls was 66 years (range, 39 to 80). The mean age of onset of symptoms of RA was 45 years (range, 16 to 72), with a median age of 47 years. The mean age for the onset of symptoms in the control group was 49 years (range, 18 to 77), with a median age of 50 years.

There were no significant differences between cases and controls for women and men in age at puberty, the month or season of onset of symptoms, birth order in the family, mother 's and father's age, sibship, socioeconomic status, frequency of changes in domicile before puberty and until the onset of symptoms, or frequency of prior respiratory infections, surgery, or major illness.

Exposure to Animals and Animal Products

Exposure to animals at any level before puberty is shown in Table 2. Exposure to dogs was recalled by a similar high proportion of cases

Table 1: Place of Birth

Birthplace Cases(%) Controls(%) Total

Adelaide 50 (41) 40 (35) 90 Elsewhere in South

Australia 19 (15) 28 (25) 47 Elsewhere in Aus-

tralia 16 (13) 13 (12) 29 United Kingdom 24 (20) 23 (20) 47 Europe 11 (9) 5 (4) 16 Other countries 2 (2) 5 (4) 7 Total 122 (100) 114 (100) 236

and controls. Exposure to cats also was recalled often, but especially in cases, yielding an OR of 3.04 (CI, 1.69 to 5.50) before puberty and an OR of 1.49 (CI, 0.80 to 2.78) after puberty. Exposure to budgerigars (parakeets) was higher in cases relative to controls before puberty, OR, 1.74 (CI, 0.83 to 3.66), and after puberty, 2.01 (CI, 1.13 to 3.61). Of the other animals surveyed, ORs were either close to unity or less, or numbers exposed were too small to allow mean- ingful comparisons.

Table 3 shows figures for recall of any grade of exposure to animals from birth to onset of symptoms, the variables being selected on the basis of an OR > 1 or an exposure rate > 50%. The frequency of recalled exposure to cats was 91% for cases and 75% for controls OR, 3.29 (CI, 1.46 to 7.54). Frequency of recalled exposure to budgerigars OR, 1.84 (CI, 1.05 to 3.23), and all pet birds OR, 1.97 (CI, 1.12 to 3.47), was also greater in cases than controls.

Recalled exposure to animal products and other factors (fowl and other carcasses, hides, raw meat, garden soil, playing in sand pits, work in abattoirs, swimming in rivers and dams, and wild animals) was similar in cases and controls.

Intimate exposure refers to exposure at grades 3, 4, or 5 according to the criteria outlined in Patients and Methods. Table 4 shows recalled intimate exposure to cats and budgerigars before puberty and between puberty and onset of symptoms. Differences between cases and controls were evident for both timeframes. The proportion of subjects who recalled intimate exposure to cats at any time before the onset of symptoms was also greater in cases than controls, 74% versus 44%; OR, 3.60 (CI, 2.01 to 6.47), P = .0001 (data not shown).

When the cat and budgerigar exposure data were analyzed, a dose-response relationship was shown between grades of recalled prior exposure and RA. Moreover, significantly more RA cases than controls described intimate exposure, both before and after puberty, with cats and budgerigars. Contact with dogs before the onset of symptoms was frequent but no more so in cases than controls.

The most striking differences between cases and controls were observed when subjects were stratified according to gender and then analyzed

RA: ARE PETS IMPUCATED IN ITS ETIOLOGY

Table 2: Exposure to Animals Before Puberty

311

Cases Controls Odds Ratio

Animals No. % Exposed No. % Exposed (95% CI)

Dog 86 70 79 69 1.06 (0.58-1.93)

Cat 91 75 56 49 3.04 (1.69-5.50)

Rabbit 21 17 25 22 0.74

(0.37-1.49)

Guinea Pig 13 11 4 4 3.28 (0,97-14.!8)

Mouse 8 7 4 4 1.93 (0,50-8.99)

Budgerigar 27 22 16 14 1.74 (0,83-3.66)

Cockatoo 18 15 12 11 1.47 (0.63-3.47)

Parrot 6 5 7 6 0.79 (0.22-2.75)

Pigeon 12 10 7 6 1.67 (0.58-4.94)

Fish 6 5 2 2 2.90 (0.50-29.81)

Fowl 69 57 70 61 0.82 (0.47-1.43)

Duck 30 25 32 28 0.84 (0.45-1.56)

Sheep 23 19 18 16 1.24 (0.59-2,59)

Cattle 42 34 32 28 1.35 (0.74-2.44)

Pigs 18 15 20 18 0.81 (0.38-1.73)

Goats 9 7 9 8 0,93

(0.32-2.69)

Horses 34 28 30 26 1.08 (0,58-2.01)

NOTE. Includes all grades of exposure according to the criteria as outlined in Patients and Methods.

Table 3: Exposure to Animals Before Onset of Symptoms


Animals No. % Exposed No. % Exposed (95% CI)

Dog 110 90 100 88 1.28 (0.52-3.15) Cat 111 91 86 75 3.29 (1.46-7.54) Budgerigar 62 51 41 36 1.84 (1.05-3.23)

All birds* 80 66 56 49 1.97 (1.12-3.47)

Fowl 90 74 84 74 1.00 (0.54-1.88)

NOTE. Includes all grades of exposure according to the criteria outiined in Patients and Methods occurring either before or after puberty. *Includes all pet birds (budgerigar, cockatoo, parrot, and pigeon).


Table 4: Intimate Exposure to Pets

Pet and Cases Controls Odds Ratio

Period No. % Exposed No. % Exposed (95% CI)

Cat before 79 65 31 27 4.92 (2.71-8.97)

puber ty P = .0001

Cat after 75 61 46 40 2.36 (1.35-4.14)

puber ty P = .0012

Budger igar 15 12 3 3 5.19 (1.40-28.56) before puber ty P = .0052

Budger igar 36 30 19 17 2.09(1.06-4.14)

a~er P = .0197

pube~y

NOTE. Intimate exposure refers to exposure at grades 3, 4, or 5 according to the criteria outlined in Patients and Methods.

for grades of recalled exposure to cats (Table 5). In men, exposure to cats was much more frequent in cases than in controls, particularly with intimate exposure before puberty (Table 6). Although female cases were more frequently exposed to cats than were female controls, the differences were less marked than seen in men.

To address the issue of latency and a possible window of vulnerability, exposure to cats and budgerigars at specific periods of life were examined as detailed in Table 7. During the first

5 years of life and during the 5-year period before disease onset, there were no significant differences between cases and controls for all grades of exposure or for intimate exposure to cats or budgerigars. However, during the 5-year period before puberty, there was a significant difference between cases and controls for exposure to cats for all grades of exposure and intimate exposure, and for budgerigars for intimate exposure.

Logistic regression was performed (using

Table 5: Exposure to Cats by Grade and Gender

Female Male

Cases Controls Cases Controls

Grade No. % Exposed No. % Exposed No. % Exposed No. % Exposed

Before puber ty* None 20 24 29 39 11 28 29 73

1 2 3 3 4 1 3 1 3

2 7 9 12 16 2 5 9 23

3 38 46 23 31 21 53 1 3

4 6 7 5 7 2 5 0 0

5 9 11 2 3 3 8 0 0

Total 82 100 74 100 40 100 40 100

Af ter puberty'i" None 17 21 19 26 11 28 16 40

1 4 5 1 1 2 5 2 5

2 10 12 17 23 3 8 13 33

3 35 43 23 31 18 45 6 15

4 7 9 12 16 5 13 3 8

5 9 11 2 3 1 3 0 0

Total 82 100 74 100 40 100 40 100

*Female: Chi square = 11.02; df = 5; P = .050954. Male: Chi square = 35.74; df = 5; P = .000001. l-Female: Chi square = 11.60; d f = 5; P = .040711. Mate: Chi square = 14.68; d f = 5; P = .011841.

RA: ARE PETS IMPLICATED IN ITS ETIOLOGY

Table 6: Intimate Exposure to Cats Before Puberty Stratified by Gender

313


Grade and Strata No. % Exposed No. % Exposed (95% CI}

Female and male 79 65 31 27 4.92 (2.71-8.97)

P < .0001

Female 53 65 30 41 2.68 (1.33-5.45) P = .0026

Male 26 65 1 3 72.43 (9.51-3042.22)

P < .0001

NOTE. Summary odds ratio: Crude OR = 4.92; ManteI-Haenszel weighted: OR = 4.80; M+H Summary chi square, 32.00; P = < .00001 Woolf's chi square, 8.73 P = .00313 (Suggests multiplicative interaction). Intimate exposure refers to exposure at grades 3, 4, or according to the criteria outlined in Patients and Methods.

SAg16), considering all possible predictors of RA and possible confounders (gender, age of onset of symptoms, exposure to cats by five grades, exposure to cats before and after puberty, exposure to birds before and after puberty, occupational status of participant and parent, years of schooling, tertiary education, place of birth, oral contraceptive use, hormone replacement therapy). The model was then modified to include the interactions: gender by cat, gender by bird, and bird by cat. Overall logistic regression showed significant associa-

tions between exposure to cats before puberty and RA cases in men, and to a lesser extent in women. The observed associations between men and women with RA and exposure to birds between puberty and onset of symptoms also was significant.

DISCUSSION

Although selection bias can never be elimi- nated entirely, steps were taken to minimize it, with cases and controls being selected essentially at random from a balance of public and

Table 7: Cat and Budgerigar Exposure in 5-Year Periods

Period Type of Cases Controls Odds Ratio

Exposure* No. % Exposed No. % Exposed (95% CI)

Cat exposure

First 5 years of life

During 5 years before puberty

During 5 years before disease onset

Budgerigar exposure First 5 years of life

During 5 years before puberty

During 5 years before disease onset

All grades 52 43 47 41 1.06 (0.61-1.84)

Intimate 44 36 27 24 1.82 (0.99-3.34)

All grades 89 72 53 46 3.10 (1.74-5.55)

Intimate 72 59 30 26 4.03 (2.24-7.28)

All grades 63 52 57 50 1.07 (0.62-1.84)

Intimate 50 41 35 31 1.57 (0.88-2.78)

All grades 11 9 8 7 1.31 (0.47-3.74) Intimate 8 7 1 1 7.93 (0.98-171.77)

All grades 31 25 17 15 1.94 (0.96-3.95) Intimate 20 16 4 4 5.39 (1.66-19.34)

All grades 34 28 23 20 1.53 (0.80-2,93) Intimate 20 16 13 11 1.52 (0.68-3,45)

*Types of exposure according to the criteria outlined in Patients and Methods.


private patients. Moreover, the overall sample of RA patients in this study is similar to that of other RA series (see Silman and Hochberg 21 for review). A rigorously consistent approach was used for all potential participants. Interviewer bias was minimized by using a specifically trained interviewer who was not informed of the purpose of the study or the subjects' status as case or control. Participants were unaware of their study status as case or control and the purpose of the study. One deficiency in this case-control study was its dependence on anamnestic information and hence selective recall bias; usually forgetfulness by controls or exaggerated remem- brance by cases. 22 This was minimized by select- ing controls who had chronic rheumatic disease. As a consequence, cases and controls likely reported their previous exposures in a similar manner.

The study by Gottlieb et al I considered exposure to pets during the 5-year period before disease onset. In the current study, childhood as well as later exposure before disease onset were documented. A further refinement of the study was that animal exposure data were graded to reflect different degrees of intimacy with an animal, thereby allowing dose-response relation- ships to be detected.

When discussing infectious agents capable of initiating RA, Gottlieb et al I stated that they arbitrarily chose the 5-year period surveyed for contact with pets in their study. They explained that this interval may be too short for slow viruses or too long for other infectious agents. Positive pet exposure was defined as "the pres- ence of an animal for more than 3 months in a person's home." Using their data, we calculated an OR of 1.57 (CI, 0.79 to 3.12) for cat exposure during the 5-year period before disease onset between cases and controls. Our data, for the same 5-year period and essentially similar exposure (grades 3, 4, or 5), showed an OR of 1.57 (CI, 0.88 to 2.78) (Table 7). To the limited extent that comparisons are possible, our data are consistent with their findings.

Migration and cluster studies and statistical approaches 3 suggest that the most likely period for onset of the initiation process of MS is between 10 and 15 years of age. There are no migration studies in the epidemiological investigation of RA. This is understandable given

methodological difficulties arising from varying patterns of migration, the heterogeneity of and lack of clear definition between rheumatic disor- ders, and the variable age at clinical onset of RA. Regardless, a time window of susceptibility for the initiation of RA may exist. The findings in Table 7 show a significant association between cases and intimate exposure to cats or budgerigars as compared with controls during the period 5 years before puberty. This con- trasts with the first 5 years of life and the period 5 years before disease onset, where associations between cases and controls with all grades or intimate exposure to cats or budgerigars were not significant. The 5-year periods, as in Gott- lieb's study, were chosen arbitrarily.

The findings of our study implicate the domestic cat, in particular, as a potential host for agents that may initiate RA. Late childhood appears to be a period of vulnerability for the effects of exposure to cats in relation to the subsequent development of RA. Domestic pets are a reservoir for many potential pathogenic organisms, which may be transmitted to humans by a variety of means, including bites, scratches, fecal-oral contact, saliva, voided urine, respiratory droplets, arthropod vectors, or simple tac- tile contact. In Western societies, cats typically inhabit their owner's house. A less intimate association is seen in some rural and Asian communities (in which RA appears to be less prevalent21). Cats frequently scratch and bite humans, especially their owners and children, thereby providing a potential portal of entry for microbial agents. They are inquisitive animals that manipulate by paw and mouth many ob- jects in their environment, including soil, birds, and vermin. Domestic cats wander over a relatively broad range that overlaps with the ranges of other cats with whom they may mate, fight, or otherwise interact. Their habits provide ample means to transfer aspects of their environment to humans.

An association between RA and prior exposure to pet birds and, in particular, to budgerigars also was noted. Late childhood is a period with significant association between exposure to budgerigars and the development of RA. The budgerigar is the bird species with which humans develop the most intimate contact, including direct handling and housing and release

RA: ARE PETS IMPLICATED IN ITS ETIOLOGY

within the home. Thus, the budgerigar is well situated to introduce avian microbial flora or other agents directly to humans. Because cats habitually stalk, kill, and mutilate birds, avian flora and other agents also may be introduced indirectly to humans by cats.

Cats and birds transfer allergenic agents to humans. Cats shed proteins, such as Fells domes- ticus allergen I (FeldI) which is found in cat hair, dander, and saliva, and can induce hypersensitivity reactions in humans. Particles containing FeldI increase in the immediate vicinity of cats and persist within houses for 20 weeks or more after cat removal. 23 Also, antigens, including feather dust and fecal material, can be trans- ferred to humans and persist within the home for prolonged periods after bird removal. 24 Thus, chronic inflammation as a result of delayed-type hypersensitivity to cat or bird antigens should be considered as a possible mechanism for induction of RA.

The putative initiating factors of RA should have the following characteristics: microbes that are not usually part of normal human flora, are not rare, are broadly distributed geographically, and can affect (perhaps in different ways) humans and domestic cats or birds. The putative arthrogenic microbes may produce no apparent to mild infection in humans, or the infection may be classified as idiopathic or another disease. A listing of microbes, many of which are true zoonoses, that generally fulfill these pre- mises are shown in Table 8. Simply experiencing an infection does not lead to RA, so other factors such as genetic predisposition are in- volved.

The much higher OR in men than in women for exposure to cats was related to the relatively low levels of exposure in male controls compared with their female counterparts. The frequency of intimate contact with cats was equal in both male and female cases (65% in grades 3, 4, and 5, as shown in Table 6). The greater frequency of RA in women than men may be related as much to behavioral differences and associated differences in exposure to environmental agents during childhood as to putative more direct effects of sex hormones on immune- pathogenic mechanisms. 25,26

This study has identified reported exposure, particularly in the prepubertal period, to cats

315

Table 8: Microorganisms Found in Cats or Birds of Potential Relevance to RA Pathogenesis

Bacterial Campy/obacter jejenj Chlamydia psittaci Cox/ella burnetii Erysipelothrix rhusiopathiae Escherichia coh' (pathogenic strains), a member of

the Enterobacteriaceae family Helicobacterpylori and other Helicobacter species

with "'Gastrospiri/lum" morphology Listeria monocyctogenes Mycobacterium avian-intracellu/are-scrofu/aceum

complex Mycobacterium tuberculosis Pasteure/la rnuRocida Rochalimaea henselae Staphylococcus species Streptococcus species, group A; in particular S,

pyogenes and S pneumoniae Yersinia pseudotubercu/osis

Fungal Aspergi/lus fumigatus Candida a/bicans and occasionally other species of

Candida C~, ptococcus neoformans and Microsporum

canis. Trichophyton mentagrophytes Helminths

Toxocara cati Protozoan

Entamoeba histolytica Cryptosporidium sp, Giardia sp, Toxoplasma gondii

Viral Paramyxovirus (Newcastle disease virus)

Data from references 27-30,

and budgerigars, as being associated with later occurrence of RA relative to the comparison group, as evinced by raised ORs. Consideration of the possible pathogenetic implications of these findings is not complete without a discussion of the reported exposure to these pets in a substantial, albeit lesser, proportion of the control group.

The increased ORs observed for intimate exposure to cats and budgerigars suggest that some causal agent is inherent in this exposure. The hypothesis that a microbial agent is in- volved is not refuted by the exposure reported in the control group, because it is well recog- nized that for many infectious agents subclinical


infections are more common than symptomatic disease. Furthermore, the long-term indirect sequelae of infections can be delayed many years, be influenced by context, including genetic factors, and be manifest in only a minority of individuals within populations at risk (eg, the various diseases that have been associated with Epstein-Barr virus infection). These consider- ations support the notion that widespread exposure to a microbial agent could increase the likelihood for subsequent development of a chronic disease in a minority of those exposed. The findings of the current study are compatible with such an interpretation.

The possible reasons why exposure to an infectious agent might lead to a chronic disease in some of those exposed, but not others, are multiple. In the case of RA, genetic factors, some probably not related directly to host de- fense against the putative triggering organism, may be important in determining whether persistent arthritic disease emerges. For example, arthritogenic DR4/DR1 subtypes appear to relate more to risk for progressive, erosive rheumatoid disease than to the occurrence of polyarthritis. 31 The studies of David et aP 2 in human class II transgenic mice suggest that these DR alleles, and the DQ alleles with which they are in linkage dysequilibrium, are associated with an increased propensity to autoreactivity to articular collagen type II. 32 This autoim- mune response, perhaps in association with

"epitope-spreading" to other targets shown in damaged joints, could explain the more persistent and destructive character of RA relative to more benign forms of polyarthritis.

In the current study, exposure to cats was relatively high, not only in cases but also in controls, especially in female controls. Al- though multilevel stratification into prepubertal and postpubertal groups, gender, and intensity of exposure produced some groups with small numbers and insignificant differences in exposure to cats, the overall picture was convincingly one of significantly higher odds for reporting prior intimate exposure to cats (and budgerigars) in the cases than in the controls.

Conclusion

Certain pets may be the reservoirs for environmental agents that interact with genetic factors during adolescence to induce an unrecognized condition that may initiate processes leading to RA. A latency period may follow before RA becomes clinically evident. A novel focus for further investigation may have been identified.

ACKNOWLEDGMENTS

The authors thank the following physicians for referral of patients included in this study; R.A. Geddes, D.W. Howie, B.W. Kirkham, T.G.C. Murrell, and H. Sheppeard. They also thank Professor T.G.C. Murrell for the supervision of the thesis from which this study was derived and colleagues at the Institute of Medical and Veterinary Science for helpful advice.

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rheumatoid arthritis: are pets implicated in its etiology?

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