The epidemiology of rheumatoid arthritis

J. chron. Dis. Vol. 15, pp. 1037-1067.

Pergamon

THE EPIDEMIOLOGY A REVIEW

WITH

Press Ltd. Printed in Great Britain

OF RHEUMATOID

SPECIAL

ATTENTION

ARTHRITIS

TO SOCIAL

FACTORS*

NORMANA. SCOTCH, Ph.D.? and H. JACK GEIGER, M.D.f (Received 1 April 1962)

INTRODUCTION

RHEUMATOID arthritis has been the focus of prolonged and intensive investigation by clinicians, microbiologists and virologists, biochemists, immunologists and pathologists. The disease has been an area of special interest in such fields as radiology, endocrinology, psychiatry and sociology, among others, for many decades. Yet its causes remain unknown, knowledge of the underlying pathologic mechanisms is incomplete, and the rationale of therapy is uncertain. Research on rheumatoid arthritis, as on all the collagen or connective-tissue diseases, has suffered from the fact that few if any of these diseases occur naturally in mammals other than man. Our understanding of the molecular biology and metabolism of connective tissue and of the role of auto-immune phenomena and genetic components in these syndromes is fragmentary, though expanding rapidly, and unifying etiologic hypotheses are scarce. One classical pathway to an understanding of etiology is epidemiologic study. As many observers have noted, however, the epidemiological problems posed by chronic disease differ in many respects from those involved in the acute infectious diseases, and (as the following pages suggest) some of the difficulties appear far from solution. The problems and past limitations of epidemiologic investigations of rheumatoid arthritis have contributed to the present inadequate knowledge of the origin of this disease; their future promise lies not only in the contribution they may make to etiological insight but also in their potential effect on the resolution of general problems in the methods of epidemiology. In this review, the possible role of social and psychological factors in the etiology of rheumatoid arthritis is a particular focus of attention. The present effort is the first in a series of proposed working papers in a “Cross-Cultural Survey of Social Factors in the Etiology of Disease,” and a similar approach is planned in reviews of hypertension, schizophrenia and a number of other major contemporary disease problems. Yet the reader will note that major attention is given to medical considerationsdefinitions and diagnostic criteria, hospital case studies, genetic and biochemical investigations, serological tests and the like-and these are reviewed extensively *This is the first in a series of review papers from the Cross-Cultural Disease Survey, jointly sponsored by the National Institute of Mental Health (Contract SA-43-oh-4369) and the Social Science Program, Harvard School of Public Health. tResearch

Associate

in Anthropology,

Social Science Program,

Harvard School of Public Health.

fSpecial Consultant, National Institute of Mental Health, and Assistant Medical Service, Boston City Hospital, Boston, Massachusetts. 1037

Resident,

II [Harvard)

1038

NORMANA. SCOTCH andH. JACKGEIGER

before special consideration of social factors is undertaken. This approach reflects a number of assumptions. First, it is assumed that rheumatoid arthritis may have a multiple, rather than unitary, etiology, and that it may be necessary to specify necessary, sufficient and contributing causes. The question is not whether social factors ‘cause’ the disease, but rather whether they contribute to its causationand if so, how much, and in what ways, and in what relationship to genetic, biochemical, environmental and other etiologic substrates? It is assumed, therefore, that social factors are best examined in the light of these other types of information. Finally, it is suggested that many of the future investigations of social factors in disease etiology may most fruitfully be conducted as part of, or in the context of: simultaneous medical research on the same problem. The following pages therefore discuss the question of definition and diagnostic criteria; outline past and current efforts at descriptive and analytic epidemiology; survey in some detail the general outlines of research effort on infectious, genetic and biochemical hypotheses of etiology and pathogenic mechanisms, and then review research on psycho-social factors. It is hoped that this approach will provide some clues to the ways in which psychological components and social variables may operate on an underlying pattern of genetically, biochemically or otherwise-determined susceptibility, and will point to some good possibilities for further research. DEFINITIONS

AND

DIAGNOSIS

Our discussion is limited to rheumatoid arthritis, including Still’s disease and Felty’s syndrome; it excludes spondylitis, rheumatoid arthritis in combination with ulcerative colitis and in combination with psoriasis, since there is clinical and epidemiologic evidence to suggest that these are separate and distinct clinical entities. It further excludes osteoarthritis, gout, ‘menopausal’ arthritis, the arthritides of rheumatic fever, the specific septic arthritides (gonococcal, tuberculous, staphylococcal, etc.), fibrositis, Reiter’s syndrome, lupus erythematosus, periarteritis nodosa and other collagen diseases, and the shoulder-hand syndrome. These exclusions do not, of course, constitute an operational clinical definition of rheumatoid arthritis. Indeed, it is only within the past decade that reasonably uniform and specific diagnostic criteria have been proposed and have gained fairly wide acceptance. Most (though not all) recent studies have employed the 1958 revision of diagnostic criteria of the American Rheumatism Association [l]. Comparisons of recent with earlier studies, of American with European findings, or even of the results of different investigators in the United States must be made with full awareness of the possibility that different fields of disease are under study. Despite agreement on the 1958 American Rheumatism Association revisions, a formidable problem of diagnosis and diagnostic criteria remains. The 1958 outline establishes not one but four categories of rheumatoid arthritis: ‘classical,’ ‘definite,’ ‘probable’ and ‘possible.’ Assignment of a case to one of these categories is based on eleven criteria. Of these, one (morning stiffness) is subjective; five (involving joint tenderness, two parameters of joint swelling, symmetry of lesions, and presence of subcutaneous nodules) require observation and judgment-according to poorly defined criteria for such rubrics as ‘swelling’ or ‘tenderness’-by an observer; one involves X-ray changes, which must similarly be interpreted; and four involve laboratory methods or pathological examination. Satisfaction of the criteria for any

The Epidemiology of Rhxmatoid

Arthritis

1039

of the four diagnostic categories may be negated by the presence of any of twentyother factors (indicative of lupus, gout, etc.), which similarly require physician judgments, laboratory tests, or both. These complexities are hardly unique to rheumatoid arthritis -indeed, the diagnostic problems in many other chronic diseases seem more difficultbut they have, nevertheless, serious implications for epidemiological and cross-cultural studies. They suggest that fairly wide variations in diagnosis will continue to exist and that, in any case, diagnosis will require extensive medical and laboratory facilities which may not be available in many areas of the world. COBB [2] has discussed the problems of a committee attempting to establish precise diagnostic criteria and the need for continuing concern with reliability and validity of diagnostic judgment. The development of more specific laboratory tests (sheep-cell agglutination, latex fixation, bentonite flocculation, and the like) has greatly furthered the exploration of aspects of the molecular biology, genetics and epidemiology of rheumatoid arthritis. Whether these tests represent advances in the accuracy of diagnosis, however, is uncertain. In a number of limited series, sheep-cell agglutination tests are reported to detect 60-75 per cent of rheumatoid arthritis (diagnosed independently by clinical or X-ray methods), with false positives occurring in 5-12 per cent of the cases. Better figures (sensitivities as high as 90 per cent, with false positives as low as 2 per cent) have been cited by some authors for the latex fixation and bentonite flocculation tests. In larger and more recent studies on population samples, however, the data suggest that there may be a high frequency of false positive serological reactions, that a population’s past experience with other diseases (e.g. tuberculosis) may seriously affect the results, and that many cases of clinically evident rheumatoid arthritis are sero-negative. Wide disagreement both in the grading and interpretation of bone and joint X-rays for rheumatoid arthritis by six experienced observers was noted by KELLGREN[3] ; though reassessment of the same films by one observer after an interval of one year showed a closer agreement, there were still appreciable changes in grading by one individual over a period of time. KELLGRENand LAWRENCE[4, 51 have subsequently attempted to establish international radiological criteria for rheumatoid arthritis, and SHARP et al. [6] have produced similar standards for spinal rheumatoid arthritis. LAWRENCE,LAINEand DEGRAAFFhave suggested that “if a comparison of two series of X-rays is to be of any value they must all be read by one observer” and that “if differences between populations are to be established their films must be read at the same time, preferably mixed so that the observer is unaware of their origin” [7]. DESCRIPTIVE

AND

ANALYTIC

EPIDEMIOLOGY

Studies made prior to 1957, comparing rates of rheumatoid arthritis in different populations, are of sharply limited value for current epidemiological purpcses since widely different diagnostic criteria were employed. While differences in reported prevalence are noted in nine studies of samples in the United States, Europe and Greenland, variations in standards and methodology make it impossible to determine whether these are true variations among populations. The data presented in Table 1 are illustrative : the variation in reported prevalence from 0.3 to 7.8 per 100 is intriguing, but the really significant information is the description of methods under the column headed ‘Comment,’ in which criteria and methodology vary from ‘Chronic arthritis known to public health nurses in their own districts’ through ‘Clinical

NORMAN A. SCOTCHand H. JACKGEIGER

1040

PREVALENCE OF RHEUMATOID ARTHRITIS. SUMMARY OF NINE RECENT SURVEY ESTIMATES [26]

TABLE1.

Prevalence per 100

Age

M

F

Total

group

Leigh, Lanes., England

1.4

3.3

2.4

15 +

Leigh, Lanes., England

2.5

11.0

(7.8)

55-64

Rhondda Fach, Wales

0.7

-

-

15+

Polyarthritis+positive X-ray.

Pittsburgh, Pa., U.S.A.

0.6

4.7

2.7

15 +

‘Probable’ and ‘definite’ rheumatoid arthritis (A.R.A. criteria), by examination plus laboratory and X-ray findings.

(1.3)

(2.7)

2.0

All

‘Chronic arthritis’ recognized by especially trained medical students in the home.

1.0

14+

Clinical diagnosis based on a brief examination.

(0.6)

All

‘Chronic arthritis’ known to Public Health Nurses in their own districts. Clinical diagnosis, based on careful examination and some laboratory and X-ray findings.

Country

Sweden

-

Netherlands Finland

-

(0.9)

(0.3)

Piestany, Slovakia

-

-

0.5

15-45

Umanak, Greenland

-

-

(0.3)

5+

(

)=computations

diagnosis arthritis

by

based (A.R.A.

COBB

on

Comment

Clinical diagnosis based on a brief examination in the home. Clinical diagnosis based on careful examination plus laboratory and X-ray findings. serologic

test

or

Clinical diagnosis.

and LAWRENCE from original authors’ data.

a brief

criteria)

examination

by examination

in the

home’

plus laboratory

to ‘Probable and X-ray

and definite

findings.’

A brief review of some of these earlier epidemiological studies may emphasize these and other limitations on the reported findings. In these data one finds considerable variation

not only in the age distribution

also in the sex ratios, and divorced also are made.

the distribution

or widowed Female

individuals;

of the disease in different populations

of the disease in marital urban-rural

seem to suggest promising leads for further comparability are recalled. The data for Finland,

and occupational

: male sex ratios that vary from

for example,

but

pairs, single, married comparisons

1 : 1 to 5 :2 or more might

study, until the pitfalls in methodological

are based on a house-to-house

canvas of 37

rural districts by public health nurses in the early 1930’s; some 1700 cases were recorded and a prevalence of 0. g/100, with a female: male ratio of 5 : 2, was reported by HOLSTI and RANTASOLA [8]. As Table 1 indicates, a later re-calculation of the authors’ data by COBB and LAWRENCE, using A.R.A. criteria, yielded a prevalence of 0.6/100. It is of some interest that HOLSTI reported finding more marital pairs afflicted with rheumatoid arthritis than would be expected by chance alone.

The Epidemiologyof RheumatoidArthritis

1041

EDSTROM [9] used specially trained medical students to make home visits and examinations in Sweden and reported an over-all prevalence of 2 .O/lOO, with a 2: 1 female :male sex ratio and an increase in prevalence with age to a peak in the fifth decade of life. The same sex ratio was noted by SITAJet al. [lo] in Czechoslovakia, but the prevalence of clinically diagnosed rheumatoidarthritis(supportedby1aboratoi-y and X-ray determinations) was 0.5/100, increasing with age but remaining constant in males after 50. Among other studies included in Table 1 is that of DEBL~COURT[ll] in the Netherlands, in which specially trained interviewers screened a population for a history of rheumatic complaints and positive responders were examined briefly by a rheumatologist; the prevalence was 1 .O/lOO, again increasing with age. The prevalence of 0.3/100 for Northern Greenland was calculated by COBB and LAWRENCEfrom EHRSTROM’S survey data [12]. In the early and mid-1950’s, major studies of the distribution of rheumatoid arthritis were undertaken in Pittsburgh and in Lancashire and Wales in the United Kingdom. In 195 1, a 10 per cent stratified random sample of dwelling units in the Arsenal Health District in Pittsburgh was used for a hou.sehold morbidity survey [13]. Individuals with rheumatic complaints subsequently were offered a physical examination, X-ray studies, and serological tests; of the 798 persons originally sampled, 89 per cent were interviewed and 60 per cent were examined. A total of 478 persons were both interviewed and examined. There was a known bias, in that patients with arthritis were found to be more likely to respond to the request for examination. Several further studies of non-participants and non-respondents were undertaken [14, 151, and interview data were compared with physicians’ findings on examination [16]. Ultimately, the correspondence between interview and examination findings in patients who had both procedures was used to post-stratify and classify all the interviews, including those of patients with no examination. On this basis, point prevalence rates of 0.7/100 for ‘definite’ rheumatoid arthritis, 2.7/100 for ‘probable plus definite,’ and 13. S/l00 for ‘possible plus probable plus definite,’ using A.R.A. criteria, were reported [17]. The estimated female :male prevalence ratio was 2.5 : 1 for all categories; for ‘probable’ rheumatoid arthritis the prevalence was 3.7/ 100 among females to 0.2/ 100 among males, an 18 : 1 ratio. This was due chiefly to a “great deal of mild arthritis in older females.” Despite the attempt at post-stratification on the basis of interview-examination correspondence, a problem is raised by the possibility that thresholds for reporting symptoms may be lower in this group; in several English studies, for example, it was noted that rheumatic complaints were only half as frequent in miners’ families as in the rest of the population, despite identical X-ray changes. The Pittsburgh investigators also reported a rapid increase in prevalence at age 25; “the age specific rates (for probable plus definite rheumatoid arthritis) show an abrupt rise in the twenties to a maximum in the thirties, which is followed by a gradual fall.” For females, the largest increase in prevalence occurred during ages 40-60. Age and sex-adjusted prevalence rates were 0.9 for single persons, 2.2 for married persons, and 3.6 for persons whose marriage had been terminated by divorce or death of spouse. COBB and his colleagues also calculated that the estimated annual prevalence of rheumatoid arthritis, defined as persons having at least one attack per year, was about 5 per cent of the population, or almost twice the number included under ‘probable and

1042

NORMAN A. SCOTCH and H. JACKGEIGER

definite’ rheumatoid arthritis. The problem of relationships between point and annual prevalences in an intermittent disease has led to re-examination of the concept of comparing populations according to ‘proportion of time in episode’ of the disease (vide infra) rather than on the basis of a division of populations into persons who do and do not have rheumatoid arthritis at a given point in time. A second major study has been in progress in Leigh, Lancashire, England, since 1950 [18], when a 10 per cent random sample of dwelling units was drawn for interview by specially trained social workers; of those with rheumatic complaints, 93 per cent subsequently were seen by a physician for a brief clinical examination. The overall prevalence was 2.4/100, rising from 2.0/100 in younger age groups to nearly 6/100 in the sixth decade; the female : male ratio was 5 : 2 in each age group. No association between the disease and climate, housing or occupation (comparing miners, office workers and laborers) was noted [191. Persons aged 50-64 in the Leigh sample were re-studied in 1954 [20]; interviews in the home were followed by clinical examination, serological tests, and X-rays of hands, feet, pelvis, lumbar and cervical spine. In this group, the over-all prevalence was 7.8/100. It is noteworthy that the rate was ll/lOO in females and 2.5/100 in males, but the sex ratio of positive serological and X-ray changes was 1 : 1 with 6 per cent positives in each sex. A third major study is represented by the efforts of MIALL and his colleagues in two Welsh communities, Rhondda Fach, an urban area, and the Vale of Clamorgan, an agricultural district [21, 221. Initially, the male population of Rhondda Fach was interviewed for a history of arthritis, with positive respondents examined clinically and given serological and X-ray tests; prevalence was found to be 0.7/100 and increased with age. Subsequent studies in Rhondda Fach and the Vale of Glamorgan, with a 95 per cent completion rate, permitted comparisons of urban-rural differences in the prevalence rates by age and sex [23-251. No urban-rural difference was observed among those aged 15-54 but in the age group 55 and older the urban prevalence was 1.3/100 and the rural 3.0/100. In each population, the sex ratio was 1 : 1. No differences between miners and other occupational groups were noted. The first attempt at utilization of standardized criteria in an international study was made by COBB and LAWRENCE [26]. Using A.R.A. standards, and allowing for differences in the interpretation of X-ray changes and in the serologic tests employedin the Pittsburgh and Leigh studies, they found a higher prevalence of rheumatoid arthritis in Leigh, as illustrated in Table 2. Though attention was drawn to a number of possibly significant differences in the two populations, e.g. ethnic homogeneity vs. heterogeneity, population density, degree of industrialization, and diurnal and seasonal variation in climate, no attempt was made to interpret the prevalence differences in etiologic terms. Some results of another international study, utilizing A.R.A. criteria, standardized interpretation and grading of X-rays of hands, feet, and cervical spine, and the sheepcell agglutination test, have recently been reported. These investigations included population samples in Leigh (urban) and Wensleydale (rural), England; an urban district of Rotterdam, Netherlands; Rhondda Fach (urban) and the Vale of Glamorgan (rural), Wales; and rural areas in Heinala, Finland, and Annandale, Scotland. The total number of persons in these samples was 4536; 3999, or 88 per cent, were examined. In Leigh and Wensleydale, the samples included all persons from age 15

The Epidemiology of Rheumatoid TABLE 2.

1043

Arthritis

PREVALENCE OF RHEUMATOID ARTHRITIS AS DEFINEDBY THEA.R.A. CRITERIA IN F%-CSBURGH AND LEIGH [26]

Prevalence rates per 100 persons

Ages 15+: Pittsburgh* Leigh Age 55-64: Pittsburgh* Leigh --

-

Probable RA

Definite RA

Probable or definite RA with X-ray changes

2.0 (17) 3.3 (21)

0.7 (13) 1 .l (7)

0.3 (6) 1.4 (9)

(1)

0.3 (1) 5.0 (8)

4.0 (5) 12.0 (20)

0.3 2.0

(4)

*Pittsburgh sample was stratified by response re arthritis on an earlier household survey, therefore the apparent denominators vary. ( ) Indicates the number of cases on which the respective prevalence estimates are based.

onwards; elsewhere, complete radiological and serological data are available only on the 55-64 group. In Leigh and Wensleydale (ages 15 onwards) the prevalence of probable plus definite rheumatoid arthritis was 2.5/100 in males and 6.0/100 in females, increasing with age; yet the prevalence of X-ray changes in the hands and feet, and in the cervical spine (3/ 100 and 5/ 100, respectively) was the same in the two sexes, aswas the prevalence of positive serological reactions (3.7/100 in males and 4.4/100 in females). The proportion of positive serological tests rose with age, reaching a maximum of 1l/l00 in males and S/l00 in females in the older age groups. Only one third of those with a positive serology had clinical or radiological evidence of rheumatoid arthritis. In the six population samples in Northern Europe on which full clinical data were available (55-64 year age group), there were no significant differences in the prevalence of definite rheumatoid arthritis, the rates ranging between 2 and 3 per cent. One statistically significant urban-rural difference was noted: the prevalence of positive serological tests in the urban areas was 5/100, against 2/100 for rural areas. This partial review of descriptive epidemiological attempts over the past 36 years makes it clear that the major task of elucidating basic variables of time, place, and person in the distribution of rheumatoid arthritis remains to be accomplished. As we have already noted, the variation in sampling methods, techniques of observation, and diagnostic criteria in all but the most recent studies make attempts at interpretation of the reported variations in prevalence by age and sex all but useless. The same must be said about the puzzling variations in reported sex ratios in different populations and about the scattered and fragmentary findings relating to housing, climate, occupation, race and ethnicity and associated disease states. Two analytic studies attempt to give close and systematic attention to these factors, but both, of necessity, were based not on population samples but rather on series of clinic and hospital patients with rheumatoid arthritis and controls (matched for age and sex) with other diseases or no apparent disease. Thus, they lay no claim to representing the distribution of rheumatoid arthritis in the populations from which their arthritics came.

1044

NORMAN

A. SCOTCHING H.JACKGEIGER

SHORT,BAUERand REYNOLDS[27] matched 293 patients with rheumatoid arthritis (admitted to Massachusetts General Hospital) with controls selected from among nonarthritic patients and hospital staff. On the basis of continuing study of the arthritics, they describe the disease in many patients as “tending to be progressive” and sequentially moving through limitation of joint motion due to pain, swelling and stiffness; destruction of cartilage, formation of fibrous and bony growths; and ultimately, bony ankylosis. While they note that a sizeable proportion of cases have migratory symptoms and spontaneous remissions, this description seems much more characteristic of highly selected, more seriously ill and hospitalized patients than of the disease as it is seen in larger population samples. Considerable attention is given to ‘prodromal symptoms’ and ‘precipitating factors,’ the latter including such rubrics as ‘unusual anxiety, excessive exertion or both’. It is impossible to distinguish prodroma from precipitants in this context. There is no certainty in the definitions of onset of arthritis, and the possibility exists that reported associations between ‘onset’ and such ‘precipitating factors’ as infection may really represent only the exacerbation of pre-existing but previously undetected arthritis. Some 64 per cent of the rheumatoid arthritics were female and an apparent excess risk among older females was described. In both patients and controls, careful and detailed consideration was given to occupation, conditions of work, home environment (urban-rural, type of housing, etc.) and climate. No associations were observed between these factors and the presence or severity of arthritis except for an observation of greater ‘exposure to cold and damp’ as a precipitating factor. Studies of 532 patients in nine medical centers in England and Scotland were described by LEWIS-FANNING[28] in 1950 under the aegis of the Empire Rheumatism Council; these patients were matched for age, sex and marital status with controls. Findings with regard to age and sex distributions, occupation, conditions of work, home environment and the like were, in general, similar to those of the Massachusetts investigation. The most recent contribution by COBBand his associates [29] suggests an approach of major interest not only for subsequent studies of arthritis in general populations but also for the study of other chronic remittent diseases such as peptic ulcer or hypertension. This effort makes the following contributions : (1) It defines clearly the inherent limitations of ordinary incidence, point prevalence and period or annual prevalence rates in the study of remittent diseases. For example, the same period prevalence rate can be derived from two quite different populations, one in which a few persons are almost continually ‘in episode,’ or presenting symptoms of a remittent disease, and another in which many more persons are spending much less time in episode. (2) It proposes a statistical method whereby successive studies of the same population at only two points in time (i.e. a panel study) are all that are required to yield a reasonably accurate estimate of the ‘frequency distribution of persons according to proportion of time in episode.’ (3) Using this method, the authors report the frequency distribution of ‘proportion of time in episode’ (Protep) for manifestations of rheumatoid arthritis in a group of 274 employed male craftsmen interviewed and examined once monthly for 16 months. The two techniques-subjects’ own estimates of the amount of time ‘in episode’ during the preceding month, and a rapid routine examination by a specially trained

The Epidemiology of Rheumatoid

1045

Arthritis

TABLE3. PARTYOFPOPULATION SPENDING GIVENFRAC~ONOFTIMEIN EPISODE BASIS OF THEIR

____

ESTZMATE

AND

ON BASIS OF PERIODIC

EXAMINATION

OF JOINT SWELLING

[29]

Fraction of time in episode

Basis of their estimate C%)

Basis of periodic examination (%)

O.OOtoO.10 0.10t00.20 0.20 to 0.30 0.30t00.40 0.40 to 0.50 0.50 to 0.60 0.60 to 0.70 0.70 to 0.80 0.80 to 0.90 0.90 to 1.00

85.9 3.5 2.2 1.6 1.3 1.2 1.1 1.0 1.0 1.3

87.8 3.9 2.3 1.6 1.2 1.0 0.8 0.6 0.5 0.3

ON

-

_~. -_

.-

found to correlate highly with each other. The results are shown in Table 3. COBB and BEALLvigorously defend the thesis that the manifestations under study are related to rheumatoid arthritis, and are not too commonly due to other causes; indeed, their data establish strong relationships between the fraction of time in episode of joint swelling and the final diagnosis of rheumatoid arthritis. This contention is supported with serological observations [30] suggesting that patients with mild symptoms resemble the group with severe rheumatoid arthritis, the only difference being in the titre of the serological reaction. On the basis of their data, they argue two further points of more general epidemiologic significance in rheumatoid arthritis : “It seems highly unlikely that the true picture should be the ‘either present or not’ picture of hemophilia, for example. This does not mean that a hereditary factor is excluded; it merely suggests that, if genes are of any great importance in the pattern of causation, there must be involvement of multiple alleles, for a strong effect from a single allele would presumably have shown itself as a substantial discontinuity in the curves . . . .” “The second point about the continuous gradient is that it argues against the oldfashioned notion of separating the population into those with no arthritis, those with fibromyositis with a benign prognosis, and those with rheumatoid arthritis who have a relatively poor prognosis. It suggests, instead, that all degrees of severity exist from the most extensive, continuously active case through moderate and mild intermittent disease, down to the individual who has rare attacks of morning stiffness. This is more in line with the majority of other disease processes, for, with the exception of genetically determined disease and human rabies which is almost uniformly fatal, one is hard put to it to name a competently studied disease that does not have a continuous gradient of severity.” The significance of this method, and the underlying concept, for international and comparative studies is apparent. As BEALL and COBB point out, “we now have a method for examining the observed difference in point prevalence of rheumatoid arthritis between Pittsburgh and Leigh to see if it is due to a different shape of the curve displaying the frequency distribution of persons according to proportion of time in episode, to a greater over-all frequency of affected persons, or to a combination ofthese.. . . From now on, all geographic studies of this disease should attempt to nurse-were

1046

NORMANA. SCOTCH and H. JACKGEIGER

give the distribution of time in episode . . . . we believe that more will be learned about significant factors in the disease when we can discriminate in this fashion.” In a later paper [31] COBB has developed the term ‘Protep’ for ‘the frequency distribution of persons according to the proportion of time spent in episode.’ Hopefully, experimental studies will also test the applicability of this model to other diseases, although it should be noted that both the shapes of the curves of frequency distribution of ‘Protep’ and the length of the appropriate period between examinations, may vary from disease to disease. RHEUMATOID

FACTOR AND THE EPIDEMIOLOGY SEROLOGICAL REACTIONS

OF

The macroglobulin complex now known as the rheumatoid factor has been the subject of intensive study since its isolation in the serum of many rheumatoid arthritics [32], and is now a major focus of attention in epidemiological, genetic and biochemical investigations of the disease. Extensive, fully documented and replicated work in many laboratories seemed to have identified the rheumatoid factor as a heavy (19s) gamma globulin molecule that reacts specifically with smaller (7s) gamma globulin molecules in the subject’s own (or other human) serum to form a heavier (22s or more) complex. Recent laboratory findings have complicated the picture. It now seems clear that rheumatoid factor, in HARBOE’Swords, “consists of a whole group of closely related but nevertheless separate macroglobulins” [33]. KUNKELand FUDENBERG[34], for example, tested the specificity of ‘rheumatoid factor’ for the patient’s own gamma globulin as well as for different genetic types of gamma globulin from other individuals by mixing, ultracentrifugation and measurement of complex formation. No genetic specificity was observed, but when other systems were utilized “at least eight different rheumatoid factors could be identified” and frequently it was observed that rheumatoid factors lacked specificity for the patient’s own gamma globulin and reacted better with that of other individuals. JONSENet al. [35], using protein chromatography, have separated rheumatoid factor into at least three peaks suggesting the presence of proteins with different mobilities. The observation of a gamma globulin reacting more or less specifically with other gamma globulin molecules in the patient’s own serum has suggested to many investigators the possibility that reactions involving rheumatoid factor are auto-immune phenomena, with rheumatoid factor as an auto-antibody. VAUGHAN[36], in a recent presentation, has outlined a general model of auto-immune and hypersensitivity reactions in rheumatoid arthritis by analogy with classical hypersensitivity reactions of the type evidenced in rheumatic fever or serum sickness. In the latter, he points out, it is presumed that an antigen stimulates lymph-node and plasma-cell production of (specific) antibodies; the subsequent antigen-antibody reaction in tissues is associated with vasculitis, fibrinoid changes, cellular infiltration and granuloma formation, and fluorescent staining techniques have demonstrated the presence both of antigen and of gamma globulin (presumably indicating antibody). Clinical manifestations of serum sickness-urticaria, arthritis, nephritis, carditis and neuropathy-are presumed to reflect tissue damage. In rheumatoid arthritis, some features consistent with this process have been identified, including hyperactive lymph tissue (possibly producing specific serum factors or antibodies), serological changes demonstrable by various tests for ‘rheumatoid factor’ in sera, and the presence of gamma globulins in arthritic

The Epidemiology of Rheumatoid Arthritis

1047

synovia and in the cytoplasm of inflammatory cells infiltrating arthritic joints. STEFFEN [37] argues for the presence of ‘connective tissue auto-antibodies’ and HESS and ZIFF [38], using indirect fluorescent antibody techniques, have recently demonstrated diffuse ‘sarcoplasmic’ staining for gamma globulin in about 26 per cent ofpatientswith rheumatoid arthritis and connective tissue diseases, and never in normal subjects. Even assuming, however, that ‘rheumatoid factor’ is an auto-antibody, produced against some component of the patient’s own tissue, and that an antigen-antibody reaction in the tissues is associated with the manifestations of rheumatoid arthritis, several crucial questions remain. How does it arise? What is the antigen? There is no known exogenous agent or antigen. The existing possibilities include the suggestions that the stimulus for antibody production is the patient’s own gamma globulin, native or altered; that some foreign protein (e.g. from an invading micro-organism) acts as the stimulus, with the reaction to gamma globulin being an incidental crossreaction; or that infection or some other process damaging host tissue alters specific host proteins which then act as a continuing stimulus for antibody production. In any case, a general phenomenon of the ‘rheumatoid factor’ type, possibly involving the presence of an unusual and specific antibody, is presumably responsible for the agglutinating action of rheumatoid arthritis sera and is at the basis of all the serological tests in rheumatoid arthritis, whether they employ red cells, as in the sheep-cell agglutination test (SCAT), or clay or plastic or other particles, as in the latex fixation and bentonite flocculation tests. Clearly, however, the rheumatoid factor (and L.E. factor and other reactant substances in the sera of patients with connective tissue syndromes) are not in themselves pathogenic or ‘causal,’ since they have been transfused into normal subjects without effect. Furthermore, not all patients with demonstrable ‘rheumatoid factor’ (as determined by the various serological tests) have rheumatoid arthritis, and not all patients with the disease have positive tests; nor do the results of such different tests as SCAT, latex fixation, bentonite flocculation and acryl fixation correlate consistently with each other. Thus, these laboratory studies (and the epidemiological and genetic studies described below) show that the identity and unity of ‘rheumatoid factor,’ the possibility of its genetic control, its relation to disease and to possible selective factors in the environment, and the relationship of positive serological tests to previous infection with other diseases, all are open to serious question. Despite their drawbacks and uncertainties, serological tests have been employed on a large scale in population studies. Results of sheep-cell agglutination tests on systematic samples from each of the seven communities in the North European study [7] have been reviewed by BALLand LAWRENCE[39] and LAINEet al. [40]. As Table 4 shows, a range of 1.6-5.4 per cent positive reactions was observed. The prevalence of positive tests was significantly greater in urban than rural populations. No difference in sex reactions was observed with the exception of a single rural sample in which there was a preponderance of female positive-reactors. When urban and rural populations were combined, the age distribution of positives showed a stepwise increase between the ages of 15 and 74, with peaks every twenty years to a maximum of ll/lOO positives in males and S/l00 in females in the older age groups; reactions to the bentonite flocculation test similarly increased with age and showed a twenty-year periodicity. LAWRENCEand his colleagues point to the possibility that “the sheep cell titre depends on past exposure to some antigen which has become less

NORMAN A. SCOTCHand H. JACK GEICIER

1048 TABLE 4.

PREVALENCEOF P~STTIVEAGGLUTINATION TESTSIN URBANAND RURAL POPULATIONSAGED 55-64 YEARS [39] __ Total available sample

Sample

C&graphical latitude

Total tested

Titre 32 or more

FeMales males

Both sexes Males

FeBoth males sexes

Males N

Rura’

Heinola Annandale Wensleydale Glamorgan

61”N 55”N 54”N 5 1“N .____

Total

Urban

Leigh Rhondda Rotterdam Total

53”N 52”N 51 “N

Females

%N

Both sexes

%N

%

175 105 63 100

214 101 76 100

389 206 139 200

104 96 55 88

123 91 62 85

245 187 117 173

3 3 0 2

2.9 3.1 0 2.3

1 1 3 4

0.8 1.1 4.8 4.7

4 4 3 6

1.6 2.1 2.6 3.5

443

491

934

343

361 -__

704

8

2.3

9

2.5

17

2.4

204 200 166

277 200 154

481 400 320

163 177 138

187 181 133

350 358 271

8 I1 6

4.9 6.2 4.3

11 7 7

5.9 3.9 5.3

19 18 13

5.4 5.0 4.8

570

631

1201 478 _-___

501

979 25 5.2 _~~ ~_~____~

25

5.0

50

5.1

frequent over the last seventy years so that the older members of the community population stand a greater chance of having acquired a positive test. This theory might syphilis and explain the twenty-year periodicity. Certain infections-tuberculosis, gonorrhea, for example-have shown an increase during each world war and would thus have had approximately a twenty-year periodicity . . . . An association between the SCAT and infection has been demonstrated in experimental animals . . . .” It is also noted, in a consideration of the genetic implications of positive serological reactions, that “the test is not positive at birth but develops in later life.” It is not clear whether past exposure to ‘some antigen’ involved in tuberculosis or otherdiseases produces cross-reactions which are ‘false positive’ tests for rheumatoid factor, or whether this hypothesized immunological experience is in some way related to susceptibility to rheumatoid arthritis or some pathogenic process leading to clinical disease. In the North European study, only about 20 per cent of the positive SCAT reactors who were studied clinically had good evidence of rheumatoid arthritis; this clearly underlines the general agreement that the SCAT cannot be used alone to determine the prevalence of the disease. Another study, in a series of Eskimo communities, presents a somewhat different picture. BLUMBERG et al. [41], using the bent&rite flocculation test (BFT) find highly variable rates of positive reactors in the different Eskimo samples; however, when the data from most Eskimo communities are compared with United States findings from somewhat different sources, the prevalence of positive BFT reactions is similar. In one Eskimo village, Wainwright, the rate of positive BFT reactions is strikingly higherthan that of other Eskimo communities and of United States samples. Again, tuberculosis, or other diseases producing a nonspecific hypergamma globulinemia may be involved in these positive reactions. The possiblity of cross-reactions is strengthened by the observation by MALAWISTA et al. [42], of a high proportion of positive serological

The Epidemiology of Rheumatoid Arthritis

1049

reactors in Liberia, in a racially homogeneous population with very little known clinical rheumatoid arthritis. In view of these data, the observation by ROTSTEIN and GOOD [43] that one-third of 41 patients with classical agammaglobulinemia have connective tissue disease is startling. These authors now suggest that connective tissue disease may result from infection, particularly virus infection, and that the connective tissue pathology may represent a direct response to the infecting agent or a hypersensitivity response of some type. Data to support these contentions have not, however, been published as yet. Recently, BROOKS and COBB [44] have found evidence, by differential heating of serum, of “several agglutinating and inhibiting substances, which are differently distributed in rheumatoids, hypertensives and normals.” Using uncoated latex particles in plastic plates and progressive saline dilutions of serum, they find agglutinating substances in ail adults; the degrees of agglutination at each dilution “form significant group reactions” and the system is considered to be a useful epidemiological rather than clinical tool. There is no evidence as yet on the molecular nature of these substances or their genetic control. THE

ROLE

OF

INFECTION

Perhaps because of the demonstrated relationship of micro-organisms to the specific septic arthritides, repeated attempts have been made to implicate infection by bacteria or viruses in the pathogenesis of rheumatoid arthritis. This theory has had remarkable viability (more than a hundred different organisms have been suspected at one time or another), considering the paucity of experimental evidence, the lack of controlled observations, and the failure to satisfy KOCH’S postulates. The search for a micro-organism directly involved in rheumatic processes was renewed in the mid-1950’s by work on pleuropneumonia-like organisms. These agents are filtrable, species-specific and apparently occur naturally in man; they differ from rickettsiae and viruses in that they can be grown in cell-free media; and some strains have in vitro susceptibility to gold salts, one of the allegedly therapeutic agents in rheumatoid arthritis. No consistent data have been found, however, to suggest that the distribution of these organisms in arthritics differs from their distribution in controls, or that their presence in arthritic joints has any causal significance. More recently, the hypothesis has been advanced that a virus is the etiologic agent either in rheumatic fever, the rheumatoid connective-tissue syndromes, or both, although attempts to produce lesions and symptoms of rheumatic diseases by injection of viruses have failed. Again, the evidence is scanty. In any case, it may be stated that infection has not been definitively ruled out, at least as a contributing factor in rheumatoid arthritis etiology, and serological findings in particular suggest the importance of undertaking intensive studies of the association of rheumatoid arthritis with a number of serious infectious processes, particularly tuberculosis. GENETIC

FACTORS

There is a long record of investigations of hereditary factors in the various rheumatic diseases. In an extensive review, DEBL~COURT and his colleagues recently pointed out [45] that 27 years ago Fox and VAN BREEMEN [46] spoke of the “red thread of secondary cases” found in the families of rheumatic patients. The subject has also been

NORMAN A. SCOTCH and H. JACKGEIGER

1050

reviewed by HANGARTER [47] in 1938 and BLUMBERG [48] in 1960, and investigated by HOLSTI and HUIJSKONEN [49] in Finland, LAWRENCE [50] in England, and others. Most of these studies have focused on the prevalence of cases in the families of rheumatoids and in control families, and familial tendency is, of course, distinct from genetic evidence in that it represents both host and environmental factors. The results of some of the more recent investigations, as summarized by DEBLBCOURT et al. [45] are presented in Table 5. TABLE5.

INCIDENCE OF SECONDARY CASES REPORTED BY OTHERAUTHORS[45] ____ -__-_

Authors _________-STECHER

Disease in probands ___-___--____----

__

Percentagesecondary cases

Date

1957

Relatives

Controls

AS

2.5

0.18

RA

3.1

0.58

RA

6.3

0.38

RA

3.1

0.60

11.0

4.60

7.0 15.0 3.8

3.00 9.00 1.80

11.9

5.10

NERI, SERNERI and BARTOLI

1956

MIALL

1955

BARTER

1952

RA

E.R.C.

1950

RA

SHORT,ABRAMSand SARTWELL

1952

RA

WHITTINGHILL

1959

RA

3.0

-

AS

First degree 6.3 Second degree 2.3 Third degree 0.7

-

-

-

Fathers Mothers Siblings --__-

LAWRENCEand BALL

1958

RA

9.0

2.0

ZIFF, SCHMID,LEWISand TANNER

1958

RA

3.4

-

BREMNER, ALEXANDER and DUTHIE

1959

RA

7.6 4.9 _

-

_-

Clinical and subclinical Clinical -_

~~_.__

DEBLBCOURT et al. [45] summarize investigations on the families of 100 cases of rheumatoid arthritis, 100 cases of ankylosing spondylitis and 100 controls, all between theagesof25and45,at the Groningen Rheumatic Center, University of Groningen, the Netherlands, using A.R.A. criteria for ‘definite’ rheumatoid arthritis both in patients and in secondary cases among grandparents, parents, siblings, children, and collateral family members, and employing one specially-trained physician to make all of the observations. Secondary cases, they report, were found in nearly three times as many of the relatives of rheumatoid arthritics as of control patients (2.35 per centvs.0.82percent); the occurrence of such secondary cases was much higher among female than among male relatives (3.48 per cent vs. 1.25 per cent). Secondary cases were found in more

The Epidemiologyof RheumatoidArthritis

1051

than 22 times as many relatives of the ankylosing spondylitis group as in the control group (1,8 per cent vs. 0.08 per cent); here, secondary cases were higher among male than female relatives (2.45 per cent vs. 1.20 per cent). In the rheumatoid arthritis group, there were 34 families with at least one secondary case each, showing a total of 58 secondary cases, a familial occurrence of 34 per cent; in the ankylosing spondylitis group there were 30 such families showing 45 secondary cases, a familial occurrence of 30 per cent; and in the control group, 19 families showing 20 ‘secondary’ cases, with only one family that included two cases. The authors report that their findings are consistent with those of an as yet unpublished mass study in the Netherlands by DE GRAAFF, and conclude : “The data indicate that both rheumatoid arthritis and ankylosing spondylitis are capable of familial occurrence and that, consequently, each probably has a hereditary component; it is also indicated that the hereditary components of the two conditions are different in kind . . . . [since] these secondary cases were seen via both the paternal and maternal lines of descent, gonasomal factors [the X- and Y-chromosomes] are unlikely to be of great importance in the hereditary mechanism of these two conditions . . . . our investigation suggests that both rheumatoid arthritis and ankylosing spondylitis probably involve a non-sex-linked dominant hereditary mechanism, with differences in penetrance between males and females.” In the North European survey, LAWRENCEand BALL [7] found the prevalence of rheumatoid arthritis to be four times greater in patients’ families than in those of controls, and the rheumatoid factor was three times as prevalent among the relatives of sero-positive patients as among controls or among the relatives of sero-negative patients. ZIFF et al. [51] found a ten-fold difference: 14 per cent of siblings, parents and progeny of rheumatoid arthritics had a positive serology, compared with only 1.4 per cent of control groups. BREMNERet al. [52] found more clinical arthritis among the relatives of seronegative arthritics, but there was more radiological disease and positive serology among relatives of sero-positive arthritics. LAWRENCE,LAINE and DEGRAAFF[40], reviewing these data, point out that “at least two causative factors must . . . . be operating in these families, one responsible for symptoms and joint swelling, the other for the positive serology and the associated tendency to severe bone erosions. These causative factors may be environmentally or genetically determined. It is not possible at present to decide definitely between these alternatives, but environmental factors during adult life can be excluded with a fair degree of certainty.” A second approach to medical-genetic investigation of rheumatoid arthritis is the study of twins, with comparison of mono- and di-zygotic twins and non-twin siblings for concordance or discordance in the incidence of the disease. Of the half dozen or more published studies, none seems adequate fortestinggenetichypothesesbecausethey involve small numbers and because the selection of cases has a known bias in favor of the inclusion of concordant twins. A recent study by EDSTROM[53] found two concordant and two discordant pairs among four sets of identical twins, while among fraternal twins one pair was concordant and three discordant. MOESMANN[54] concluded that data from a study of heterozygotic and homozygotic twins do not support the hypotheses that heredity is an important factor. A third method of genetic study, the analysis of pedigrees, has been attempted infrequently; according to BLUMBERG[48], the results are “suggestive but not con-

1052

NORMAN A. SCOTCHand

H. JACKGEIGER

elusive,” that is, consistent with a genetic hypothesis but equally explicable by other etiologic mechanisms. What is the relevance of such findings to epidemiological studies? DEBLBCOURT has emphasized that “a possible ‘hereditary factor’ does not per se determine the manifestation of a rheumatic condition . . . other endogenous and exogenous factors also govern the actual appearance of the rheumatic affection.” The problem, then, may be more accurately stated: in a disease of possibly multi-causal etiology, how are infectious, genetic, environmental, social and other hypotheses to be integrated in an epidemiologic approach ? Recent reflections by DUBLIN and BLUMBERG[55] have a direct bearing on this question. These authors state : “Epidemiologists are now concerned with a broad array of diseases in which a specific invading parasite or toxic substance cannot be identified as of etiological significance. In such conditions, innate characteristics of the host assume critical importance. In some, long periods of latent abnormal metabolism or even frank tissue pathology precede manifest disease . . . . In studying these conditions the epidemiologist is challenged by the tasks of identifying the susceptible individual, determining the basic defect, and then assessing the factors or stresses which break through the reserve of the susceptible individual and cause disease . . . .” “For many common diseases in which the evidence for inherited predisposition is impressive the genetic mechanisms involved appear to be . . . . complex. It has been postulated that tuberculosis, diabetes, rheumatoid arthritis, and hypertension, for example, depend on ‘polygenic’ factors and . . . . are due to the interaction of several and perhaps many genes.” These authors suggest that a better understanding of the individual genes and the traits they determine in a polygenic system may be obtained from the study of genetic polymorphisms, the occurrence together in the same habitat of two or more discontinuous (readily distinguished) forms of a species in such numbers that the rarest form could not be maintained by recurrent mutation alone. This suggests that these genes are maintained in the population by selective forces which may include diseases or protection against diseases, some phenotypes being associated with increased susceptibility, others with increased protection. Examples of polymorphisms which appear to be associated with disease susceptibility or distribution are the ABO blood groups, sickle-cell hemoglobin, glucose-6-phosphate-dehydrogenase deficiency and favism, etc. DUBLIN and BLUMBERGsuggest that polymorphic systems with the following characteristics are likely to be most useful for study: 1. The phenotypes are easily distinguished and preferably are qualitatively different. 2. The expression of the gene is more or less invariable during life . . . . 3. The genetics of the system is explicit. The genotype or genotypes can be determined directly from the phenotype. 4. The genes are expressed as chemical units, such as enzymes, antigens, antibodies, co-factors, proteins and mucopolysaccharides, which can be isolated for characterization and biochemical and physiological studies. Obvious relations to a physiological, pathological or selective factor are of particular value. 5. The phenotypes are fairly common in the population. Two known polymorphisms, both involving serum factors, already are under investigation in rheumatoid arthritis. The so-called GM serum type (involving a

The Epidemiology of Rheumatoid Arthritis

1053

gamma globulin) investigated by GRUBB and LAURELL [56] and more recently by HARBOE[33], and shown clearly to be a hereditary trait, seems in some way to be related to rheumatoid factor, since it inhibits an agglutination reaction by rheumatoid sera. The level of one genetically determined pattern of serum haptoglobin has been found to be increased in the serum of rheumatoid arthritics. SOCIAL

FACTORS

In this section we broaden the concept of etiology and include the study of a number of factors that may or may not be etiologically significant. We recognize that any social

variable found to be associated with rheumatoid arthritis may be a consequence rather than a cause of the disease. But so little is known regarding the role of these factors that it would be unwise to exclude them simply because they may presently seem more relevant to the course than to the cause of the disease. Clues to the course may eventually lead to greater understanding of the cause. Studies of social factors in rheumatoid arthritis may conveniently be divided into those prior to 1955 and those following. This temporal separation is made possible by an excellent and comprehensive review by KING [57] which appeared in 1955 and summarizes the literature as far back as the earliest psychosocial studies of rheumatoid arthritis, in the 1920’s. KING groups diverse findings into the following categories: 1. Personality factors; 2. Psychosocial background factors; 3. Precipitating factors; 4. Mechanisms; and 5. Rheumatoid arthritis and schizophrenia. Let us very briefly examine these categories. 1.

Personality factors

A variety of studies have yielded the following personality traits of arthritics : lead quiet lives [58], shy and socially inadequate [59], inferiority feelings [60], selfsacrificing and overly-conscientious [61, 621, and depressed [63,64]. There has been a consistent finding of ‘marked emotional self-restriction’ and an inability to show anger overtly [63, 58, 62, 60, 65, 591. Arthritics do not develop close relationships [66, 63, 60, 671 and yet they have difficulty in achieving separation from key persons [63, 601. Sexual maladjustment has also been noted by a number of investigators [66,68, 62,65, 641. In evaluating these studies KING appropriately notes their singular lackofcontrols, imprecise definitions and concepts, lack of precise instruments for measuring almost all these variables, and the use of variable diagnostic criteria for the disease itself. In short, the studies are without scientific merit. The consistency of certain findings (i.e. controlled hostility), however, is at least provocative and deserves attention in reasonably systematic and controlled studies. 2.

Psychosocial background factors

“It has been reported that arthritic patients frequently perceived one or both of their parents as rather strict and uncompromising in discipline” [66, 59, 58 621. Another repeated observation is that the patient has suffered the loss of a parent or other key relative through death or separation [66,63,68,59,69,60]. Finally, it has been claimed that arthritic patients, as a result of a dominating mother, manifest inadequate feelings of security early in life [60] ; another worker has noted histories of severe emotional or physical deprivation early in life [63]. KING does not really evaluate these studies, but-perhaps because of his own interests and previous studies on stress-he seems to

1054

NORMAN A. SCOTCH and H. JACKGEIGER

feel that work in this area is potentially valuable. Our own view is that these studies suffer from the same fundamental defects noted above in connection with personality factors. 3. Precipitating factors Those reported are worry over financial matters [70-731, illness of relatives [74,70, 71, 75,721, grief [74, 71, 731 and unrelieved anger [62,73]. In evaluating this material, KING points out that only two of the studies used controls [71 and 761 and that each of these arrived at a different conclusion regarding the presence or absence of traumatic events preceding the illness. 4.

Mechanisms

If one assumes that at least some of these ‘emotional’ factors are acting in the early pathogenesis of rheumatoid arthritis, an important question is raised: how? Three types of processes or mechanisms are discussed. The first deals with muscle tension as an emergency reaction or as a result of emotional conflict [77, 78, 62, 791; the second sees arthritic pain as a symbolic manifestation of underlying emotional difficulty (‘what a pain in the neck’), an interpretation consistent with psychoanalytic concepts of ‘organ language,’ [80, 68, 82, 831, and the third views arthritic symptoms as a means of symbolic control over or containment of the expression of hostile impulses l-59, 84, 651. KING notes that this is the weakest area of research in psychosocial factors, and that only one of these studies used a control group (and found no difference in muscle tension between rheumatoid arthritics and hypertensives [78]). 5.

Rheumatoid arthritis and schizophrenia

Two uncontrolled but interesting studies suggest a relationship of rheumatoid arthritis to schizophrenia. In these studies, certain similarities in personality are noted between those suffering from each disease [85] despite the reported striking absence of arthritis among schizophrenics [86,87]. Thus, personality patterns in the two diseases are similar (as shown, for example, in RORSCHACH protocols [59]), while it is rare to find the two diseases in the same individual. Again, however KING notes a number of serious deficiencies in the diagnosis of arthritis in these large populations of schizophrenics. The evidence is weak and the relationships can only be considered suggestive. In summary, KING concludes that we still do not have a clear picture of the relationship of social and psychological factors to rheumatoid arthritis but that there aremany suggestive leads. He suggests that future studies utilize control groups, large samples, objective measures of psychosocial factors, and follow cohorts longitudinally. Among the variables which he feels are worthy of further attention are losses and separations, bodily activities, dreams and ego control, sexual identification, parental authority roles, and the symbolization of symptoms. Further, he identifies new areas worthy of study: self-concepts in body images and personality characteristics, social mobility, and religiosity. While KING’Sreview is comprehensive and critical enough, it never really comes to grips with the problem of distinguishing psychological from social variables. Most of the studies cited are almost purely involved in psychological rather than social factors. Though many of the factors do indeed have social dimensions, all the cited studies treat them as psychological, or individual, variables. This is, of course, almost

The Epidemiology of Rheumatoid Arthritis

IO55

since none of these investigations utilize general populations in which quantifiable sociological data can be controlled and studied. When the study population consists of known arthritics and there are no controls, it is impossible to see whether or not any characteristics associated with the subjects are also features of the general population. Studies dealing with psychosocial factors appearing after KING’S review have tended to follow three earlier themes: 1. The handling of aggression; 2. Parental relationships; 3. Physical activity and bodily image. Difficulty in the handling of aggression has been a persistent hypothesis in the psychiatric literature on rheumatoid arthritis, as already noted. Recent studies by LUDWIG [88] and by CORMIERet al. [89] are highly reminiscent of earlier work. LUDWIG reports on long-term psychoanalysis of eight rheumatoid arthritis patients and states : “The outstanding feature is marked impairment of ego function manifested by extreme dependence, insecurity, feelings of inadequacy, difficulty in the usual methods of mastery or coping with the environment and with other poeple, and severe blocking of the external expression of emotion with internalization of feeling and autonomic activity.” This type of finding, while of potential interest, is subject to the by now familiar methodologic criticisms and can be interpreted only with extreme caution. Psychiatric studies by workers who do use controls, unfortunately, are riddled with other methodological problems. For example, CORMIERand his colleagues, studying 18 rheumatoid arthritis patients, use as controls the patients’ siblings and, in addition, make use of Rorschach protocols to support their clinical and psychiatric observations. In this study the 18 pairs were interviewed by medical social workers, psychologists and psychiatrists and detailed histories were taken (it is not noted by whom) regarding different periods of the subjects’ lives with particular attention to their handling of aggression. As independent measures, projective tests such as the Rorschach and TAT were administered to 13 of the 18 pairs. The authors report: “The most significant difference between the two groups of siblings has been the manner in which they dealt with their aggressive drives. The rheumatoid arthritis patients were inhibited in display of aggression (before their illness) whereas, by and large, no such inhibitions existed in non-arthritic brothers and sisters.” It is unfortunate that such interesting findings are quantifiable only to the following extent: this difference was ‘very strong’ in 3 pairs of siblings, ‘non-existent’ in 3 other pairs, and of ‘variable strength’ in the remaining 12 pairs. Further, while the authors state that “psychological studies of these 13 pairs (a sub-sample of the original 18), when correlated with the clinical findings, closely corroborated the clinical assessment,” their discussion of the results fails to support this statement in an unambiguous way. That is, the authors found that in 8 of the 13 pairs, the rheumatoid arthritis patient tended to ‘liberate his energy’ in an ‘introversive’ way, and the non-rheumatoid arthritic in an ‘extroversive’ way, and that the rheumatoid arthritics exhibited more restrictive control than their siblings. In 3 of the remaining 5 pairs only slight differences were found, and in the final 2 pairs reverse findings were noted (i.e. the nonrheumatoid arthritics were ‘introversive’). Such data do not appear to support the assertions of the authors with as great clarity as they suggest. Further, the failure to consider age and sex of the siblings carefully, and the failure to discuss the independence, or lack of it, of the observations by the social workers, psychologists and

inevitable

1056

NORMANA. SCOTCHand H. JACKGEIOER

psychiatrists all suggest that studies such as these are not susceptible to orderly scientific assessment. Several recent papers by COBB and KING, however, are superior both in their epidemiological sophistication and in the comprehensiveness with which they examine psychological, sociological and diagnostic factors. The following discussion therefore treats them in greater detail. The first [90], describes a questionnaire for screening arthritics developed in an attempt to provide a quicker and cheaper alternative to clinical examination for population studies. The interviews were found to be quite reliable in terms of specificity (95 per cent) but less so in terms of sensitivity (65 per cent). That is, using a Rheumatoid Arthritis Index based on three questions from the questionnaire they were able to determine 65 of every 100 clinically diagnosed cases of rheumatoid arthritis, and less than 5 in 100 of their questionnaire ‘positives’ were in fact nonarthritic. The Rheumatoid Arthritis Index is discussed in the second paper in the series [91]. “This index is defined as a ‘yes’ answer to all three of the following questions: (1) Have you ever had arthritis or rheumatism ? (2) Have you ever had swelling in any joints? (3) Do you wake up with stiffness or aching in your joints or muscles?” As noted above, a postive index (“yes” to all three questions) is taken as a reasonably good indication of the disease. The authors’ summary states : 1. A sample of 1323 persons was interviewed about history of arthritic symptoms and the occurrence of certain social factors. Respondents were classified as having a positive or negative Index of Rheumatoid Arthritis and the two groups were then compared on the social data. 2. Low income, low education, and termination of marriage were associated with higher prevalence of the index for men. In the case of women the most striking factors were low education, having four or more children, reporting no spare time in the third decade of life, and worrying more than other people. The cumulative effect of grouping these factors in each sex was especially striking. 3. In particular, education and income were interrelated, with high prevalence rates noted for respondents with low education and high income, and for respondents with high education but low income. 4. The items found to be associated with a positive index were discussed in terms of the extent to which they could be considered stressful in our society, and suggestions for further research have been made. An index which has been empirically shown to relate to clinical diagnosis of arthritis is a highly desirable instrument. Its applicability across a wide socioeconomic range of respondents, however,. may require further demonstration. Responses to a question like “Have you ever had arthritis or rheumatism ?’ do not distinguish between those patients who have been diagnosed by a physician and those who simply believe they have rheumatoid arthritis. In population groups with differential access to, or use of, physicians, and with possibly differing definitions of ‘arthritis or rheumatism,’ responses may be misleading. The correspondence of COBB’SIndex with clinical diagnosis is satisfactory, but COBB’Sgroups may have been fairly homogeneous with regard to social class. Unfortunately, no data are provided which would indicate the relative homogeneity or heterogeneity of the group. In a sample including significant numbers of upper middle class patients, with high use of physicians, high concern with

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diagnosis, and, perhaps, a lower threshold for symptom-reporting, COBB’SIndex might result in overestimates of the prevalence of rheumatoid arthritis among these patients, underestimates of its prevalence among others, or both. The essential point is that correspondence between questionnaire responses and clinical diagnosis must be investigated with particular attention to social class and subcultural factors, since, as Koos [92] and others have shown, the recognition of symptoms, the importance attached to them, the concepts of disease and the use of physicians varies so widely. A second shortcoming of the paper is that while it states that significant relationships were found between rheumatoid arthritis and six independent variables, it fails to state how many other variables were examined and not found to be related. If, in fact, there were many more, one would have good reason for assuming that those relationships found significant might well have been due to chance, since it is well known that if a large number of relationships are examined a certain number of these will appear (by chance alone) to be significant. For the six variables found to be associated with rheumatoid arthritis not a single one was consistent for both sexes: (1) Income-Lower-income men had a higher rate of positive Rheumatoid Arthritis Index; no such difference was noted among women. (2) Education-The authors state that low education is related to rheumatoid arthritis. We fail to see this in the case of the men. They divide the men into three education groups: low, middle and high. The positive index rates are then given respectively as 3.9, 1.3, 3.5. For the women, on the other hand, there appears to be a very striking relationship: rates of 39.1, 8.3, 5.7 for the three educational groups. (3) Terminated marriages-Male divorcees have a higher rate of rheumatoid arthritis than married persons, whose rate is inturnhigherthanthatof single men. For women : no difference. (4) Children-For men, fewer children (one or two) are associated with rheumatoid arthritis, but for women, more children (four or more) are associated with rheumatoid arthritis. (5) Leisure activity in third decade-The difference between much leisure and little is very slight for males and females and in opposite directions for each, despite the authors’ claim of significance. (6) Worry-Men who reported themselves as ‘worrying more than most people’ have more rheumatoid arthritis; women ‘worriers’ exhibit no difference from non-worriers. These are findings worthy of interest but it is unfortunate that the authors do not take up the problem of differential findings for the sexes. The fact that no variable is consistently significant in the same direction for each sex must raise some question regarding the authors’ interpretation. Furthermore, these differences between the sexes may be a significant clue to the disease. We already know that prevalence rates vary, as does age of onset, for the sexes. It would be of interest, then, if the social factors which may trigger or exacerbate the disease also vary by sex. In addition to the sex inconsistencies other aspects of the study, in particular certain interpretations, are open to question. An example is the discussion of the findings on education and income. The authors note that people with low education and high income have higher rates of rheumatoid arthritis, and that those with high education and low income also have high rheumatoid arthritis. In contrast, low income and low education and high income and high education both are associated with low rates of rheumatoid arthritis. Here is the discussion of this finding:

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“We suggest that the data on education and income make sense in terms of the hypothesis of social mobility, which postulates that those who are moving upward or downward in the social class structure are under more stress than those whose position in the structure is stable. It seems likely that low education and relatively high income may represent those who are upwardly mobile in the class structure, while high education and relatively low income may represent those who are maintaining their position precariously or moving downward in the class scale. It is thus possible that our data show an association between stress resulting from conflicts in the social structure and risk of rheumatoid arthritis.” The finding is of considerable interest but there areatleasttwoproblemsassociated with the interpretation. In the first place, the authors’ sample may be relatively homogeneous. We cannot tell whether this is so from the data presented since, for example, the education categories are : less than fifth grade, grades 5-8, grade 9 or higher. These do not include such groupings as high school graduates, or college graduates, both of which would be important for the study of social mobility in the United States. The same problem holds for the economic categories (less than $3000 per year, $3000$4499 and $4500 and above) where, again, high income categories are not used. In the absence of some idea of the economic and educational spread, particularly in the upper groups, the reader has little idea regarding the group’s homogeneity.* In the second place there are at least two theoretical assumptions in the interpretations, one of which may not be warranted. If we accept the first assumption that high education and low income represents downward mobility in this case, and that the reverse represents upward mobility, we are still faced with the question of whether these patterns represent stress as the authors assert. Why is upward mobility stressful? Are not people in the middle groups, who may wish to be in the upper group, also undergoing stress ? The use of the concepts of social mobility and subsequent stress, it seems to us, is not a happy choice for explaining the findings. Nevertheless, the findings remain and their significance demands attention. A third paper in the series [93] compared a group of women suffering severe rheumatoid arthritis with other non-arthritic women. The arthritics are found to : identify less with mother than non-arthritics, perceive more rejection and less affection from mother, and perceive their parents as being strict in discipline. “It is suggested that the data on lack of identification with mother help explain the difficulties in sexual identification and adjustment which other investigators have reported to be true of women with rheumatoid arthritis.” In contrast: “Our data do not confirm evidence from other studies on the importance of separation events in early life in the etiology of rheumatoid arthritis. This is especially striking with regard to death of parents. At least three studies [66,68, 691 had shown that in 50 per cent of the cases there had been a separation from one or both parents by the time of adolescence. In fact, in our sample there were fewer separations in childhood among those with rheumatoid arthritis than those without the disease. We have no explanation for the finding of no association on this factor

*In a personal communication, Dr. COBBhas informed us that the population is, in fact, hetero-

Therefore, it may be feasible to re-examine the data, using geneous with respect to these variables. more detailed groupings, in evaluating the relevance of the concepts of incongruence as well as social mobility.

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in our study, but suggest that it does not prove lack of association and that separation events should continue to be taken into consideration in future research.” This study struggles with all the problems inherent in retrospective, questionnairebased exploration of emotional factors. There must be some reservation about the construction of such sweeping categories as ‘identification with parent’ on the basis of responses to a few forced-choice, pre-coded questions. Nevertheless, such common methodological problems will not be resolved without continuing experimentation of the sort represented by this study. The results contain an inconsistency not discussed by the authors. Responses in the categories above from non-arthritic, mild arthritic, and severely arthritic patients do not fall on a continuum in the case of identification with mother, father and others (p. 324); on the contrary, ‘mild arthritic’ patients differ more from the severely arthritic than do normal subjects! A fourth paper in the series [94] does not warrant extended attention in an epidemiologic review since the data consists of the clinical, social and psychological history of a single case of rheumatoid arthritis. COBBuses this case to review the literature on the relationships of ‘contained hostility’ to rheumatoid arthritis. The last paper [95] contains findings of some interest. In observations on the relationship between divorce and rheumatoid arthritis, COBB,MILLER and WIELAND again make use of the Rheumatoid Arthritis Index to find that arthritics are more liable to divorce, but put up with an unsatisfactory marriage longer than thosewhoare free of the disease. In this, COBBsees support for the ‘contained hostility’ hypothesis. It is of course equally possible that the disease preceded or even ‘caused’ the divorce or that the association merely masks a third or fourth factor. Nevertheless, since disease, its duration, and divorce are observable and reasonably quantifiable phenomena, further study might be fruitful. The dangers of unrestricted speculation in the face of major methodological deficiencies in sampling, in experimental procedure, or in the instrument employed are graphically illustrated by the publications of CLEVELANDand FISHER [59, 96, 971. On the basis of Rorschach tests on arthritics, hypertensives and other patients, these investigators conclude that arthritics have markedly different ‘body image fantasies,’ ‘styles of orientation’ toward one’s body and one’s environment, etc., and further. that this reveals different methods of ‘channeling excitation’ofpossible etiologic significance. It is hardly surprising that the ‘body images’ of arthritics already affected with the disease are altered, since their bodies are; beyond this, the terms used have no precise definition and there is no evidence that interpretation of the same protocols by other investigators would yield the same results. In summary, this section on research in social factors in rheumatoid arthritis makes one fact dramatically clear: there have been very few studies that meet even minimal criteria for scientific evidence and inference. This is particularly noteworthy in view of the frequent contention of physicians and others that social factors are ‘undoubtedly’ operating in the disease and therefore ‘must’ be studied for a clearer understanding of the whole disease process. For the most part, ‘social’ factors that have been studied have been limited to psychological or individual dimensions. Psychiatric studies of rheumatoid arthritis personality and personality conflict have been stimulating, but virtually untested by acceptable epidemiological or other scientific methods. Characteristics attributed by psychiatrists and others to arthritics may also be characteristics of the population at large. Indeed, there is evidence that hyper-

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tensives, neurotics, psychotics and arthritics have many personality traits in common with each other, and many in common with ‘normal’ subjects. The studies of COBB and KING do deal with social dimensions, though they treat relatively few variables in one fairly homogeneous district in Pittsburgh. A few ‘social’ traits are listed in passing in the descriptive epidemiological studies. Fortunately, epidemiological efforts are increasing, and forthcoming publications of the Pittsburgh study by COBBand his associates should add much to this area. SUMMARY AND IMPLICATIONS

FOR FURTHER

RESEARCH

This review of etiological and epidemiological research on rheumatoid arthritis points most clearly, in our opinion, to the primary need for an adequate, international descriptive epidemiology. The lack of firm and comparable data on the basic variables of time, place and person in the distribution of rheumatoid arthritis is hardly surprising in view of the methodological problems, and it is true that the efforts in Pittsburgh, Leigh, Northern Europe and among Eskimo and American Indian populations are well advanced. Nevertheless, we still need much more comprehensive data on such fundamental questions as: What is the prevalence of rheumatoid arthritis in various populations, in various cultures and sub-cultures, for various religious and ethnic groups? What is the racial and geographic distribution of the disease? Do arthritics tend to be found in particular occupational and class groupings, or in particular age and sex distributions, in different places and populations? This basic knowledge of prevalence, and the identification of high- and low-prevalence populations, is important in its own right and as a basis for the design of more specific investigations in serological,‘genetic, social and other aspects of the disease. Though there is still a great need for the types of contributions made by independent and autonomous workers, it seems clear that studies of such variables as race, climate, income, social class, occupation and the like can be conducted fruitfully on a cooperative international basis. International epidemiological efforts will require further agreement on criteria for diagnosis, on the performance of clinical examination, the interpretation of X-rays, and the standardization of serological and other laboratory procedures. It will, equally, require agreement on definitions of class, occupation, marital and economic status and the like, though these will vary from society to society. As we have already noted, it will require especially careful attention to the construction, validation and comparability of questionnaires to be used with varying sub- and cross-cultural populations. It will, finally, be made more difficult by the relative scarcity, in many areas, of adequate medical facilities and personnel. None of these formidable problems is specific to the investigation of rheumatoid arthritis; they are being faced now in international studies of this and of other diseases, and, while they will require a multitude of specific research studies, there is reason to be optimistic about their solution. The rapid pace of recent technical developments in serological testing, for example, suggests that relatively simple, rapid and inexpensive methods may be available soon for international standardization. It should be emphasized, however, that this plea for the obvious-an adequate descriptive epidemiology-does not mean that other research projects need be delayed until the primary task is completed. Opportunities exist for the continuation or extension of studies in at least four areas with great bearing on the etiology of rheu-

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matoid arthritis: serological testing; the relation of the disease (and of positive serology) to previous infection; genetics; and social and ‘stress’ factors. At the risk of once again belaboring the self-evident, for example, we must point out that it is not yet at all clear what such serological tests as SCAT or BFT are measuring. Is it susceptibility to rheumatoid arthritis, or an early and clinically undetectable biochemical aberration in the first stage of the disease process, or merely exposure to other (and possibly unrelated) diseases in the past? What is the relation of the rheumatoid factor(s) to the disease ? What are the specific genetics of the rheumatoid factor(s)? Little has been reported on the presence or absence of rheumatoid factor(s) or positive serology at birth, its time of appearance during life, changes in titer during life, or the possibility of alternation between positive and negative serological reactions in the same individual over time. These directly measurable variables might be studied in relation to specific environmental events: infections, social changes and stresses. The paucity of data on environmental and ‘stress’ factors in rheumatoid arthritis, as compared with hypertension or diabetes, for examples, reflects in part the lack of an easily measurable variable whose fluctuations can be observed in relation to other variables as easily as can blood pressure, blood sugar, or insulin requirement. If the appearance or quantitative variation in serologically reactive substances in rheumatoid arthritis proves to be both easily measurable and useful, the way will be opened to rapid accumulation of data on childhood and adult environmental factors, within and between populations, possibly associated with the disease. Studies of this sort, probably of the cohort or panel type, are analogous to clinical studies of ‘proportion of time in episode’ and might be conducted in conjunction with them. Interesting questions also are raised by the differences in sex ratios of clinical rheumatoid arthritis and positive serology. The consistency and age distribution of this difference in sex ratios, and its relation both to endogenous factors (e.g. hormonal) and exogenous factors (e.g. other diseases, social class, occupation) invite attention. The genetics of rheumatoid factor(s) are already under investigation, as we have noted, and it is presumed that these studies will continue and be enlarged. The relationship of positive serology to the past experience of populations with infections, however, opens a whole series of new and largely unexplored questions. Studies of the relationship of rheumatoid arthritis to infection, in the sense of searching for specific micro-organisms as causal agents, have been unrewarding, although some interest continues in hypotheses of viral etiology. The results of clinical and serological investigation in a variety of populations points clearly, however to a major reconsideration of the possible etiological role of infection, or, at least, of certain infections, in altering immunological states toward susceptibility to rheumatoid arthritis. Is a positive rheumatoid serology merely an artefact, the result of a nonspecific hypergammaglobulinemia related to numerous past infections or to hepatic disease? Or is it also a clue to potentially pathological immune or autoimmune processes triggered by past exposure to other diseases such as tuberculosis? While this invites basic biochemical research, the question has numerous epidemiological implications. BALL and LAWRENCE, KELLGREN and others have already noted a 20-year periodicity, in random samples, of seropositive reactions, and BLUMBERG et al. have found some suggestive clues among tuberculosis-ridden Eskimo populations. No similar periodicity in peaks or troughs of prevalence of clinical rheumatoid

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arthritis itself has been reported. Cohort studies and prospective studies beginning with younger age groups would permit examination in parallel of the incidence and prevalence of rheumatoid arthritis, seropositivity, and exposure to tuberculosis and other infections. Such studies also might consider the effect of seasonal, annual or longer-interval waves of infection (e.g. influenza), examine (for both rheumatoid arthritis and infections) urban-rural differences, social class differences, rates in small and large families and the like. Areas in which control of specific infectious diseases is rapidly being accomplished, and in which the experience of different age cohorts is therefore likely to vary markedly, would be particularly useful for study in this regard. Observations on the prevalence and mechanisms of rheumatoid arthritis and other collagen diseases among agammaglobulinemics, following up the reports of ROTSTEINand Goon, also are clearly indicated. Work on the major aspects of genetic study-the separation of genetic and environmental factors, and the delineation of modes of inheritance-is already under way with regard to the disease, the serological reactions and the distribution of associated factors such as the GM system and the level of haptoglobins in sera. It is expected that further studies of twins (in the same and different environments) and of spouses will be undertaken. Recent developments in applied anthropology indicate that a thorough understanding of the kinship systems in nonliterate or ‘primitive’ societies can be used to construct detailed and accurate pedigrees; lack of such a technique has, until now, seriously hampered genetic studies among nonliterate, isolated (and possibly genetically homogeneous) groups. DUBLINand BLUMFSERG, among others, have called attention to the usefulness of such societies as objects of study in the search for selective factors maintaining polymorphic traits possibly related to rheumatoid arthritis. It should be noted, however, that it is not always necessary to specify selective factors in the existence of polymorphisms and that, in any case, balancing selective forces may mask the initial effect. In the absence of any specific hypothesis like that linking sicklecell genes to the distribution of malaria, the first task therefore would seem to be the identification of groups in which the prevalence of rheumatoid arthritis is unusually high or low. This consideration of other areas of research helps to explain the relative poverty of study of social factors in rheumatoid arthritis. In the absence of adequate general epidemiological data on the distribution of the disease, it has been difficult to determine whether rheumatoid arthritics share social characteristics that are unique to them and that are not characteristics of non-arthritic populations. The lack of this information, in turn, has made it difficult to move from a discussion of characteristics or ‘social traits’ to a consideration of processes, in the effort to link social behavior with physiological and biochemical mechanisms in etiology. The anticipated accumulation of information on variations in the distribution of rheumatoid arthritis by area, age, sex, race, residence, etc., should simplify the task of developing a frame of reference for studies of social factors in the disease and stimulate additional and more sophisticated research. Again, however, many research tasks can be undertaken now, without waiting for the development of a full-scale epidemiology. For example, sex differences in social factors, such as those we have noted in the Pittsburgh data of COBBand his colleagues on education, income, fertility, and amount of leisure time, invite replication and further exploration. The same is true of observations on marital status. Fortunately,

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variables such as these are susceptible to systematic observation and quantitative measurement. It should also be possible, in smaller-scale studies, to attempt a more logical exploration of the repeated suggestion that ‘contained hostility’ is an etiological or associated factor in rheumatoid arthritis. Relevant groups for study might include prison populations and minority groups in the United States. This is an area in which careful cross-cultural study also may be valuable; while it is misleading to characterize societies too broadly in such terms as ‘modal personality,’ and while the dangers of ‘trait’ studies are as great in ethnography as in medicine, there are societies of relatively similar biological populations which differ sharply in their permissiveness toward, or encouragement of, the expression of hostile and aggressive impulses. Variations in types of parental control (also found to be associated with rheumatoid arthritis by COBB) may be studied cross-culturally in much the same way. Some question has been raised as to whether the COBB and BEALL techniques of estimating and measuring proportion of time in episode is feasible for large populations or whether it is best applied to small and relatively closed groups. Further study is needed to identify the special advantages and the limits of usefulness of this method. In any case, the ‘Protep’ model seems particularly pertinent to an examination of social variables possibly related to exacerbations and remissions in the natural history of rheumatoid arthritis. Are periods ‘in episode’ also periods of changes in the patient’s family or occupational status, social mobility, incongruence in status, ‘crisis’ episodes in emotional life, or other types of ‘stress’? Study of these factors in persons without arthritis, in those with stabilized or remittant disease, and in those with rapidly progressive arthritis may help to clarify the distinction between those ‘social factors’ that refer to variation (for example, by social class) in the distribution of an etiological agent and those that refer to ‘stressful’ life situations or behaviors. Differences between short-term and fluctuant ‘stresses’ and those that operate more subtly over longer periods of time also may become evident. It is almost platitudinous, in this connection, to point to the need for improved instruments to detect and measure ‘stress.’ This difficulty is hardly specific to the investigation of rheumatoid arthritis. Relatively little use has been made to date on arthritics and controls, however, of such existing techniques of psychophysiological investigation as measurement of muscle tension, galvanic skin response, or epinephrine-norepinephrine secretion. Neither the resources, the manpower, the opportunity-nor the wisdom-are available to begin or conduct all of these suggested investigations. Priorities are essential. While the establishment of priorities is, indeed, a most important task, any suggested listing is likely to draw in very small part on wisdom and in very large part on personal preferences, biases, hunches or roughly calculated gambles. With these reservations it is suggested, in conclusion, that descriptive epidemiology, the epidemiology of serological reactions and their relationship to infection, and the study of selected hypotheses involving ‘stress’ factors should have first call on available resources. Acknowledgements-We wishto acknowledgethe advice and guidanceof the Advisory Committee of the Cross Cultural Disease Survey (DR. JOSEPHBOBBY, DR.WILLIAM CAUDILL, DR.ALBERT DAMON, DR.STANLEY DLUHOND,DR.MELVIN KOHN,DR.BENJAMINPAUL, DR. ROBERT RAPOPORT, DR. ROBERT REED). We wishalso to thank the followinguho read earlier versionsof this paper and kindly made valuable and salient suggestions: DR. THOMAS BIRCH,DR. BARUCH BLUMBERG, DR.

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JOSEPHBUNIM, DR. SIDNEYCOBB, DR. THOMASDUBLIN, DR. JEREMIAHSTAMLER.A special debt is acknowledged to DR. WILLIAMKLQICK, who made available to us his comprehensive annotated bibliography on rheumatoid arthritis which called to our attention a number of recent important papers. The superior editorial assistance of MISS CAROLYNScorr is gratefully appreciated. This fmal version of the paper is, of course, completely the responsibility of the authors. REFERENCES 1. ROPES, M. W., BENNETT,G. A., COBB, S., JACOX, R. and JESSAR,R. A.: 1958 Revision of diagnostic criteria for rheumatoid arthritis, BUN. rheum. Dis. 9, 175, 1958. 2. COBB,S.: On the development of diagnostic criteria, Arthr. Rheum. 3,91, 1960. 3. KELLGREN,J. H. : Radiological signs of rheumatoid arthritis: A study of observer differences in the reading of hand films, Ann. rheum. Dis. 15,55, 1956. 4. KELLGREN,J. H. and LAWRENCE,J. S.: Radiological assessment of rheumatoid arthritis, Ann. rheum. Dis. 16,485, 1957. 5. KELLGREN,J. H. and LAWRENCE,J. S.: Radiological assessment of osteoarthritis, Ann. rheum. Dis. 16,494, 1957. 6. SHARP,J., PURSER,D. W. and LAWRENCE,J. S. : Rheumatoid arthritis of the cervical spine in the adult, Ann. rheum. Dis. 17, 303, 1958. 7. LAWRENCE,J. S., LAINE,V. A. I. and de GRAAFF,R. : The epidemiology of rheumatoid arthritis in Northern Europe, Proc. R. Sot. Med. 54,454,1961. 8. HOLSTI,6. and RANTASOLA,V. : On the occurrence of arthritis in Finland, Acta med. scund. 88, 180, 1936. 9. EDSTROM,G. : The frequency of rheumatic disease in Sweden, UppsaIa tik. F&en, Forh. N.F. 49, 303, 1944. Translation: Graduate School of Public Health, University of Pittsburgh. 10. srrZ4J, s., STRAKA,L. and N~ZPEL,G.: The occurrence of rheumatic disease on the basis of examination of the population as a whole, Bratisl. Lek. Listy 34, 612, 1954. Translation: Graduate School of Public Health, University of Pittsburgh. J. J. : Screening of the population for rheumatic disease, Ann. rheum. Dis. 13,338, 11. DEBLI?COURT, 1954. 12. EHRSTROM,M. C.: Medical studies in North Greenland. V. Rheumatic disease. Comparative investigation of incidence, Acta med. stand. 140,412,1951. 13. HORWITZ,D. G.: Sampling and field procedure of the Pittsburgh Morbidity Survey, Publ. Hlth. Rep., Wash. 67,1003, 1952. problems in a morbidity survey 14. CHEN, E. and COBB, S.: Further study of non-participation involving clinical examination, J. chron. Dis. 7,321,1958. 15. COBB, S., KING, S. H. and CHEN, E. : Difference between respondents and non-respondents in a morbidity survey involving clinical examination, J. chrorz. Dis. 6,95,1957. J. : A comparison of specific symptom data obtained by non-medical 16. COBB, S. and ROSENBAUM, interviews and by physicians, J. chron. Dis. 4,425, 1956. 17. COBB, S., WARREN,J. E., MERCHANT,W. R. and THOMPSON,D. J. : An estimate of the prevalence of rheumatoid arthritis, J. chron. Dis. 5,636, 1957. 18. KELLGREN,J. H., LAWRENCE,J. S. and AITKEN-SWAN,J.: Rheumatic complaints in an urban population, Ann. rheum. Dis. 12,5, 1953. 19. LAWRENCE,J. S. and A~TKEN-SWAN,J.: Rheumatism in miners: I. Rheumatic complaints, Brit. J. industr. Med. 9, 1, 1952. 20. KELLGREN,J. H. and LAWRENCE,J. S.: Rheumatoid arthritis in a population sample, Ann. rheum. Dis. 15, 1, 1956. 21. MULL, W. E.: Rheumatoid arthritis in males: an epidemiologic study of a Welsh mining community, Ann. rheum. Dis. 14,150, 1955. 22. MIALL, W., CAPLAN,A., COCHRANE,A. L., KILPATIUCK,G. S. and OLDHAM, P. D. : An epidemiology study of rheumatoid arthritis association with characteristic chest X-ray appearance in coal workers, Brit. med. J. ii, 1231, 1953. 23. LAWRENCE,J. S.: Prevalence of rheumatoid arthritis in urban and rural population in the United Kingdom, in “Population Studies in Rheumatoid Arthritis,” Transactions of the First International Conference at National Institutes of Health, Bethesda, Maryland, 18 June 1957 (Edited by KELLGREN,J. H.), Washington, 1958. 24. MIALL, W. E. : Prevalence of rheumatoid arthritis in a mining valley and an agricultural plain in South Wales, in “Population Studies in Rheumatoid Arthritis.” Transactions of the First Internationai Conference at National Institutes of Health, Bethesda, Maryland, 18 June 1957 (Edited by KELLGREN,J. H.), Washington, 1958. 25. MIALL, W. E., BALL, J. and KELLGREN,J. H. : Prevalence of rheumatoid arthritis in urban and rural populations in South Wales, Ann. rheum. Dis. 17,263, 1958.

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Arthritis

26. COBB, S. and LAWRENCE,_I.: Towards a geography of rheumatoid arthritis, Bull. rheum. Dis. 7, 133, 1957. 21. SHORT,C. L., BAUER.W. and REYNOLDS,W. E.: Rheumatoid Arthritis, Harvard University Press, Cambridge, 1957. 28. LEWIS-FANNING,E.: Empire Rheumatism Council Scientific Advisory Committee Report on an enquiry into aetiological factors associated with rheumatoid arthritis, Ann. rheum. Dis. 9, (Suppl.) 1950. 29. BEALL, G. and COBB, S.: The frequency distribution of episodes of rheumatoid arthritis as shown by periodic examination, J. chron. Dis. 14,291, 1961. 30. BROOKS,G. and COBB, S.: Patterns of latex agglutination and its inhibition in rheumatoids, hypertensives, and normals, Arthr. Rheum. 3,435 (Abstract), 1961. 31. COBB, S.: A method for the epidemiologic study of remittent disease, presented before the epidemiology section of the American Public Health Association, 15 November 1961. 32. ZIFF, M.: The agglutination reaction in rheumatoid arthritis, J. chron. Dis. 5, 644, 1957. 33. IIARBOE,M.: Heterogeneity of the ‘rheumatoid factor,’ Atti de1 X Congresso della Lega Internazionale contra il Reumatismo, Vol. 1, p. 282, 1961. 34. KUNKEL, H. G. and FUDENBERG,H. H.: Auto- and iso-specificity of rheumatoid factors for ;;-gl;bulin, Atti de1 X Congress0 della Lega Znternazionale contra il Reumatismo, Vol. 1, p. 292, 35. JON&N, J., KASS, E. and HYATUM,M. : Chromatography of proteins from sera with rheumatoid factor, Atti de1 X Congress0 della Lega Internazionale contra il Reumatismo, Vol. 1, p. 286, 1961. 36. VAUGEIAN.J. H.: Serum resnonses in rheumatoid arthritis. Amer. J. Med. 26. 596. 1959. 37. STEFFEN,C. : Demonstration and comparative investigation of connective tissue auto-antibody in rheumatoid arthritis, Atti de1 X Congress0 della Lega Znternazionale contra il Reumatismo, Vol. 1, p. 278, 1961. 38. HESS, E. and ZIFF, M.: Immunofluorescent studies in rheumatic fever, rheumatoid arthritis and ulcerative colitis, Atti de1 X Congress0 della Lega Znternazionale contra il Reumatismo, Vol. 1, p. 275,196l. 39. BALL, J. and LAWRENCE,J. S.: Epidemiology of the sheep cell agglutination test, Ann. Rheum. Dis. 20, 235, 1961. 40. LAINE, V., deGRAAFF, R. and LAWRENCE,J. S.: Rheumatoid arthritis in Northern Europe; an epidemiological study, Atti de1 X Congress0 della Lega lnternazionale contra il Reumatismo, Vol. 1, p. 31, 1961. 41. BLUMBERG,B. S., BLOCH, K. J., BLACK, R. L. and DOTTER,C.: A Study of the prevalence of arthritis in Alaskan Eskimos, Arthr. Rheum. 4,325, 1961. 42. MALAWISTA.W. E.. BOIES.L. R. and SEIDES.S. : Evaluation of an eddemiologic method. Ann. rheum. Dis. k3, 305; 1959..

43. ROTSTEIN,J. and Goon, R. A.: The significance of the simultaneous occurrence of connective tissue disease and the agammaglobulinemic state, Atti de1 X Congress0 della Lega Internazionale contra il Reumatismo, Vol. 1,217, 1961. 44. [See reference 301. T.: Hereditary factors in 45. DEBLBCOURT,J. J., POLMAN, A. and DEBLBCOURT-MEINDERSMA, rheumatoid arthritis and ankylosing spondylitis, Ann. rheum. Dis. 20,215, 1961. 46. Fox, R. F. and VANBREEMEN,J. : Chronic Rheumatism, Churchill, London, 1934. 47. HANGARTER,W.: Der Rheumatismus, No. 13, Steinkopff, Dresden, 1938. 48. BLUMBERG,B. S.: Genetics and rheumatoid arthritis, Arthr. Rheum. 3,178,1960. 49. HOLSTI,0. and HUUSKONEN,A. J. : Heredo-familial arthritis; a study of four generations of an arthritis-family, Acta med. stand. Suppl. 89, 128, 1938. 50. LAWRENCE,J. S. and BALL,J.: Genetic studies on rheumatoid arthritis, Ann. rheum. Dis. 17,160, 1958.

ZIFF, M., SCHMID,F. R., LEWIS, A. J. and TANNER,M. : Familial occurrence of the rheumatoid factor, Arthr. Rheum. 1,392,1958. 52. BREMNER,J. M., ALEXANDER,W. R. M. and DUTHIE, J. J. R. : Familial incidence of rheumatoid arthritis, Ann. rheum. Dis. 18,279, 1939. Acta med. 53. EDSTROM, G. : Klinische Studien uber den chronischen Gelenk-Rheumatismus, stand. 108, 398, 1941. 54. MOESMANN,G. : Factors precipitating and predisposing to rheumatoid arthritis as illustrated by studies on mono-zygotic twins, Acta med. stand. 5,291,1959. 55. DUBLIN, T. D. and BLUMBERG,B. S.: Inherited disease susceptibility, Publ. Hlth. Rep., Wash. 51.

76, 499, 1961.

56. GRUBB, R. and LAURELL, A. B.: microbial.

seand. 39,390,

1956.

Hereditary

serological

human

serum groups,

Acta path,

1066 57. 58. 59. 60.

61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78.

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