Studying the Epidemiology of Rheumatoid Arthritis in Israel : Methodological Considerations

Bg J. H. ABRAMSON, E. ADLER, S. BEN HADER, ZIPORA ELKAN, K. R. GABRIEL AND MIRIAM WAHL

The outline of the epidemiological study of rheumatoid arthritis in the Western region of Jerusalem (population about 14,000, interview sample about 8,000, examination sample about 2,000), is given. The semantic difficulties, reli- ability of diagnostic criteria, evaluation of x-ray pictures, validity of Rh. A. in- dex with regard to cultural, social and ethnical background, and its special significance within the population of Israel, influence of non-response to inter- view and/or examination on statistical results, and repeated examinations of a part of the sample in a remittant chronic disease like rheumatoid arthritis, are dis- cussed. The relatively large number of the sample in this present study may render possible to overcome the many pitfalls involved.

Es presentate un plano general del studio epidemiologic de arthritis rheumatoide in le region del west de Jerusalem (popu- lation circa 14.000, gruppo de interview circa 8.000, gruppo de examine circa 2.000). Es discutite le difficultates se- mantic, le fidelitate del criterios diag- nostic, le evalutation del radiogrammas, le validitate del indice de arthritis rheu- matoide con respecto a1 ambiente cul- tural, social, e ethnic e su signification special intra le population de Israel, le inflnentia super le resultatos statistic de non-responsa a1 interview e/o a1 exam- ine, e le influentia de repetite examines de un parte del gruppo in un remit- tente morbo chronic como arthritis rheu- matoide. Forsan le relativemente grande numero del population specimen in le presente studio va facer possibile le su- peration del multe obstaculos que es implicate.

HERE IS A GROWING recognition of the potential contribution of T epidemiological studies to an understanding of rheumatoid arthritk6 Such studies unfortunately present considerable difficulties. The purpose of the present paper is to review a number of methodological considerations, illustrated by problems encountered in the planning and first nine months of operation of a study of the epidemiology of the disease in Israel.

The Israel study was commenced in 1962,' with two initial aims: to study the epidemiology of the condition in a part of Jerusalem (the western region of the city, with a population of about 14,000); and in so doing, to establish the methodology for an investigation extending beyond this study area.

Estim nting Prevalence It is recognized that hospitaI and other service records provide an unsat-

isfactory picture of the occurrence of the diseasell and that the most accu-

From the Dapartiizents of Physical Alrtlicine rind Rrhahilitation, and of Social Medicine, Hebrew Ilniuersity-Hadasmh Medicnl School, and the Dcpnrtment of Statistics, Hebrew Uniuersity, Jemcsalem, Ismel.

*With the support of the U. S. Nat io~i~d Tnstitiitr of Hedth. The project is directed by Dr. E. Adler.

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ARTHRITIS AND RHEUMATISM, VOL. 7, No. 2 (APRIL), 1964

154 ABRAMSON ET AL.

rate picture is one based on clinical examinations of a population or popula- tion sample. In view of the relatively low prevalence of the condition at a given time, however (27 cases of probable or definite disease per 1000 adults, on the basis of Pittsburgh findingsll), the examination sample re- quires to be large, and on a big scale this method is expensive or impractical. Accordingly, the use of screening procedures has been suggested as a basis for sampling, and study has been made of the use of interview methods in estimating prevalence.

An approach offering much promise, and the one which is being tested in the Israel study, is that proposed by Cobb and his associates. These work- ers found, in the Pittsburgh Arthritis Study, that positive replies to three questions (morning stiffness, a history of joint swelling, and a history of arthritis or rheumatism) comprised a useful “index of rheumatoid arthrit- is.”11j26 Of persons with probable or definite rheumatoid arthritis, 66 per cent had a positive index (sensitivity = 0.66); while of persons without the disease, only 5 per cent had a positive index (specificity = 0.95). The value of this index was subsequently confirmed in a further US. study.1° In the Pittsburg study, estimates of prevalence were based on the examination find- ings in those members of a random population sample whom it was possible to examine, and on the interview responses of other members, interpreted in the light of the relationships revealed in the first group between interview responses and examination findings.l* The present Israel study is based on the use of a similar method.

It can however not be assumed that the validity of interview questions is the same in different populations. Our early findings in fact suggest that both the sensitivity and the specificity of the “index of rheumatoid arthritis” are lower in Jerusalem than in Pittsburgh. To take but one factor, the literal Hebrew translation of “arthritis” has for years been used, by laymen and many doctors in Israel, as a synonym for rheumatic fever, as well as for many cther conditions. This may affect the meaning of the reply to the question “Have you ever had arthritis or rheumatism?.” Because of such doubts, the first phase of this investigation has been planned to include a study, in a region of Jerusalem, of the validity of interview responses. The inquiry is based on interviews with as many as possible of the adult residents of the area, who are then stratified according to their responses, and on the sub- sequent clinical examination of a random sample within each stratum. Four questions are used-the three used by Cobb et al., and one other (difficulty in making a fist).

Diugnosing the Disease With a disease which, in its milder and less typical forms, presents so

much diagnostic uncertainty, it is only by the use of uniform criteria that results can be obtained which are at all comparable with those of other studies. In the Israel study, rigid use is being made of the diagnostic criteria for rheumatoid arthritis prepared by the American Rheumatism Association (1958 revisionz3). The diagnosis depends on the number of these criteria

EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS IN ISRAEL 155

present, and on the absence of evidence of other specified disorders, such as rheumatic fever and acute infectious arthritis.

However, the use of the A.R.A. criteria presents difficulties. For one thing, they are not absolutely valid: there are cases whom most clinicians would consider definite rheumatoid arthritis which do not meet the criteria, and there are some cases which meet the criteria but which most clinicians would not consider to be rheumatoid arthritk7J2 This leaves the door open for a possible tendency to use the criteria only for confirmation of a positive clini- cal diagnosis, rather than as the sole basis for the diagnosis. In order to guard against this possibility, we have insisted that the absence or presence of each diagnostic criterion be systematically recorded in each case; and further, that the clinician’s case history must not precede the physical exami- nation.

Unfortunately too, although the use of the A.R.A. criteria reduces inter- observer variation, it cannot completely exclude such variation. There has, for example, been shown to be considerable observer variation in interpret- ing the radiological signs16 which comprise one of the criteria. Similar con- siderations may well apply to the criteria which depend on clinical observa- tion and judgment, such as pain on motion, joint tenderness and swelling.

There is, in addition, one important criterion, morning stiffness, the ap- praisal of which depends on subjective factors on the part of both clinician and patient. Kellgren and Lawrence found a wide difference between physi- cians in their records of morning stiffness in the same indi~idua1s.l~ The Jerusalem study gives similar evidence of the role played by subjective fac- tors: a comparison of the interview data with the clinical records of the first 758 persons examined shows that of the 324 persons who answered “Yes” to the interview question “Do you wake up with stiffness or aching in your joints or muscles?”, only 19 per cent were recorded by the clinician as hav- ing definite morning stiffness; of 434 persons who answered “No” to the interview question, 1 per cent were recorded as having the symptom. The use of these interview responses instead of the clinical data, in making the diagnosis, would considerably raise the estimate of the prevalence of proba- ble or definite rheumatoid arthritis.

Observer variation of this sort may be of considerable importance. It is noteworthy that in the first comparative investigation of two populations to use the A.R.A. criteria, it was found necessary to make a comparative study of readings of the same x-ray plates by the investigators in the two s t u d i e ~ . ~ Similarly, in a study of seven North European communities, where the prevalence of rheumatoid arthritis in one area was shown to be higher than in the others (using the A.R.A. criteria), a decision could not be reached as to whether this was or was not a reflection of inter-observer variation in the clinical appraisal.lg

Of the four other A.R.A. criteria for the diagnosis of probable or definite rheumatoid arthritis, three, which depend on examinations of synovial fluid, synovial membrane, and biopsy of a subcutaneous nodule, respectively, are of little value in a population study; the other criterion is a positive aggluti-

156 ABRAMSON ET AL.

nation test. The agglutination tests being used in the Israel study are two tests for the “rheumatoid factor,” the Rose-Waaler ( sensitized sheep cell agglutination) and latex fixation tests, the validity of which has been studied among Jerusalem patients.24 While the A.R.A. proposals leave room for varia- tion both in the selection of tests and in the choice of critical titres, this is of relatively little moment. Laboratory methods can be easily defined, and their reliability measured.

Unfortunately, serological tests can only partly replace diagnoses in a study of this sort. More objective though they may be, there is ample evidence that they may be measuring something different. It has been shown that differ- ences (e.g. between the sexes) in the prevalence of the disease may not be reflected in similar serological differences1 Studies of the epidemiology of the “rheumatoid factor” have however already contributed to our under- standing of the disease, and must form an intrinsic part of a prevalence study of this sort.

Sampling: Problems of Non-response In deciding on sampling ratios for the seletcion of subjects for examina-

tion, it was necessary to take into account not only the need for reliable estimates of prevalence, but also the need to find sufficient cases of the disease to enable estimates to be made of the sensitivity of the screening questions as indicators of the disease. The suggestion that sensitivity should be evaluated in a clinic sample rather than in a population sample? was rejected, on the grounds that rheumatoid arthritics attending clinics tend to manifest the more severe forms of the disease-the proportion of cases with various signs and symptoms tend to be high, and as a result estimates of sensitivity are high; this is shown by the comparative figures cited by Ropes et a1.22

The problem of non-response is unavoidable in studies of this sort. It is however hoped that it will not loom unduly large in the Jerusalem study, as the work is being carried out in close association with a well-established Health Centre of the Department of Social Medicine, which has established extremely good accord with the population. In order to assess the representa- tiveness of the interview sample, we are endeavoring to obtain at least a modicum of information about persons who are not available for interview, or refuse to be interviewed. As far as bias in the examination sample is concerned, estimates of prevalence will, as indicated above, be based both on the examination findings in respondents, and on the interview findings in non-respondents. This method assumes, however, that the prevalence of the disease is the same among persons who refuse to be examined, as it is among persons who give the same number of positive replies to the inter- view questions but who agree to be examined. This may not necessarily be so. In the Pittsburgh study, it was found that a history of arthritis or its manifestations was considerably commoner among persons who were ex- amined than among those who were not examined.8 It is not inconceivable that, even among persons giving the same number of positive replies, those with rheumatoid arthritis will be more likely to agree to examination. It is hoped to obtain some light on this by comparing persons who have shown

EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS IN ISHAEL 157

differing degree of reluctance to be cxamined, as measured by the number of broken appointments.

In the circumstances of this study, a high non-response rate was antici- pated for radiological examinations, as such examinations could not be done at the same time or place as the physical examination. For this reason, it was decided to perform radiological examinations not as a routine, but only where it was apparent from the other findings that they would be crucial for the establishment of the diagnosis, or where rheumatoid arthritis had been diagnosed on other grounds.

Studying the Correlates of Rheumatoid Arthritis The main value of studies of the prevalence of rheumatoid arthritis lies

in the light they may cast on the correlates of the disease-in particular, on its differing prevalence in differing groups, defined on the basis of various biological, social and cultural characteristics. As Scotch and Geiger have pointed out, there is a great need for studies of such basic epidemiological variables as ethnic group, occupation, and social class, to which investigators of rheumatoid arthritis have paid relatively little attention.'? The difficulty in comparing the findings of studies by different investigators makes it es- pecially important that comparisons oi various groups should be planned as an intrinsic part of prevalence studies.

Ideally, this should be done on the basis of examination findings. How- ever, the size of the examination sample will not usually permit the study of more than a very few variables in this way.

To meet this problem, Cobb and his associates have proposed that the index of rheumatoid arthritis, based on interview data, be used for this purpose,"j and have in fact been able, by using the index, to demonstrate relationships with education, occupation, parity, divorce, and other varia- bles.jJ0J8 For this reason, and in order to allow for the consideration of as many variables as possible, it was decided to attempt to interview all, rather than a sample of, the members of the Jerusalem study population.

However, a basic problem attends the use of this method. As has been been amply pointed O U ~ , ~ J ~ , ~ ~ ~ ~ ~ it assumes that the validity of the index is the same in the various groups compared-a hypothesis of which the size of the examination sample may not permit a definitive test. This may be only partly met by our decision to make the examination sample large (ZOOO), in order to permit fuller tests of validity.

The possibility that groups being compared may tend to differ in their interview responses, irrespective of their status vis-a-vis rheumatoid arthritis, presents a considerable problem. The possibility that such differences may in fact exist, at least in relation to some variables, is suggested by our pre- liminary findings of a relationship between Cornell Medical Index (C.M.I.) responses and the interview questions comprising Cobbs index of rheuma- toid arthritis. (The C.M.I.,3 a health questionnaire which has been validated in the U.S. and Britiain, is being administered to a random population sample drawn from among the persons who are examined.). Our early findings show a positive relationship between responses to the Cobb questions and two scores derived from the C.M.1.-one expressing complaints relating to

158 ABRAMSON ET AL.

bodily systems other than the musculoskeletal, and the other derived from the section of the C.M.I. dealing with “moods and feelings.” These relation- ships exist both among persons with no suspicion of rheumatoid arthritis, and among those with possible, probable or definite rheumatoid arthritis.

Whatever the meaning of high C.M.I. scores among Israeli subjects- whether they indicate emotional disturbance or other factors-it is clearly possible that if groups are being compared who differ in their C.M.I. scores, they may also differ in their responses to the Cobb questions, without neces- sarily differing in their prevalence of rheumatoid arthritis. This considera- tion may be especially relevant when relationships are sought with social factors (such as widowhood and divorce) which are possibly likely to pro- duce emotional stress and thus elevated C.M.I. scores.

Such considerations are of special importance with a heterogeneous study population. Responses to the Cobb questions may, for example, vary with ethnic group membership, irrespective of the presence or absence of rheuma- toid arthritis.

Associations of background factors with diagnosis must be inferred partly from data on associations of the factors with Cobbs questions. Suitable statis- tical methods require assumptions on the character of the association^;^^^"^'^^(^ for instance, one might assume that there is no association between diagnosis and background factor among people with positive answers to Cobb‘s ques- tions, as well as among people with negative answers to these questions. The validity of some of these assumptons is being considered. Relevant empirical evidence is to be obtained from the present examination sample, and will be analysed by the appropriate statistical techniques.25

It may be noted that King and Cobb, having found associations between the index of rheumatoid factors and various factors which they regarded as stressful, sought and found confirmatory associations between diagnosis and these factors, among subjects who had been examined.ls The number of diagnosed cases was however so small that some doubt remains as to wheth- er the conclusions or method can be regarded as decisively justified.

A further problem facing us in studying the correlates of rheumatoid arthritis arises from the fact that Israel is a country both of rapid develop- ment and of rapid immigration. As a result, not only are social and cul- tural differences wide and numerous, but the combination of these charac- teristics are manifold, and the health implications of a given characteristic are very likely to differ in its different combinations. The complexity of such studies in the Israeli melting-pot is illustrated by a recent inquiry into the inter-related associations between the haemoglobin pitcure in parturient women in Jerusalem and their country of birth, occupational class, and neigh- bourhood of living.15 It is hoped that the data collected in the present study will contribute to the methodology of such studies in developing countries.

The Time Factor Although the present study is nominally one of “point prevalence,” i.e. of

prevalence at a point in time, it has been necessary to spread the study over a considerable period. That is, each person is studied at a different point in

EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS IN ISRAEL 159

time. This may produce problems if there are seasonal differences in the occurrence of either rheumatoid arthritis or the manifestations covered by the interview questions. It may be noted that in the Empire Rheumatism Council’s study of rheumatoid arthritics it was found that half the patients who were questioned reported a seasonal difference, almost all of these stat- ing that the arthritis was most severe in winter.20 We are investigating the effect of this factor on the responses to the screening questions.

A major problem in studying the epidemiology of rheumatoid arthritis is that, in view of the remittent nature of the disease, a study of prevalence at one point in time may reveal only “the top of the iceberg.”2 We are ac- cordingly conducting a single re-examination of a sample of subjects, six months after the initial examination, with the double object of finding fur- ther cases, and of assessing chronicity. It may be noted that the fact that the initial examinations are spread over a period serves the useful piir- pose of helping to neutralize the possible effect of seasonal variation.

SUMMARY A number of methodological difficulties in the study of the epidemiology

of rheumatoid arthritis are reviewed, illustrated by problems encountered in the planning and first nine months of operation of a study in Israel.

ACKNOWLEDGMENTS We wish to express our thanks to Drs. S. L. Kark and C. Slome for their valuable

contributions to the planning of this study.

REFERENCES 1. Ball, J., and Lawrence, J. S . : Epidemi- nonrespondents in a morbidity sur-

ology of the sheep cell agglutination vey involving clinical examination, J. test. Ann. Rheumat. Dis. 20:235-243, Chron. Dis. 6:95-108, 1957. 1961. 9. Cobb, S., and Lawrence, J.: Towards

2. Beall, C., and Cobb, S.: The frequency a geography of rheumatoid arthritis. distribution of episodes of rheumaJ Bull. Rheumat. Dis. 7:133-134, 1957. toid arthritis as shown by periodic 10. Cobb, S., Miller, M., and Wieland, M.: examination. J. Chron. Dis. 14:2911- On the relationship between divorce 310, 1961. and rheumatoid arthritis. Arth. &

3. Brodman, K., Erdman, A. J., Jr., and Rheumat. 2:414-418, 1959. Wolff, H. G.: Cornell Medical Index 11. Cobb, S., Warren, J. E., Merchant, Health Questionnaire (Manual), New W. R., and Thompson, D. J.: An es- York, Cornell University Medical Col- timate of the prevalence of rheuma- lege, 1956. toid arthritis. J. Chron. Dis. 5:636-

4. Bross, I.: Misclassification in 2 x 2 643, 1957. tabIes. Biometrics, 10:47&486, 1954. 12. CuIpan, R. H., Davies, R. M., and Op-

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6. Cobb, S.: The place of epidemiology neU Medical Index. Brit. Med. J. 1: in the study of rheumatic disease. 855-859, 1960. Arth. & Rheumat. 1:253-255, 1958. 13. Diamond, E. L., and Lilienfeld, A. M.:

7. Cobb, S.: On the development of diag- Effects of errors in classification and nostic criteria. Arth. & Rheumat. 3: diagnosis in various types of epide- 91-95, 1980. miological studies. Amer. J. Pub. Hlth.

ferences between respondents and 14. Feldman, J, J.: The household inter- 8. Cobb, S., King, E., and Chen, E.: Dif- 52:1137-1144, 1962.

ABXAMSON ET AL. 160

view survey as a technique for the collection of morbidity data. J. Chron. Dis. 11 : 535-557, 1960.

15. Kark, S. L., Peretz, E., Shiloh, A., and Slome, C. : Epidemiological analysis of the haemoglobin picture in par- turient women of Jerusalem. Amer. J. Pub. Hlth., in press.

16. Kellgren, J. H., and Bier, P.: Radi- ological signs of rheumatoid arthritis. Ann. Rheumat. Dis. 15:55-60, 1956.

17. Kellgren, J. H., and Lawrence, J. S.: Rheumatoid arthritis in a population sample. Ann. Rheumat. Dis. 15: 1-11, 1956.

18. King, S. H., and Cobb, S.: Psychosocial factors in the epidemiology of rheu- matoid arthritis. J. Chron. Dis. 7:

19. Laine, V., de G r d , R., and Lawrence, J.: Rheumatoid arthritis in Northern Europe: An epidemiological study. Atti del X Congress0 della Lega In- ternazionale contro il Reumatismo.

466-475, 1958.

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22. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A.: Pro- posed diagnostic criteria for rheuma- toid arthritis. Ann. Rheumat. Dis. 16:118-125, 1957.

23. Ropes, M. W., et al.: Diagnostic criteria for rheumatoid arthritis 1958 revision, Ann. Rheumat. Dis. 18:49-53, 1959.

24. Rozansky, R., Adler, E., and Magora, A.: Laboratory tests in rheumatoid arthritis, Israel Med. J. 19:9-18, 1960.

25. Roy, S. N., and Mitra, S. K.: An intro- duction to some nonparametric gen- eralization of analysis of variance and multivariate analysis. Biometrika, 43:

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1067, 1962.

J . H. Abranwon, M.R., B.Ch., Be., Visiting Senior Lecturer iii Social Medicine and Public Health, Hebrew University-

Hadassah Medical School, Jerumlem, Isrclel.

E. Adler, M.D., Associate Professor for Physical Medicine Clr Rehabilitation, Hebrew University-Hadassah Medical School, and Head of Department, Hadassah University Hos@tal,

Jerusalem, Israd.

S . Ben-Hador, M.D., Senior Physician, Hadussah University Hospital, Jerusalem, Israel.

Ziporah Elkan, M.D., Senior Physician, Hadassah UniuersitFy Hospital, Jerusalem, Israel.

K . R. Gabriel, Ph.D., Assistant, Dept. for Statistics, Hebrew University, Jerma.lem, Israel.

Miriam Wahl, B.A., Statistics, Hebrew Unioersity, Jerusalem, Israel.