Epidemiology of rheumatic disorders in the pacific with particular emphasis on hyperuricaemia and gout

Epidemiology of Rheumatic Disorders in the Pacific With Particular Emphasis on Hyperuricaemia and Gout By Ian Prior

T

HE PACIFIC and its people provide a diversity of ethnic groups living in many different environments that offer a wide range of opportunities for epidemiological studies. In the cardiovascular field, studies have shown considerable differences between populations in such variables as blood pressure, weight and coronary risk factors that have provided unusual opportunities for research.’ The rapid changes taking place with urbanisation, migration and increasing affluence have been associated with increasing obesity, diabetes mellitus, hypertension and coronary heart disease in a number of groups.’ There has been considerably less activity in the region in the area of the epidemiology of rheumatic disorders. The data that are available, however, provide some indication of priority areas that could be studied further given resources, people and funds. The establishment by SEAPAL of an Epidemiological Subcommittee to examine priorities and areas for possible collaborative study is an important step forward. The involvement of WHO in this assessment is an indication of their awareness of the need for further population based research in these fields. The Wellington Hospital Epidemiology Unit based in New Zealand (NZ), is primarily working in the field of cardiovascular epidemiology but has a real interest in associated metabolic disorders, including obesity, diabetes mellitus, hyperuricaemia, and gout, particularly in NZ Maori, European and other Polynesian groups. The Unit has also been involved in risk factor and life style studies in adolescents that have provided information in these age groups concerning patterns in Maori and Non-Maori in NZ.34 Rheumatic fever and rheumatic heart disease remain important public health problems in some countries within the Asian Pacific region such as the Philippines, and in certain ethnic groups such as the NZ Maori. The establishment of Rheumatic Fever and Rheumatic Heart Disease Registers, aiming for high quality seconSeminws

in Arthritis

and Rheumatism,

Vol. Xl, No. 1 (August),

198 1

dary prevention, must be stressed as an area requiring continuing development. The limited available data have suggested lower rates of rheumatoid arthritis in certain groups such as Polynesians, compared with Caucasians and there is a need for further work in this field.’ The epidemiological study of chronic diseases is increasingly concerned with means to examine the complex genetic and environmental interactions that contribute to the disorders being studied, whether hypertension, diabetes mellitus, rheumatoid, or osteoarthroses. Problems arise in the rheumatic field because of the difficulties of ascertainment and definition of cases. The insidious onset, chronic and often remitting nature of conditions such as rheumatoid arthritis, may lead to underestimation of cases. Their outcome is usually not fatal and so mortality statistics which have proved of real value in cancer and cardiovascular epidemiology, are of little use. Kempthorne6 in a recent contribution on genetic epidemiology of chronic diseases, has emphasised the need for studies where subjects of the same genetic make up are distributed in two environments so that a quasi experimental situation is present that allows a more critical evaluation of the genetic and environmental interactions controlling for temporal trends. A good example of such a situation would be the studies by the group in Johannesburg7 where the rate of rheumatoid arthritis was much higher in the urban black group, 2.6% males, 3.7% females, than in the people of the same genetic make up living in traditional rural villages, 0.87%. The Tokelau Island Migrant Study with examination of subjects in Tokelau and migrants in NZ provides a similar quasi experimental situation.’

From the Epidemiology Unit, Wellington Hospital. Wellington, New Zealand. Address reprint requests to Ian A. M. Prior, M.D.. FRCP. FRACP. Director, Epidemiology Unit, Wellington Hospital, Wellington. New Zealand. 8 1981 by Grune & Stratton, Inc. 0049-0172/81/1101-0006%01.200/0

213

214

IAN

There have been many difficulties in the development of epidemiological studies of rheumatic disorders in the Asian Pacific region not because of a shortage of problems but because of shortage of trained epidemiologists interested in working in the field. There have not been studies comparable to the classical ones on rheumatoid and osteoarthrosis by Lawrence’-” with detailed history, serology and multiple joint X-rays. These requirements, particularly for multiple X-rays, have been impossible to implement in the course of surveys primarily oriented to cardiovascular disease. This presentation will review some of the work that has been done in hyperuricaemia and gout in different populations in the Pacific and will examine the statement made by Kellgren” “That people of the Pacific belong to one large gouty family.” The outline and findings of the Tokelau Island Migrant Study will be reviewed and some data on rheumatoid arthritis and osteoarthrosis considered. Finally, some of the problems to be faced before there will be an expansion of epidemiological activities in the region, will be considered. HYPERURICAEMIA, GOUT AND DIABETIC ABNORMALITY IN POLYNESIAN PEOPLE

The early voyagers to the Pacific were impressed with the apparent good health of the Polynesian people and nineteenth century medical writers commented on the absence of gout in Hawaii and NZ Maoris.‘*-” Episodic in its initial phases, it is likely that cases may have been missed by these early observers. In 1962 and 1963, the Wellington Hospital Unit in association with Rose of the Queen Elizabeth Hospital for Rheumatic Diseases, carried out epidemiological studies on the NZ Maori that confirmed an extraordinarily high gout rate associated with hyperuricaemia, obesity, diabetes mellitus, hypertension and coronary heart disease.16 A history of gout based on podagra and uric acid above 7 mg/lOO ml (0.42 mmol/l) was found in 38 of 370 men, 10.2%. Among 385 women there were six definite cases based on podagra and uric acid above 6 mg (0.36 mmol/l) and one probable case, the combined prevalence was 1.8%. In the Maori men, 87% were in the

PRIOR

40-59 age group at the time of examination. In the total of 38, gout had commenced at 9 yr in one, at 22 yr in one, and over 60 yr in one, while 66% had their first symptoms between 30 and 50 yr of age. The gouty men were heavier, had more hypertension, higher cholesterol and uric acid levels than the non-gouty. Diabetic abnormality was found in ten of the 38 male gouty subjects and two of the seven gouty females, suggesting a relationship between the two disorders.” Surveys were next undertaken in 1964 in the Cook Islands, in Rarotonga, a lush high island where they were moving on to a Western cash economy, eating and living pattern, and Pukapuka, an isolated traditional atoll society in the Northern Cooks where the 800 inhabitants were on a subsistence economy largely dependent on coconut, fish, pulaka, and limited imported rice, sugar and other goods. The results confirmed essentially similar uric acid patterns and distributions as in the NZ Maori. The overall percentage of males with hyperuricaemia above 7 mg/ 100 ml (0.42 mmol/l) was 47.5% in the NZ Maori, 44% in the Rarotongans and 48.5% in Pukapukans. In females, the percentage above 6 mg/mmol (0.36 mmol/l) was 40% in NZ Maori, 43.5% in Rarotongans and 49% of the Pukapukans. The mean levels by age for males from the three areas are shown in Fig. 1 and for females in Fig. 2. Using the same criteria, the gout rates in Rarotongan males were six in 243, 2.4% and nine definite and one probable in 188 men; 5.3%, in Pukapuka. No female cases were identified. The lower rate in Rarotonga could have been due to a sampling error or to environmental differences that were in some way lessening the risk status for gout, despite elevated uric acid levels. The Pukapukans showed intermediate gout rates with little increase in blood pressure with age or obesity and low diabetes mellitus rates. The pattern of uric acid distributions with a skew to the right, suggested a widely dispersed polygenic pattern. No evidence of bimodality could be demonstrated. The evidence was interpreted as indicating a strong genetic predisposition to hyperuricaemia in view of the considerable environmental differences of these three groups and essentially similar uric acid distributions.

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

PACIFIC

215

MEAN SERUM URIC ACID BY AGE ,‘;jPOLYNESIAN MALES

s---y: -+. d-z=+i-

+---Jh / +------+’

A

Y

“h ‘*,\

NZ MAO& RAROTONOAN-------PUKAPUKA

5o

t

20-29

’

30-39

’

40-49

’

’

50-59

’

60-69

’

-

-

7OPlus.

’

M3E IN YEARS

Mean

Fig. 1.

Serum

Uric

Acid

A much greater alcohol intake in NZ Maori than in Rarotongans and a negligible intake in Pukapukans, was considered as a factor contributing to the high Maori gout rate. Fat intake has also been put forward as influencing uric acid levels and renal handling of urates. Certainly,

5

20-29

’

Fig. 2.

30-s

Mean

’

Serum

by Age Polynesian

the levels of fat intake varied in these groups with 44% of energy from fat in NZ Maori compared with 35% in Pukapukans and 27% in Rarotongans, this follows the same gradient as the gout rates. A survey of NZ Europeans in 1965 showed 23% of males and 16% of females

40-49 ’ 50-S AOE IN YEARS

Uric Acid

Males.

by Age

’

Polynesian

6063

’

Females.

7cIPl”S

’

IAN PRIOR

216

were hyperuricaemic and with a 2% gout rate in males and nil in females.”

197 I, with no changes occurring in the more traditional outer island groups. Diabetes admission rates have shown similar increases.*’

Attack Rate of Gout in Relation to SUA Level Cobb and others” had related gout attack rates to levels of serum uric acid over 8 mg and examination of the South Pacific data are shown in Table 1. The essentially similar rates of 23% 25% in Europeans, NZ Maori and Pukapukans support the critical part played by uric acid level. The low rates in Rarotonga suggest some protective effect. In the Framingham Study the attack rate in those above 8 mg reached 38 per hundred based on multiple observations over a IO-yr period.*’ Hawaiian Polynesians and Their Lack of Hyperuricaemia and Gout An indication that hyperuricaemia did not affect all Polynesians came from a study of near pure Hawaiians by Healy and others in 1966*’ who showed an essentially similar pattern of obesity, hypertension, diabetes mellitus, and ischaemic heart disease to what had been described in the NZ Maori, but no hyperuricaemia or gout. This study was reported in 1966 and involved a comparison of uric acid measurements between the Wellington Hospital Unit and the Hawaii group. Results were comparable and the differences clearly require explanation, particularly since Hawaiians are involved in the process of culture change, increasing affluence and life style changes. French Polynesia-a

The Kingdom of Tonga A survey of hypertension, diabetes mellitus and coronary disease risk factors, including blood lipids and serum uric acid was undertaken by WHO and the Ministry of Health in Tonga in 1973.23 The general planning of the study including sampling, questionnaire development and biochemistry was carried out by the Wellington Hospital Epidemiology Unit. Hypotheses were tested relating to effects of urbanisation, comparing a probability sample of adults who had lived for 10 yr or more in Nuku’alofa, the main urban centre, with subjects from the traditional island of Foa in the Haiapai group. In Nuku’alofa, both men and women were heavier than those in Foa, and also had higher blood pressures and higher uric acid levels. The mean levels for males and females in Nuku’alofa and Foa are shown in Figs. 3 and 4. Those in Nuku’alofa are in the hyperuricaemic range similar to those described in the NZ

Ij ’‘\ ’ / ,,-SC’ \\\ -, t{ ,,I‘1 I

High Risk Group

The increasing affluence and changing life style of Polynesians in French Polynesia, particularly Tahiti, has led to concern about developing health hazards, including diabetes mellitus and gout. A recent WHO report has brought together hospital based data and included a limited community study. The hospital consultations or admissions for gout in Tahiti and Moorea increased from 40 in 1963 to 664 in Table

1. Gout

Attack

Rates/100

b - - -

at Risk--Males I

>7 mg Carterton NZ Mawis Pukapuka Rarotonga

Europeans

8.5 16.3 9.9 5.4

FaIrlo Nuku’rlolr 2 a.

>8 mg 23.0 25.5 23.0 5.5

Fig. 3.

Mean

Serum

Uric Acid

Levels:

Tongan

Males.

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

217

PACIFIC

data illustrates the capacity for such studies to bring forward results that require more detailed investigations and yet the resources and laboratory facilities to do this are often not available.

0.45

Uric Acid Levels and Gout in Other Populations in the Region

0.40 ---

Faleloa Nuku’alofa

I

2 se

0.35 A 2 c E

0.30

0.2! 15 20

25 30

40

50

60

Age in Years Fig. 4.

Mean

Serum

Uric Acid

Levels:

Tongan

Females.

Maori, Rarotongans and Pukapukans while those in Foa are notably lower. The overall gout rate was low with five cases in the 384 males examined from the two areas. These findings raise a number of questions and a variety of analyses have been undertaken. The partial correlation coefficients of serum uric acid and other variables controlling for age are shown in Table 2. These follow the same direction in the two groups and the strongest correlations are with body mass. An analysis of covariance has been undertaken which showed that the differences in uric acids between the two groups could not be explained by differences in age, weight, skin folds or blood pressure. Dietary patterns were examined and an overall higher calorie, fat intake and use of sugar, along with greater availability and use of alcohol in those in Nuku’alofa, needs to be considered. The Foa group have more habitual exercise as part of their subsistence economy than those in Nuku’alofa and this is another possible factor. The presence of some uricosuric agent in the diet, lowering SUA needs to be considered. This

A wide range of studies have shown populations in the Asian Pacific region that have mean serum urate levels significantly higher than in Caucasian populations (the rates of gout have varied) high in some but low or absent in others. Studies of Filipinos in Hawaii and Alaska, by Healy and others in 1962 and 1966 showed high gout rates and SUA levels, suggesting a response to migration since the levels were higher than in Filipinos in the Philippines.24 Similar findings were reported from Malaysia in 196425 and in the Chamorrus and Carolinians of the Caroline Group.26 It was these findings that led Kellgren to suggest that people of the Pacific belonged to one large gouty family in a review of the epidemiology of rheumatic diseases in 1966.” Healy had explained the higher urates in those in Westernised environments as due to an inherited defect in renal excretion of uric acid which became manifest when Filipinos changed to a high purine Western diet.*’ Further studies among Chamorrus and Palau populations of Micronesia by Reed, Labarthe and Stallones in 1972*’ confirmed high levels that did not follow any pattern of association with sociocultural indices but were associated with daily caloric intake. Correlation analysis of individual characteristics indicated that serum uric acid levels were positively associated with blood pressure, Table

2.

Partial

Other

Correlation

Coefficients

of Uric Acid

and

Variables Controlling for Age and SexNUKUALOFA and FOA Subjects BOdY Weight

MESS

MlSCle

Nuku’alofa Males

r 0.319 df 171

0.356 171

df

0.350 194

0.356 194

df

0.246 194

0.254 194 0.349 169

Females

0.259 171 0.305 194

Foa Males Females

r 0.340 df 166

0.169 196 0.303 169

-

218

IAN PRIOR

obesity and triglycerides as has been noted in other groups. Rates of gout in Chamorrus were 5.3% for males and 2% of females. A study of serum urate concentrations in Australian aboriginals by Emmerson and othersz9 showed levels which were in the hyperuricaemic range, mean 6.02 mg/ 1OOml, compared with 5.23 mg/lOOml in Caucasian controls. They are still lower than NZ Maori and some other groups. There was no correlation between serum urate and weight in males and only a small one in females in this group. Emmerson concluded that relative hyperuricaemia in this group is not attributable to body build or obesity and not related to overnutrition and other dietary factors. The alcohol intake was low in this group. Gout attacks, however, are rare in aboriginals. The pattern of change has accelerated for many aboriginals who are now involved in urban migration and altered life style and the pattern may now be different. Western Samoa A survey in Western Samoa conducted by the Ministry of Health, Western Samoa and WHO has shown somewhat similar patterns to those found in NZ Maori and Rarotongans.30 Hyperuricaemia is present in both males and females, urban and rural. The levels are in the same range as those found in Nuku’alofa in Tonga, are lower than those in Nauru, Tokelau and NZ Maori, but still represent a hyperuricaemic distribution. Gout was found in 2.3% of urban and rural males and 1.3% of urban females. Republic of Nauru-Afluence

Unlimited

The Republic of Nauru has one of the highest per capita incomes in the world for its 4,500 subjects. This is derived from the phosphate industry which the Nauruans took over from the British Phosphate Commission in 1969 when they became independent. The lifestyle of the Nauruans has changed considerably with recently acquired affluence. It is Westernised and as the soil is infertile, almost all food is imported from Australia. Obesity has become a widespread problem in the community and they have one of the highest rates of diabetes mellitus, second only to the Pima Indians.3’ Analysis of fasting and 2-hr plasma glucose level have shown bimodality similar to that

found in the Pima Indians.32 Analysis of SUA levels show Nauruans to be a hyperuricaemic group with levels that are higher than those reported in NZ Maori and Tokelauans with 63% of males having levels above 7 mg (0.42 mmol/l) and 60% of females above 6 mg (0.36 mmol/l). A history of gout was found in 6.9% of men, Comparisons of Nauruans with Pima Indians have been important and while the Pima group have a high rate of diabetes mellitus, their serum uric acid levels are not high and they have a low rate of gout. The dissociation of effect would suggest that they lack the genetic predisposition shown by Nauruans and the majority of Polynesians. Nauruans are Micronesians and there is no adequate data concerning their preaffluence state. The investments now being made of their income are likely to total 2,000 million dollars or more by the year 2,000 when the phosphate will have been used up. It is clear that their affluent state with the attendant health hazards of obesity, hypertension, diabetes mellitus, hyperuricaemia and gout will continue unless some realistic way can be developed of inducing the society to look critically at their situation and decide to take appropriate interventions. New Guinea Serum urate levels have been reported in New Guineans living in different environments. Jeremy and Rhodes studied three adult male groups in the Eastern Highlands.33 Villagers from the Lufa and Gumine districts whose diet consisted almost entirely of carbohydrate; employed indigene workers from the town of Goroka, on a more Western diet with use of fresh and tinned meat and a control group of Caucasians. The results are given in Table 3. The villagers were found to be hyperuricaemic compared with the other groups. This is all the more remarkable considering their diet, absence of obesity and abstinence of alcohol compared with the other groups. The village groups did not Table

3.

Serum

Lufa Gumine Employed high-landers Caucasians

Uric Acid

in New

N

M

SD

8.98 8.79 8.55 8.48

0.83 0.89 1.05 1.37

98 100 110 99

Guinea SEM 0.09 0.09 0.10 0.14

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

219

PACIFIC

Genetic Studies in the NZ Maori

show a positive correlation with measures of physique and in fact, one group had a negative correlation with body weight. This was not due to starvation and the question of an effect of low salt was considered. Initial contact in town led to fall in SUA but it rose again in those with longer periods in urban settings which could be due to increased protein and alcohol consumption. Gout is rarely seen in villagers and clearly some factors are protective. In urban dwellers, gout is much less common than in Caucasian. MAORI AND

EUROPEAN

CHILDREN

Genetic analyses of the SUA levels in two Maori samples showed by estimates of heritability that additive genetic factors were of paramount importance in determining the resemblance between relatives.34 The most isolated Tuhoe group showed values close to 100% while the values for the hereditability of SUA scores in the Tiki Tiki group were approximately 50% This suggests a different set of genes in the two populations or the presence of environmental influences yielding greater variation in the Tiki Tiki population which thereby led to a reduction in heritability.

STUDIES

A child growth study of Maori and European infants from first to fifth year of life allowed SUA estimations to be examined in the 2-yr olds. The Maori girls had higher levels than European, while differences between boys were not significant. Serum uric acid has been measured in studies of risk factors for CHD in early teenage Maori and Europeans. The levels were significantly higher in both Maori boys and girls.3’ The results are shown in Table 4. This was examined in a further survey of 700 school children when higher SUA levels in Maori were again shown.4s In addition, the Maori showed lower low density lipoprotein cholesterol, lower high density lipoprotein cholesterol and higher triglyceride levels than the Europeans. These changes are similar to those shown in the adult studies. The consistent trend gives support for important genetic contributions to hyperuricaemia, a family aggregation of gout cases is common in the Maori. Table

4.

Serum

Uric Acid

14

10.373 6.49

+ 0.24 (10) f 0.014) f 0.17 (37)

15

(0.386 6.37

+ 0.010) f 0.21 (32)

(0.379 6.02 (0.358

f 0.012) f 0.44 (4) + 0.026)

16 Total

6.39 f 0.11 (83) (0.380 i 0.007) +0.35 +0.368

(g) with body bulk (r) with haemoglobin f standard

by Sex,

Race,

and Age Female

European

l 6.27

*Mean

Levels

Maori

13

Correlation

The NZ Maori sample was followed over an 11 -yr period from 1962 and 1963 through to 1974.” In the prospective survey, it was considered desirable that a diagnosis of gout should be independent of serum uric acid level in order to allow study of the latter as a risk factor. A medical history of two or more typical attacks of podagra affecting the great toe was used for the clinical diagnosis of gout. Of the 388 males and 378 non pregnant females examined a$ baseline, 34 males and three females were diagnosed as having gout, with these revised criteria, a prevalence of 8.8% and 0.8%, respectively, was shown. Over the follow up period of 11 yr, 96 of the 388 men died, 20 were lost to follow-up and 272 were seen. Of the 378 fe-

M&3

Age IWU)

Skewness Correlation

MORE RECENT NZ MAORI ANALYSESPREVALENCE AND INCIDENCE STUDIES

(r)

errc+ in mg/lOO

fO.046 ml (no. of subjects

5.37 (0.32

Mauri

EUrOpaall

f 0.53 (9) f 0.032)

5.90 10.351

f 0.40 (2) f 0.024)

5.17 (0.308

f 0.15 (39) + 0.0’39)

5.19 (0.309

f 0.15 (36) f 0.009)

5.76 (0.343

f 0.27 (23) + 0.016)

5.49 (0.327

* 0.29 (15) + 0.017)

5.23 (0.311 5.38

+ 0.13 (3) zt 0.008) k 0.13 (74)

(0.320 zt 0.008) +0.61 +0.285 +0.202

in subgroup

in parentheses),

6.30

f 0.13

k 0.30

f 0.018) +_ 0.14 (25)

(0.280 4.81 (0.286

k 0.008) * 0.15 (25) f 0.009) -

(53)

-IO.002 in parentheses

(11)

(0.287 4.71

(0)

10.3 15 f 0.008) +0.14 +0.412

and in mmol/l

4.83

4.77

(0) + 0.10

10.284 it 0.006) +0.34 +0.315 +0.289 underneath.

(61)

220

IAN PRIOR

males, 77 died, 2 1 were lost to follow-up and 280 were seen. The incidence study was based on 252 males and 279 females who did not suffer from gout at the baseline examination and who were reexamined 11 years later. This represented a response rate of 90% of eligible subjects. Twenty six males and 12 females reported recurrent podagra in the great toe, an incidence of 10.3% in males and 4.3% in females, respectively. Risk Factors Contributing

to Gout

Those subjects with and those without subsequent gout were compared on the basis of their baseline variables. The results are given in Table 5. Risk factors for gout common to both males and females were found to be weight, BMI, blood pressure and serum uric acid. Age was a risk factor in females, reflecting the effect of age on serum uric acid. Upper arm muscle circumference was greater in gouty males, but the difference was not significant in females. In addition to univariate analyses to determine individual risk factors, stepwise discriminant function was undertaken to find the statistically “best” set of baseline variables which would discriminate between those subjects who developed gout and those who remained gout free. In males, SUA and muscle size, age adjusted by Z-score transformation, together provided the best discrimination while in females SUA Z-score provided the best separation. In the males on the basis of discriminant function, SUA and muscle size correctly classified 7 1.1% into gouty and non gouty which indicates a high measure of prediction. Table

6. NZ Msori

Gout

Incidence: in Males

Baseline

Comparisons

Gout Subsequent to Baseline

Aga Weight

(kg)

Upper Arm circ (cm) Muscle circ km) SYst. blood pressure BMI SUA (mmol/l)

YES MWl(W)

NO MWllSd

1126

” 226

(1.9) (3.8)

38.9 78.2

(0.9) (0.9)

NS 0.001

32.9

(0.7)

30.3

(0.2)

0.001

29.2

(0.5)

28.9

(0.2)

0.001

141.4

(3.7)

130.8

(1.0)

0.002

(0.03) (0.005)

0.001 0.001

(0.11) (0.016)

2.69 0.404

6. NZ Maori Age Standardised Prevalence in Males by Baseline SUA Class SUA Classes (mmde/l)

Less than 0.42 0.42 or more 0.48 or mom 0.54

or more

of Gout

Relative Risk to Prevalence 6EhW 0.42 mmol/l

NO. at Risk

Cases

200 188 102

9 25 23

4.5 13.4 18.8

2.96 4.55

40

13

21.5

4.80

Gout Of

The study establishes baseline SUA as the most important predictor. The age standardised incidence and relative risk within baseline SUA classes in males over the 1 1-yr period are set out in Table 6. This represents a five and ten fold increase respectively of the risk of subsequent gout, relative to the next lower SUA class of 0.36-0.48 mmole (6.0-8.0 mg/lOOml). These findings have important implications and suggest that the occurrence of clinical gout is dependent to a much greater extent on SUA levels than on sex or other possible precipitating factors. In the NZ Maori, the discrimination value of 0.48 mmole/l (8.0mg/ 100ml) would provide a more useful cut off level than the traditional sex specific values and as a basis for intervention programmes. The relationship between muscle size and the incidence of gout has not been previously reported and the purine rich nature of muscle tissue may be a contributing factor. The correlation between SUA and muscle size (r = 0.237, p 0.001) disappeared when corrected for body mass index. The relationship of SUA to lean body mass was found to be positive by Sturge,36 but when entered into a stepwise regression, together with a measure of total body mass, the lean body mass no longer explained a significant amount of the SUA variation. Areas for Interventions in NZ Maori

P

38.8 91.8

3.09 0.486

Table

The effect of long term asymptomatic hyperuricaemia on renal function and overall morbidity and mortality has not yet been determined in these studies. A recent report on the renal outcomes of gout and hyperuricaemia indicate that over a long period of time very little progressive impairment of renal function takes place, independent of development of renal calculi3’ Investigations by Gibson at Guy’s Hospital have shown reductions of glomerular

EPIDEMIDLDGY

RHEUMATIC

DISDRDERS

filtration rates and urine concentrating ability in gout subjects, together with low urine pH values and relative reduction to ammonium excretion in non treated gout subjects, compared to age matched controls.38 The association shown with higher blood pressure, body weight in both prevalence and incidence Maori male gout cases lends support to the case for interventions aimed at weight, blood pressure control and reduction of serum uric acid if above 0.48 mmole/l(8mg/ 1OOml) in asymptomatic subjects. Much still remains to be learnt, however, regarding the basic mechanisms of hyperuricaemia in Polynesians. TOKELAU

ISLAND

MIGRANT

221

PACIFIC

STUDY

Migrant studies of adults and children from small traditional isolated Pacific societies to modern urbanised countries, provides an opportunity to test a number of hypotheses concerning such disorders as hypertension, diabetes mellitus and coronary heart disease. The influence on rheumatic disorders, such as the inflammatory arthritis group has not been well documented. Tokelau consists of three small atolls some 480 kilometres northwest of Western Samoa and 8”-loo south of the equator. The people are predominantly Polynesian with a small amount of admixture from European and other Polynesians who began to settle in 1860. They have remained somewhat isolated and have a strong society where traditional customs are adhered to. They became a New Zealand dependency in 1925 and were granted NZ citizenship in 1948. A pattern of migration to Samoa developed in the 50s and early 6Os, but it was a major hurricane in 1966 that led the NZ government to establish the State assisted resettlement programme aiming at bringing a number of their people to NZ. The Tokelau Migrant Study was established in 1966 with a view to documenting the effects of migration and testing specific hypotheses relating to blood pressure and other changes8 The population in Tokelau in 1966 was approximately 2000, while there were about 500 in NZ and a similar number in Western Samoa. The flow of migrants has increased from Tokelau and also from Western Samoa to NZ-many adults and families coming through the resettlement

programme and others by a chain migration process through family members. A register of all Tokelauans in NZ has been established and maintained by liaison staff. Major surveys were carried out in Tokelau in 1968, 1971 and 1976 and in NZ in the period 1967-1970, 1972-1974, and 1975-1977. The population in Tokelau in 1976 was 1,560 while the NZ population had increased to 2,534 in 1977. Participation in Tokelau has been approximately 98% in successive surveys while in NZ it has been approximately 94% in the two major series of examinations. The advantage of the longitudinal study are as follows: (1) A large number of the migrants were examined in Tokelau in 1968 or 197 1 prior to migration. This has allowed the characteristics of migrants versus non migrants to be examined; (2) The prospective nature of the survey is allowing examination of subjects of the same genetic make up in two distinctive environments; traditional Tokelau and urbanised New Zealand. The pattern of changes can be critically examined seeking to help identify the interaction of environmental and genetic factors; and (3) The detailed genealogies collected by the social anthropologists have been built up into a major complex pedigree computer file and so the extent of familial aggregation and other measures of genetic influence can be examined for a range of variables in subjects living in two environments. The principal research effort up to the present has been in examining questions relating to blood pressure, body weight, serum lipids and diabetes mellitus, both in cross sectional and longitudinal analyses of adults and children. In this presentation, the main emphasis will be on patterns of rheumatic disorders, including osteoarthroses, rheumatoid arthritis, uric acid levels, and clinical gout. Brief mention will be made of some of the other key findings including blood pressure and body weight changes in order to provide the broader perspective and potential of the study. Blood Pressure

The cross sectional surveys show higher blood pressures in the migrants in both male and female adults and in children in NZ than in those in Tokelau.w’

IAN PRIOR

!:?:i Males

040

Females Tlse

0.20 0.10

TOKELAU

0.00 NEW

-0.10

ZEALAND

-0.20, -0.30, Fig. 6. Weight: Tokelauans Aged 15-74 Age Standardized Divergence.

-0.40.

Body Weight Changes Body weight and its influence on weight bearing joints has been advanced as one of the factors contributing to osteoarthroses; the wear and tear hypotheses. Data obtained from a survey by a NZ team in Tokelau in 1963 included heights, weights and blood pressure, this has enabled our unit to look at the changing trends over the period 1963-76 in Tokelau and in 1972-77 in NZ. The results are shown in Fig. 5. These are expressed as Z-scores deviations from the overall means and illustrate the trend for weight to increase in Tokelau over this period. Cross sectional comparison of the weights of migrants in NZ in 1972-1974 and nonmigrant adults in Tokelau in 1971 are given in Fig. 6. The heavier weights in NZ can be seen for males

and females. The longitudinal weight changes in the period 1968-1971-1976 in Tokelau or 19751977 in New Zealand show that the greater weight gain is occurring in New Zealand migrants. Osteoarthrosis in the Two Environments There is more severe osteoarthrosis of the hip in old people in Tokelau and a number of these had been confined to their houses for a number of years with relatively fixed, flexed, painful joints that barely tolerated weight bearing. One man had a history of widespread polyarthritis that had been treated by rest and had fixed flexed hips and knees and was transported by his family in a wheelbarrow during our first visit in 1968. Uncertainties about diagnosis and man-

KG 66

%A

Fig. grant

6.

Tokelau

Study

Mean

Island Weights.

Mi-

1

4 15

T."

'

z ,

20

I-

1971 Tokelau 1972 2se - 73 New

I

I

I

I

I

30

40

60

60

70 Age

Zealand

I 15

In Years

t 20

I 30

I 40

I 60

1 60

1 70

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

223

PACIFIC

agement and lack of other facilities mean that symptomatic aspirin may be all that can be offered in an acute polyarthritis and lack of active mobilisation can lead to serious joint deformities. Criteria

Osteoarthrosis has been recognised by concurrence of at least two of the following: (1) a painful joint without evidence suggesting gout, (2) bony overgrowth around the joint, and (3) crepitus of the joint. Limitation of movement and restriction of internal rotation of hip joint was almost always present in those cases diagnosed as osteoarthrosis of the hip.

Table

8.

Osteoarthrosis

Crude Prevalence Rates/ 1ooo TdWlSJ 1968171

New Zealand 1976

Shoulder Shoulder Elbow

R. L. R.

7 3 2

6 1 1

1972174

1976177

8 4 0

5 3 0

Elbow

L.

0

0

0

0

Wrist Wrist Hip

R. L. R.

1 1 9

1 1 7

6 6 4

5 5

Hip Ankle Ankle

L. R. L.

10 2 5

13 3 6

2 2 0

1 1 0

1

difference between the areas for the other joints and no changes of note in the different surveys in the two areas.

X-rays

It has not been possible to systematically X-ray joints in the Tokelau surveys. In 1968, X-rays of hands were taken, as well as chests, on two islands. The condenser of the portable unit was then damaged while being‘brought across the reef and became unserviceable. Earlier experience in the Maori surveys in 1962 and 1963 had established some difficulty in obtaining films of sufficient quality to be of value. This illustrates one of the difficulties of epidemiological studies of rheumatic disorders in isolated communities. The age adjusted prevalences per 1000 for osteoarthrosis of the knees are set out in Table 7 in subjects in Tokelau and in NZ. Female rates are higher than males and there are no significant differences between the two groups. The crude prevalence rates per 1000 for hips and other joints are given in Table 8. The results are not age standardised and the greater number of elderly in Tokelau with hip lesions accounts for the differences. There is no Table

7. Osteoarthrosis

of Knees

Age Adjusted Prevalence/1000 TOk.3lall 196817 1

Right Knee M F

New Zealand 1976

1972174

1975177

21

11

13

18

36

32

30

40

10 35

8 29

8 31

8 44

Left Knee M F

RHEUMATOID

ARTHRITIS

IN TOKELAU

Criteria

(1) classic history of inflammation of metacarpophalangeal joints with morning stiffness and residual deformity, and (2) or widespread deformity with soft tissue swelling of hands, wrists, feet or knees on examination In Tokelau in the 1968 and 1971 surveys, there was one male regarded as positive and in NZ 1972-1974, one male and one female. Total sample aged 15 an ver was 1,900 and so the rates are low. One cIf 1 d in NZ developed classical juvenile rheumatoid with widespread and severe involvement. Hyperuricaemia New Zealand

and Gout in Tokelau and in

The Tokelau community on their atolls present a number of unusual dietary features including one of the highest documented use of coconut, a rich source of short chain fatty acids, lauric and myristic. Their overall fat intake was estimated at approximately 56% of energy, of which 80% was derived from coconut in a variety of ways.” The effects of their diet pattern on coronary disease risk factors, including LDL cholesterol and HDL cholesterol, triglycerides and serum uric acid and urea nitrogen, is being studied in two environments. An hypothesis has been put forward linking high fat intake with serum urate levels and this is being examined. Sugar

224

IAN PRIOR

consumption is also low in Tokelau compared with NZ. The weight and skin fold data indicate that they tend to be heavy and obese and that this could be a factor in both environments. In NZ, the overall fat intake declined to around 40% of energy; with carbohydrate increasing along with a modest alcohol increase in men. Traditionally, the atoll societies had real constraints on alcohol use but these are changing with more opening up of the group and with the return to Tokelau of people who had spent time in NZ. The migration to the NZ environment, therefore, provided opportunities to examine effects of certain of these dietary changes. Serum Uric Acid Levels The results in subjects aged 15 and over are set out for Tokelau and NZ in Figs. 7 and 8. The pattern with age shows little change in adult males from 20 and over while the levels in females increase to the period of the 70s. The mean levels are higher in young males than females and remain higher in older age groups. In females, the trend is higher in Tokelau, in males this is so in 4th and 6th decades but they are lower in younger males. Certainly, no consistent pattern has emerged. In children, however, the levels in Tokelau are significantly higher than in those in NZ from 6 yr and beyond. 0.45 -

0.40 -

0.35

-

Tokrlw

- - -

Now Zealand

I

i

2

1276 1975 -77

0.45

1 - - -

I

0.30

Tokelau 1976 New Zealand 2 se

Jf,j, 152025

30

I , 15202630

I

Fig. 8. Mean Tokelau Females.

Uric

50

60

70

Serum

Uric

Acid

in Two

Environments

Gout Gout criteria have been similar to those used in Maori and other studies and require at least two episodes of podagra involving the big toe or toes. Information has also been collected about previous diagnosis, how it was established and treatment. Intermittent, acute treatment with phenylbutazone or colchicine, has been the usual pattern while a smaller number were on long term allopurinal. The age adjusted prevalence per 1000 of gout are set out in Table 9. There has been no significant difference between Tokelau and NZ and no evidence of increased rates developing up to this stage. From a clinical view point, cases are occurring where the background of hyperuricaemia and gout has not been properly recognised. One such subject, presented with recurrent haematuria and renal colic, X-ray was negative and survey notes confirmed a history of gout and raised uric acid levels that

l

Table

4b

5b

1 60

9.

Gout

in Tokelauans

Acid

Levels

in Two

Environ-

in NZ and Tokelau

Prevalence per 1000

Tokelau

I 70

New Zealand

196817 1

1976

1972174

1975177

M

29

18

34

38

F

11

15

12

10

Ago In Yosrr Fig. 7. Mean Serum ments: Tokelau Males.

40

Age in Years

Aw Adjusted

0.30 1.

1975 -77

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

PACIFIC

had not been brought to light by the clinicians, perhaps due to language problems. Subsequent therapy included allopurinal, fluid management, and weight reduction has produced excellent control. The discipline of weight control, lower or nil alcohol intake, regular checks of serum uric acid and blood pressure and compliance with an overall regime are necessary for the gouty subject. Nevertheless this poses many problems. It is in this area that more effective research is needed-particularly relating to blood pressure and weight control. Alcohol Use by Tokelauans

In Tokelau, there has been effective constraints against use of alcohol that have operated over many years, reinforced by their elders and church leaders. Since 1968, changes have occurred and appear to be doing so more quickly in Nukunonu, the totally Catholic island, compared to Fakaofo and Atafu. In NZ, an increasing number are using alcohol, but their intake is still modest by NZ standards where both Maori and European have a high intake, particularly the Maori.4’

225

Campion. This should be developed further with examination in other Polynesian groups. The intermittent high alcohol intake and feasting that has been a characteristic of some NZ Maoris could contribute to their high rate of gout. In Pukapuka, alcohol was barely used but they have been exposed to periods of considerable food shortages, followed by periods of abundance, this could contribute to gout rates that ranked second to NZ Maori. If genetic factors are of considerable importance in Polynesian hyperuricaemia then the lower levels reported by Healy in Hawaiians*’ and in rural Tonga (Foa) needs to be explained. The possibility that these groups may have uricosuric components in their daily diet which protects them from hyperuricaemia and gout should be considered. If this was so, such groups should have increased uric acid clearance, high urinary uric acid and potentially higher incidence of uric acid stones. More detailed examinations of this type are now needed and the two areas of Tonga, urban and rural, would be suitable for this. This illustrates the way in which epidemiological studies can set the pathway for clinical and laboratory studies if progress is to be made.

Alcohol Intake and Uric Acid Levels

Early work by our group showed a relationship between uric acid levels and alcohol intake in Cook Islanders with higher levels in drinkers versus non drinkers.43 No significant differences were shown in Tokelau and NZ but their low overall alcohol use could influence this. On the other hand, we have not shown a relationship in NZ Maori where the percentage of drinkers is much greater. FURTHER STUDIES

ON HYPERURICAEMIA

The patterns of hyperuricaemia and the different rates of gout in the different Polynesian groups raise a number of questions that will only be answered by more detailed non invasive laboratory studies to estimate the extent to which there is excess production of purines and uric acid and how it is handled by the kidney. This will involve studies of 24-hour excretion and uric acid clearances on carefully defined low purine diets. The binding of urate to albumin has been examined and evidence of an abnormal binding in hyperuricaemic Maoris has been reported by

Rheumatoid and Osteoarthritis in NZ in Maori and Non Maori (Europeans)

Lennane, Rose and Isdale made an important contribution to the epidemiology of rheumatic disease in the South Pacific when they showed a high prevalence of gout and a low prevalence of rheumatoid arthritis in the NZ Maori, compared with NZ European.’ These observations were based on a history obtained by a standardised questionnaire, and medical examination in subjects with joint symptoms. In 1962, the Wellington Hospital Medical Unit undertook its first epidemiological studies of NZ Maori and Rose became a collaborator. An attempt was made to examine the problem employing standardised questions regarding morning stiffness of 5-min or more in joints involved, specific questions re podagra, rheumatoid serum agglutination tests, serum uric acids and X-rays of hands. The 1962 criteria of the American Rheumatism Association were used relating to rheumatoid arthritis.45 The distribution of rheumatic disorders

226

IAN PRIOR

Table

10.

Joint

Disorders

Rheumatoid

and European Rheumatoid and Osteoarthritis

NO

Definite

Probable

Mauri M F

110 102

2 2

2 1

European M

202

F

230

5

3

among 212 adults, 15 yr and over (110 males and 102 females) in the Maori community of Ruatahuna studied in 1962 and in Europeans in Carterton in 1964 are set out in Table 10. Note that in the Maori, there were two males with definite rheumatoid and 2 probable and two female with definite rheumatoid and one probable. These are certainly not low rates although the sample is small. In the Europeans, a small sample, there was one male with definite rheumatoid but eight definite or probable female cases of whom four had both rheumatoid and osteoarthritis. In the Maori sample, 5.2% had positive latex agglutination tests, this included one of the definite male and two probable cases. Overall, 5.2% of Maori sample had positive latex agglutination tests. In round three of the Maori studies in 1974 in the sample of 982 subjects, there were one male and three females regarded as definite rheumatoid but also four subjects with recurrent polyarthritis and three with monoarthritis of a knee. Osteoarthritis involving large joints was found more commonly in Maori than European. The Maori group showed a large number with history of non specific polyarthralgia. This would need to be assessed by more strict and defined criteria. Inflammatory Polyarthritis South West PaciJic

in Maori

in the

There seems little doubt that certain ethnic groups in the Pacific have low rates of inflammatory polyarthritis, compared with Caucasians of Australia and NZ. The important question now arises as to whether well planned epidemiological studies in such groups could contribute new and worthwhile knowledge of the causative factors of the disorder. If they were feasible, would careful case control studies be most valuable or are there other opportunities that could be taken advantage of given people with exper-

Definite

Rate/100

Osteoarthrosis (large joint)

3.6 3.0

7 6

1

0.5

6

4

5.2

a

tise, drive, interest and the financial and other support needed. The part a specific viral infection may play in the development of rheumatoid arthritis is being increasingly considered as more arthritogenic virus infections are recognised. The recent widespread epidemic of Ross River arbor borne virus infection in Fiji could provide an opportunity to determine whether this is followed by an increase in relapsing chronic arthritis.46 Data available have suggested that both Fijians and Fiji Indians have had a low frequency of rheumatoid arthritis up until the present. The Ross River virus is an arbor virus epidemic in the Northern part of Australia occurring every 3 yr since 1928.47 After an initial febrile phase, there is an acute polyarthritis with effusions and in half the cases a rash which may persist for 4 days. If further epidemics occur on a 3-yr basis in Fiji, as seems likely, then demonstration of a higher rate of chronic polyarthritis could suggest that the virus infection helped initiate a chronic polyarthritis. The epidemic was widely distributed and provided an opportunity to identify areas at low risk to compare with higher risk areas. Opportunities such as this arise as part of “natures experiments” and we need to develop the resources, courage and initiative to explore them with confidence. It is important to recognise that such projects have to be planned with the collaboration of the country involved who will have limited resources of people and finance and who may not see the problem as warranting any priority in their overall service. It is in these areas that WHO, the Arthritis and Rheumatism Foundation and ILAR and SEAPAL have an opportunity to collaborate and contribute. CONCLUSIONS

This presentation would be incomplete without a mention of some of the problems facing

EPIDEMIOLOGY

RHEUMATIC

DISORDERS

PACIFIC

epidemiological research in rheumatic diseases. There is firstly a varying tmderstanding of epidemiology and its methods. Secondly, there are few epidemiological groups working in the area of rheumatic disorders in the region and data have often been collected as part of other studies. Thirdly, developing countries may not give high priority to research in chronic joint disorders, particularly those that may be disabling but not a cause of mortality. It is useful to look at the problem of rheumatic fever and rheumatic heart disease in the region as an example of how the gap between knowledge and prevention and its application is considerable and needs to be studied. The areas contributing to this relate to the pattern and organization of health care, the cost of secondary prevention and whether this has to be met by the patient and their family or whether the cost of IM Benzathene penicillin is an accepted cost by the State Health Service. The priority placed on health and health care by the individual, the family and the state must also be considered. In some countries, health is not seen as a high priority area that influences general economic growth and development in the community; in consequence budgets will be restricted and resources for encouraging worthwhile research in different areas will be limited. Collaborative research with workers taking part from different countries looking at a particular problem is becoming a more practical proposition. Such joint research projects, however, are difficult to initiate and sustain because of differing resources and commitment. The reorganization of WHO with greater strengthening of research activities in the regions has been one of the important positive factors in recent years that should lead to better opportunities for coordinated research. This is starting to take place in the cardiovascular field where the Western Pacific Region of WHO is playing an important part in encouraging rheumatic fever and rheumatic heart disease research and programmes on streptococcal epidemiology. The development of rheumatic fever and rheumatic heart disease registers in high risk areas is being encouraged as a way of improving secondary prevention and testing out different ways of delivering regular IM Benzathene penicillin and supervision. In the field of cardiovascular epidemiology,

227

there has been a continuing effort to train epidemiologists and the major research programmes have been able to attract support because of the importance of cardiovascular disease, particularly CHD, hypertension and stroke. The Western Pacific region of WHO has now accepted a commitment for training and held a 2-wk training course in epidemiology and community control of cardiovascular disease in Wellington in 1978 and in Singapore in 1980. These types of developments in the epidemiology of rheumatic disorders would strengthen the quality of work undertaken within countries and this would improve the likelihood of effective international collaborative studies being undertaken. The involvement of WHO in this field is important and appears to be taking place. There is no doubt that the rheumatic disorders are important in the public view, at least in NZ where the Arthritis and Rheumatism Foundation was able to collect $3 million in a telethon appeal. The use of some of such funds, together with those from other sources towards training and research could open up exciting opportunities in NZ that should have an important effect within the SEAPAL region. The SEAPAL Bulletin, October 1979, contains valuable reports from Allander, Chairman of the ILAR Standing Committee on Epidemiology and also from the EULAR Committee. These raise a number of points, some of which have already been covered. Several bear repetition: The postgraduate training situation deserves high priority. It is felt in years to come, there will exist definite possibilities for an international training programme. There are many and increasing numbers of problems which can be fruitfully worked at within the epidemiological sphere of rheumatology. Special attention must, however, be given to the formulation and contents of questions to be asked and the theories and hypotheses to be tested. The part of the health service research as applied to rheumatic diseases is full of possibilities as so many procedures and treatments need to be initially evaluated.

The region of the South East Asian and Pacific League against Rheumatism provides many unusual patterns of arthritis and rheumatism. The predominant hyperuricaemia and

228

IAN PRIOR

predisposition to gout occuring among Polynesians and the reasons why there is sparing in some groups, such as Hawaiians and rural Tongans, raise interesting questions. Answers will only come from further detailed research exploring mechanisms of uric acid production and handling. The part played by affluence in hyperuricaemia and gout is suggested by the reports from Nauru where major changes in lifestyle are occurring as they take up the income from their phosphate resources. In some groups, such as Rarotonga and Western Samoa, it is traditional subsistence affluence that is now being augmented by changes to a Western type diet. Obesity is common in both groups, particulalry in the women. The limited data from the NZ Maori studies suggests that rheumatoid arthritis is occurring at rates that are in the same range as those reported from European samples. The Tokelau data indicates a much lower rate for rheumatoid arthritis, with no evidence as yet of an increase occurring in the migrants in NZ. Many of the inherent difficulties in how to best obtain standardized information on joint problems still needs to be solved. The 1967 New York criteria for rheumatoid and polyarthritis remain the most applicable but joint X-rays can provide

real difficulties in studies in isolated groups and may need to be dispensed with. The present review has brought together much of the first generation of epidemiological data in the region. The next phase has many problems to examine and at the same time, methods for intervention in some of the disorders must be developed and tested. The discipline of epidemiology has much to contribute towards a greater understanding of the rheumatic disorders and properly planned studies identifying “risk factors” that are contributing to such conditions as osteoarthroses could lead to interventions aimed at prevention. The time span needed for such studies, however, could tax the endurance of the investigators. In other conditions, such as rheumatoid arthritis, with a lower prevalence, case control studies could be used to test specific hypotheses. These activities could require the combined initiatives and skills of ILAR, SEAPAL, WHO and strong national groups if progress is to be made. ACKNOWLEDGMENT The research support of the Medical Research Council of New Zealand, the Cardiovacscular Disease Unit of the World Health Organization and the Wellington Hospital Board is acknowledged.

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Solomon L, Robin G, Valkenburg HA. Rheumatoid arthritis in an urban South African Negro population. Ann Rheum Dis 1975; 34:128-135. 8. Prior IAM, Stanhope JM, Evans JG, et al: The Tokelau Island migrant study. lnt J Epidemiol 1974; 3:225-232. 9. Lawrence JS. Prevalence of rheumatoid arthritis. Ann Rheum Dis 1961; 2O:l I-17. 7.

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EPIDEMIOLOGY

RHEUMATIC

DISORDERS

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26. Burch TA, O’Brien WM. Need R. Hyperuricaemia and gout in the Mariana Islands. Ann Rheum Dis 1966; 25:114-116. 27. Healey LA, Bayani-Sioson PS. A defect in the renal excretion or uric acid in Filipinos. Arthritis Rheum 1971; 14:721-726. 28. Reed D, Labarthe D, Stallones R. Epidemiologic studies of serum uric acid levels among Micronesians. Arthritis Rheum 1972; 15:381-390. 29. Emmerson BT, Douglas W, Doherty RL, Feigel P. Serum urate concentrations in the Australian Aborigine. Ann Rheum Dis 1969; 28:150-156. 30. Zimmett PZ. Metabolic and Cardiovascular Disease Survey. Western Samoa. WHO Report 1979. 31. Zimmett PZ, Whitehouse J, Jackson L, Thoma K. High prevalence of hyperuricaemia and gout in an urban&d Micronesian population. Br Med J 1978; 1:1237-1239. 32. Zimmett PZ. Epidemiology of diabetes and its macrovascular manifestations in Pacific populations: The medical effects of social progress. Diabetes Care 1979; 2:144-153. 33. Jeremy R, Rhodes FA. Studies of serum urate levels in New Guineans living in different environments. Med J Aust 1971; 1:897-899.

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34. Veale AOM. Polygenic inheritance. NZ Med J 1968; 67~344-347. 35. Brauer GW, Prior IAM. A prospective study of gout in New Zealand Maoris. Ann Rheum Dis 1978; 37:466-472. 36. Sturge RA, Scott JT, Kennedy AC, et al: Serum uric acid in England and Scotland. Ann Rheum Dis 1977; 36:42&427. 37. Fessel WJ. Renal outcomes of gout and hyperuricemia. Am J Med 1979; 67:74-82. 38. Gibson T, Grahame R. Gout and hyperuricaemia. Ann Rheum Dis 1974; 33:298-303. 39. Prior IAM, Hooper A, Huntsman JW, et al: The Tokelau Island migrant study. In: Harrison GA, ed. Population Structure and Human Variation. Int Biol Prog., Cambridge University Press, 1977; 2:165-186. 40. Prior IAM. Isolated groups, particular populations and their contributions. In: Hayase S, Murao S, eds. Proceedings VIII World Congress of Cardiology. Toyko, Sept. 17-23, 1978. Excerpta Medica. Amsterdam: OxfordPrinceton, 1979; 13 l-l 36. 41. Beaglehole R, Eyles E, Salmond CE, et al: Blood pressure in Tokelauan children in two contrasting environments. Am J Epidemiol 1978; 108:283-288. 42. Stanhope JM, Prior IAM. The Tokelau Island migrant study: Alcohol consumption in two environments. NZ Med J 1979; 90:419-421. 43. Evans JG, Prior IAM, Harvey HPB. Relation of serum uric acid to body bulk, haemoglobin and alcohol intake in two South Pacific Polynesian populations. Ann Rheum Dis 1968; 27:319-325. 44. Campion DS, OlsenR, Bluestone R, et al: Binding of urate by serum proteins. Arthritis Rheum 1975; 18:747750. 45. Rose BS, Prior IAM. A survey of rheumatism in a rural New Zealand Maori community. Ann Rheum Dis 1963; 22:41&415. 46. Miles JAR. Ross river fever comes to Fiji. Fiji Med J 1979; 216. 47. Halliday JH, Horan JP. An epidemic of polyarthritis in the Northern territory. Med J Aust 1943; 2:293-295.