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Medical geography and the aetiology of the rare connective tissue diseases in New Zealand
MEDICAL GEOGRAPHY AND THE AETIOLOGY THE RARE CONNECTIVE TISSUE DISEASES IN NEW ZEALAND
OF
RICHARII WIGLEY and BARKY BOKMAN Research Laboratory.
Palmerston North, Puhhc Hospital and P.O. Box 6314. Wellington. New Zealand
Abstract-Case records of patients discharged from puhEc hospitals in the southern half of New Zealand with connective tissue diseases (CTDs) during the period 195&1973 were reviewed. Onl} clinically “definite” and “probable” cas& were included. Systemic lupus erythematosus (SLE) cases were scored bq computer usmg a modified version of the American Rheumatism Assoclatron’s prehmmary crtterla (1971) for SLE diagnosis. Similar scormg systems were developed IO classify cases of systemic sclerosis (SD). poiyarteritis nodosa (PN). and polymyositis and dermatomyositis combined (PMS~DMS). Although the age-sex structures of these populations were comparable to those reported elsewhere, CTD incidence generally but especially SLE. was low m New Zealand Probablhty testmg and mapping were employed to define the spatial and temporal dlstributlons of CTDs, as a group and severally. at the time of disease onset. There was a significantly increased morbidity of all CTDs as a group and for scleroderma in particular. m the Otago Hospital Board District. No consistent temporal or rural/urban differences in incidence were found. SLE occurrence was not significantly related to areas with high sunshine hours.
INTRODIJCTlOK “Whoever wishes to investigate medicine properly, should proceed thus.. consider the seasons of the year., the winds.. qualities of the waters.. the ground.. . the mode in which the inhabitants live and what are their pursuits.” Htppocrates [I]
Knowledge of the causation of the rare connective tissue diseases (CTDs). dermatomyositis (DMS). polyarteritis nodosa (PN), polymyositis (PMS). systemic sclerosis (SD). and systemic lupus erythromatosus (SLE) is limited. Generally, epidemiological studies have been restricted to urban populations [2-IO]. A previous New Zealand report [I 1J. based on official morbidity data. suggested areal differences in the incidence of these diseases. The present retrospective stud> was aimed principally at defining the spatial and temporal distributions of CTD morbidity. both as a group and severally. in New Zealand [I?].
THE MEDlCAL
DATA
ANlD METHODS
About SO’, of all hospital patients in New Zealand are treated in public hospitals [133. Four fifths of those entering private hospitals are surgical cases [14]. The long duration required to treat these diseases, with the accompanying and increasmg financial burden for those admitted to private hospitals, would mean that most patients would eventually attend a public hospital. Some cases ma> be diagnosed and treated as outpatients or at home. but an examination of Palmerston North cases indicated these would seldom have overt disease scormg more than three points (see below). Therefore. more rhan 95”, of overt CTD cases are believed to be recorded in public hospital inpatient files. 55\I I4 :,>-cj
Time and finance limited the area in which the study was conducted (Fig. 1). Case files categorized under the International Classijication of Diseases (KID) 8th revision rubies 446.97 16.0, 7 16.1,734.0 and 734.1 (and equivalents for the 7th revision) for patients discharged from public hospitals in this area between January, 1950 and August, 1973 (inclusive) were retrieved and examined. Patient demographic data, plus certain clinical and laboratory features were extracted from transfer to computer punch cards. The physician (RDW) determined the time of first disease symptoms and arbitrarily classified cases into three groups: “definite” when it was considered that most physicians would agree on the diagnosis; “possible” if there was insufficient evidence to justify a diagnosis (these were discarded): and “probable” which together with the “definite” cases were subjected to classification by computer. The American Rheumatism Association’s preliminary criteria for SLE diagnosis [153 were modified. As recommended by Fries and Siegel [I63 an antinuclear antibody titre (ANF) of more than 1:lO was considered equivalent to positive LE cells. Earlier, using the same ANF method, no titre above 5 was found in a population sample [ 171. Also an additional point was allowed for definite histological evidence of SLE. Scoring systems were developed for the remaining disease subsets and adjusted. by trial and error. until no further improvement in fit was achieved with cases considered clinically definite. Scoring was designed to exclude possible cases achieving less than 4 points (Tables i and 2). In addition to the case numbers of the individual subsets the total data base included 17 “combination” cases. These did not score 4 or more for a specific disease but accumulated 5 or more from an! of the four disease categories (SLE, PN. SD. and PMS.IDMS). 175
176
RICHARD
WIGLEY
and
BARRY
BORMAN
PALMbNO&T&
0
I
20
60
40
’
’
1
0
MAIN
-
HOSPITAL
MILES
CITIES BOARDS
I. Definite
/A
DISTRICTS
Fig. 1. The Geographic
Table
Counties,
and probable
clinical
Hospital Board Districts, and mam study was conducted.
diagnoses,
mcluding percentage
-
MARLBOROUGH
the interrelationshtps of agreement
Cittes of the area
of clmical
assessment
SLE PN SD PMS/DMS All probable Total f%)
cases
agreement
m whtch
Total
SLE 4
PN 4
SD 4
PMS/DMS 4
89 I 1
I
2
7
3 47 1 3
47 2
98
54
91
87
CTD 4
the
and score diagnoses
Score
Clinical
/
Remamder
and the
agreement
(7;)
43 2
3 I 3 1 9
13 4 6 3 -
Ill 53 57 48 23
50
41
17
26
292
94
91
80 89 82 90
Connecttve
Table (1)
(2)
(3)
(4)
(5
(6)
2 Scores allocated
ttssue dtseases
to the chnical
m New Zealand
features
for each disease
177
category
Svstemtc lupus erythematosus As in the American Rheumattsm Associatton’s system 15, but add 2 for posttive htstology of post-mortem (PM) examination and one for ANF l/IO or greater unless LE cells positive. Polyar&trs nodosa Mononeurttts or 2 maximum Peripheral neurttts Serosttts. Perttonitis or Pertcardttts or Pleuritis. pleural effusion Arthritis without deformity Psychosts or Encephahtis or I Myelitis or Convulsions Asthma Nasal granuloma Large artery occlusion Necrottc ulcer or gangrene Livedo reticularis Dtgital arteritts Testicular arterttis (pain, swelling or atrophy) Protemuria. red cells or white cells Urinary casts Eosinophiha Posittve histology or PM Pneumonitis Myocardttts Hypertension Fever Raynaud’s phenomenon Systemrc sclerosis Raynaud’s phenomenon Skin thickening: fingers face general morphoea Finger ulcers Oesophagus (dysphagia and/or X-ray postttve) Calcinosts of fingers Telangrectasrs on fingers Histology positive or PM positve Ftbrosts of lung Protemurta, cells or casts Ratsed urea or creatinine or Hvoertension Poiymyositts Myositis shown by biopsy and/or PM Muscle weakness Muscle wasting Muscle tenderness Electromyograph posttive Mononeuritis or Polyneurttis subtract 3 Dermatomyosrtis Skm btopsy posittve 1 Erythema or Skm oedema Violaceous colour of eyehds Collodton patches on knuckles Calcinosts of muscle PMSDMS = sums of scores in (4) and (5)
E'P
O'E
9'65
Z'E9
901
I'L
58
9'11
O'LI
P81
f.P
PE
6P1
S'fl
0'09 WZ ,0'81
0'2 OPI
1.99 L'E P.L L'E
CO;:
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asoyl
aie suowmaJqqe
asoasla
Z'P9
5‘29
6'E
0'2
P’6
f‘f I
S'S 6'0;:
O'E
t'oz
* WOL
1118JE3JNII
(~ar%so~ 8wprq3xa) ulpauna nmm~ q3JtlqWIJq3 WlJlJOd
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i
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JO
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Connective
ussue diseases
rn New Zealand
179
Fig 2. An isomell map showmg statrstically srgnificant divergences of observed m Geographic Countres from those expected. single disease entity (PMS/DMS), had the fewest cases (47) and the lowest rate (4.5/100,000). SLE, PN. and PMS/CMS case numbers did not vary significantly from the study area norm in any district. More SD cases were recorded in the Otago district (P < 0.05) than expected. Temporal distribution
A chi-square test revealed that CTD onsets as a group (P < 0.01) and specifically those of SLE (P < 0.01) and PMSjDMS (P < 0.01) had significantly increased in the period since 1962. SD case numbers however, had declined (P < 0.05). At the distract scale CTD onsets had risen in Marlborough (P < 0.01). Waitaki (P < 0.01). and Otago (P < O.Ol), while falling in Wellington (P < 0.05) and North Canterbury (P -c 0.01). Of the subsets, SLE case numbers were significantly higher in the second period in Otago (P < 0.01) and Waitaki (P -c 0.05). but lower in North Canterbury (P < 0.01). Onsets of SD had decreased over time m North Canterbury (P < 0.01) and Wellington (P < 0.01). To summarise these trends it can be recognized that the decline of SD onsets experienced by the study
Table 4. Percentages
numbers
of CTD
areas as a whole was primarily due to a similar situation prevailing in the North Canterbury and Wellington districts. Conversely, the effect of reduced onsets of SLE, and CTD generally, in these two districts was minimized by the significant increase recorded in Otago especially, but also in Waitaki and Marlborough. Climate
Two aetiological hypotheses involving climatic variables were tested. Firstly, Raynaud’s phenomenon, often the presenting feature of SD, is considered in part to result from excessive constriction of the arteries of the fingers in response to the cold. Therefore, it would be expected that this condition would occur or be detected more frequently with increasing latitude south as this is where the colder temperatures generally prevailed. However, the proportion of SD patients with Raynaud’s phenomenon was highest in the northernmost regions (Table 5). Secondly, exposure to excessive amounts of sunshine with resulting sunburn, has been suggested as a precipitating factor in SLE [9]. Using a method proposed by McGlashan [20,21] no statistically signifi-
of the total cases of connective
tissue diseases
m each region
O0Total populatron Region I II III IV V
cases
(1961)
SLE
PN
SD
14.5 27.0 32.9 25.6 16.4
19 4 20.4 28.6 31.6 25.5
38.9 31.5 20.3 16 7 16.7
16.0 24 0 20.0 40.0 32.0
PMS/DMS 17.0 17.0 25.5 40.5 ‘7.7
CTD 16.2 244 ‘7.1 32.3 25.2
RICHARD WIGLEY and BARR\ BORMA~
180 Table 5. The latitude
and mean
normal
temperatures
Mean
Region (mam population area)
of the regions. S.D. cases
normal
temperature* ‘C
Latitudet
(of mam population area)
12.4
I (Palmerston
and the proportlon
of Raynaud’s
SD
No ofSD cases
phenomenon
m
cases with.
Raynaud’s phenomenon 0 No 0
8
6
7
12
IO
83
IO
7
70
20
10
50
50
33
66
40’ 21’
North) 11.7
II
41’ 17’
(Wellington) III (Christchurch) IV (Dunedin) Total
106 43. 32’ 9.6 45’ 53’
* Calculated by averagmg the mean daily maximum and mean dally minimum temperatures of meteorological statlons in the regions during 1931-60. Adapted from NZ Meteorological Service. Summaries of Climatologlcal Observations to 1970. NZ. Met. S. Misc. Pub. 143, 1973. Ministry of Transport, Wellington, NZ. t To the nearest minute.
cant association was found between SLE incidence and areas with high sunshine hours [22] (Fig. 3). DISCUSSION
CTDs, especially SLE, had very low rates of incidence in New Zealand. The age-sex structures of the morbid populations showed females at greater risk and at younger ages than males (Fig. 4). The spatial analysis showed a high CTD morbidity in the Otago region (V). Successive disaggregation of the area1 scale established that this elevated incidence derived from the Otago district and then the Taieri county. Palmerston North district experienced moderately high disease occurrence. Fluctuations in onsets of disease between the two time periods over the study area and in individual districts were noted. These patterns were not considered to be an artefact of either diagnostic bias or classification error. The scoring systems were objectively applied to the data base and selected only patients with overi disease for subsequent analysis. Despite the presence of a medical school in Dunedin, the possible effects of increased staff availability and/or laboratory facilities on the results were believed to be minimal. The high ratio of hospital medical personnel to population-atrisk in region V (Table 6) may have been conducive to a more assiduous disease search for teaching purposes, but many additional cases discovered would have had less developed disease and failed to score four points from the computer classification. The Otago district also had a significant rise in disease onsets in the period since 1962 although there was no corresponding or recent increase in medical services. It seems unlikely that the low recorded morbidity of the areas including and adjacent to Wellington and Christchurch reflect an actual morbidity rate below that of the whole study area and especially that prevailing in Otago. While clinical schools were established in both cities toward the end of the study period CTD case numbers declined in the contiguous districts over time. Similarly, although Marlborough and Waitaki recorded significantly more cases in the second than the first period there was no accompanying provision of new health facilities.
Further factors were evaluated m attempting to account for the defined spatio-temporal patterns. The failure to find any association between Raynaud’s phenomenon and cold climate suggests that arteritis is more important than vaso-constrlction in the narrowing of the arteries. Medsger and Masl [23] also could not support this cold sensitivity hypothesis on epidemiological grounds. No relationship between the occurrence of SLE and areas of high annual sunshine hours was found in this study. This does not, however, disprove the hypothesis of such an association as sunburn often occurs at holiday resorts selected principally for the amount of sunshine received and vacation addresses could not be established. Neither Morton rt al. [24] nor Fries and Holman [25] found epidemiological evidence to support the role of sunshine at the place of residence in provoking SLE. Kay et al. [26] postulated that SLE incidence may be increased by the advent of the oral contraceptive pill which became available in New Zealand about 1962. The findings of this study do not support this hypothesis despite a general rise in SLE onsets being observed for the total study area. Only in the Waitaki and Otago districts was there a significant case increase in the period since 1962, while there was a decline in onsets of disease in North Canterbury over time. The present work failed to corroborate the finding from the earlier New Zealand study of a ruralurban difference in incidence. The predominance of patients resident in urban areas in that study, which used the officially published morbidity data based on address at the time of hospital admission, may reflect a trend for patients developing these diseases in rural areas to migrate to cities for specialized medical or nursing care. If the onset address had been used a patient would have been “returned” to the domicile where first disease symptoms occurred. A crucial factor in this research was that the geographic patterns were those at the time of the first symptoms. If the occurrence of a disease is related to physical, biological, and/or soclo-economic variables, whether in time or space or both. It will be prior to. and at disease onset that such factors will have their
Connectwe tissue diseases in New Zealand
Fig. 3 The spatial distribution
181
of SLE cases plotted against mean annual sunshine hours [22] and the correlation tested for statistical significance.
greatest impact upon the human organism. It will be at this time that a patient will be at greatest risk of developing that disease. In the aetiological research of chronic diseases. like CTDs, spurious conclusions can be drawn if the data pertains to a time other than that of the first symptoms. For such cases there may be a long time gap between onset and first hospital admission and/or drsease diagnosis. In the interim, especially in areas like New Zealand which have a high populatton mobility. a patient may change residence after developing the disease and consequently he/she will be exposed to environmental factors different from those causative or precipitating agents culpable at disease onset.
This study illustrates the need to include in the ICD an indication of the degree of certainty with which a diagnosis was made. Currently, every case must be classified, with a consequent tendency to code a case of uncertain diagnosis in a specific category, rather than in a less specific code. National statistics are thereby inflated with “indefinite” cases which could easily be excluded if the data were required to contain the degree of diagnostic certainty. The morbid population could then be more rigorously defined without recourse to a time consuming study of patient case files: this is rarely feasible for common diseases. The published morbidity statistics in New Zealand have some admmistrative value but
RICHARD W~GLE~ and BARR) QOR\IA>
182
lems The medtcal professton has a responstbiliiy to recognize the uttln~ of a geographic perspective m medtcme as Hippocrates did m the fourth century From the close collaboratton of the two dtsclplmes new advances can be made toward the eventual understanding and eliminatton of diseases. and the alleviatton of human suffering. -Ic~rlorclC[IYQ)tIY)Irs-Theauthors are Indebted to Dr N D McGlashan. Untverstty of Tasmanta. for hts asststance throughout thus proJect Acknowledgement ts also made of assistance recetbed from Mrs M. Fowles, SRN. who atded tn the data collectton. and Messrs B Reay. B SC (Honst. and P H111. B SC. for the computer uroerammme. This studs was suooorted . ._ b a grant from the New Zealand Medtcal Research Coun1
L
Cll
REFERENCES I Fig. 4. The
age-sex
morbtdtty rates onset.
of CTD
by age
at
2
are of minimal utility in aetiological research especially concerning chronic diseases. In conclusion, the importance of incorporating stochastrc tests in studies of the spatial distribution of the morbidity or mortality of uncommon diseases was emphasized. Although rates and ratios are frequently employed they have severe limitations in more rigorous aeticlogical research which seeks an explanation for patterns [27]. It is crucial to distinguish between area1 umts in which disease or death occurrences are the result of random influences and those in which the variation in incidence is beyond being a mere chance event. A statistically significant variation implies that there is an underlying cause for which an explanation should be sought. In the present work 6 districts had rates greater than the study area norm while those for Maniototo and Vincent were very much higher. However, only 2 districts had a statistically significant deviation of observed cases from those expected. This study represents the fusion of geography and medicine. The multtple aetiology of most diseases necessitates a multidisciplinary approach which attempts to elucidate, and hopefully, break a disease causative chain. Geographers have shown that they have an important contribution to make to medical science [27729]. Whether they become integral participators on research teams depends on the continuous demonstration of their skills and involvement in all facets of the investigation of human health prob-
Table
6
Hospttal
Ratio
Board
of hosprtal
Dtstrtct
Palmerston North Wellington North Canterhury Otago
medical
3
4. 5.
6
7 8
9 IO.
I1
54. 1972.
11. Borman
staff (semor Census) StaR [30] 56 192 152 113
Adams F (Trans.) Tltr GUIUUI~ Ck’orks 01‘ Hlppocrares. Vol. I, pp 179-222. Sydenham Soctety. London. 1849. Reproduced m Barkhuus Arne Medical surveys from Hippocrates to the world travellers. CIBA Symp.6, 1986. 1945. Fessel W. J. Systemic lupus erythematosus in the commumty. Arch. intern Med 134. 1027, 1974. Kurland L. T.. Hauser W A.. Ferguson R. H. and Holley K. E. Eptdemtologtc features of dtffuse connecttve ttssue dtsorders in Rochester. Minnesota, 1951 through 1967. wtth spectal reference to systemrc lupus erythematosus. Mayo C/in. Proc 44. 649. 1969 Leonhardt T Family studies m systemtc lupus erythematosus. .&a. med. x-and. 176 (suppl. 416). 1, 1964. Mast A. T. and D’Angelo W A. Eptdemtology of fatal systemic sclerosis (dtffuse scleroderma): a 15 year survey m Balttmore. .411n. intern. Med. 66, 570, 1967. Medsger T. A. and Mast A. T. Epidemtology of systemtc scleroses (scleroderma). .4mr. mtern. Med. 74, 714, 1971 Medsger T. A.. Dawson H. and Mast A. T The eptdemiology of polymyosttts. .4m. J Med. 48. 715. 1970. Nobrega F T. Ferguson R. H.. Kurland L. T. and Hargreaves M. M. Lupus erythematosus m Rochester, Minnesota. 1950-1965. a prehminary study. In Popularm Srudws of‘ rhe Rhewmc Dueasrs (Edited by Bennett P. H. and Wood P. H N.I pp. 2599265. Internattonal Congress Serves no. 148. Evcerpta Medica Foundatton, Amsterdam. 1968. Siegel M. and Lee S L. The eptdemtology of systemtc lupus erythematosus. Semrrt. -trrltrrr. Rheutn. 3, I, 1973. Stegel M.. Lee S. L.. Widelock D.. Reilly E. B.. Wtse G. J.. Zmgale S. B. and Fuerst H T. The eptdemtology of systemtc lupus erythematosus prelimmary results m New York ctty. J chrorr Dr.\. IS. 131. 1962. Couchman K G. and Wigley R. D The distrtbution of systemic connective ttssue dtseases. N.Z. Med. J. 76.
+ Juntor)
B. Me&cat
geography
to populatton-at-rusk
Populatton 96.225 260.3 I3 270.666 I2 I .J37
Ratto
I 1718 I 1355 I.1780
I :I074
and Its contributton
(1961
to
Connective tissue diseases in New Zealand the aetiology of rare systemic connecttve tissue diseases. Masters thesis, Department of Geography, Massey University. Palmers& North, N.Z., 1975. Data. 1964 and Hosoi13. Hosmtal and Selected Morbiditv tal and Selected Morbidity Data, 2971. National Heaith Statistics Centre. Department of Health, Wellington, N.Z. 14. Private HospIrals Prelimmary Sraremenr. 1974. Natlonal Health Statlstlcs Centre, Department of Health, Wellmgton. N.Z. IS. Cohen A. S., Reynolds W. E., Franklin E. C., Kulka J P.. Ropes M. W.. Shulman L. E. and Wallace S. L. Prelimmary criteria for the classification of systemic lupus erythematosus. Bull. rheum. Dis. 21, 643, 1971.
16. Fries J. and Siegel R. C. Testing the ‘preliminary criteria for classification of SLE’. Ann. rheum. Du. 32, 171, 1973.
17. Couchman K. G., Wlgley R. D. and Prior I. A. M. Autoanttbodies in the Carterton population survey: the prevalence of thyroid and gastric antibodies. anti-nuclear and rheumatotd factors, in a probability based population sample. J. chron. Dis. 23, 45, 1970. 18. McGlashan N. D and Harington J. S. Some techmques for mapping mortahty. S. Afr. geogr. J. 58, 18, 1976. 19. Epstein J. H. and Tuffanelli D. L. DIscoid lupus erythematosus. In Lupus Erwhematosus. A Review of the Currenf Starus of DIscoid and Systemic fosus and Their Variants (Edited bv
Lupus
Erythema-
Dubois E. L.). 2nd edn., pp. 21&231. Umv: Southein Califorma Press, Los Angeles. 1974.
183
20. McGlashan N. D. The African lymphoma m Central Africa. Inr. J. Cancer 4, 113, 1969. 21. McGlashan N. D. The implications of spatial varlations of ill-health. N.Z. Med. J. 82. 131. 1975 22. Garnier B. J. The Climate of New Zenland. Arnold, London, 1958. 23. Medsger T. A. and Mast A. T. The epidemiology of systemic sclerosis (scleroderma) among male U.S. veterans. J. chron. Dis. 31, 73, 1978. 24 Morton R. 0.. Gershwm M. E., Brady C. and Stemberg A. D. The incidence of systemic lupus erythematosus in North Amerxan Indians. J. Rheumatol 3, 186, 1976. 25. Fries J. F. and Holman H. R. Systemic Lupus Eryfhematosus a C’hnical Analysis. Saunders, Philadelphia. 1975. 26. Kay D. R., Bole G G. and Ledger W. J. Anti-nuclear antibodies, rheumatoid factor and C-reactive protein in serum of normal women using oral contraceptives. Arthrit. Rheumat. 14, 239. 1971. 27. McGlashan N. D. Spatial variations in cause-specific mortality tn Austraha. In Studies m Ausrrahan Mortality (Edited by McGlashan N. D.), pp. l-28. University of Tasmania Environmental Studies Occasional Paper No. 4, Hobart. 1977. 28. McGlashan N. D. (Ed.) Medical Geography. Techniques and Field Studies. Methuen, London, 1972. 29. Hunter J. M. (Ed.) The Geography of Health and Disease. University of North Carolina at Chapel Hill. Department of Geography, Studies in Geography, No. 6, 1974. 30. Hospital Starwics of New Zealand, March 1961. Department of Health, Wellington, N.Z.
OF
RICHARII WIGLEY and BARKY BOKMAN Research Laboratory.
Palmerston North, Puhhc Hospital and P.O. Box 6314. Wellington. New Zealand
Abstract-Case records of patients discharged from puhEc hospitals in the southern half of New Zealand with connective tissue diseases (CTDs) during the period 195&1973 were reviewed. Onl} clinically “definite” and “probable” cas& were included. Systemic lupus erythematosus (SLE) cases were scored bq computer usmg a modified version of the American Rheumatism Assoclatron’s prehmmary crtterla (1971) for SLE diagnosis. Similar scormg systems were developed IO classify cases of systemic sclerosis (SD). poiyarteritis nodosa (PN). and polymyositis and dermatomyositis combined (PMS~DMS). Although the age-sex structures of these populations were comparable to those reported elsewhere, CTD incidence generally but especially SLE. was low m New Zealand Probablhty testmg and mapping were employed to define the spatial and temporal dlstributlons of CTDs, as a group and severally. at the time of disease onset. There was a significantly increased morbidity of all CTDs as a group and for scleroderma in particular. m the Otago Hospital Board District. No consistent temporal or rural/urban differences in incidence were found. SLE occurrence was not significantly related to areas with high sunshine hours.
INTRODIJCTlOK “Whoever wishes to investigate medicine properly, should proceed thus.. consider the seasons of the year., the winds.. qualities of the waters.. the ground.. . the mode in which the inhabitants live and what are their pursuits.” Htppocrates [I]
Knowledge of the causation of the rare connective tissue diseases (CTDs). dermatomyositis (DMS). polyarteritis nodosa (PN), polymyositis (PMS). systemic sclerosis (SD). and systemic lupus erythromatosus (SLE) is limited. Generally, epidemiological studies have been restricted to urban populations [2-IO]. A previous New Zealand report [I 1J. based on official morbidity data. suggested areal differences in the incidence of these diseases. The present retrospective stud> was aimed principally at defining the spatial and temporal distributions of CTD morbidity. both as a group and severally. in New Zealand [I?].
THE MEDlCAL
DATA
ANlD METHODS
About SO’, of all hospital patients in New Zealand are treated in public hospitals [133. Four fifths of those entering private hospitals are surgical cases [14]. The long duration required to treat these diseases, with the accompanying and increasmg financial burden for those admitted to private hospitals, would mean that most patients would eventually attend a public hospital. Some cases ma> be diagnosed and treated as outpatients or at home. but an examination of Palmerston North cases indicated these would seldom have overt disease scormg more than three points (see below). Therefore. more rhan 95”, of overt CTD cases are believed to be recorded in public hospital inpatient files. 55\I I4 :,>-cj
Time and finance limited the area in which the study was conducted (Fig. 1). Case files categorized under the International Classijication of Diseases (KID) 8th revision rubies 446.97 16.0, 7 16.1,734.0 and 734.1 (and equivalents for the 7th revision) for patients discharged from public hospitals in this area between January, 1950 and August, 1973 (inclusive) were retrieved and examined. Patient demographic data, plus certain clinical and laboratory features were extracted from transfer to computer punch cards. The physician (RDW) determined the time of first disease symptoms and arbitrarily classified cases into three groups: “definite” when it was considered that most physicians would agree on the diagnosis; “possible” if there was insufficient evidence to justify a diagnosis (these were discarded): and “probable” which together with the “definite” cases were subjected to classification by computer. The American Rheumatism Association’s preliminary criteria for SLE diagnosis [153 were modified. As recommended by Fries and Siegel [I63 an antinuclear antibody titre (ANF) of more than 1:lO was considered equivalent to positive LE cells. Earlier, using the same ANF method, no titre above 5 was found in a population sample [ 171. Also an additional point was allowed for definite histological evidence of SLE. Scoring systems were developed for the remaining disease subsets and adjusted. by trial and error. until no further improvement in fit was achieved with cases considered clinically definite. Scoring was designed to exclude possible cases achieving less than 4 points (Tables i and 2). In addition to the case numbers of the individual subsets the total data base included 17 “combination” cases. These did not score 4 or more for a specific disease but accumulated 5 or more from an! of the four disease categories (SLE, PN. SD. and PMS.IDMS). 175
176
RICHARD
WIGLEY
and
BARRY
BORMAN
PALMbNO&T&
0
I
20
60
40
’
’
1
0
MAIN
-
HOSPITAL
MILES
CITIES BOARDS
I. Definite
/A
DISTRICTS
Fig. 1. The Geographic
Table
Counties,
and probable
clinical
Hospital Board Districts, and mam study was conducted.
diagnoses,
mcluding percentage
-
MARLBOROUGH
the interrelationshtps of agreement
Cittes of the area
of clmical
assessment
SLE PN SD PMS/DMS All probable Total f%)
cases
agreement
m whtch
Total
SLE 4
PN 4
SD 4
PMS/DMS 4
89 I 1
I
2
7
3 47 1 3
47 2
98
54
91
87
CTD 4
the
and score diagnoses
Score
Clinical
/
Remamder
and the
agreement
(7;)
43 2
3 I 3 1 9
13 4 6 3 -
Ill 53 57 48 23
50
41
17
26
292
94
91
80 89 82 90
Connecttve
Table (1)
(2)
(3)
(4)
(5
(6)
2 Scores allocated
ttssue dtseases
to the chnical
m New Zealand
features
for each disease
177
category
Svstemtc lupus erythematosus As in the American Rheumattsm Associatton’s system 15, but add 2 for posttive htstology of post-mortem (PM) examination and one for ANF l/IO or greater unless LE cells positive. Polyar&trs nodosa Mononeurttts or 2 maximum Peripheral neurttts Serosttts. Perttonitis or Pertcardttts or Pleuritis. pleural effusion Arthritis without deformity Psychosts or Encephahtis or I Myelitis or Convulsions Asthma Nasal granuloma Large artery occlusion Necrottc ulcer or gangrene Livedo reticularis Dtgital arteritts Testicular arterttis (pain, swelling or atrophy) Protemuria. red cells or white cells Urinary casts Eosinophiha Posittve histology or PM Pneumonitis Myocardttts Hypertension Fever Raynaud’s phenomenon Systemrc sclerosis Raynaud’s phenomenon Skin thickening: fingers face general morphoea Finger ulcers Oesophagus (dysphagia and/or X-ray postttve) Calcinosts of fingers Telangrectasrs on fingers Histology positive or PM positve Ftbrosts of lung Protemurta, cells or casts Ratsed urea or creatinine or Hvoertension Poiymyositts Myositis shown by biopsy and/or PM Muscle weakness Muscle wasting Muscle tenderness Electromyograph posttive Mononeuritis or Polyneurttis subtract 3 Dermatomyosrtis Skm btopsy posittve 1 Erythema or Skm oedema Violaceous colour of eyehds Collodton patches on knuckles Calcinosts of muscle PMSDMS = sums of scores in (4) and (5)
E'P
O'E
9'65
Z'E9
901
I'L
58
9'11
O'LI
P81
f.P
PE
6P1
S'fl
0'09 WZ ,0'81
0'2 OPI
1.99 L'E P.L L'E
CO;:
‘)xai aql u1 paw
asoyl
aie suowmaJqqe
asoasla
Z'P9
5‘29
6'E
0'2
P’6
f‘f I
S'S 6'0;:
O'E
t'oz
* WOL
1118JE3JNII
(~ar%so~ 8wprq3xa) ulpauna nmm~ q3JtlqWIJq3 WlJlJOd
0‘0;
9'65
IlnH
L‘EZ
E'SI
i
cu.3
aql JO sari!3
sluaiwd
O'P
as
6'1
Nd
Z'S
31s
umxu aql ulqi!Msaw3 +sawas!p anssg aAwauuo3
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aXIapyuo3 g)'rJaq1 01 [aAalaXIe3y!Le?!saqi
6'E
YlJON
uolsu!llaM UOlSJXU[l?d
(1961) w’e Kpnis JO uogelndod O0
p3olJo uowqws!p
aWua3Jad
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'awl .IaAoslasuo (7L3 paseaI3ap JO pasea.w! d[~ue3yru%!s pawa!ladxa q3!qM slc?!.~is!p au!ru -.!alap01 pahlasqo ieql ql!M laqtunu a%3 papadxa lueqnsaJ aql aledmo3 01 pazqgn u!e% SBM uognq!Jl -s!p uoss!od aqL .suo!lr?lndodsnsua3 9961 aA!lDadsaj .I!aql01 payddE alaM (uogelndod snsuaa 9561 aql uo paseq) po!Jad 1s.1~aql JOJ saiw Ll!p!qJoLu3ypads xas-a% s,lgs!p q3vg .(aA!snIw) EL61 )sn%ny II!I pur! 2961 8U!Jnp sluo1dru.k 1sJy ql!M asoql pUv‘1961 ihupnpu! pue '01 Jo!.Idlasuo q]!M asoql :spo!Jad aI_u!l ; olu! paleFia&ZieaJaM sases‘s!si(~ewIelodwal .ro~ .ynsaJ aqi Ou!wwns pur! snsuaa ZN 1961 aqi Jo atug aq1 w i!un [vale q3ea Jo UO!l -eIndod aql 01 salm aDuappu! Dypads xas-a% IIeJano Su$dde 1cq paleJaw aJaM SapuanbaJJ pawdx3 .a3ueq3 01 a~qelnqpll~ leqi moiaq 10 aAoqe .Iaql!a set icl!p!q.'our aL3 q3!qM u! sl!un p2a~e aie3oI 01 laplo u! laqtunu asw ,,palDadxa,, aql qi!M ,,paAJasqo,, aql aJedu.IoD01 pasn WM uo!lnqpls!p uoss!od aqL 'Bale o%eio aqi JO %uge~s snoJaua8 aql aAEq IOU p!p qwM wis!p puewms aqi papnl3xa inq AI UOF8a.I01 XI!LI.I!S St?M A UO$aa 'AI UO$kI WaM Sl+Il -s!p pueIqInos pue‘olo~o~ue~ 'lua3u!A 'o%t?loqlnos 'oSt?lg ‘!yel!e~ aql al!qm :si3gs!p LlnqJaluo3 qlnos pue ‘uol.Inqqsv ‘hqJalue3 qiloN 111 uo!la.I:si~g -sipq8noloqlle~ pue uol8uglaM aql 11 uo!8aJ :sl3!~1 -s!p edww!eM puv ‘a+I!AaUUEa 'qlJON uols.IauI~ed aql pas!JdwoD 1 uo!%a .sIel!dsoq3gqnd p?d!cw!Jdaql JO sauoz luaurq3le3 luaged aql paleruIxoJdde q%qM (SUO@J) suo!%ax pue :s!s@3ua aql JOJ sl!un p2aJE 3!seq aql paI.woJ q3!qm ,'(spgs!p) wpis!a pleog IQ!dsoH :(saguno3) saguno3 3!qd&oaf) :(I $i!d) paLo[dwa SI?M suo!s!~rp legeds JO i(q3.Iela!qv 'iasuo aseastp it!va_n2.Cpnlsaql ap!slno luap!sa.I aJaM JO ssalppe uo!ss!rupr!lel!dsoq pawyuown ue .Iaqi!apeq Layi asnesaq aseq w2p aql WO~J papnl3xa a.IaM o& Jaqurnu waged 1~2101aql JO ,paldasae WM iasuo aseas!p IB a[I3II_uop aql d[uo 'IOU JI w.uoldruKs asvas!p wy ~0 amg aql le ieql 01 papuodsalJo2 WOJ uo!ssype Iwrdsoq [etl!u!aql uo ssalppe s‘luaged r! leql iJI.IaA01 paqs_Iaas ,~laA!l3adSOJlaJ alaM ~1103 [woi3aIa .i.wuaurw~Jed pue sa!Jolsa.upauoqdalal
Connective
ussue diseases
rn New Zealand
179
Fig 2. An isomell map showmg statrstically srgnificant divergences of observed m Geographic Countres from those expected. single disease entity (PMS/DMS), had the fewest cases (47) and the lowest rate (4.5/100,000). SLE, PN. and PMS/CMS case numbers did not vary significantly from the study area norm in any district. More SD cases were recorded in the Otago district (P < 0.05) than expected. Temporal distribution
A chi-square test revealed that CTD onsets as a group (P < 0.01) and specifically those of SLE (P < 0.01) and PMSjDMS (P < 0.01) had significantly increased in the period since 1962. SD case numbers however, had declined (P < 0.05). At the distract scale CTD onsets had risen in Marlborough (P < 0.01). Waitaki (P < 0.01). and Otago (P < O.Ol), while falling in Wellington (P < 0.05) and North Canterbury (P -c 0.01). Of the subsets, SLE case numbers were significantly higher in the second period in Otago (P < 0.01) and Waitaki (P -c 0.05). but lower in North Canterbury (P < 0.01). Onsets of SD had decreased over time m North Canterbury (P < 0.01) and Wellington (P < 0.01). To summarise these trends it can be recognized that the decline of SD onsets experienced by the study
Table 4. Percentages
numbers
of CTD
areas as a whole was primarily due to a similar situation prevailing in the North Canterbury and Wellington districts. Conversely, the effect of reduced onsets of SLE, and CTD generally, in these two districts was minimized by the significant increase recorded in Otago especially, but also in Waitaki and Marlborough. Climate
Two aetiological hypotheses involving climatic variables were tested. Firstly, Raynaud’s phenomenon, often the presenting feature of SD, is considered in part to result from excessive constriction of the arteries of the fingers in response to the cold. Therefore, it would be expected that this condition would occur or be detected more frequently with increasing latitude south as this is where the colder temperatures generally prevailed. However, the proportion of SD patients with Raynaud’s phenomenon was highest in the northernmost regions (Table 5). Secondly, exposure to excessive amounts of sunshine with resulting sunburn, has been suggested as a precipitating factor in SLE [9]. Using a method proposed by McGlashan [20,21] no statistically signifi-
of the total cases of connective
tissue diseases
m each region
O0Total populatron Region I II III IV V
cases
(1961)
SLE
PN
SD
14.5 27.0 32.9 25.6 16.4
19 4 20.4 28.6 31.6 25.5
38.9 31.5 20.3 16 7 16.7
16.0 24 0 20.0 40.0 32.0
PMS/DMS 17.0 17.0 25.5 40.5 ‘7.7
CTD 16.2 244 ‘7.1 32.3 25.2
RICHARD WIGLEY and BARR\ BORMA~
180 Table 5. The latitude
and mean
normal
temperatures
Mean
Region (mam population area)
of the regions. S.D. cases
normal
temperature* ‘C
Latitudet
(of mam population area)
12.4
I (Palmerston
and the proportlon
of Raynaud’s
SD
No ofSD cases
phenomenon
m
cases with.
Raynaud’s phenomenon 0 No 0
8
6
7
12
IO
83
IO
7
70
20
10
50
50
33
66
40’ 21’
North) 11.7
II
41’ 17’
(Wellington) III (Christchurch) IV (Dunedin) Total
106 43. 32’ 9.6 45’ 53’
* Calculated by averagmg the mean daily maximum and mean dally minimum temperatures of meteorological statlons in the regions during 1931-60. Adapted from NZ Meteorological Service. Summaries of Climatologlcal Observations to 1970. NZ. Met. S. Misc. Pub. 143, 1973. Ministry of Transport, Wellington, NZ. t To the nearest minute.
cant association was found between SLE incidence and areas with high sunshine hours [22] (Fig. 3). DISCUSSION
CTDs, especially SLE, had very low rates of incidence in New Zealand. The age-sex structures of the morbid populations showed females at greater risk and at younger ages than males (Fig. 4). The spatial analysis showed a high CTD morbidity in the Otago region (V). Successive disaggregation of the area1 scale established that this elevated incidence derived from the Otago district and then the Taieri county. Palmerston North district experienced moderately high disease occurrence. Fluctuations in onsets of disease between the two time periods over the study area and in individual districts were noted. These patterns were not considered to be an artefact of either diagnostic bias or classification error. The scoring systems were objectively applied to the data base and selected only patients with overi disease for subsequent analysis. Despite the presence of a medical school in Dunedin, the possible effects of increased staff availability and/or laboratory facilities on the results were believed to be minimal. The high ratio of hospital medical personnel to population-atrisk in region V (Table 6) may have been conducive to a more assiduous disease search for teaching purposes, but many additional cases discovered would have had less developed disease and failed to score four points from the computer classification. The Otago district also had a significant rise in disease onsets in the period since 1962 although there was no corresponding or recent increase in medical services. It seems unlikely that the low recorded morbidity of the areas including and adjacent to Wellington and Christchurch reflect an actual morbidity rate below that of the whole study area and especially that prevailing in Otago. While clinical schools were established in both cities toward the end of the study period CTD case numbers declined in the contiguous districts over time. Similarly, although Marlborough and Waitaki recorded significantly more cases in the second than the first period there was no accompanying provision of new health facilities.
Further factors were evaluated m attempting to account for the defined spatio-temporal patterns. The failure to find any association between Raynaud’s phenomenon and cold climate suggests that arteritis is more important than vaso-constrlction in the narrowing of the arteries. Medsger and Masl [23] also could not support this cold sensitivity hypothesis on epidemiological grounds. No relationship between the occurrence of SLE and areas of high annual sunshine hours was found in this study. This does not, however, disprove the hypothesis of such an association as sunburn often occurs at holiday resorts selected principally for the amount of sunshine received and vacation addresses could not be established. Neither Morton rt al. [24] nor Fries and Holman [25] found epidemiological evidence to support the role of sunshine at the place of residence in provoking SLE. Kay et al. [26] postulated that SLE incidence may be increased by the advent of the oral contraceptive pill which became available in New Zealand about 1962. The findings of this study do not support this hypothesis despite a general rise in SLE onsets being observed for the total study area. Only in the Waitaki and Otago districts was there a significant case increase in the period since 1962, while there was a decline in onsets of disease in North Canterbury over time. The present work failed to corroborate the finding from the earlier New Zealand study of a ruralurban difference in incidence. The predominance of patients resident in urban areas in that study, which used the officially published morbidity data based on address at the time of hospital admission, may reflect a trend for patients developing these diseases in rural areas to migrate to cities for specialized medical or nursing care. If the onset address had been used a patient would have been “returned” to the domicile where first disease symptoms occurred. A crucial factor in this research was that the geographic patterns were those at the time of the first symptoms. If the occurrence of a disease is related to physical, biological, and/or soclo-economic variables, whether in time or space or both. It will be prior to. and at disease onset that such factors will have their
Connectwe tissue diseases in New Zealand
Fig. 3 The spatial distribution
181
of SLE cases plotted against mean annual sunshine hours [22] and the correlation tested for statistical significance.
greatest impact upon the human organism. It will be at this time that a patient will be at greatest risk of developing that disease. In the aetiological research of chronic diseases. like CTDs, spurious conclusions can be drawn if the data pertains to a time other than that of the first symptoms. For such cases there may be a long time gap between onset and first hospital admission and/or drsease diagnosis. In the interim, especially in areas like New Zealand which have a high populatton mobility. a patient may change residence after developing the disease and consequently he/she will be exposed to environmental factors different from those causative or precipitating agents culpable at disease onset.
This study illustrates the need to include in the ICD an indication of the degree of certainty with which a diagnosis was made. Currently, every case must be classified, with a consequent tendency to code a case of uncertain diagnosis in a specific category, rather than in a less specific code. National statistics are thereby inflated with “indefinite” cases which could easily be excluded if the data were required to contain the degree of diagnostic certainty. The morbid population could then be more rigorously defined without recourse to a time consuming study of patient case files: this is rarely feasible for common diseases. The published morbidity statistics in New Zealand have some admmistrative value but
RICHARD W~GLE~ and BARR) QOR\IA>
182
lems The medtcal professton has a responstbiliiy to recognize the uttln~ of a geographic perspective m medtcme as Hippocrates did m the fourth century From the close collaboratton of the two dtsclplmes new advances can be made toward the eventual understanding and eliminatton of diseases. and the alleviatton of human suffering. -Ic~rlorclC[IYQ)tIY)Irs-Theauthors are Indebted to Dr N D McGlashan. Untverstty of Tasmanta. for hts asststance throughout thus proJect Acknowledgement ts also made of assistance recetbed from Mrs M. Fowles, SRN. who atded tn the data collectton. and Messrs B Reay. B SC (Honst. and P H111. B SC. for the computer uroerammme. This studs was suooorted . ._ b a grant from the New Zealand Medtcal Research Coun1
L
Cll
REFERENCES I Fig. 4. The
age-sex
morbtdtty rates onset.
of CTD
by age
at
2
are of minimal utility in aetiological research especially concerning chronic diseases. In conclusion, the importance of incorporating stochastrc tests in studies of the spatial distribution of the morbidity or mortality of uncommon diseases was emphasized. Although rates and ratios are frequently employed they have severe limitations in more rigorous aeticlogical research which seeks an explanation for patterns [27]. It is crucial to distinguish between area1 umts in which disease or death occurrences are the result of random influences and those in which the variation in incidence is beyond being a mere chance event. A statistically significant variation implies that there is an underlying cause for which an explanation should be sought. In the present work 6 districts had rates greater than the study area norm while those for Maniototo and Vincent were very much higher. However, only 2 districts had a statistically significant deviation of observed cases from those expected. This study represents the fusion of geography and medicine. The multtple aetiology of most diseases necessitates a multidisciplinary approach which attempts to elucidate, and hopefully, break a disease causative chain. Geographers have shown that they have an important contribution to make to medical science [27729]. Whether they become integral participators on research teams depends on the continuous demonstration of their skills and involvement in all facets of the investigation of human health prob-
Table
6
Hospttal
Ratio
Board
of hosprtal
Dtstrtct
Palmerston North Wellington North Canterhury Otago
medical
3
4. 5.
6
7 8
9 IO.
I1
54. 1972.
11. Borman
staff (semor Census) StaR [30] 56 192 152 113
Adams F (Trans.) Tltr GUIUUI~ Ck’orks 01‘ Hlppocrares. Vol. I, pp 179-222. Sydenham Soctety. London. 1849. Reproduced m Barkhuus Arne Medical surveys from Hippocrates to the world travellers. CIBA Symp.6, 1986. 1945. Fessel W. J. Systemic lupus erythematosus in the commumty. Arch. intern Med 134. 1027, 1974. Kurland L. T.. Hauser W A.. Ferguson R. H. and Holley K. E. Eptdemtologtc features of dtffuse connecttve ttssue dtsorders in Rochester. Minnesota, 1951 through 1967. wtth spectal reference to systemrc lupus erythematosus. Mayo C/in. Proc 44. 649. 1969 Leonhardt T Family studies m systemtc lupus erythematosus. .&a. med. x-and. 176 (suppl. 416). 1, 1964. Mast A. T. and D’Angelo W A. Eptdemtology of fatal systemic sclerosis (dtffuse scleroderma): a 15 year survey m Balttmore. .411n. intern. Med. 66, 570, 1967. Medsger T. A. and Mast A. T. Epidemtology of systemtc scleroses (scleroderma). .4mr. mtern. Med. 74, 714, 1971 Medsger T. A.. Dawson H. and Mast A. T The eptdemiology of polymyosttts. .4m. J Med. 48. 715. 1970. Nobrega F T. Ferguson R. H.. Kurland L. T. and Hargreaves M. M. Lupus erythematosus m Rochester, Minnesota. 1950-1965. a prehminary study. In Popularm Srudws of‘ rhe Rhewmc Dueasrs (Edited by Bennett P. H. and Wood P. H N.I pp. 2599265. Internattonal Congress Serves no. 148. Evcerpta Medica Foundatton, Amsterdam. 1968. Siegel M. and Lee S L. The eptdemtology of systemtc lupus erythematosus. Semrrt. -trrltrrr. Rheutn. 3, I, 1973. Stegel M.. Lee S. L.. Widelock D.. Reilly E. B.. Wtse G. J.. Zmgale S. B. and Fuerst H T. The eptdemtology of systemtc lupus erythematosus prelimmary results m New York ctty. J chrorr Dr.\. IS. 131. 1962. Couchman K G. and Wigley R. D The distrtbution of systemic connective ttssue dtseases. N.Z. Med. J. 76.
+ Juntor)
B. Me&cat
geography
to populatton-at-rusk
Populatton 96.225 260.3 I3 270.666 I2 I .J37
Ratto
I 1718 I 1355 I.1780
I :I074
and Its contributton
(1961
to
Connective tissue diseases in New Zealand the aetiology of rare systemic connecttve tissue diseases. Masters thesis, Department of Geography, Massey University. Palmers& North, N.Z., 1975. Data. 1964 and Hosoi13. Hosmtal and Selected Morbiditv tal and Selected Morbidity Data, 2971. National Heaith Statistics Centre. Department of Health, Wellington, N.Z. 14. Private HospIrals Prelimmary Sraremenr. 1974. Natlonal Health Statlstlcs Centre, Department of Health, Wellmgton. N.Z. IS. Cohen A. S., Reynolds W. E., Franklin E. C., Kulka J P.. Ropes M. W.. Shulman L. E. and Wallace S. L. Prelimmary criteria for the classification of systemic lupus erythematosus. Bull. rheum. Dis. 21, 643, 1971.
16. Fries J. and Siegel R. C. Testing the ‘preliminary criteria for classification of SLE’. Ann. rheum. Du. 32, 171, 1973.
17. Couchman K. G., Wlgley R. D. and Prior I. A. M. Autoanttbodies in the Carterton population survey: the prevalence of thyroid and gastric antibodies. anti-nuclear and rheumatotd factors, in a probability based population sample. J. chron. Dis. 23, 45, 1970. 18. McGlashan N. D and Harington J. S. Some techmques for mapping mortahty. S. Afr. geogr. J. 58, 18, 1976. 19. Epstein J. H. and Tuffanelli D. L. DIscoid lupus erythematosus. In Lupus Erwhematosus. A Review of the Currenf Starus of DIscoid and Systemic fosus and Their Variants (Edited bv
Lupus
Erythema-
Dubois E. L.). 2nd edn., pp. 21&231. Umv: Southein Califorma Press, Los Angeles. 1974.
183
20. McGlashan N. D. The African lymphoma m Central Africa. Inr. J. Cancer 4, 113, 1969. 21. McGlashan N. D. The implications of spatial varlations of ill-health. N.Z. Med. J. 82. 131. 1975 22. Garnier B. J. The Climate of New Zenland. Arnold, London, 1958. 23. Medsger T. A. and Mast A. T. The epidemiology of systemic sclerosis (scleroderma) among male U.S. veterans. J. chron. Dis. 31, 73, 1978. 24 Morton R. 0.. Gershwm M. E., Brady C. and Stemberg A. D. The incidence of systemic lupus erythematosus in North Amerxan Indians. J. Rheumatol 3, 186, 1976. 25. Fries J. F. and Holman H. R. Systemic Lupus Eryfhematosus a C’hnical Analysis. Saunders, Philadelphia. 1975. 26. Kay D. R., Bole G G. and Ledger W. J. Anti-nuclear antibodies, rheumatoid factor and C-reactive protein in serum of normal women using oral contraceptives. Arthrit. Rheumat. 14, 239. 1971. 27. McGlashan N. D. Spatial variations in cause-specific mortality tn Austraha. In Studies m Ausrrahan Mortality (Edited by McGlashan N. D.), pp. l-28. University of Tasmania Environmental Studies Occasional Paper No. 4, Hobart. 1977. 28. McGlashan N. D. (Ed.) Medical Geography. Techniques and Field Studies. Methuen, London, 1972. 29. Hunter J. M. (Ed.) The Geography of Health and Disease. University of North Carolina at Chapel Hill. Department of Geography, Studies in Geography, No. 6, 1974. 30. Hospital Starwics of New Zealand, March 1961. Department of Health, Wellington, N.Z.