Histocompatibility

Antigens and Rheumatic

Diseases

ByJ.C. Woodrow

R

HEUMATIC

DISEASES for which important associations with the HLA system have been demonstrated’ belong to the category of diseases in which it is likely that genetic and environmental factors both have a role. They cannot be explained on the basis of a single gene being necessary and sufficient to produce the disease, but the pattern of familial aggregation often identified in these diseases suggests that environmental agencies alone are not sufficient cause. A genetically determined host response to an environmental agent seems to be the most likely basis for pathogenesis in the diseases under consideration. Until recently the genetics of such disorders as ankylosing spondylitis and psoriasis could only be analyzed in terms of a theoretical model of polygenic inheritance; the discovery that genes of major importance in determining susceptibility are present in the HLA chromosomal region gives the opportunity of much greater understanding of etiological mechanisms. HLA SYSTEM

Figure 1 gives a simple picture of some of the known genetic loci in the region of the HLA complex on chromosome 6.” HLA loci A, B, and C are defined serologitally and D by the mixed lymphocyte reaction. Current knowledge of these systems and agreed nomenclature have been embodied in a recent report.3 Linkage and Association Genetic linkage refers to the close proximity of genetic loci on the chromosome. Close linkage between two loci results in alleles at the two respective loci on the same chromosome tending to segregate together during the inheritance of genetic material, in contrast with the independent segregation seen for nonlinked genes. Thus an allele at one locus will tend within a family to be associated with a particular allele at a closely linked locus. Because of the close linkage of the four HLA loci (A--D), the alleles at these loci tend to be inherited together, the genetic information thus constituted on one chromosome being the haplotype. Thus the full HLA genotype of an individual is made up of two haplotypes. Recombination within the HLA region is well documented, so that a new haplotype may occasionally appear within a family. Until recently it had been accepted as the general rule that even with closely linked loci a particular allele at one locus will not be positively or negatively associated in the general population with any particular allele or alleles at the linked locus. The reason for this is that if a mutant allele appears at the first locus it will tend to segregate at first with the particular alleles which happen to be present at adjacent loci. However, in later generations occasional recombinations

From the Nujield Unit oJMedical Genetics. University of Liverpool. Liverpool, England. Address for reprint requests: J. C. Woodrow, M.D., F.R.C.P., Reader in Medicine, Nufield Medical Genetics, University of Liverpool, Liverpool, England. ‘L:1977 bv Grune & Stratton. Inc. Seminars in Arthritis and Rheumatism, Vol 6. No. 3 (February),

1977

Unit OJ

257

258

PGM3 I--u

J. C. WOODROW

r

Chido Gb 1

Fig. 1. Representation the loci in the HLA region.

of the relative location of some of

will occur, so that the mutant allele will become associated with alternative alleles at the adjacent loci and eventually attain equilibrium with the polymorphic systems determined by these loci. The result is that when individuals with a mutant allele are tested for the frequency of the different polymorphic genes at a linked locus there will be no difference from that seen in a control population of individuals without the mutant gene. Therefore if a particular allele at one locus is found to be nonrandomly associated with a particular genetic polymorphism determined by a second closely linked locus, a situation of linkage disequilibrium is present. The allele is found to be present in association with one or more particular phenotypes determined by the polymorphism. In theory this could arise if the allele has appeared in the population relatively recently, so that an insufficient number of generations have elapsed for equilibrium to be reached. However, in most instances of linkage disequilibrium some selective forces are thought likely to be involved to maintain the disequilibrium.4 Where it is found that a particular phenotype or phenotypes of the HLA system occur with significantly increased frequency in individuals with a particular disease, two main possibilities are to be considered. First, the gene product of the HLA gene in question may play a role directly in producing increased susceptibility to the disease. Second, the gene giving rise to susceptibility to the disease may be at a locus in the HLA chromosomal region, this gene being in linkage disequilibrium with the HLA system.5 This is an important theoretical concept in our attempts to understand the nature of HLA and disease associations.6 HLA genotyping of members of families in which two or more individuals with a particular disease are present can provide valuable information additional to and complementary to population studies. The association of the presence of disease in members of a family with a particular HLA haplotype can be studied. This resembles the study of genetic linkage between two defined genetic loci, but some caution is necessary. Because the diseases under consideration are not necessarily homogeneous from the etiological point of view, it is possible that while one or more affected individuals in a family may possess an HLA-linked gene, causing susceptibility, a further affected member might have the disorder with a completely different genetic basis. In addition, if the disease in question is relatively common, e.g., psoriasis, there is the possibility that more than one HLA -linked gene for the disease may be segregating in a family. Because it is assumed that the hypothetical gene for disease susceptibility is not sufficient in itself to give rise to the disease, it is to be expected that some individuals in the family will inherit the gene in question but will not show the disease. In some instances the pattern of inheritance of HLA haplotypes in families can give important information about the inheritance of a disease. For example, if affected siblings are studied, it may be possible to show that they inherit the same HLA haplotype from one or both parents to a degree which departs from the random pattern of zygotic assortment. This can provide strong evidence for the

HISTOCOMPATIBILITY

259

ANTIGENS

presence of a gene producing susceptibility to a disease closely linked to the HLA system, e.g., as has been done for juvenile onset diabetes.’ A related type of analysis has been applied to families with multiple sclerosis.’ Family studies are necessary to establish the HLA genotype, as opposed to the phenotype, and this may yield important information, e.g., whether disease susceptibility is increased in the presence of homozygocity for an HLA phenotype as opposed to the heterozygous state. Some Problems

of Methodology

In the study of HLA and disease associations it is important to take note of certain points which can cause difficulties. Putient series. Series of patients, collected as a rule at special centers, tend to involve bias in ascertainment. There may be differences between centers in the application of diagnostic criteria and in the interpretation of clinical and radiological findings. These points must be borne in mind when comparing the results of studies carried out in different centers. Control series. The ideal control series is not easy to achieve. It has not been shown that variations in sex and age have any important effect on HLA antigen frequencies. There are, however, important racial variations in the relative frequencies of the different HLA antigens .g In populations where there is considerable racial heterogeneity the constitution of the control series becomes very relevant. Statistical problems. Study of HLA associations implies that multiple comparisons are being made between two groups, and caution is required in interpreting the less obvious differences in the frequencies of particular HLA antigens. This problem has been documented and analysed by Svejgaard et al.‘” Commonly, results are expressed as the relative risk, i.e., the risk of developing the disease in an individual with the HLA antigen relative to that in one without the antigen. This is measured by the cross-product ratio of Woolf” or its modification by Haldane.” The latter is given by (2a+

1)(2d+

1)

(26 + 1)(2c + 1) where a is the number the number of controls relative risk is unity.

of patients with the antigen and b the number without, ( with it and d the number without. With no association the

HLA-B27 HLA-B27

and Ankylosing

Spondylitis

Further studies have largely served to confirm the very high relative risk, found by the original studies, for ankylosing spondylitis in B27-positive individuals (Table I). No doubt some of these studies have been much enlarged and many unpublished ones have been carried out. Although there is some variation in the documented frequencies of B27 in ankylosing spondylitis, there is in fact no signifi cant heterogeneity. The overall frequency of B27 is 88.3%, with a combined relative risk of 76.

260

J. C. WDODROW

Table 1. Association of HLA B27 With Ankylosing Spondylitis

Series (First author)

Number of PatlelltS

Relative Risk

With 827 I%1 PatlMltS

COlltKllS

(Haldane)

Brewerton’

75

96.0

4.0

Schlosstein”

40

87.5

7.9

429 74

Amor”

53

81.1

4.0

92

Nagant de Deuxchaisnes”

31

90.3

8.5

85

Sachs”

67

94.0

9.8

127

Cross’R

47

91.5

7.8

111

MillsI

27

96.3

9.1

175

van Rood”’

80

85.0

5.5

92

126

85.7

12.0

42

Mb;ller*’

35

91.4

8.7

134

Van den Berg-Loonen’”

SanyZZ

115

82.6

9.9

42

Woodrow-

116

90.0

8.7

87

Combined relative risk, 76. x’ for heterogeneity, 15 68: 11 d.f (degrees of freedom), p = 0.15.

Eflect of gender. The reason for the preponderant involvement of males by ankylosing spondylitis is not understood. Comparing the frequency of B27 in male and female spondylitics, three series provide evidence that there is no significant difference in this respect.20~24~25 In a total of 171 males with spondylitis, 150 (87.7%) were B27 positive, as were 49 out of 56 females (87.5%). Thus B27 does not appear to be relevant to the differing sex incidence of spondylitis. Age of onset. It is not always easy to determine with any accuracy the age of onset of ankylosing spondylitis. The symptoms may initially be episodic, patients with established disease may have an uncertain memory of the early symptoms, and indeed advanced changes may be present in patients who recall little of pain and stiffness over the years. Nevertheless, it has been suggested that there is a higher frequency of B27 in those patients with an earlier age of onset. Feldmann et a1.26 found two B27-positive patients among five whose apparent age of onset was later than 40 yr, in contrast with 35 out of 40 with an earlier age of onset. Berg-Loonen et a1.23 claimed a statistically significant variability in the frequency of B27 according to age of onset, e.g., four out of ten with onset at 45 yr and older had B27, contrasting with 30 out of 32 with onset up to 20 yr of age. This relationship is not obvious in a personal series. Of 13 B27-negative patients, 7 had an age of onset 20-34 yr, 5 had onset at 35544 yr and 1 had apparent onset later than 45 yr. The possibility that there is heterogeneity in respect to age of onset is worthy of further study, since, if confirmed, it might imply etiological heterogeneity with perhaps different environmental factors operating at different ages. A clearcut heterogeneity in this regard has been demonstrated for HLA-B17 and psoriasis.27,28 Severity of disease. Ankylosing spondylitis varies markedly in clinical severity and in the extent of involvement of sacroiliac joints, spine, and peripheral joints. It has been suggested that the milder, more localized cases show a lower frequency of B27. For example, MSller and Olhagen 21 found all 66 patients with radiologically demonstrable syndesmophytes in the spine to be B27 positive, while 70% of 60 patients with sacroiliitis as the only radiological manifestation had B27. Simi-

HISTOCOMPATIBILITY

261

ANTIGENS

patients among 25 with milder larly, Feldmann et al. 26 found 6 B27-negative disease and only 1 among 25 with moderate or severe disease. However, this has not been the universal experience; Berg-Loonen et al.23 found no correlation between the frequency of B27 and the severity of radiological sacroiliitis. Jeannet et al.‘,s found 3 B27-negative patients among 14 females with radiological involvement of the spine. Among the 13 B27-negative patients in a series of 116, several had quite severe progressive spinal disease.‘? It remains therefore to be proved that there is a significant difference in the course of the disease in B27-negative patients in contrast with B27-positive patients. Differences in findings relating to severity could arise in two ways. First, with increasing mildness of disease, uncertainty of diagnosis becomes a factor, and the detailed application of available clinical and radiological criteria may vary from one group to another. Second, patients with mild disease might be etiologitally more variable than well-established cases. Presence of peripheral small joint involvement. It is likely that chronic peripheral small joint arthropathy in patients with ankylosing spondylitis is etiologitally heterogeneous. Occasionally coincident seropositive rheumatoid arthritis may be present. For example, this was seen in one male out of 116 successive patients with spondy1itis.24 Patients may have both ankylosing spondylitis and one or more attacks of Reiter’s syndrome. It could be that chronic peripheral joint arthropathy may be related to the Reiter’s syndrome in some patients. Patients with psoriasis may have both ankylosing spondylitis and peripheral arthropathy. The psoriasis may appear subsequent to either the spondylitis or peripheral arthropathy. This was seen strikingly in one patient who developed chronic peripheral arthropathy at the age of 12 yr; back symptoms at 19 yr with

Table

2.

Association

of HLA

in Patients

With

827

With

Spondylitis

Inflammatory

Bowel

and

Sacroiliitis

Disease Ankylosmg

Ankylosmg

Spondylltls

Spondyhtls

or Sacraliltls 827 Posltlve

NO

Brewerton’Y

18

13

20

13

Nagant

11

3

21

3

11

10 12

8

7

3’

de Deuxchaisnes”

Russell30 Bluestone”’ Goods2 Van den

Berg-Loonenz3

Woodrow= Combwed

39

20

15

9

risk

13.4

X2, 1 d.f X2+

9.6 0.048 I” combined

heterogeneity.

analysis,

since

control

data

Posltlve

17

9 12.2

127

P+ * Not included +For

827

NO

80 (4 d.f.1

11 .5 (3 d.f.) 001

not given

262

J. C. WOODROW

subsequent development of severe ankylosing spondylitis, and evidence of psoriasis at the age of 29 yr. There remains a group of patients with peripheral joint disease not including hip or shoulder involvement. In a series of 116 patients, three had peripheral arthropathy, with clinical or radiological evidence in each case suggestive of psoriatic arthritis, although none had psoriasis and all were B27 negative.24 Ankylosing spondylitis and injiammatory bowel disease. Table 2 documents published data on the frequency of B27 in patients with inflammatory bowel disease and ankylosing spondylitis or sacroiliitis. Combining the data, 58.5% of patients with definite spondylitis were B27 positive. However, there does appear to be significant variation between the different centers in this regard. This suggests differences in criteria used for diagnosis of the inflammatory bowel disease or of the arthropathy. Data from three series 23,24,30can be combined to show that 18 out of 35 (5 1%) B27-positive patients with bowel disease had ankylosing spondylitis or sacroiliitis. Assuming that the frequency of B27 in patients with inflammatory bowel disease is 8%, the implication is that 7% of patients should develop spondylitis or sacroiliitis. This estimate fits well with previous studies in respect of ankylosing spondylitis, but estimates for all cases, including those with sacroiliitis may lie partly in the alone, are of the order of 17%-18%. 33*34The discrepancy different radiological assessments of sacroiliitis. The frequency of B27 in patients with ankylosing spondylitis and inflammatory bowel disease is significantly lower than 88% seen in ankylosing spondylitis without bowel disease. A genetic explanation is that one or more of the pool of genes involved in susceptibility in inflammatory bowel disease also increase susceptibility to ankylosing spondylitis. Such genetic overlap would explain their occurrence together more than would be expected by chance and also their aggregation in families.3” B27 and the Genetics

of Ankylosing

Spondylitis

Familial aggregation of ankylosing spondylitis has been repeatedly shown.36.37 The pattern of familial occurrence of spondylitis in these studies cannot be explained on the basis of a single gene being necessary and sufficient to cause the disease. It is now evident that what is almost certainly the major genetic factor, called for convenience the AS gene, is in the HLA chromosomal region and is either HLA B27 itself or a gene in very marked linkage disequilibrium with B27. Its importance is shown by the high relative risk, i.e., 76, in B27-positive individuals. In attempting to elucidate the relationship of B27 to the aetiology of ankylosing spondylitis the following interrelated parameters must be considered: (a) the frequency of B27 in the population; (b) the proportion of B27 positive individuals in the population who develop spondylitis; (c) the prevalence of spondylitis; (d) the proportion of spondylitics who are B27 positive; and (e) the relative risk of spondylitis in B27 positive individuals. Parameters (a), (d), and (e) are now known fairly accurately for white populations. In regard to (c), the prevalence of spondylitis is still not certain. West’s extrapolation from patients seen at one hospital38 and the particular control popudata. lation for a family study of de Blicourt et al. 36 do not provide satisfactory

HISTOCOMPATIBILITY

ANTIGENS

263

The population studies carried out by Lawrence and his co11eagues37~3g~40represent the best attempt to document prevalence in a white population. It was concluded that something of the order of 0.4% of males have clinical ankylosing spondylitis, but the frequency of radiological sacroiliitis was in the region of 5%. In females the prevalence of clinical disease was considerably less, and the frequency of sacroiliitis was about 1.5%. The standard errors of these estimates must be considerable. In relation to parameter (b), the proportion of B27-positive individuals who develop spondylitis, some direct evidence has recently been documented. Calin and Fries4’ ascertained by questionnaire a group of patients with symptoms suggestive of inflammatory sacroiliac disease or spondylitis from a population of 90 B27 individuals who were part of a large HLA-typed population. Nineteen of these had been X-rayed, thirteen were found to have grade 3 or 4 sacroiliitis, and one with grade 2 changes had physical signs suggestive of spondylitis. Thus 8 of 48 females (17%) and 6 of 30 males (20%) were thought to have definite spondylitis. Most of the 14 patients diagnosed as having spondylitis would, on the evidence given, have been readily diagnosed as definite or probable cases of spondylitis if seen by rheumatologists. What is surprising is that of the 14 definite cases ascertained, eight were females. Common experience suggests that spondylitis is much less prevalent in females. The authors suggest that equivalent symptoms in females may, in contrast with those in males, be more difficult to distinguish from the multiple causes of low back pain, and that appropriate X-rays may not be so frequently carried out. However, this is unlikely to be the complete explanation. In a study carried out in Liverpool 24 both parents of 21 B27-positive spondylitic patients were studied clinically and radiologically for evidence of spondylitis. Five of thirteen B27-positive fathers had definite spondylitis or sacroiliitis, a frequency of 38%. None of eleven B27-positive mothers had any clinical or radiological changes. Cohen et al.“2 have reported a study of 24 B27-positive males ascertained from a large population of HLA-typed individuals. Three were thought to have definite spondylitis and three others possibly had spondylitis. This would imply a prevalence in males of 1.5%-2%, with a frequency of disease in B27-positive males of up to 25%. If the various sources of evidence detailed above are somewhere near the truth, it can be computed that of 1000 males in a white population 80 are B27 positive and something like 16 develop spondylitis or sacroiliitis. A further 2 B27-negative individuals would develop spondylitis, giving a total prevalence of 1.8%. This estimate lies between the 0.4% prevalence of clinical spondylitis and the 5% incidence of radiological sacroiliitis found by Emery and Lawrence.“’ It can be presumed that in many instances the condition would be mild or nonprogressive. Is the gene for B27 the AS gene? If the AS gene were B27 itself it would be expected that in families where two or more patients with spondylitis occurred, all affected members would be B27 positive. In an investigation of 15 families in which two or more close relatives had spondylitis no such disassociation has been found.‘4 In the published literature there are just two reports of B27-negative spondylitic siblings of B27-positive probands. 43*44These families have been interpreted as possibly showing a recombination between the AS gene and B27.

264

J. C. WOOOROW

However, it cannot be ruled out that other genes predisposing to spondylitis might be segregating in these families. In relation to this it is necessary to explain the B27-negative patients in a more general context. Some B27-negative cases may occur largely on environmental basis, and others may depend on the presence of genes not in the HLA region. In regard to the latter it is relevant that not infrequently sacroiliitis or spondylitis occur in B27 negative individuals who also develop inflammatory bowel disease or psoriasis. Mentioned previously was the finding that 3 of 13 B27-negative patients had peripheral small joint arthropathy with features suggestive of psoriatic arthritis, although they did not have psoriasis, nor was there a positive family history of psoriasis.24 Moreover, a further B27-negative patient had a mother and a sister, also B27 negative, each with ulcerative colitis and spondylitis. These observations suggest that in some instances genes related to the pathogenesis of inflammatory bowel disease or psoriasis might predispose to ankylosing spondylitis. This could occur in the absence of clinical manifestations of these disorders. Decker-Saeys et al.45 carried out a thorough study of a series of patients with ankylosing spondylitis, looking for undiagnosed inflammatory bowel disease, and found no cases not previously recognized. The possibility that B27-negative spondylitis might occasionally occur as an autosomal recessive trait is raised by the study of a family described by van der Linden,46 in which such a patient resulted from a consanguineous marriage. It would be of interest to know whether there is an increase in the consanguinity rate among parents of B27-negative spondylitics. Also to be considered is the evidence relating to the possibility that the AS gene is not the B27 gene, but being in strong linkage disequilibrium with B27 is nearly always associated with this gene on the chromosome although occasionally being associated with other B-series genes, i.e., in B27-negative spondylitics. One would expect such patients to show disease identical clinically and genetically with the B27-positive patients. As stated above some evidence has been put forward to suggest some clinical heterogeneity in this respect, but this remains to be confirmed. From the genetic point of view it appears that so far no family has been documented in which two or more B27-negative individuals have spondylitis. This is somewhat surprising if in fact most B27-negative spondylitics have the same AS gene as B27-positive patients and if one takes into account the fact that clinical evidence of spondylitis is evident in one or more close relatives in at least 12% of families.37 The evidence concerning the relationship of the AS gene to the B27 gene cannot be interpreted conclusively at present. Evidence was quoted above to suggest that something of the order of 20% of B27-positive males develop ankylosing spondylitis or sacroiliitis. Possible explanations are as follows: (1) The B27 gene is the AS gene, but another interacting gene(s) is needed to produce susceptibility. Some evidence for the latter has been produced in family studies.46,48 (2) The AS gene is present in only a proportion of B27-positive individuals, e.g., 20%. (3) Important environmental factors are operative. This can be seen as likely from personal observation of two pairs of identical twins, both pairs being B27

HISTOCOMPATIBILITY

265

ANTIGENS

Table

3.

Frequency

of HLA

827

in Different

Racial

Groups Phenotype

Frequency of 827 (%)

Population’ Haida

Coola

Pima

Indians

Other

19

Eskimos

Mongoloids

lndlans

14 6-27 4-17

Japanese

1

Caucasians

8

American W. African S African S American Australian ‘From

25

Indians

N. American

Greenland Asian

50

Indians

Bella

Negroes Negroes Bantu Indians Aborigines

1.8 0 0 0 0

Refs. 9 and 49-51.

positive with, in each case, only one of the twins having spondylitis. The ages of the pairs of twins are 45 and 52 yr, and it is unlikely that the unaffected twins will get the disease. Evidence from d#erent racial groups. Table 3 shows that the B27 gene is widespread among many different races. It appears to be absent from certain racial groups in the southern hemisphere, but in other geographical areas the gene frequency varies from approximately 0.005 in the Japanese to approximately 0.29 in the Haida Indians of British Columbia, Canada. A remarkably high prevalence of ankylosing spondylitis has been documented in British Columbian coastal Indians.50~“2 The Haida Indian males were considered in a recent survey to have a prevalence of sacroiliitis of approximately lo%, and it was found that all 17 males with sacroiliitis had B27 and that 50% of 222 individuals free from sacroiliitis were B27 positive. 5o There was evidence of an excess of B27 homozygotes in the population, suggesting considerable inbreeding. The data suggest that approximately 20% of the B27-positive males would get sacroiliitis. The frequency of B27 in the Bella Coola Indians was 25%, and the prevalence of sacroiliitis was somewhat uncertain, but possibly just over 2%. Only three affected males were tested, and all had B27. It can be estimated that about 8% of B27-positive males would get sacroiliitis. In regard to the Pima Indians there is evidence that 4.5% of males over the age of 25 yr have grade 334 sacroiliitis”3 and that 19% are B27 positive.Q If most males with sacroiliitis are B27 positive, this would imply that approximately 23% of B27-positive males develop sacroiliitis. In regard to the American black 1.8% have B27.“’ There is indirect evidence that the prevalence of spondylitis in the American black is less than that for the white population, perhaps by a factor of 3.54 Three studies of the frequency of B27 in the American black with spondylitis give a combined figure of 28 of 48 (58%). 14,32.55 The frequency of B27 in the Japanese population is approximately I%,@ and Sonozaki et a1.56 found that 66% of their patients with spondylitis were B27 positive, which appears to be significantly lower than that for white populations. It is interesting to note that as the frequency of B27 in the population rises, e.g.,

266

J.

C. WOODROW

1%-2% in American blacks and in Japanese to 8% in whites, and to 50% in the Haida Indians, the frequency of B27 in patients with ankylosing spondylitis also rises, i.e., from approximately 60% to 88% to lOO%, respectively, in the above populations. Although the data on which these estimates are based require confirmation in some instances, there is an implication that the relative risk for spondylitis in B27 individuals may not vary a great deal from population to population. The implication would be that the contribution of the AS gene, whether it be the gene for B27 or not, to the total of genetic and environmental factors which underly spondylitis is relatively constant. The high relative risk seen in all the racial groups studied cannot itself help in the argument as to whether the AS gene is B27 or a gene in linkage disequilibrium with B27. Homozygocity for B27. There is some evidence “,38.24*26that the ratio of possible homozygous to heterozygous B27-positive patients is appreciably higher than the I:46 in the typical white population as a whole. If this is confirmed it implies a greater susceptibility of the homozygote B27 individual to spondylitis. Juvenile Chronic Polyarthritis The problem of clinical heterogeneity looms large in children with chronic polyarthritis. In relation to the frequency of B27 this was clearly demonstrated by Edmonds et al.,57 who studied selected groups of patients followed up for many years. Six of the seven who eventually developed spondylitis and all eight who developed radiological sacroiliitis were B27 positive. This reflects the atypical presentation of ankylosing spondylitis in children. Of the 20 seronegative patients who did not develop sacroiliitis, four were B27 positive. Gibson et al.58 studied a group of patients from which those with ankylosing spondylitis had been excluded. Of 123, 18 (14.6%) were B27 positive (control 6%). Unselected groups of patients have given frequencies of B27 of 29.4%, 42%, and 17% (controls 8.6%, 6%, 14%, respectively). 5g-61 The inclusion of patients in whom the peripheral arthropathy is a forerunner of ankylosing spondylitis might be expected to increase the frequency of B27 to perhaps 20%-25%. There is no clear evidence of a relationship of B27 to seronegative arthropathy in those who do not develop sacroiliitis or spondylitis. Table SS?WZS

4.

Association

of HLA

827

With

Number

Reiter’s

Syndrome Relative

With 627 (%I

Risk

(First

of

author)

Patients

Patients

Brewertone

33

75.8

6.1

38

Murise

24

95.8

8.1

178

ColltrOlS

(Haldane)

Woodrow+-’

76

69.7

8.7

24

Aho@

40

90.0

14.0

49

Amorls

46

80.4

4.0

88

Zachariae”

48

64.6

8.1

20

Mills?

23

73.9

9.1

27

Harris!’

25

56.0

8.8

13

Isomaki”8

18

83.3

14.0

27

McCluskeve8

30

63.3

4.0

43

Combined

risk 27.

* Reported

series

x2 (1 d.f.) 488. included

x2 for heterogeneity

50 patients.

15.7.

9 d.f.. p = 0.07

HISTOCOMPATIBILITY

ANTIGENS

267

HLA B27 and Reiter’s Syndrome Table 4 documents the association between B27 and Reiter’s syndrome, as reported by various researchers. It is clear that the association is less strong than for ankylosing spondylitis, with an overall frequency of B27 of 74.5%, compared with 88.3% for ankylosing spondylitis. There is suggestion of variation between the different centers, corresponding possibly to clinical heterogeneity because of the method of ascertaining the patients. It has been suggested that patients whose disease is more prolonged and relapsing are more likely to be B27 positive,” but this has not been found by others.66.67 Of 39 documented patients with radiological sacroiliitis or spondylitis, all but one had B27. There is insufficient evidence on a possible association with chronic peripheral joint changes, but Brewerton et al. 62 found that of seven patients with peripheral arthritis of more than 5 yr duration, two were B27 negative. The occurrence at some stage of anterior uveitis was noted in 40 patients, and of these 38 were B27 positive. This implies that anterior uveitis is uncommon in B27-negative individuals who develop Reiter’s syndrome, although it is by no means uncommon in B27-negative individuals without rheumatic disease (see below). The implication is that the genetic and environmental factors in most if not all cases of B27-negative Reiter’s syndrome differ in some degree from those in B27-positive cases. Relationship to ankylosing spondylitis. The relationship between Reiter’s syndrome and ankylosing spondylitis can now be seen to be a complex one. Both tend to occur predominantly in the same 8% or so of the male population, and it is to be expected that they should not uncommonly occur in the same individual@j4 or in close relatives.64s70 In a series of 50 patients with Reiter’s syndrome64 four were of interest in that three showed radiological sacroiliitis at the first attack and gave a history of symptoms suggestive of sacroiliitis over several years prior to this acute episode, while the fourth developed the first symptoms of progressive spondylitis 11 yr after an episode of Reiter’s syndrome that occurred at the age of 17 yr. It is likely that the Reiter’s syndrome and ankylosing spondylitis in these individuals were separate pathogenetic processes occurring in the same genetically predisposed individual. Indeed, it is to be expected on the basis of the studies noted above4’,*” that the prevalence of sacroiliitis or spondylitis should be, at a minimum, 75% of that in random B27-positive males, perhaps of the order of 15%. In other words, 15% of males who have Reiter’s syndrome should be expected to quite independently develop ankylosing spondylitis in some degree. In addition, spondylitis may develop in some as a consequence of the Reiter’s disease itself.

Fig. 2. Diagram of a family in which a patient with ankylosing spondylitis (III 3) and patient with biter’s syndrome (IV 1) wereindependently ascertained.

268

J. C. WOODROW

q I

REITER’S

SYNOROME

nNK”LOSlNG SPONDYLITIS

Fig. 3. Diagram of two HLA BP7-negative brothers. one with Reiter’s syndrome and the other with ankylosing spondylitis. (WlO = W40.1

The prevalence of sacroiliitis in patients who have had Reiter’s syndrome has been reported as 20%, with an average followup period of about 7 yr.” Although sacroiliitis does occasionally occur in B27-negative males who have had Reiter’s syndrome, it is clearly much less common than in B27-positive patients. This is to be expected on the basis that possession of B27 is associated with a greater risk of sacroiliitis. That the B27 gene itself or the associated AS gene can cause susceptibility to both conditions is seen in families where one member has Reiter’s syndrome and another ankylosing spondylitis;64 a further example is shown in Fig. 2. Of considerable interest is that approximately 25% of Reiter’s syndrome patients are B27 negative. This suggests a greater genetic heterogeneity and a wider spectrum of relevant environmental agents, especially infective, in these patients than in those with ankylosing spondylitis. The observation by Lawrence” that the prevalence of psoriasis in the relatives of probands with Reiter’s syndrome was similar to that in relatives of probands with psoriatic arthritis suggests the possibility that psoriatic genes may play an important role in susceptibility to Reiter’s syndrome in some instances. The family diagrammed in Fig.3 is of particular interest because both the proband with Reiter’s syndrome and his brother with clinical and radiological sacroiliitis were B27 negative. It could be that the AS gene was present but associated in this family with BW40 and not B27. Relationship of Reiter’s syndrome to psoriasis. The clinical observations of among others, and the family studies of Lawrence7’ emWright and Reed,72 phasize the close etiological relationship between the two conditions. The patients who show a development from acute Reiter’s syndrome with severe keratoderma blenorrhagica, and widespread psoriasiform lesions, to chronic arthropathy showing features of psoriatic arthritis, sometimes with sacroiliitis and chronic psoriasis, appear usually to be B27 positive.64 Two reports suggest that there is no increase in the freGonococcal arthritis. quency of B27 in patients with gonococcal arthritis.63,73 HLA

B27 and the Psoriatic Arthropathies

Sacroiliitis

tion between

and spondylitis.

Most studies have shown that there is an associaB27 and the sacroiliitis or spondylitis which occur, with or without

HlSTOCOMPATlBlLlTY

269

ANTIGENS

Table 5. Association of HLA 627 With Spondylitis or Sacroiliitis in Patients With Psoriasis

With or WIthout

Peripheral

Peripheral Arthntts

Arthntls’

Absent

SerleS No. With

(First author)

Total

827

No With Total

827

11

3

7

?

7

7

13

Brewertor?

19

Metzger74

23

8

MarCUSSen7~

22

10

Zachariae76

13

7

Sany’”

18

3

Feldmann”

26

13

Karvonen7R

25

15

Eastmond’g

28

18

‘Combmed risk 1 1, x2 (1 d.f.) 182. x2 for heterogeneity 15.1, 7 d f , p

= 0.03

peripheral arthritis, in patients with psoriasis (Table 5). The overall frequency of B27 in this group of patients is 50%. There does appear to be some variation; e.g., Sany et a1.22 reported only a 17% frequency of B27. Comparing those patients showing radiological sacroiliitis only with those showing spinal changes in addition, combined data from three series2g~77~7gshow 16 of 3 1 (52%) of the former group and 28 of 42 (67%) of the latter to be B27 positive, the two figures not differing significantly. In one series there was also no difference between those showing marginal and those with nonmarginal syndesmophytes.7g Few workers report data for patients with sacroiliitis or spondylitis in the absence of peripheral arthritis. Marcussen et a1.75 report 3 of 11 such patients to be B27 positive, but their series appears to be selected in an unusual way, in that only three patients of the series of 25 did not have sacroiliitis. In contrast, the seven patients falling into this category in the Liverpool study7Q were all B27 positive. Notable was that six were males, and the age of onset of symptoms was always less than 40 yr. This pattern is compatible with a coincidental occurrence of ankylosing spondylitis in patients with psoriasis. In contrast, of the 21 patients showing peripheral psoriatic arthritis, 7 were female, 10 were B27 negative, and of the 16 in whom a reasonable history of the age of onset of back symptoms was available, the age of onset was over 40 yr in seven. The ten patients who had sacroiliitis but lacked B27 all had peripheral arthritis. The evidence suggests the hypothesis that in most instances, at least genes for psoriatic arthritis were involved in the pathogenesis of the sacroiliitis as well as the peripheral arthropathy. Peripheral psoriatic arthropathy. Table 6 gives available data on the frequency of B27 in these patients. The overall frequency of B27 irrespective of the presence or absence of sacroiliitis is 30%; in those without sacroiliitis it is 18%. In both instances the frequency of B27 is significantly greater than in controls, and although there appear to be appreciable differences between the series, there is no significant heterogeneity. Thus there is good evidence that B27, or the AS gene associated with it, increases susceptibility to peripheral psoriatic arthritis. One problem is clinical heterogeneity. 8o A detailed analysis of 40 patients with distal interphalangeal joint disease and psoriasis in a Liverpool study showed the

270

J.

C. WOODROW

Table 6. Association of HLA 827 With Peripheral Arthritis in Patients With Psoriasis Peripheral Arthritis With or Without

Without

Sacroililtls

Sacrolliitis

Series (First

No. With

author)

Total

B27

No. With Total

B27

?

Brewertonz9

41

10

Metzger74

40

11

17

Marcussen”

14

9

3

Zachariae76

44

13

29

SanyZZ

52

6

43

5

Feldmann”

63

?

44

3

KaNO”e”‘8

65

26

40

11

Eastmond”

52

17

30

7

Combined x2,

risk

3 2 6

4.4

1 d.f.

2.7

104

P x2 for heterogeneity

25 1O-24

1.8

x

8.7

(6 d.f.1

1O-7

4.0

16 d.f.)

0.68

0.19

P

6 x

following:” 32.5% were B27 positive, and of the 26 without sacroiliitis 26.9% had B27. In both instances the frequency of B27 was significantly higher than the 8% found in controls. Of 12 patients with peripheral arthropathy not involving distal interphalangeal joints but with features, clinical or radiological, making rheumatoid arthritis unlikely, 4 had B27 and all 4 had sacroiliitis. Six patients had various radiological changes in the spine, sometimes florid, in the absence of sacroiliac changes, and all lacked B27. Table 7 suggests a possible interpretation of these findings. Psoriatic patients with peripheral arthritis have genes predisposing to psoriasis, some of which may be particularly involved in the pathogenesis of the arthropathy, and B27 also increases susceptibility to this form of arthropathy. The same genes are involved in those who develop sacroiliitis in addition to peripheral arthritis. In the absence of B27, genes for psoriasis are involved in the pathogenesis of the sacroiliitis. Some, at least, of the psoriatic patients with sacroiliitis or spondylitis in the absence of peripheral arthropathy represent the coincidental occurrence of the two diseases. Genes for psoriasis may play a role in some B27-negative spondylitics in the absence of psoriasis (see above). Other HLA antigens. The frequency of BW38 (W16.1) has been found to be Table 7.

Relationship

Between

Spondylitis.

Peripheral Arthritis.

and Psoriasis: Genetic Interpretation

Patients

with

psoriasis

Peripheral

arthritis

Peripheral

arthritis

plus sacrolhitis

Genes for Psoriasis’

HLA 827

+

+

+

Patients *These

without may

psoriasis

include

genes

827~negative particularly

predisposing

+ +

Sacroiliitis ankylosing

spondylitis

to arthropathy.

+

HISTOCOMPATIBILITY

271

ANTIGENS

increased in patients with various forms of psoriatic arthropathy compared with controls 22,77 but since a significant increase of “HLA W16” was found in a general series of patients with psoriasis, ~3’the relevance of this finding is uncertain. There is some evidence that there is a lowered frequency of BW17 in patients with sacroiliitis or spondylitis compared with that in psoriatic patients generally.22,75,77.7g Gastrointestinal

Infections

and Arthritis

Data are available from two separate epidemics of Salmonella typhimurium infectionx2,83 in which a total of 19 individuals out of 696 infected cases developed arthritis. Of the 18 affected patients who were HLA typed, 12 (67%) were B27 positive. It can be computed from the available data that approximately 20% of the B27-positive individuals with infection developed arthritis. Aho et a1.81 reported that 15 of 16 patients with Salmonella arthritis were B27 positive. Assuming that the incidence of arthritis in the relevant population of infected individuals was similar to that in the above two epidemics, it can be computed that about 19% of infected B27-positive individuals developed arthritis. Aho et a1.65 reported that 43 of 49 patients with Yersinia enterocolitica arthritis were B27 positive (control 14%). It was thought that the arthritis was more localized and less persistent in B27-negative patients. The relative risk of getting arthritis after the infection in B27-positive individuals was 40. Seven patients who subsequently developed sacroiliitis were all B27 positive. Of interest was that only 2 of the 43 who were B27 positive could have been homozygous for B27. This proportion is very similar to the 1 of 26 that can be computed to occur in the general population of Finland,65 suggesting that homozygous B27 individuals and those heterozygous are equally susceptible. This contrasts with the pattern shown by patients with Reiter’s syndrome, reported by the same group, the ratio of possible B27 homozygotes and heterozygotes being 15. If this difference is a real one it could imply some important difference between the two conditions in respect to the mechanism of the arthritis. In relation to patients with Shigella dysentery, Aho et a1.84 found 11 of 13 with arthropathy to be B27 positive. Calin and FrieP traced five of nine males who had developed Reiter’s syndrome following an epidemic of Shigella infection affecting 602 males; four were B27 positive. Making certain assumptions about the frequency of B27 in the affected population, an approximate conclusion might be that something like 20% of B27-infected males developed arthritis. Other Seronegative

Arthropathies

Apart from the more or less well-defined diseases already dealt with, certain other arthropathies are of interest in the present context. This is largely because they present clinical features similar to those seen with the major clinical entities. Characteristic features are predominant male involvement, asymmetrical lower limb oligoarthropathy, sometimes with Achilles tendon bursitis, tendonitis, plantar calcaneal periostitis, and sometimes associated skin lesions, especially keratoderma blenorrhagica. The picture may be episodic or persistent. The absence of clear evidence of ankylosing spondylitis or of local infection in the form of nonspecific urethritis or gastroenteritis renders it difficult to categorize these

272

J. C. WOODROW

patients. However, sacroiliitis or spondylitis may develop subsequently and evidence for urethritis may be difficult to establish, especially if antibiotics have been administered. The majority of such patients are B27 positive. Such a clinical picture may appear in a close relative of a B27-positive patient with spondylitis or Reiter’s syndrome. At present it appears therefore most satisfactory to regard these clinical syndromes as part of the natural history of joint disease in B27-positive individuals. Such a series has been documented under the label “incomplete Reiter’s syndrome.“ss What is not known is the exact risk for these individuals of developing ankylosing spondylitis subsequently.

Anterior Uveitis The known association of nongranulomatous anterior uveitis with ankylosing spondylitis and Reiter’s syndrome has led to the study of the frequency of B27 in this condition. Brewerton et al. 87 found 26 of 50 (52%) to be B27 positive (controls 2 of 50), while Woodrow et al. 88 found 51 of 90 (56%) to be positive. In the latter study, of the 63 patients without evidence of systemic disease, 28 were B27 positive (44%), a significantly higher rate than for controls. The relative risk in B27positive individuals is thus 14, appreciably less than for ankylosing spondylitis and Reiter’s syndrome. There is thus strong evidence that susceptibility to nongranulomatous anterior uveitis is increased in B27-positive individuals; this is the likely explanation for its clinical association with ankylosing spondylitis and Reiter’s syndrome. Firstdegree B27-positive relatives of B27-positive patients with ankylosing spondylitis or Reiter’s syndrome may have uveitis only. Notable is that the great majority of patients with either of these two diseases who develop uveitis at some stage are B27 positive. The lower relative risk for ankylosing spondylitis and Reiter’s syndrome, on the other hand, implies possibly that the pathogenetic processes involved in anterior uveitis are not so dependent on the presence of B27 or the AS gene, and this, it seems, may imply a greater heterogeneity of environmental agents, e.g., infective, which can initiate the process. A clinical characteristic is that the anterior uveitis syndrome seen in B27-positive individuals tends to be unilateral, more common in males, showing a diffusely red photophobic lachrymating eye, often showing ptosis, and lasting longer than 3 wk.8g The B27-negative cases tend not to show all these features.

Rheumatoid Arthritis Two reports have suggested a positive association between rheumatoid arthritis and the HLA system. Seignalet et al.g0 suggested a possible increased frequency of BW40. Combined analysis of seven published series’4*68~go-i4 gives a combined relative risk of 1.4, x2 = 4.8, p = 0.03. This result is not very impressive, and in addition there is variation between the studies (x2 = 18.4, p = 0.005). This association seems very doubtful. A Finnish report documents an increase in the frequency of B27 in patients with a peripheral arthropathy of relatively short duration.6s Of 30 seropositive cases, 13 (43%) were B27 positive. Combined data from five other series’4~go~92*g3~94 give a combined relative risk of 1.5 (x2 = 4.1, p = 0.04). There appears to be variation

HlSTOCOMPATlBlLlTY

273

ANTIGENS

Table 8.

Estimate of Incidence of Various Arthropathies in 827-oositive

Ankylosing

Individuals

Source of Data (Ref.)

Clinical Svndrome spondylitis

41.42.50

Salmonella Arthritis

82-84

Shigella Arthritis

85

Reiter’s syndrome

827 lndivtduals Affected (%I 20-25 20 20 9

between different centers, and further evidence is needed to make it possible to decide whether or not being B27 positive is indeed associated with having an increased risk of developing rheumatoid arthritis. Pasternack et a1.g* have reported that 16 out of 26 patients with rheumatoid arthritis and secondary amyloidosis were B27 positive. Male seronegative patients predominated in the B27-positive group. This interesting observation requires confirmation. FINAL

NOTE

Table 8 lists the data that, if confirmed, imply that within the general population of B27-positive individuals there is a subpopulation of approximately 20% that is susceptible to all the arthropathies under consideration here. The lower figure for Reiter’s syndrome, i.e., 9%, is derived from the reported incidence of the syndrome seen by veneriologists in males with nonspecific urethritis, i.e., 0.8%.g5 However, since this is a minimum figure and many cases of Reiter’s syndrome are not seen by veneriologists, the true incidence is likely to be higher; if it were in the region of 2% this would imply that approximately 20% of B27-positive males with nonspecific urethritis develop Reiter’s syndrome. It is now possible to attempt a synthesis of all the findings under the hypothesis that the AS gene is a major factor in producing susceptibility to all these arthropathies. It can be asked whether the figure of 20% arises because this is the frequency of the AS gene on chromosomes bearing the gene for B27 or whether 20% of individuals carry another interacting gene possibly segregating independently of the HLA system. Family studies should help here, because if the former were true virtually all B27-positive close relatives of B27-positive spondylitics would have the AS gene and be highly susceptible, but if the latter possibility were the explanation such relatives would have the interacting gene (segregating independently and acting as a dominant) in 50% of cases as a rule. It was noted above that one study showed 5 of 13 B27-positive fathers of spondylitic probands do have definite sacroiliitis or spondylitis, and this probably favors the second possibility, i.e., a second important gene interacting with the AS gene. REFERENCES I. Brewerton DA, James DCO: The histocompatibility antigen (HL-A 27) and disease. Semin Arthritis Rheum 4:191, 1975 2. Teisberg P, Olaisen B, Gedde-Dahl T Jr, et al: On the localization of the Gb locus within the MHS region of chromosome No. 6. Tissue Antigens 5:257, 1975

3. WHO-IUIS Terminology Committee: Nomenclature for factors of the HLA system. Eur J Immunol5:889, 1975 4. Bodmer WF: Evolutionary significance of the HL-A system. Nature 237:139, 1972 5. Bodmer W: HL-A type and disease entities, in McDevitt HO, Landy M (eds): Genetic Con-

274

trot of Immune Responsiveness. New York, Academic, 1972, p 338 6. McDevitt HO, Bodmer WF: HL-A immune responsegenes anddisease. Lancet 1:1269, 1974 7. Cudworth AC, Woodrow JC: Evidence for HL-A linked genes in “juvenile” diabetes mellitus. Br Med J 3: 133, 1975 8. Alter M, Harshe M, Anderson E, et al: Genetic association of multiple sclerosis and HL-A determinants. Neurology 26:31, 1976 9. Dausset J, Colombani J (eds): Histocom1972. patibility Testing Copenhagen, Munksgaard, 1973 10. Svejgaard A, Jersild C, Staub-Nielsen L, et al: HL-A antigens and disease. Statistical and genetical considerations. Tissue Antigens 4:95, 1974 11. Woolf B: On estimating the variation between blood groups and disease. Ann Hum Genet 19:251, 1955 12. Haldane JBS: The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 20:309, 1955 13. Brewerton DA., Hart FD, Nicholls A, et al: Ankylosing spondylitis and HL-A 27. Lancet 1:904, 1973 14. Schlosstein L, Terasaki PI, Bluestone R, et al: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704, 1973 15. Amor B, Feldmann JL, Delbarre F, et al: L’antigene HL-A W27 sa frequence dans la spondylarthrite ankylosante et le syndrome de Fiessinger-Leroy-Reiter. Nouv Presse Med 3:1373, 1974 16. Nagant de Deuxchaisnes C, Huaux JP, Fiasse R, et al: Ankylosing spondylitis, sacroiliitis, regional enteritis and HL-A 27. Lancet 1:1238, 1974 17. Sachs JA, Sterioff S, Robinette M, et al: Ankylosing spondylitis and the major histocompatibility system. Tissue Antigens 5: 120, 1975 18. Cross RA, Rigby R, Dawkins RL: The significance of HL-A W27 in ankylosing spondylitis and Reiter’s syndrome with three family studies. Aust NZ J Med 5:108, 1975 19. Mills DM, Arai Y, Gupta RC: HL-A antigens and sacroiliitis. JAMA 231:268, 1975 20. van Rood JJ, van Hooff JP, Keuning JJ: Disease predisposition, immune responsiveness and the fine structure of the HL-A supergene. Transplant Rev 22:75, 1975 21. MBIler E, Olbagen B: Studies on the major histocompatibility system in patients with ankylosing spondylitis. Tissue Antigens 6:237, 1975 22. Sany J, Seignalet J,Guilhou JJ, et al:

J. C. WOODROW

HL-A et rhumatisme psoriasique. Rev Rhum Ma1 Osteoartic 42:45 I, 1975 23. Van den Berg-Loonen EM, Dekker-Saeys BJ, Meuwissen SGM, et al: Histocompatibility antigens and other genetic markers in ankylosing spondylitis and inflammatory bowel diseases (in press) 24. Woodrow JC, Eastmond CJ: The association between HL-A B27 and ankylosing spondylitis. J Rheum 1976 (in press) 25. Jeannet M, Saudan Y, Bitter T: HL-A27 in female patients with ankylosing spondylitis. Tissue Antigens 6:262, 1975 26. Feldmann JL, Amor B, Kahan A, et al: Antigene HL-A W27 interet diagnostique en rhumatologie. Rev Rhum Ma1 Osteoartic 42:85, 1975 27. Svejgaard A, Svejgaard E, Staub Nielsen L, et al: HL-A in psoriasis vulgaris and in pustular psoriasis-Population and family studies. Br J Dermatol91:145, 1974 28. Woodrow JC, Dave VK, Usher N, et al: The HL-A system and psoriasis. Br J Dermatol 92~427, 1975 29. Brewerton DA, Caffrey M, Nicholls A, et al: HL-A 27 and arthropathies associated with ulcerative colitis and psoriasis. Lancet 1:956, 1974 30. Russell AS, Percy JS, Schlaut J, et al: Transplantation antigen’s in Crohn’s disease. Linkage of associated ankylosing spondylitis with HL-A W27. Digestive Dis 20:359, 1975 31. Bluestone R, Morris RI, Metzger AL, et al: (HL-A) W27 and the spondylitis of chronic inflammatory bowel disease and psoriasis. Ann Rheum Dis 34 [Suppl 1]:31, 1975 32. Good AE, Kawanishi H, Schultz JS: HLA B27 in blacks with ankylosing spondylitis or Reiter’s disease. N Engl J Med 294: 166, 1976 33. Wright V, Watkinson G: Sacroiliitis and ulcerative colitis. Br Med J 2:675, 1965 34. Haslock I, Wright V: The musculoskeletal complications of Crohn’s disease. Medicine (Baltimore) 52:217, 1973 35. Macrae I, Wright V: A family study of ulcerative colitis with particular reference to ankylosing spondylitis and sacroiliitis. Ann Rheum Dis 32: 16, 1973 36. de BlCcourt JJ, Polman A, de BlCcourtMeindersma T: Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 20:215, 1961 37. Emery AEH, Lawrence JS: Genetics of ankylosing spondylitis. J Med Genet 4:239, 1967 38. West HF: The aetiology of ankylosing spondylitis. Ann Rheum Dis 8:143, 1949 39. Ansell BM, Lawrence JS: Fluoridation and the rheumatic diseases. A comparison of rheu-

HlSTOCOMPATlBlLlTY

ANTIGENS

matism in Watford and Leigh. Ann Rheum Dis 25~61, 1965 40. Lawrence JS: The prevalence of arthritis. Br J Clin Pratt 17:699, 1963 41. Calin A, Fries JF: Striking prevalence of ankylosing spondylitis in “healthy” W27 positive males and females. N Engl J Med 293:835, 1975 42. Cohen LM, Mittal KK, Schmid FR, et al: Increased risk for spondylitis stigmata in apparently healthy HL-A W27 men. Ann Intern Med 84:1, 1976 43. Dick HM, Sturrock RD. Goel GK, et al: The association between HL-A antigens, ankylosing spondylitis and sacroiliitis. Tissue Antigens 5:26, 1975 44. Strosberg JM, Allen FH Jr, Calabro JJ, et al: Ankylosing spondylitis in a large kindred: Clinical and genetic studies. Tissue Antigens 5:205, 1975 45. Dekker-Saeys BJ, Meuwissen SCM, van den Berg-Loonen EM, et al: Inflammatory bowel disease and ankylosing spondylitis (in press) 46. Van Der Linden JMJP, Keuning JJ, Wuisman JHC, et al: HL-A 27 and ankylosing spondylitis. Lancet 1:520, 1975 47. Woodrow JC: Symposium on histocompatibility and rheumatic disease-Family studies. Ann Rheum Dis 34 [Suppl 1]:42, 1975 48. Woodrow JC: HL-A and its association with clinical disease. Proc R Sot Med 68:802, 1975 49. Kissmeyer-Nielsen S (ed): Histocompatibility Testing, 1975. Copenhagen, Munksgaard, 1976 50. Gofton JP, Chalmers A, Price GE, et al: HL-A 27 and ankylosing spondylitis in B.C. Indians. J Rheum 2:314, 1975 5 I. Julia Bodmer: Personal communication, 1976 52. Gofton JP, Robinson HS, Trueman GE: Ankylosing spondylitis in a Canadian Indian population. Ann Rheum Dis 25:525, 1966 53. Gofton JP, Bennett PH. Smythe HA, et al: Sacroiliitis and ankylosing spondylitis in North American Indians. Ann Rheum Dis 31:474, 1972 54. Baum J, Ziff M: The rarity of ankylosing spondylitis in the black race. Arthritis Rheum 14:12, 1971 55. Khan AM, Kushner I, Braun WE: Low incidence of HLA-B27 in American blacks with spondyloentropathies. Lancet 1:483, 1976 56. Sonozaki H, Seki H, Chang S, et al: Human lymphocyte antigen, HL-A27, in Japanese patients with ankylosing spondylitis. Tissue Antigens 5:131, 1975 57. Edmonds J, Morris RI, Metzger AL, et al: Follow-up study of juvenile chronic polyarthritis

275

with particular reference to histocompatibility antigen W27. Ann Rheum Dis 33:289, 1974 58. Gibson DJ, Carpenter CB, Stillman JS, et al: Reexamination of histocompatibility antigens found in patients with juvenile rheumatoid arthritis. N Engl J Med 293:636, 1975 59. But M, Nyulassy S, Stefanovic J, et al: HL-A system and juvenile rheumatoid arthritis. Tissue Antigens 4:395, 1974 60. Rachelefsky GS, Terasaki PI, Katz R, et al: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 290:892, 1974 61. Nissila M, Elomaa L, Tiilikainen A: HL-A antigens in juvenile rheumatoid arthritis. N Engl J Med 292:430, 1975 62. Brewerton DA, Nicholls A, Oates JK, et al: Reiter’s disease and HL-A 27. Lancet 2:996, 1973 63. Morris R, Metzger AL, Bluestone R, et al: HL-A W27-A clue to the diagnosis and pathogenesis of Reiter’s syndrome. N Engl J Med 290:554, 1974 64. Woodrow JC, Treanor B, Usher N: The HL-A system in Reiter’s syndrome. Tissue Antigens 4:533, 1974 65. Aho K, Ahvonen P, Lassus A, et al: HL-A 27 in reactive arthritis: A study of Yersinia arthritis and Reiter’s disease. Arthritis Rheum 17:521, 1974 66. Zachariae H, Friis J, Graudal H, et al: Reiter’s disease and the histocompatibility antigen, HL-A A27. Stand J Rheum 4:13, 1974 67. Harris JRW, Gelsthorpe K, Doughty RW. et al: HL-A 27 and WI0 in Reiter’s syndrome and nonspecific urethritis. Acta Dermatol 55: 127, 1975 68. Isomaki H, Koota K, Martio J, Nissila M, et al: HL-A 27 and arthritis. Ann Clin Res 7: 138, 1975 69. McClusky OE, Lorton RE, Arnett FC Jr: HL-A 27 in Reiter’s syndrome and psoriatic arthritis: A genetic factor in disease susceptibility and expression. J Rheumatol 1:263, 1974 70. Lawrence JS: Family survey of Reiter’s disease. Br J Vener Dis 50: 140, 1974 71. Csonka GW: Significance of sacroiliitis in Reiter’s disease. Br J Vener Dis 35:77, 1959 72. Wright V, Reed WB: The link between Reiter’s syndrome and psoriatic arthritis. Ann Rheum Dis 23:12, 1964 73. Wagner LP, Fessel WJ: HL-A 27 (W27) absent in gonococcal arthritis. Lancet I :1094, 1975 74. Metzger AL, Morris RI, Bluestone R, et al: HL-A W27 in psoriatic arthropathy. Arthritis Rheum 18:111, 1975 75. Marcussen J, MGller E, Thyresson N:

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HL-A antigens (17, 27, ups) in psoriasis with special reference to patients with arthritic lesions. Acta Dermatol55:297, 1975 76. Zachariae H, Hjortshoj A, KissmeyerNielsen F, Svejgaard E, et al: HL-A antigens and psoriatic arthritis. Acta Dermatol Venereol 541443, 1974 77. Feldman JL, Amor B, Cazalis P, et al: Antigens HLA chez les malades atteints de rhumatisme psoriasique. Nom Presse Med 5:477, 1976 78. Karvonen J: HL-A antigens in psoriasis with special reference to the clinical type, age of onset, exacerbations after respiratory infections and occurrence of arthritis. Ann Clin Res 7:301, 1975 79. Eastmond CJ, Woodrow JC: The system and the arthropathies associated psoriasis. Ann Rheum Dis 1976 (in press) 80. Moll JMH, Wright V: Psoriatic Semin Arthritis Rheum 3:55, 1973

HLA with

arthritis.

81. Krulig L, Farber EM, Grumet C, et al: Histocompatibility (HL-A) antigens in psoriasis. Arch Dermatol 1I1:857, 1975 82. Friis J, Svejgaard A: Salmonella and HL-A 27. Lancet 1:1350,.1974

arthritis

83. Hakansson U, Low B, Eitrem R, et al: HL-A27 and reactive arthritis in an outbreak of salmonellosis. Tissue Antigens 6:366, 1975 84. Aho K, Ahvonen P, Alkio P, et al: HL-A 27 in reactive arthritis following infection. Ann Rheum Dis 34 [Suppl 1]:29, 1975

85. Calin A, Fries JF: Epidemic Reiter’s syndrome, genetics and environment. Arthritis Rheum 18:390, 1975 (Abstr) 86. Arnett FC, McClusky OE, Schacter BZ, et al: Incomplete Reiter’s syndrome: Discriminating features and HL-A W27 in diagnosis. Ann Intern Med 84:8, 1976 87. Brewerton DA, Caffrey M, Nicholls A, et al: Acute anterior uveitis and HLA 27. Lancet 21994, 1973 88. Woodrow JC, Mapstone R, Anderson J, et al: HL-A27 and anterior uveitis. Tissue Antigens 6:116, 1975 89. Mapstone R, Woodrow JC: HL-A 27 and acute anterior uveitis. Br J Ophthalmol 59:270, 1975 90. Seignalet J, Clot J, Sany J, et al: HL-A antigens in rheumatoid arthritis. VOX Sang 23:468, 1972 91. Lies RB, Messner RP, Troup GM: Histocompatibility antigens and rheumatoid arthritis. Arthritis Rheum 15:524, 1972 92. Nyulassy S, Ravingerova G, Zvarova E, et al: HL-A antigens in rheumatoid arthritis. Lancet 1:450, 1974 93. Brackertz D, Mueller-Eckhardt CH, Heinrich D, et al: Histocompatibility antigens of patients with rheumatoid arthritis. Z Immunitaetsforsch 146:108, 1973 94. Pasternack A, Tiilikainen A: HLA-B27 in Rheumatoid Arthritis and Amyloidosis (in press) 95. Csonka GW: The course of Reiter’s syndrome. Br Med J 1:1088, 1958