Family Studies with HLA Typing in Reiter’s Syndrome

MUHAMMAD YUNUS, M.D.

Peoria, Illinois

JOHN J. CALABRO. M.D. KENNETH A. MILLER, M.D.*

Worcester. Massachusetts

ALFONSE T. MASI, M.D., DR.P.H.

Peoria, Illinois

From the Division of Rheumatology, Department of Medicine, St. Vincent Hospital, Worcester, Massachusetts; and the Division of Rheumato- logy, Department of Medicine, Peoria School of Medicine, Peoria, Illinois. This study was sup ported by Grant CA 19569 from the National Institutes of Health. Requests for reprints should be addressed to Dr. Muhammad Yunus, Peoria School of Medicine, 123 S. W. Glendale Avenue, P. 0. Box 1649, Peoria, IL 61656. Manuscript ac- cepted December 15,196O.

* Present address: Danbury Hospital, Dan- bury, CT 06810.

Twelve consecutive patients with Reiter’s syndrome, nine with the B27 antigen (B27 positive) and three without (B27 negative), and their 45 first degree relatives were studied clinically and with HLA typing. Two of the four adult male first degree relatives with the B27 antigen had classic Reiter’s syndrome. In addition, one of two B27 positive adult male second degree relatives studied in one family had classic Reiter’s syndrome. The data, although limited, suggest that the fa- milial occurrence of Reiter’s syndrome is higher than previously recognized, especially in adult male first degree relatives with the B27 antigen, and is similar to the degree of familial aggregation rel ported in ankylosing spondylitis.

Although a number of cases of familial Reiter’s syndrome have been reported [l-5] (Table I), its genetic predisposition has become more evident recently since the establishment of a strong association of this disease with HLA B27 antigen [6-81. Only a few pedigree [7,9] and family [lO,ll] studies are available in Reiter’s syndrome. Of two published family studies [lO,ll], one was carried out without HLA typing [lo], and the other [ll] includes only selected probands with a family history of arthritis. However, none included evaluation and HLA typing of all available probands with Reiter’s syndrome and their first degree relatives. This study was undertaken to determine the frequency of Reiter’s syndrome and other HLA-related disease manifestations among first degree relatives of a consecutive sample of probands with Reiter’s syndrome, and to examine the relationship between disease features and HLA antigens in these subjects.

MATERIALS AND METHODS

Probands. Twelve consecutive patients with Reiter’s syndrome constitute the probands in this study; all were male Caucasians seen in consultation in a private rheumatology practice in Worcester, Massachusetts. Of these, nine had the HLA B27 antigen and three did not. Of the nine probands with the B27 antigen, five had the classic Reiter’s syndrome triad of arthritis, conjunctivitis and urethritis, with or without mucocutaneolis lesions; three had arthritis and mucocutaneous lesions with either urethritis or conjunctivitis but not both, and one had arthritis, urethritis, heel pain and backache. Of the three probands without the B27 antigen, one had classic Reiter’s syndrome, one had asymmetric polyarthritis, conjunctivitis and balanitis, and the remaining one had arthritis, heel pain, urethritis, history of preceding diarrhea, evidence of sacroiliitis on roentgenograms as well as syndesmophytes. Sacroiliitis was found on the roentgenograms in six probands, five had B27 and three of them had syndes- mophytes. First Degree Relatives. Parents, siblings and children were included as first degree relatives. No consanguineous marriage occurred in any family. All probands and first degree relatives were asked about any knowledge of arthritis or other HLA related symptoms, e.g., skin involvement, backache, eye symp-

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HLA TYPING IN REITER’S SYNDROME-YIINUS ET AL.

TABLE I Case Reports of Reiter’s Syndrome in First Degree Relatives

Koster, 1946 Glauner, 1947 Paronen, 1946 [4]

Schoeneich, 1950 Trier, 1950 Fabregoule, 195 1 Gough, 1962 Mowat, 1968 Csonka, 1969

Davis, 1969 Good, 1971 [5] Engleman, 1972 [3] Calabro, 1977 [l]

Three brothers Two brothers Mother, child Two sisters Five siblings Brother, sister Two brothers Father, son Father, son Two brothers Two brothers Two brothers Father, 2 sons Father, 2 sons Mother, 2 sons Three brothers Two brothers Two brothers Two brothers

Gelfand, 1977 Jones, 1979 [2]

l From Calabro et al. [l] and Good [5], unless otherwise marked.

Affected Flrsf Degree Relatives -

toms, bowel disorders, urethritis or mucocutaneous lesions. Eight (15 percent] of 53 first degree relatives were not available for interviews, most often due to residence in distant states. Blood was drawn from all of the probands and interviewed relatives for HLA-A, B and C typing [12], but only those with a positive history were examined for relevant signs. In addi- tion, four available second degree relatives from one family (Family 1) were studied with HLA typing. The first degree

relatives had been observed for a mean of 24 months at the time of analysis.

RESULTS

Classic Reiter’s syndrome was found in two first degree relatives, one in each of two families. Both were male and both had B27. One relative was ascertained at the time of initial examination and another had the onset one year after the survey was completed.

One was a son in Family 1 (Figure 1) and the other a brother in Family 4 [Figure 21 of the respective pro- bands. Thus, in this study, multiple cases of Reiter’s syndrome were observed in two (16 percent] of the 12 families. In addition, one second degree male relative in Family 1 (Figure 1) also had classic Reiter’s syndrome. He was the son of the proband’s sister and inherited the B27 trait from his mother. In another second degree relative, who is the son of another sister of that same proband (Figure l), a history of uveitis was diagnosed by an ophthalmologist, and he has B27. His mother does not have the B27 and related Creg antigens (i.e., B7, BW22, B27, B40 and BW42) [13,14].

In Family 4, a sister of the proband, aged 29, had a history of backache since age 19, which worsened after an accident five years later. She has the B27 antigen but roentgenograms of sacroiliac joints did not reveal any abnormalities at the time of study. Although the mother of the proband of Family 4 had died, it is evident that she contributed the B27 genotype.

The father of another proband in Family 3 (Figure 31 had clinical and roentgenologic evidence of ankylosing spondylitis with sacroiliitis and syndesmophytes noted

17 c!l 11-27-l

3-40-3

;

q n

2-40-3 * 11.27- 1

29 -44- 2a -35-4

ii-a- 29-44m 2-40-3 29-44- 29 -44s 2-40-3 2-7- --- -- -_ 3-40-3 11-27-I 28-35-4 28- 35-4 28-35-4 llL27mI - 25-44

11-27-I 25-44- 2-7 - 25-44 - 25-44 - - -

3-40-3 2-40-3- 11-27-I 11-27-l 11-27-l

Age In Years

Numbers indicate HLA-A, Band C types, respectively: missing numbers are nonidentifiable antigens.

Uveitis by History: HLA 827 positive (full HLA typing not done)

Reiter’s syndrome

Figure 1. HLA types of Family 1 with three cases of Reiter’s syndrome.

June 1981 The American Journal of Medicine Volume 70 1211

HLA TYPING IN REITER’S SYNDROME-YUNUS ET AL.

t DlXeaWd

n Reiter’s syndrome

Chronic back pain

54 ot Z-44 -2

24-40-2

2-44 -2 2-44-2 2-44-2

-27 -5 -27-5 -27 -5

L I

Figure 2. HLA types of Family 4 with two cases of Reiter’s syndrome.

since age 24. He denied any other symptoms, possibly attributable to Reiter’s syndrome. Both the proband and his father had the B27 antigen. A sister of another pro- band in Family 6, age 42, had a history of a swollen, painful right ankle cm and off for 20 years aS well as a history of pain in the left heel, urinary tract infecti,on and occasional backache. Exainination revealed tenderness over the left sacroiliac area but roentgenograms of the sacroiliac joints, reviewed by a physician in another state, were said to show no abnormalities. This relative did not have the B27 antigen, but she did have A3 and

66 66

X1-27-2 1 -B-

24-44-

20-27-2

1 -8-

l- s- I- e-

10-40-S 10-40-S

q Ankylosing spondylitis

n Raiter’s syndrome

L

Figure 3. HLA types of Family 3 with one.case each of ankylosing spondylitis and Reiter’s syndrome.

B7. No other relatives had definite evidence of in- flammatory peripheral arthritis, spondylitis, uveitis or mucocutaneous lesions.

In the families of the nine probands with the B27 antigen (group l), six of 13 male members and 12 of 22 female members had the B27 antigen. Thus, 18 (51 percent) of the 25 group 1 relatives had the B.27 ahtigen, as would be expected. Among the 10 first degree rela- tives of the three probands without the B27 antigen (group 2), all four male members and six female mem- bers were without the B27 antigen. The over-all sex distribution in both groups showed 17 males and 28 fe- males. Among the six male first degree relatives with the B27 antigen, four were age 15 or older and among them, two had clinical manifestations of classic Reiter’s syn- drome. Thus, two of the four first degree relatives with the B27 antigen, age 15 or older, had Reiter’s syn- drome.

No Creg or other HLA antigen, except B27, was found in significantly higher frequency than expected among the probands or their first degree relatives in this study.

COMMENTS

Although several pedigree and family studies of pro- bands with Reiter’s syndrome have been reported [6,8,9,10,15], none included evaluation of all available probands and first degree relatives as well as HLA typing. In order to derive a more representative estimate of the familial occurrence of Reiter’s syndroine and oiher B27-related manifestations, consecutive probands with Reiter’s syndrome were included in this study and all available first degree relatives (85 percent) were in- terviewed by protocol. All had full HLA serologic typing and those with positive history of any rheumatic-related symptoms were examined.

In view of the high association of Reiter’s syndrome with the presence of the B27 tintigen and ihe prepon- derance of Reiter’s syndrome in young male adults, familial occurrence m&j be qualified according to these factors. For example, although only two (4.5 percent) of the total 45 first degree relatjves had cl&sic Reiter’s syndrome, both were among the four male adults with the B27 antigen. Thus, a proper comparison of familial occurrence of Reiter’s syndrome among various popu- lations should include specification of age, sex and B27 status. Additionally, the period of observation during which the first degree relatives are at risk for the de- velopment of Reiter’s syndrome needs to be considered, in order to fully evaluate familial predisposition to this disease.

Two (16 percent] of the 12 families included in this study had affected first degree relatives. This frequency is higher than the 8 percent found by Hochberg and associates [7] in the U.S.A., and the 2 percent found by Woodrow et al. [9] in England. However, all available first degree relatives were not interviewed in those

1212 June 1991 The American Journal of Medicine Volume 70

studies. It is interesting that no additional case of Reiter’s syndrome was found in another family study from En- gland [lo], involving 35 probands with Reiter’s syn- drome and 194 of their first degree relatives.

Kousa and his colleagues [Ill from Finland found Reiter’s syndrome in eight (16 percent] of 50 selected first degree relatives of 12 probands with Reiter’s syn- drome who were, in turn, selected for a positive family history of arthritis. The total number of patients with Reiter’s syndrome from which the 12 probands were selected is not specified. Another eight first degree relatives had arthritis, although the nature was not specified. In that study, an unusually high frequency of B27 and related Creg antigens was present among the probands and their relatives, which might be expected with such selected sampling. All probands and 70 per- cent of the first degree relatives had the B27 antigen as opposed to an expected 50 percent with such probands. Seven (14 percent) of 50 first degree relatives and three (25 percent] of 12 probands were homozygous for this antigen. Five of the seven relatives homozygous for B27 had arthritis. Sixty percent of the first degree relatives in that study were male. Thus, the higher than expected frequency of B27 and related arthropathies among first degree relatives in that study [ll] may be attributed, at least in part, to selection of probands and relatives with manifestations of arthritis.

A study of B27 homozygosity in ankylosing spondylitis suggested that homozygotes are more susceptible to ankylosing spondylitis and have greater involvement of peripheral joints, as compared to the B.27 heterozy- gotes [16]. The prevalence of B27 in Finland is 14 per- cent [17], as compared to 8 percent of the Caucasian population of the Boston area of U.S.A. (Yunis EJ: Per- sonal communication; data collected at Sidney Farber Cancer Institute). The higher prevalence of B27 in Finland may account for a greater risk of B27-related diseases in that population. Combined host susceptibility and patient selection factors may explain the unusually high prevalence of familial Reiter’s syndrome in the study of Kousa et al. Ill].

Data on the frequency of Reiter’s syndrome in the general population are scant, especially in the absence of nonspecific urethritis or Shigella dysentery expo- sures. It has been estimated that Reiter’s syndrome at- tacks four/lOO,OOO Navy personnel annually [18]. From such data, it is difficult to estimate the expected fre- quency of secondary cases of Reiter’s syndrome in first degree relatives. Other data indicate that Reiter’s syn- drome develops in about 2 percent of male adults ex- posed to either nongonococcal urethritis or Shigella dysentery [19]. However, the risk of Reiter’s syndrome among subjects with the B27 antigen so exposed is about 20 percent [20]. The risk of Reiter’s syndrome in those with the B27 antigen is IO-fold higher than in the pop- ulation at large, which includes people with the B27 antigen; it is about 50-fold higher than in people without the B27 antigen, i.e., relative risk [21]. In Caucasians,

HLA TYPING IN REITER’S SYNDROME-YIJNUS ET AL.

about 80 percent of the patients with Reiter’s syndrome have the B27 antigen as compared to 8 percent of the population who have the B27 antigen. If a 20 percent risk of developing Reiter’s syndrome among those with the B27 antigen so exposed were applied to the four adult male first degree relatives with the B27 antigen in our study, less than one case would be expected, compared to the two observed.

Our data, although limited, would be consistent with a familial aggregation of Reiter’s syndrome above ex- pectation based upon B27 frequency alone. The familial occurrence of Reiter’s syndrome in first degree relatives with the B27 antigen in our study is similar to the fre- quency of ankylosing spondylitis in comparable rela- tives [22-241, and higher than previously estimated [7,9,10]. However, in view of the small number of such first degree relatives in our study, no firm conclusion regarding the true prevalence of familial Reiter’s syn- drome can be made.

Further study is needed to evaluate factors other than B27 which may predispose to Reiter’s syndrome. In- terestingly, Reiter’s syndrome developed in a brother of a proband who had Reiter’s syndrome but no B27 antigen [7], but the brother’s HLA type was not speci- fied. In another report, two brothers who did not have the B27 antigen but who did have the B7 antigen had Reiter’s syndrome [9]. Arnett et al. [13] described 10 patients without the B27 antigen but with Reiter’s syn- drome, seven of whom (70 percent) had another B locus antigen that is known to be immunologically cross re- active with B27; two patients had B7, four BW22 and one BW42 [13]. Also, a higher than expected frequency of B7 was found among black patients with ankylosing spondylitis but no B27 [25]. One may presume that fac- tor(s) other than B27, perhaps, common host or envi- ronmental factors may predispose certain families to an increased susceptibility to Reiter’s syndrome. This would be suggested by Family 1 in our study.

Except for B27, no other HLA-A, B or C antigens were found in higher than expected frequency among our probands or their first degree relatives. None of our three probands without the B27 antigen (Cases lo,11 and 12) had any of the other cross reactive (Greg) anti- gens, i.e., B7, BW22, B40 or BW42.

Question exists as to whether familial predisposition to spondyloarthropathy syndromes is specific to the particular disease, Reiter’s syndrome in this study, or to all B27-related disorders in general. Hochberg et al. [7], suggest that ankylosing spondylitis, with predominant axial involvement, and Reiter’s syndrome, with pre- dominant peripheral arthropathy, tend to “breed true.” Woodrow [9] described three patients who had spon- dylitis for several years before the features of Reiter’s syndrome developed and contended that spondylitis has a separate mechanism.

In our study, in addition to three cases of Reiter’s syndrome among first and second degree relatives, one male first degree relative had definite ankylosing

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HLA TYPING IN REITER’S SYNDROME-YUNUS ET AL.

spondylitis, and two female first degree relatives, one with the B27 antigen and the other with the B7 antigen, had chronic low back pain but no sacroiliitis roentgen- ographically. Another second degree male relative with B27 had uveitis. He appeared to have inherited this antigen from his father who was not genetically related to the proband of this family. Among relatives [first degree plus grandparents] of patients with Reiter’s syndrome, the prevalence of sacroiliitis on roentgeno- grams was found to be 12 percent among male and fe- male members over age 45, compared to 5 percent among controls [lo]. In other family studies of Reiter’s syndrome the findings of sacroiliitis on roentgenograms among first degree relatives have been reported, but no conclusions have been drawn regarding familial aggregation [5,6,8]. Interestingly, sacroiliitis in the rel- atives occurred independently of HLA B27 in several studies [7,9].

An additional set of brothers with the I327 antigen has been encountered outside of this study which further demonstrates an overlap of spondyloarthropathy manifestations among family members. The 27 year old proband has a two year history, clinical and scinti-

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

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graphic evidence of asymmetrical sacroiliitis plus chronic arthritis of one ankle which underwent syno- vectomy, but no history of urethritis, conjunctivitis or mucocuianeous lesions. His 47 year old brother had an episode of classic Reiter’s syndrome at age 84, but mainly back pain and stiffness over the past 20 years with roentgenographic evidence of asymmetrical sa- croiliitis and syndesmophytes of the lumbar and thoracic spines. one of his six sons has a history of elbow and knee arthritis and has the B27 antigen.

Thus, it seems from our observations and those of others that the familial occurrence of these spondy- loarthropathy syndromes overlap to some extent, as is found in individual patients. One may expect that multiple factors, genetic, environmental and, possibly, infectious agents, contribute to the predisposition and onset of these disorders and to their clinical character- ization.

ACKNOWLEDGMENT

We are indebted to Dr. Edmond J. Yunis of Sidney Farber Cancer Institute, Boston, for his kind assistance in HLA typing in his laboratory.

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