Tissue Antigens (1978), 11, 357-361 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s)

Association of HLA Antigen A9 with Progressive Systemic Sclerosis (Scleroderma)

Philip J. Clements, Gerhard Opelz, Paul I. Terasaki, M. Ray Mickey and Daniel Furst Departments of Medicine/Surgery, School of Medicine, University of California, Los Angeles, California, U.S.A. Upon evaluation of 4 0 subjects with progressive systemic sclerosis (PSS), a significant association of HLA antigens A9 and Aw24 (a subgroup of A9) was found with diffuse scleroderrna. HLAAw23 ( a second subgroup of A9) was also increased in the patients, however, this was not statistically significant. Diffuse scleroderma appears t o be one of the few diseases that shows an association with the HLA-A locus. Received for publication 1 August, revised, accepted 19 September 1977

Most associations between HLA antigens and diseases have been reported for antigens of the HLA-B or -D loci (Svejgaard e t al. 1973). The strongest association discovered thus far is that between ankylosing spondylitis and HLA-B27 (Brewerton et al. 1973, Schlosstein et al. 1973). Recently, Rabin et al. (1975) suggested an association of HLA with another rheumatologic disorder, progressive systemic sclerosis (PSS). HLA-A9, B8, and B27 were found elevated in certain diagnostic subgroups of PSS patients compared with control subjects; however, these associations were not very strong. The present study re-examines this issue and

puts forward an argument in support of an association of diffuse scleroderma (a subset of PSS patients having diffuse or generalized involvement of the skin) with HLA-A9. Material and Methods Patients. HLA typing was performed on a total of 40 white patients (37 female and three male). These 40 represented all the Caucasian PSS subjects who were participating in prospective studies of PSS at UCLA during the period from September 1973 to January 1977. Of these, 34 fulfilled criteria for diffuse scleroderma while six met criteria for the diagnosis of CREST

This study was supported in part by USPHS Grants, GM-15759 and RR-865.

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syndrome without scleroderma (i.e. subcutaneous calcinosis, Raynaud’s phenomenon, esophageal hypomotility, sclerodactyly, telangiectasia). The major criterion for the diagnosis of diffuse scleroderma was taut or hidebound skin diffusely involving the skin of at least one area of the body beyond the fingers and face (i.e. forearms, upper arms or trunk). The diagnosis of CREST syndrome was based on the presence of three or more of the syndrome’s five signs (of which Raynaud’s phenomenon and sclerodactyly were absolute requirements) with or without involvement of facial skin. All subjects with CREST and all but two with diffuse scleroderma were noted also to have characteristic PSS involvement of at least one of five organ systems (pulmonary, cardiac, gastrointestinal, renal, muscle) employing the criteria outlined in Table 1. All subjects were tested for the presence of Sm antigen or ribonucleoprotein fraction of extractable nuclear antigen, using a hemagglutination technique similar to that described by Sharp et al. (1972). HLA typing was performed on each patient using the microdroplet lymphocyte cytotoxicity test (Mittal et al. 1968). T o test the validity of the findings of Rabin et al. (1975), all patients and controls were tested for the HLA-antigens A9, Aw23, Aw24, B8, and B27. Among Caucasians, the antigen HLA-A9 has been subdivided into two subgroups, HLA-Aw23 and HLA-Aw24 (Histocompatibility Testing 1975). In addition, the patients were also tested for all other HLA specificities of the A and B loci listed in Table 3. Two hundred healthy white subjects served as controls. The statistical significance of deviations from the control population was tested by chi-square analysis.

Table 1 Criteria for organ system involvement+ A. Pulmonary

1. DCO (diffusing capacity) < 70%predicted 2. TLC (total lung capacity) or VC (vital capacity) < 80%predicted 3. Bibasilar interstitial markings B. Cardiac 1. Elevated pulmonary capillary wedge pressure 2. Pericardial effusion 3 . Cardiomegaly 4. Conduction abnormalities, ventricular tachycardia, multifocal PVC’s C. Gastrointestinal (excluding esophagus) 1. Duodenal, small bowel dilatation 2. Pseudosacculations 3. Pneumatosis intestinalis 4. Malabsorption (> lOgm fecal fat per day) D. Muscular 1. Inflammatory myositis E. Renal 1. Malignant hypertension 2. Elevated serum creatinine 3 . Creatinine clearance < 60 ml/min *Involvement of an organ system was considered present if one or more criterion within that system were positive.

Results Table 2 gives the percentages of involvement in various organs in patients with CREST or with diffuse scleroderma. Of our 40 patients, 36 had three o r more of the criteria for CREST; but because of the extent of skin involvement in 30 of these subjects, they were considered as having diffuse scleroderma. Within each organ system, there were, a t most, two patients with data insufficient t o exclude involvement of that organ. Upon testing for antibody to ENA, two subjects were positive (with titers greater than 1:100,000) for the ribonucleoprotein fraction and no subject was positive for Sm antigen. Exclusion of these two subjects

HLA ANTIGENS IN SCLERODERMA

3 59

Table 2 Percentages of patients with CREST syndrome or with diffuse scleroderma having van'ous manifestations of PSS

-~ The Five Signs of CREST Subcutaneous calcinosis Raynaud's phenomenon Esophageal hypomotility Sclerodactyly Telangiectasias

CREST Syndrome (N = 6 )

Diffuse Scleroderma (N = 34)

67

71 97 91

~

Organ System Involvement Gastrointestinal (other than esophagus) Cardiac Pulmonary Muscle Renal

from the analysis of disease-antigen association did not significantly alter the results. The only antigens significantly more prevalent than normal were A9 and Aw24 (Table 3 ) and they were significantly increased in the subgroup with diffuse scleroderma ( P < 0.001 and P < 0.002, respectively, by chi-square analysis) as well as in the entire group ( P < 0.001 and P < 0.003). A similar increase of HLA antigen frequencies was noted in several subsets of patients with involvement of individual organ systems (Table 3).

Discussion Since several variants of PSS (i.e. CREST syndrome, diffuse scleroderma, mixed connective tissue disease) are known to exist, we were careful t o characterize our patients thoroughly. Six patients fulfilled criteria for CREST syndrome without scleroderma and 34 had taut or hidebound skin extending beyond the face and fingers (diffuse scleroderma). Only two of the patients with diffuse skin involvement were found to have antibody to ENA, suggesting the possibility that the sclerodermatous

100 50 100

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100 80

100 33

56 50

50

80

0 0

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skin involvement was in association with mixed connective tissue disease. Visceral involvement by PSS was also vigorously sought, and as a result few patients lacked sufficient data to exclude individual organ involvement. Rabin et al. (1975) reported possible associations of PSS with three antigens: A9, B8, and B27. These three antigens were selected on the basis of a nominal statistical significance after separation of patients into two diagnostic subgroups (similar to our subgroups) and without regard t o the noted consideration that it would not be unusual t o find at least some cases of nominal significance among all the comparisons, even in the absence of diseaseantigen associations. We may use their results, however, t o examine potentially significant antigens. Therefore, in correcting our results for the number of HLA antigens tested in our study, we may multiply the P value obtained for HLA-A9 (P

Association of HLA antigen a9 with progressive systemic sclerosis (scleroderma).

Tissue Antigens (1978), 11, 357-361 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission f...
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