Human leukocyte antigen distribution in Israeli patients with psoriatic arthritis

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1 Rheumatol Int (2004) 24: DOI /s ORIGINAL ARTICLE Ori Elkayam Æ Refael Segal Æ Dan Caspi Human leukocyte antigen distribution in Israeli patients with psoriatic arthritis Received: 17 October 2002 / Accepted: 20 March 2003 / Published online: 17 June 2003 Ó Springer-Verlag 2003 Abstract Objectives This study was designed to investigate the distribution of human leukocyte antigen (HLA) classes I and II in a group of Israeli Jewish patients with psoriatic arthritis (PsA) and identify HLA markers related to disease manifestation in PsA. Patients and methods Human leukocyte antigens class I and class II (both serologically and from oligotyping) were tested in a group of 50 consecutive patients with PsA, 32 with skin psoriasis (PSO), and 255 healthy persons. Data on age, gender, disease duration, and pattern of rheumatological manifestations oligoarthritis, polyarthritis, spinal involvement, involvement of distal interphalangeal joints (DIPs), and enthesitis were registered. Results Human leukocyte antigens A3, B13, and B38 alleles were found to be significantly prevalent in PsA compared with PSO patients and healthy controls. HLA-B27 was found in only two out of 50 patients with PsA. Patients with PSO and PsA had significantly increased incidence of HLA-DRB0101 and -DRB0301, while the frequency of HLA-DRB0403 was significantly higher among patients with PsA of Ashkenazi origin. We found a statistically significant association between DIP involvement and the presence of HLA-A26 and -B38, while HLA-DRB0301 was related to spinal involvement. Conclusions Psoriatic arthritis in Israeli patients seems to be associated with the presence of HLA-A3, -B13, -B38, O. Elkayam Æ D. Caspi Department of Rheumatology, Sourasky Medical Center, Tel Aviv, Israel R. Segal Shmuel Harofeh Geriatric Medical Center, Beer-Yaakov, Israel O. Elkayam Æ R. Segal Æ D. Caspi Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel O. Elkayam (&) Department of Rheumatology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel oribe14@netvision.net.il Fax: DRB0101, and -DRB0301. HLA-B27 was not a marker of PsA in this cohort of patients, including patients with psoriatic spondyloarthropathy. Keywords Distal interphalangeal joints Æ Human leukocyte antigen Æ Psoriasis Introduction Psoriasis (PSO) is a common disease affecting 1 3% of the population [1]. The association between psoriasis and joint disease was first recognized by Alibert [2] and later defined as an inflammatory arthritis, usually seronegative for rheumatoid factor, associated with psoriasis [3]. The pathogenesis of psoriatic arthritis (PsA) is not clear, but genetic, environmental, and immunological factors are considered to play a role in development and perpetuation of the disease [4, 5]. The pronounced difference in concordance rates of PsA between monozygous and dizygotic twins [6] and the clustering of both psoriasis [7] and PsA in families provide strong evidence of the importance of genetic factors in PsA. Furthermore, several studies reported linkage between specific HLAs and PsA [8, 9]. However, divergent distributions of HLAs were documented among different cohorts, suggesting that HLA distribution may depend upon ethnic origin [8, 9]. The Jewish population of Israel includes inhabitants of heterogeneous ethnic background [10]. The distribution of HLA antigens in different diseases may differ from that reported in other populations. For example, in rheumatoid arthritis (RA), HLA-DR1 is prominent in Israeli patients [11], while in other Caucasian populations, HLA-DR4 is clearly related to RA [12]. The aim of this study was to investigate the distribution of HLA classes I and II both serologically and by oligotyping in a group of Israeli patients with PsA and to compare it to that of a normal control population and

2 94 PSO patients without joint involvement. Secondly, we tried to identify specific HLA markers associated with the variety of rheumatic manifestations among patients with PsA. Material and methods Patients Fifty consecutive, unrelated patients with PsA seen at the Department of Rheumatology during were consecutively and unselectively recruited and evaluated. All patients fulfilled the currently accepted criteria for psoriasis defined as the presence of typical skin lesions confirmed by a dermatologist and PsA, namely an inflammatory arthritis, usually rheumatoid factornegative, associated with psoriasis [3]. Other joint diseases such as typical RA, systemic lupus erythematosus, and gout were excluded. Controls The control group was comprised of 32 unrelated patients with chronic plaque psoriasis and 255 healthy subjects from the same ethnic background as the patients. Human leukocyte antigen typing Typing for HLA class I (A, B, C) antigens was performed by the standard two-stage microlymphocytotoxic assay [13] using sera of local origin and from other laboratories. Genomic DNA was isolated from whole blood by a salting out procedure as described by Miller et al. [14]. The DRB and DQB genes were amplified using the 11th International Histocompatibility Workshop primers probes and recommended amplification profiles [15]. The amplified DNA was denatured and blotted on nylon membrane filters. The filters were then prehybridized and hybridized with three-tailed sequence-specific oligonucleotide probes 9SSOP with dig-ddutp [16]. Dots were visualized by means of chemiluminescence detection after min exposure on Kodak XAR-5 film. Clinical evaluation The clinical charts of the 50 patients with PsA were thoroughly evaluated using specially designed forms recording age, sex, duration of skin and joint disease, family history of psoriasis and PsA, and age at onset of both skin and joint disease. Patients were divided according to the classification of Wright into five patterns: oligoarthritis patients with four or fewer involved joints, polyarthritis patients with five or more affected joints, patients with spinal involvement, distal interphalangeal joint (DIP) PsA, and arthritis mutilans. Since the numbers of patients in the last two categories was small, they were included in the three first groups according to clinical involvement. Patients were considered to have back involvement based on the presence of grade 2 or higher sacroiliitis alone, or grade 1 sacroiliitis accompanied by syndesmophytes and/or inflammatory back pain (defined as back pain and stiffness not relieved by rest). Enthesitis was defined as plantar fasciitis or tendoachilles tendinitis, while cervical spondylitis was defined as inflammatory symptoms attributed to the cervical spine with evidence of tenderness and/or range limitation on physical examination. Statistical analysis Comparison between origin groups and other background variables regarding the prevalence of the various alleles was performed using the chi-squared or Fisher s exact test in which the number of expected observations per cell was less than five. This analysis was carried out for each allele separately and for the distribution of alleles in each locus. Gene frequencies were calculated according to the formula gf=1-sqrt(1-af) as described by Baur and Danilovs. Comparison between observed allele frequencies and expected frequencies (Roitberg-Tambur et al.) was done using the multinomial test. Results The demographic and clinical data of patients with PsA are shown in Table 1 and Table 2. The most common pattern of joint involvement was oligoarthritis. Evidence of inflammatory back involvement was found in 18 patients (36%). The differences in distribution of HLA gene frequencies in 50 patients with PsA, compared to 32 with psoriasis and 255 healthy unrelated persons, are summarized in Table 3 and Table 4. Human leukocyte antigen class I As can be seen in Table 3, we found a statistically significantly increased incidence of HLA-A3, -B13, and - B38 in patients with PsA in comparison with those with psoriasis vulgaris or healthy controls. HLA-A3 and -B13 alleles were found, respectively, in 12% and 7% of Ashkenazi patients with PsA, in comparison with 5.7% Table 1 Demographic characteristics of 50 patients with PsA Male:female 30:20 Mean age (years) 58±15 Ashkenazi:Sephardi 34:16 Age at onset skin lesions (years SD) 36±16 Age at onset joint disease (years SD) 40±15 Table 2 Clinical patterns of psoriatic arthritis. DIP distal interphalangeal Oligoarthritis 38 (76%) Polyarthritis 12 (24%) Spinal involvement 18 (36%) DIP involvement 33 (63%) Table 3 Different gene frequencies (%) of serologically defined HLA antigens in patients with psoriatic arthritis (PsA), psoriasis (PSO) and healthy controls. S Sephardic, A Ashkenazi HLA Controls PsA PSO S A S A S A A * 20 12* 10 0** B * 6. 7* 0 0** B38 7.8* * 21 0** 35 B ** Cw ** *P<0.05 between PsA and healthy controls **P<0.05 between patients with PsA and PSO

3 95 Table 4 Different gene frequencies (%) of HLA-DR and -DQ allele variants in patients with psoriatic arthritis and psoriasis and healthy controls. S Sephardic, A Ashkenazi, NT not tested HLA Controls PsA PSO S A S A S A DRB * 10* DRB * DRB ** DRB * 3.3 0** DRB ** 14** DRB ** 14** DRB ** DRB ** DQB10503 NT NT ** 0 5 DQB ** *Statistically significant (P<0.05) between patients psoriatic arthritis and healthy controls **Statistically significant (P<0.05) between psoriatic arthritis and psoriasis vulgaris and 1.6% in healthy controls, respectively, and 0% in patients with psoriasis. HLA-B38 was found in 20% of non-ashkenazi patients with PsA, as compared to 7.8% of healthy controls and 0% of psoriatic patients (P<0.05). HLA-B27 was positive in only two patients one of them with spinal involvement in comparison with 3% in the healthy population (Table 3). Human leukocyte antigen class II A significantly higher incidence of HLA-DRB0101 was found in both PsA and PSO than in healthy subjects. This was shown in both Ashkenazi and non-ashkenazi patients (6.4% of Sephardic and in 10% of Ashkenazi patients with PsA, compared with 1.9% and 0.5% in healthy controls). We could also show a significant increase in HLA-DRB0301 among non-ashkenazi patients with psoriasis and PsA in comparison with healthy controls. On the other hand, HLA-DRB0403 was significantly increased in Ashkenazi patients with PsA, while the rate in PSO patients was similar to that of healthy controls (Table 4). Correlation between human leukocyte antigens and clinical variables Human leukocyte antigen class I We found a statistically significant association between DIP involvement and the presence of HLA-A26 and - B38. HLA-A26 was found in ten patients, nine of them (90%) with DIP involvement, while 21 out of 38 patients (55%) who were HLA-A26-negative showed DIP involvement (P=0.04). Likewise, 15 of 18 patients (83%) with HLA-B38 had DIP involvement, vs 50% in HLA-B38-negative patients (P=0.02). A significant association was found between HLA-B35 and axial inflammatory involvement (P<0.05). HLA-B27 was extremely rare in our patients, and no association was found between its presence and clinical or radiological sacroiliac or spinal involvement. Only one patient with inflammatory and radiological spinal involvement was HLA-B27-positive, while 17 were negative. Human leukocyte antigen class II HLA-DRB0301 was found to be associated with spinal involvement. Five out of six patients with HLA- DRB0301 (84%) presented inflammatory back pain, as compared to 25% of those who were HLA-DRB0301- negative (P =0.04). HLA-DRB0301 was also found to be increased in patients with inflammatory spinal involvement (67% vs 8% in patients with other clinical patterns of joint involvement, P=0.01). Although HLA- DRB0101 was clearly related to PsA, we could not find any specific clinical characteristics of this antigen. Likewise, HLA distribution was similar within groups of patients with oligoarthritis or polyarthritis. Discussion In our study on 50 patients with PsA, we have shown an association between PsA and HLA-A3, -B13, -B38, -DRB0101, -DRB0301, and -DRB0403. The proportion of patients with HLA-B27 was low and similar to that of the general population. We could show a significant association between HLA-A26, HLA-B38, and DIP involvement as well as between HLA-B35, HLA- DRB0301, and inflammatory spinal involvement. Our results are concordant with other reports of increased frequency of HLA-B13 in PsA [17, 18] as well as an association between HLA-B38 and the polyarthritis pattern of PsA [9, 19, 20]. However, in several ways our results differ from most of the known associations between HLA antigens and PsA, supporting the assumption of this study that Israeli patients with PsA may present different HLA associations, which is possibly related to the varied ethnic origin of this population. One of the most striking findings of this study was the low frequency of HLA-B27 in our cohort of patients. In none of the rheumatic diseases has the genetic contribution to pathogenesis been so well characterized as in seronegative spondyloarthropathies, in which HLA-B27 has a central role [21]. Although the frequency of HLA- B27 in PsA is lower than in ankylosing spondylitis or Reiter s syndrome, it still is considered a predisposing factor to PsA, especially with axial involvement [22, 23, 24, 25]. However, the clear relationship between spondyloarthropathy and HLA-B27 is based on Caucasian populations, in which the background frequency of this gene is 8 11%. In our cohort, only two out of 50 patients (4%) were HLA-B27-positive, although 18

4 96 (36%) had evidence of axial involvement. This finding may reflect the low representation of HLA-B27 in the Israeli population ( %) and in our healthy controls [26]. Following the same trend, the frequency of HLA-B27 among Israeli patients with ankylosing spondylitis is only 79%, in comparison with 95% in other Caucasian populations [24]. Although it is significantly higher than in the Israeli population, it is much lower than is found in other populations of ankylosing spondylitis [27]. With regard to the expression of class II HLAs, we could clearly show a statistically significant increase in the distribution of HLA-DRBO1O1 and -DRB0403, which were found in 10% and 6.6% of Ashkenazi patients, respectively, while their prevalence in the Israeli population is less than 2%. HLA-DRB0101 is one of the alleles previously characterized as HLA-DR1 in the former classification of HLA class II. Interestingly, HLA-DR1 is also frequent in Israeli patients with RA, although the predominant HLA-DR1 subtype in these patients is DRB1*0102 [28]. We could find no increased incidence of HLA-DR4, as reported by others [1]. Gladman et al. reported that HLA-DRB0401 and -DRB0402 are the most frequent alleles found in PsA. Sequencing studies in Caucasians have shown that HLA-DR4 and -DR1 antigen molecules share a common amino sequence in the third hypervariable region of the DR molecule, suggesting that this sequence is primarily associated with RA [28]. The same argument may be true in PsA. Some reports have suggested an association between certain HLA and the degree of severity of PsA. Erosive disease has been associated with HLA-DR4 and -B27 in the presence of HLA-DR7, while HLA-B22 seems to provide protection through all states [29]. Our study was not designed to investigate longitudinally the prognostic value of HLAs. However, if polyarthritis is considered the most severe form of PsA, we could not demonstrate a clear correlation between any HLA and the degree of severity of PsA in our cohort. In conclusion, in 50 patients with PsA, we showed increases in the distribution of HLA-B13, -B38, -DRB0101, and -DRB0301, while HLA-B27 and -DR4 were distributed in a way similar to that of the healthy Israeli population. These results suggest that, as in rheumatoid arthritis, Israeli patients with PsA present a different HLA distribution than reported until now. This study included a relatively small number of patients, and further studies based on larger populations of Israeli patients with PsA may be warranted. References 1. Gladman D, Farewell VT, Nadeau C (1995) Clinical indicators of progression in psoriatic arthritis multivariate relative risk model. J Rheumatol 22: Alibert JL (1918) Pre cis théorique sur les maladies de la peau. Ravier, Paris 3. Gladman DD, Shuckett R, Russel ML, Thorne JC, Shachter RH (1987) Psoriatic arthritis an analysis of 220 patients. Q J Med 62: Espinoza LR (1985) Psoriatic arthritis: further epidemiologic and genetic consideration. In: Gerber LH, Espinoza LR (eds) Psoriatic arthritis. Grune and Stratton, Orlando, pp Gladmam DD (1985) The role of immunological factors in the pathogenesis and etiology of psoriatic arthritis. In: Gerber LH, Espinoza LR (eds) Psoriatic arthritis. Grune and Stratton, Orlando, pp Farber EM, Nall ML (1971) Genetics of psoriasis twin study. In: Farber EM, Cox AJ (eds) Psoriasis. Proceeding of the International Symposium, Stanford University. Stanford University Press, Stanford, pp Moll JMH, Wright V (1973) Familial occurrence of psoriatic arthritis. Ann Rheum Dis 32: Kammer GM, Soter NA, Gibson DJ et al (1979) Psoriatic arthritis: a clinical, immunologic and HLA study of 100 patients. Semin Arthritis Rheum 9: Gladman DD, Anhorn KAB, Schachter RK, Mervart H (1986) HLA antigens in psoriatic arthritis. J Rheumatol 13: Roiterg-Tambur CS, Friedman AW, Safirman C, Sherman L, Battat S, Nelken D, Brautbar C (1995) Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews. Tissue Antigens 46: Schiff B, Mizrahi Y, Orgad S, Yaron M, Gazit E (1982) Association of HLA-Aw31 and HLA-DR1 in patients with adult rheumatoid arthritis. Ann Rheum Dis 4: Roudier J (2000) Association of MHC and Rheumatoid arthritis with HLA-DR4: the role of repertoire selection. Arthritis Res 2: Terasaki PI, Bernoco D, Park MS, Ozturk G, Iwaki Y (1978) Microdoplet testing for HLA-A, B, C and D antigens. Isr J Clin Pathol 69: Miller SA, Dykes DD, Polesky HF (1988) A sampling salting out procedure for extracting DNA from human nucleated cells. 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Evidence for the influence of multiple genes in the major histocompatibility complex. J Clin Invest 66: Braun J, Bollow M, Reminger G, Eggens U, Rudwaleit M, Distler A, Sieper J (1998) Prevalence of spondyloarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 41: Lambert JR, Wright S, Rajah SM, Moll MH (1976) Histocompatibility antigens in psoriatic arthritis. Ann Rheum Dis 35: Eastmond CJ, Woodrow JC (1977) The HLA system and the arthropathies associated with psoriasis. Ann Rheum Dis 36: Amstrong RD, Panayi GS, Welsh KI (1983) Histocompatibility antigens in psoriasis, psoriatic arthritis and ankylosing spondylitis. Ann Rheum Dis 42:

5 Marsal S, Armandans-Gil L, Martinez M, Gallardo D, Ribera A, Lience E (1999) Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis. Rheumatology (Oxford) 38: Brautbar C, Porat S, Nerken D, Gabriel KR, Cohen T (1977) HLA B27 and ankylosing spondylitis in the Israeli population. J Rheumatol Suppl 3: Schlosstein L, Terasaki PI, Bluestone R et al (1973) High association of an HLA antigen w27 with ankylosing spondylitis. N Engl J Med 288: De Vries N, Ronningen KS, Tilanus MG, Bouwns-Rombouts A, Segal R, Egeland T, Thorsby E, van de Putte LB, Brautbar C (1993) HLA-DR1 and rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB1*0102 is the predominant HLA- DR1 subtype. Tissue Antigens 41: Gladman D, Farewell VT, Kopciuk KA, Cook RJ (1998) HLA markers and progression in psoriatic arthritis. J Rheumatol 25:

Discordance for ankylosing spondylitis in monozygotic twins

Annals of the Rheumatic Diseases, 1977, 36, 360-364 Discordance for ankylosing spondylitis in monozygotic twins C. J. EASTMOND* AND J. C. WOODROW From the Nuffield Unit of Medical Genetics, Department