Genetics of spondyloarthritis

Best Practice & Research Clinical Rheumatology Vol. 20, No. 3, pp. 593–599, 2006 doi:10.1016/j.berh.2006.03.002 available online at http://www.sciencedirect.com

12 Genetics of spondyloarthritis Maxime Breban*

MD, PhD

Professor of Rheumatology Institut Cochin, INSERM U567/CNRS UMR8104/IFR116, Hoˆpital Cochin, Paris, France Service de Rhumatologie, Hoˆpital Ambroise Pare´, Boulogne, France

This chapter reviews evidence from family and twin studies supporting the strong genetic predisposition of the spondyloarthritides (SpA), which is only partially attributable to the major histocompatibility locus. The current concept of SpA heterogeneity has been challenged by family studies which showed that all articular and extra-articular manifestations were linked together, and most likely to the same genetic factors. Key words: genetic; spondyloarthritis; ankylosing spondylitis; family study; psoriatic arthritis.

WHAT HAVE WE LEARNT FROM FAMILY STUDIES? With an estimated prevalence of 0.3% in the adult Caucasian population, the spondyloarthritides (SpA) represent the second most common group of chronic inflammatory rheumatic disorders, along with rheumatoid arthritis.1 A major characteristic of SpA is the great variability of clinical presentation, which frequently combines skeletal inflammation with extra-articular features. The articular disease itself typically predominates on the axial skeleton (i.e. spinal, thoracic and pelvic joints), although peripheral arthritis may affect as many as 50% of patients and peripheral enthesitis is even more frequent. The unifying target of skeletal inflammation is thought to be the fibrocartilaginous enthesis, i.e. the attachment of tendons, ligaments and joint capsules to bone.2 Inflammation in SpA frequently involves the skin (psoriasis) and several mucosae (anterior uveitis, inflammatory bowel disease and urethritis). Typically, some of these manifestations tend to remit and may only be retrieved from past medical history. SpA recognition results from the grouping of disorders that were initially considered to be distinct, i.e. ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis

* Address: Institut Cochin, INSERM U567/CNRS UMR8104/IFR116, Hoˆpital Cochin, 27 rue du Fg saintJacques, 75014 Paris, France. Tel.: C33 1490 94555; fax: C33 1490 95865. E-mail addresses: [email protected] (M. Breban), [email protected] (M. Breban).

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594 M. Breban

(ReA), and arthritis associated with idiopathic inflammatory bowel disease (AIBD). This grouping was proposed on the basis of three observations: (1) these disorders may arise consecutively in the same patient (e.g. AS ‘secondary’ to PsA, ReA or AIBD); (2) it is sometimes virtually impossible to distinguish between these disorders; and (3) several of these disorders may affect different individuals within the same family.3 Indeed, all these observations could be explained if predisposing factors were shared between SpA conditions. Genetic epidemiology studies in SpA have largely focused on AS, the most frequent and also the best defined form of SpA, as its diagnosis relies on advanced radiographic sacroiliitis which is a highly specific finding.4 However, the radiographic criterion is only met after a variable time course of disease, and a number of patients lacking this criterion can be misclassified as unaffected in such studies, leading to erroneous conclusions. Such bias could be avoided by considering all SpA patients to be affected rather than AS patients alone.5,6 A major difficulty with the latter approach is the reliable identification of early SpA. Classification criteria developed in the early 1990s can assist with this.7,8 Family studies in AS Evaluation of familial aggregation of a disease gives a sense of its heritability. This type of investigation is routinely performed by comparing the frequency of a disease among relatives of randomly selected patients with its prevalence in the general population. The result is returned as a relative recurrence risk denoted as lR, where R represents the category of relatives studied. Several studies have assessed the frequency of AS among first-degree relatives of patients. A recent meta-analysis of published studies yielded a l1 value of 80, assuming a 0.1% population prevalence of AS.9 Such a striking increase in AS recurrence among patients’ relatives compared with the general population suggests a strong genetic component. Furthermore, the similarity of l1 between siblings and parent–child pairs, as suggested from two of the studies included in the meta-analysis, is consistent with a dominant genetic effect. Finally, in a single study of AS recurrence among second-degree relatives, a fivefold drop in the l value was observed between first- and second-degree relatives, arguing for a multiplicative model of several genes interacting with each other. However, based on available data, the number of predisposing genes could not be determined confidently and may range between 3 and 9.9 Among relatives of AS patients, recurrence of disease is almost entirely restricted to HLA-B27-positive individals.10–13 It is of particular interest to estimate the genetic load of non-HLA genes by calculating the lnon-HLAB27, which is the relative recurrence risk of disease among HLA-B27-positive relatives of patients compared with HLA-B27positive individuals in the general population. Several studies have estimated the prevalence of AS among HLA-B27-positive individuals to be between 1.2 and 1.3% in the general population, and between 15 and 21% in first-degree relatives of patients, yielding a lnon-HLAB27 between 12 and 16.13,14 Accordingly, in a multiplicative model dependent on HLA-B27, the lHLA value should fall to between 5 and 6, which corresponds to calculations derived from linkage analysis.15–17 Twin studies in AS Determining the recurrence of a disease among twins is another classical method to estimate the strength of genetic predisposition. Basically, discordance of a trait between

Genetics of spondyloarthritis 595

monozygotic (MZ) twins is attributable to environmental factors, whereas a variation in the concordance rate between MZ and dizygotic (DZ) twins is best explained by genetic factors. Few twin studies have been published in AS. They have consistently reported very high concordance rates for MZ twin pairs (50–75%) and much lower rates for DZ twins (12.5–15%).9 However, these numbers should be interpreted with caution because this type of study is inherently exposed to bias that could lead to overestimation of the actual frequency of concordant pairs.18 First, there is a general tendancy to over-report concordant pairs; this can only be minimized by conducting systematic studies. Second, the probability of recruiting concordant pairs at random is twice as high as that of selecting discordant pairs if the whole population is not ascertained comprehensively. Numbers should be corrected for that bias in proband-based studies, and this was not performed in all reports. On the contrary, some true concordant pairs could be missed if the SpA cotwin lacks radiographic sacroiliitis, as shown in one study.19 Keeping these limitations in mind, it can be inferred from twin studies that AS bears a strong genetic load, the extent of which cannot be determined accurately from the available data. Importantly, twin studies have shown a greater concordance rate among MZ twins than among DZ twins concordant for HLA-B27, indicating that gene(s) distinct from the major histocompatibility complex (MHC) region are likely to contribute(s) to disease susceptibility. Family studies in SpA Few family studies have embraced the full spectrum of SpA, which has generally been considered to be more heterogenous than AS. However, SpA patients who do not fulfill AS diagnostic criteria because they lack advanced radiographic sacroiliitis are frequent among AS relatives; including these cases would definitely change appraisal of the genetic load.10,19,20 Therefore, to allow meaningful data interpretation, it is important to clarify the issue of heterogeneity. The Groupe Franc¸ais d’Etudes Ge´ne´tiques des Spondylarthropathies (GFEGS) reported a comprehensive phenotypic study of SpA in multi-case families.11,12,21 According to the classical model of SpA heterogeneity, it was expected that: (1) SpA subtypes would aggregate within families, as reported previously for AS and ReA22; (2) conversely, manifestations specific for each subtype, i.e. axial disease, peripheral arthritis, psoriasis, uveitis or IBD, would display some degree of independence; (3) HLA-B27 would exclusively predispose to articular manifestations and uveitis; and (4) genes predisposing to lone extra-articular manifestations (uveitis, psoriasis or IBD) would be increased in the corresponding subtypes. However, results from GFEGS studies contradicted most of these predictions: (1) with the notable exception of AIBD, SpA subypes were distributed randomly within families11,21; (2) all articular and extraarticular SpA manifestations appeared to be linked together, most likely due to shared genetic factors12; (3) in agreement with the latter interpretation, HLA-B27 was associated not only with articular manifestations and uveitis, but also with psoriasis and presumably with IBD12; and (4) the first gene implicated in lone Crohn’s disease (CARD15/NOD2) was not found to be associated with SpA, even when IBD was present.23 This work from the GFEGS showed that in the context of multi-case families, SpA subtypes corresponded to phenotypic variants of the same disease, which should be studied together in genetic studies. Whether this finding also applies to sporadic SpA

596 M. Breban

remains to be determined, although no striking difference distinguishes familial from sporadic SpA.24 The classical SpA subdivision was not supported by the GFEGS studies. Such failure is best explained by the major influence of disease duration on presenting symptoms, which has previously been under-rated. Hence, the occurrence of manifestations such as radiographic sacroiliitis, uveitis and IBD is strikingly related to disease duration, which is itself linked to disease onset, in cross-sectional studies as a consequence of left censoring effect.25 To overcome such difficulty, the GFEGS applied cluster analysis methods to familial SpA, which resulted in the identification of two major subtypes independent of disease duration.26 Phenotype ‘A’ has a late onset and presents predominantly as an isolated axial disease, whereas phenotype ‘B’ has an earlier onset and is characterized by the great frequency of peripheral joint (arthritis, enthesitis, dactylitis) and extra-articular manifestations (psoriasis and IBD), in addition to axial disease (Table 1). The rates of uveitis and advanced radiographic sacroilliitis were similar in both phenotypes. Validity of these two phenotypes was supported by a significant trend towards their familial aggregation, suggesting that they were determined by widespread genetic factors.26 Most interestingly, the only difference between the genders in both phenotypes was radiographic sacroillitis, which was more frequent in males (Table 1). These phenotypes are likely to correspond to different severity patterns, as the characteristics of phenotype ‘B’ have been identified as severity markers for SpA.27 The GFEGS conducted a systematic study of SpA recurrence among first-degree relatives of SpA probands. This unpublished study found a similar rate of SpA recurrence (12%) among siblings and parents. Considering an SpA prevalence of 0.3% in the general population, the l1 value would be 40 (Dernis-Labous E, Said-Nahal R, D’Agostino MA, Breban M, manuscript in preparation).

Table 1. Characteristics of two familial spondyloarthritis phenotypes, constructed by cluster analysis. Characteristic

Mean age at onset (years) Inflammatory back/buttock pain (%) Advanced radiological sacroiliitis (%) Uveitis (%) Peripheral enthesitis (%) Peripheral arthritis (%) Dactylitis (%) Psoriasis, (%) Inflammatory bowel disease (%)

Phenotype A (nZ234)

Phenotype B (nZ270)

Males (59%)

Females (41%)

Males (54%)

Females (46%)

26

28

21

22

99

99

95

98

76

53

73

50

33 34 18 7 7 0

21 33 13 17 10 3

28 70 60 27 39 4

27 72 50 29 23 9

All patients belonged to families with multiple cases of spondyloarthritis recruited by Groupe Franc¸ais d’Etude Ge´ne´tique des Spondylarthropathies. The results shown concern 504 HLA-B27-positive patients. Bold type indicates characteristics that are significantly different between both phenotypes, and italic type indicates characteristics that are significantly different between genders. Data source: Ref. [26].

Genetics of spondyloarthritis 597

WHAT HAVE WE LEARNT FROM ANIMAL MODELS? HLA-B27 transgenic models of SpA HLA-B27 remains the only genetic factor that has been reproducibly associated with SpA. Despite the strength of this association, its implication remains formally unproven because of the lack of functional explanation. From this perspective, the most convincing evidence has been provided by animal models. Hence, several lines of rats transgenic for HLA-B27 and human b2 microglobulin develop a spontaneous multisystemic inflammatory disorder that reproduces the characteristic features of SpA. This SpA in rats combines gut inflammation resembling ulcerative colitis with peripheral sterile arthritis in the hind limbs, and with inflammatory lesions of intervertebral discs, reminiscent of AS. Lesions of the skin and nails that resemble psoriasis histologically are also present.28 Rats from the original HLA-B27 transgenic lines uniformly developed disease. These were inbred rats produced on Lewis and Fisher backgrounds. However, breeding experiments have shown that one of the backgrounds tested (Dark Agouti) conferred disease resistance by a mechanism distinct from MHC.29 Therefore, it appears that, as in humans, SpA in rats is genetically determined by a combination of HLA-B27 and other gene(s). In contrast to rats, HLA-B27 transgenic mice usually remain healthy. However, mice transgenic for HLA-B*2702 developed a higher incidence of ANKENT, a progressive ankylosing enthesopathy that affects ankle and/or tarsal joints of ageing mice of susceptible genetic background. Spontaneous arthritis of the hindpaws and nail changes with hyperkeratosis were also reported in B27 transgenic mouse lacking b2 microglobulin (mb2m0). However, specificity of the latter findings for HLA-B27 remains unclear as mb2m0 mice were also found to exhibit a high frequency of spontaneous arthritis of the hindpaws and nail hyperkeratosis, irrespective of the presence of a B27 transgene.28 Experimental auto-immune SpA in mice Immunization of susceptible mouse strains (BALB/c and C3H) with cartilage or intervertebral disc proteoglycan provokes a disease that is histopathologically very similar to AS. A recent linkage analysis perfomed in this model identified MHC as the major locus controlling spondylitis. Interestingly, two non-MHC loci were significantly linked to disease. These two loci, situated on mouse chromosomes 2 and 18, are homologous with human chromosomic regions showing linkage to AS in genome screens.30

SUMMARY High recurrence of SpA in relatives of patients and twins is consistent with a strong genetic load, with the greatest contribution coming from MHC. However, it is estimated that half of the genetic predisposition depends on non-MHC loci. In familial SpA, all phenotypes appear to be linked to the same factors and should be considered to be phenotypic variants of the same disease with two major subtypes: a predominantly axial disease, and a more diffuse articular and extra-articular disorder.

598 M. Breban

HLA-B27 transgenic animal models of SpA have provided the strongest evidence to implicate HLA-B27 directly in SpA pathogenesis.

Practice points † a 12% recurrence rate of SpA was observed in first-degree relatives of patients † in family studies, all SpA phenotypes appear to be linked together and should be considered as phenotypic variants of the same disease † two major subtypes of SpA are distinguished in familial disease: a predominantly axial disease, and a more diffuse pattern of articular and extra-articular manifestations

Research agenda † more studies are needed on the recurrence of SpA in relatives of patients to allow accurate genetic modelling † prospective cohorts enrolling early patients are needed to allow better definition of SpA subtypes REFERENCES 1. Saraux A, Guillemin F, Guggenbuhl P et al. Prevalence of spondyloarthropathies in France: 2001. Annals of the Rheumatic Diseases 2005; 64: 1431–1435. 2. McGonagle D, Gibbon W & Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998; 353: 1137–1140. 3. Wright V. Seronegative polyarthritis: a unified concept. Arthritis and Rheumatism 1978; 21: 619–633. 4. van der Linden S, Valkenburg HA & Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis and Rheumatism 1984; 27: 361–368. 5. Baudoin P, van der Horst-Bruinsma IE, Dekker-Saeys AJ et al. Increased risk of developing ankylosing spondylitis among first-born children. Arthritis and Rheumatism 2000; 43: 2818–2822. 6. Said-Nahal R, Miceli-Richard C, Dougados M et al. Increased risk of ankylosing spondylitis among firstborn children: comment on the article by Baudoin et al.. Arthritis and Rheumatism 2001; 44: 1964–1965. 7. Amor B, Dougados M, Listrat V et al. Evaluation des crite`res des spondylarthropathies d’Amor et de l’European Spondylarthropathy Study Group (ESSG). Une e´tude transversale de 2228 patients. Annales de Medecine Interne 1991; 142: 85–89. 8. Dougados M, Van der Linden S, Juhlin R et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis and Rheumatism 1991; 34: 1218–1227. 9. Brown MA, Laval SH, Brophy S et al. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Annals of the Rheumatic Diseases 2000; 59: 883–886. 10. Chou CT, Lin KC, Wei JC et al. Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands. Rheumatology (Oxford) 2005; 44: 662–665. 11. Said-Nahal R, Miceli-Richard C, Berthelot J-M et al. The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Arthritis and Rheumatism 2000; 43: 1356–1365. 12. Said-Nahal R, Miceli-Richard C, D’Agostino MA et al. Phenotypic diversity is not determined by independent genetic factors in familial spondylarthropathy. Arthritis and Rheumatism (Arthritis Care and Research) 2001; 45: 478–484.

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