Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands

C. T. Chou1, K. C. Lin2, J. C. C. Wei3, W. C. Tsai4, H. H. Ho5, C. M. Hwang6, J. M. Cherng7, C. M. Hsu8 and D. T. Y. Yu9

1 Veterans General Hospital and 2 National Taipei College of Nursing, Taipei, 3 Chung Shan Medical University, Taichung, 4 Kaohsiung Medical University Hospital, Kaohsiung, 5 Chang Gung Memorial Hospital, Lin-Ko, 6 China Medical College Hospital, Taichung, 7 Buddhist Tzu Chi General Hospital, Hualien, 8 Ping-Tung Christian Hospital, Ping-Tung, Taiwan and 9 University of California, Los Angeles, CA, USA.

Correspondence to: C. T. Chou, Division of Allergy-Immunology-Rheumatology, Veterans General Hospital-Taipei, No. 201, Sec. 2, Shipai Road, Beitou Chiu, Taipei, Taiwan 112. E-mail: ctchou{at}vghtpe.gov.tw


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To estimate in a Chinese population the prevalence of undifferentiated spondyloarthropathy (USpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) probands, and to compare the clinical features of familial USpA with those of sporadic USpA.

Methods. The FDRs of two separate cohorts of consecutive AS probands were evaluated for the prevalence of USpA, using the Modified New York criteria and the European Spondylitis Study Group criteria for AS and SpA, respectively. Sporadic USpA and FDRs of non-SpA rheumatic patient probands served as separate controls.

Results. Among the 301 FDRs of 102 AS probands, 7.0% were USpA. This was 1000 times higher than the 147 FDRs of 40 non-SpA probands (P = 0.00230). Within the AS families, USpA was less male-dominated than AS (33.3 vs 72.5%) (P = 0.006). The only feature distinguishing familial from sporadic USpA was that the percentages of HLA B27 were 100 and 50%, respectively (P<0.001).

Conclusion. USpA and AS coexist in the same Chinese families, both being predisposed by HLA B27. In these families, a female gender favours the development of USpA rather than AS. A significant subset of sporadic USpA (HLA B27-negative group) has a different genetic predisposition compared with familial USpA.

KEY WORDS: Undifferentiated spondyloarthropathy, Ankylosing spondylitis, First-degree relatives, HLA B27


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
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Spondyloarthropathy (SpA) is a family of arthritis [1] composed minimally of ankylosing spondylitis (AS), reactive arthritis (Reiter's syndrome; RS), SpA associated with Crohn's disease or ulcerative colitis (IBD), SpA associated with psoriasis (PSA), and patients sharing features of SpA but not carrying any of the above designations. The latter group is termed ‘undifferentiated spondyloarthropathy’ (USpA) [2]. The most common SpA members are AS and USpA [2–6]. For the purpose of study, AS is an entity well defined by tradition and classification criteria, the latest set of which is the 1984 modified New York criteria [7]. USpA, on the other hand, is less well defined by tradition. For precise identification, USpA requires the classification criteria provided by the Amor or the European Spondylitis Study Group (ESSG) criteria published in 1990 and 1991, respectively [1, 8].

The factors causing AS are largely genetic and have been addressed by multiple family studies since the 1980s [9–14]. In comparison, there are fewer publications on the family relationship of USpA to AS. This is partly because the term USpA requires the definition provided by classification criteria, only publications after 1991 would provide a clear universally accepted definition for USpA [8]. In a review of the existing peer-reviewed full-length papers, we notice that no investigators have addressed the question by first using more than 100 consecutive AS patients as index cases, then estimating the prevalence and clinical features of USpA in the family members, then validating these results by a subsequent cohort study as well as a family study of probands who do not have SpA, and finally comparing the features of familial USpA with those of sporadic USpA. Such a study would address fully whether the prevalence of USpA is as high as that of AS in families of AS probands, and also whether familial and sporadic USpA patients are very different. If familial and sporadic USpA are indeed different, then future studies towards their diagnosis, genetics, course, prognosis and response to treatment would have to address the two groups separately.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
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Cases and controls
Patients were adults who were recruited randomly from a rheumatology out-patient setting. Subjects were classified as AS or SpA according to the Modified New York criteria for AS [7] or the ESSG criteria for SpA, respectively. USpA is defined as SpA, lacking the diagnosis of AS, PSA, RS or IBD [1]. The control groups in this study consisted of (i) a second cohort of 30 additional consecutive AS patients and their 126 first-degree relatives (FDRs), (ii) a third cohort of 40 rheumatic patients without AS/SpA and also their 147 FDRs, and (iii) 32 sporadic USpA patients with a negative SpA family history.

All first-degree family members, mainly AS probands’ parents or siblings with an average of two or three members in each family, aged above 16 were invited to participate in this study. A consent form was obtained from patients and their relatives before they were enrolled. This study was approved by the local institutional review boards.

Evaluations
All study subjects, including patients and family members, were personally evaluated by one of the rheumatology co-authors. The history and physical examination contained at least all the parameters listed in the classification criteria for AS and SpA. For this study, peripheral arthritis was defined as pain plus swelling in one or more peripheral joints (excluding hips and shoulders), and enthesopathy as pain or swelling at the heel area, including the Achilles tendons and the plantar fascia. The scoring method was proposed by Mander et al. [15]. Upon pressure on entheseal sites, pain is graded 0–3 to represent no pain, mild pain, moderate pain, or a withdrawal reaction. Diagnoses of psoriasis or uveitis or conjunctivitis were accepted only if they were made by dermatologists or ophthalmologists, respectively.

X-rays of the pelvis in an anterior–posterior view were carried out for all AS probands and their FDRs regardless of symptoms. Positivity for sacroiliitis was defined as least grade II bilateral or grade III unilateral changes. HLA B27 typing was carried out in all AS probands and their relatives using the flow cytometry method [16].

Statistical analysis
Values following the ± sign denote standard deviations. The statistical analyses used were ANOVA with Bonferroni correction for multiple comparisons, Fisher's exact test and the {chi}2 test with Yates’ correction. A P value less than 0.05 was considered significant.


    Results
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 Materials and methods
 Results
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 References
 
Initial recruitment
In the years 1999–2001, we interviewed 112 consecutive AS patients as potential probands. One hundred and two of them (91%) agreed to participate. We then contacted 330 of their adult first-, second- and third-degree relatives. Three hundred and thirteen of them (95%) complied. Among the 313 volunteer relatives, 301 (96%) were FDRs. Because the numbers of second- and third-degree relatives were very small, only FDRs were included in subsequent evaluations. Among the FDRs, 138/301 (45.8%) were parents of the probands, while 163/301 (54.2%) were siblings of the probands. All were submitted to a standard rheumatological evaluation, which would include all the parameters in the ESSG and AS criteria.

Prevalence of USpA among FDRs
Twenty-one of 301 FDRs (7.0%) were determined by ESSG criteria to be USpA (Table 1). Among these 21 USpA patients, seven (33.3%) were parents of probands and 14 (66.7%) were siblings of probands. Compared with the probands, these USpA patients were not different in their mean age or HLA B27. All of these USpA patients were HLA B27-positive. It is unlikely that these FDRs represent early AS that have not yet progressed to fulfil the AS criteria. This is because the mean duration of disease of the USpA was not different from that of the AS probands (P>0.05). What is striking is that the male:female ratio in the USpA subjects was only 0.5:1, which was significantly less than the 2.6:1 in the AS probands (P = 0.006). This was not because of a bias towards the male gender when we first selected the AS probands, because the ratio in these USpA subjects was also smaller than that among the AS of the FDRs (P = 0.0042).


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TABLE 1. Demographic data and HLA B27 examination in 102 AS probands and their 301 first-degree relatives

 
Although no validated epidemiological survey data for our population are available, the 7.0% prevalence of USpA appeared to be much higher than observed in the general population. To verify that the high prevalence of USpA among FDRs was not influenced by recruitment factors involved in family studies, we randomly selected 40 other adult patients with rheumatic disease from our Veterans General Hospital rheumatology clinics as probands. None of these 40 patients could be diagnosed clinically or classified by criteria as SpA or AS. Their mean age was 29.98 ± 11.17 yr and 28 (70%) were male. These parameters were not significantly different from those of the probands of the AS cohort in Table 1. We then recruited their adult FDRs and evaluated the prevalence of USpA among these FDRs. The recruitment rate for this group of non-AS probands’ FDRs was also high (92%). One hundred and forty-seven FDRs were available, with 55 (37.4%) parents and 92 (62.6%) siblings. The mean age of these FDRs was 37.93 ± 15.97 yr, which was not different from that of the FDRs of the 102 AS probands (41.87 ± 15.88 yr, P>0.05) (Table 2). The male:female ratio of these 147 FDRs was 68:79, which was not different from that of the FDRs of the 102 AS probands (141:160, P>0.05). None of the 147 FDRs of the non-AS probands could be classified as AS. Only one could be classified as USpA. This frequency of 0.007% is much lower than the 7.0% observed with the FDRs of AS probands (P = 0.0023) (Table 2).


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TABLE 2. Demographic data and prevalence of USpA or AS in FDRs of 102 AS probands, 30 AS probands and 40 non-AS probands

 
There is a possibility that the high prevalence of USpA among the FDRs of the 102 AS probands recruited in 1999–2001 was peculiar to that particular cohort. To exclude this possibility, we recruited in 2003 a second and smaller cohort of 30 AS patients and their 126 FDRs. The mean age and male:female ratio of these 30 AS probands were 29.87 ± 7.98 yr and 7:3, respectively. The recruitment rate of FDRs in this second cohort was 93%. Of these 126 FDRs, 51 (40.5%) were parents and 75 (59.5%) were siblings. The mean age of these 126 FDRs was 40.52 ± 17.38 yr, which was not different from that of the first cohort (Table 2). The male:female ratio of these 126 FDRs was 69:57, which was not different from that of the 301 FDRs of the first AS cohort (141:160, P>0.05). Eight of these 126 FDRs (6.4%) were classified as USpA. This was again higher than the 0.007% in the FDRs of the non-AS cohort (Table 2), but not different from the 7.0% of the FDRs of the first AS cohort (P = 0.5). In these eight FDR USpA patients, the male:female ratio was 3:5 and seven out of eight were positive for HLA B27.

Comparing familial USpA with sporadic USpA
Next, we addressed the question of whether the familial USpA of the first AS cohort was clinically distinct from sporadic USpA. Thirty-two sporadic USpA patients were randomly selected from the clinics. The male:female ratio was 1.3:1, which was higher than that of the familial USpA patients (P = 0.01). The mean age was 32.1 ± 8.6 yr, which was not different from that of the familial USpA cases (36.7 ± 12.7 yr). Twenty-two out of 32 patients had a pelvis X-ray and none had more than Class II sacroiliitis. All familial USpA patients had an X-ray but none had more than Class II sacroiliitis, which showed no significant difference from the 22 sporadic USpA patients in the presence of radiographically detected sacroiliitis. These two groups of USpA patients were compared using the parameters in the ESSG criteria, some of which are listed in Table 3. There was no statistical difference between the two groups, especially after Bonferroni correction. Most interestingly, when the percentages of HLA B27 were compared, they were 100% in the familial group but only 50% in the sporadic group (P<0.001).


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TABLE 3. Initial clinical manifestation and prevalence of HLA B27 of USpA in relatives with AS or USpA and USpA in relatives without AS or USpA

 
Prevalence of AS in FDRs
To ensure that in our population AS is indeed a familial disease, we analysed the prevalence of AS among FDRs in our three cohorts. Among the 301 FDRs of the first 102 AS cohort, 61 (20.3%) were classified as AS. (Table 1). In contrast, among the 147 FDRs of the non-AS cohort, none had AS. The difference is statistically significant (P<0.0001) (Table 2). In the second AS cohort, 22 (17.5%) of the 126 FDRs were classified as AS. This is again higher than the number of AS among the non-AS cohort (Table 2), and not different from the value derived from the first AS cohort (P = 0.81).


    Discussion
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 Materials and methods
 Results
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Many studies have been published to evaluate the prevalence of AS among FDRs of AS probands. The prevalences of 17.46–20.27% found in the two present family studies are very similar to those reported previously by ourselves [12] from South China [13] and most other parts of the world [17–19]. This degree of agreement, as well as the similarity in the results of our two consecutive but separate cohorts reported here, validates the quality and reproducibility of our present survey. It also indicates that the degree of genetic contribution to AS in our population is probably as high as that in most other ethnicities, regardless of any differences in HLA B27 subtypes.

Unlike AS, USpA was not defined by classification criteria until 1990/1991 [1, 2, 8]. However, even prior to that it was noticed that relatives of AS probands might show SpA features, even though they could not be strictly classified as AS [20]. Since 1990, the most extensive study of the coexistence of AS and criteria-defined USpA among family members was the one reported in 115–146 French families by Said-Nahal et al. [14, 21]. To collect probands, their group used as index cases those patients fulfilling the classification criteria for all SpA subtypes and not just AS. The major question they addressed was whether familial SpA was a homogeneous group. This is because they wished to know if all SpA patients in a multiplex family can be used for genome scanning purpose, irrespective of the particular subtypes of SpA. Because they discovered that all their familial SpA patients shared similar clinical features, they concluded that they were homogeneous whether they were classified as AS or USpA.

The design of our study differs from that of the French study in several ways. First, the subjects of our study were Chinese, who constitute 1 in 6 of the world population. Second, our index cases were AS, and not USpA. This is out of necessity, because when we interview USpA patients who come to our clinics very few of them carry a family history of SpA. Third, we verified the results of our study by using two consecutive but separate cohorts of AS probands. Fourth, we also used a cohort whose probands are rheumatic disease patients who do not suffer from SpA. Lastly, and importantly, we compared the features of the familial USpA patients with those of sporadic cases seen in our clinics.

Our first interesting USpA finding is that 7.0% of the FDRs are classified as USpA. This is much more than the 0.007% we observed among FDRs of the non-AS/SpA cohort. This is probably a correct assessment because all the familial USpA patients are HLA B27-positive, which is our second and most surprising finding. This high percentage of HLA B27 noted among familial USpA is not because our ability to diagnose USpA in these patients is biased by whether a patient is positive for HLA B27. In this study, the diagnosis of USpA was entirely based upon the classification criteria, and blind to the result of the HLA B27 testing. To our knowledge, this is the first report in a Chinese population that the prevalence of USpA is increased among FDRs of AS probands. To validate this conclusion, we recruited a second cohort of AS probands. The result was the same. The prevalence of USpA among FDRs we have discovered in Taiwan is less than the 23% reported in French families. However, in the French families, probands consisted of AS as well as SpA members other than AS. The publication of these results does not provide information parallel to our study for precise comparison. In any case, it is certain that, in our Taiwan population, USpA is increased among AS families, and that similar to AS, familial USpA are also HLA B27-positive.

Our third interesting finding is that in the first and larger cohort there is less male predominance in USpA compared with AS in the same families. In contrast, compared with the AS probands, the mean age and duration of arthritis are the same. This suggests that gender might influence the clinical manifestations of SpA within the same family.

The last question we addressed is whether familial and sporadic USpA are identical diseases. To our knowledge, this has been neglected in recent publications. When we compare our sporadic USpA with our familial USpA patients, we do not find any differences in the prevalence of peripheral arthritis or enthesitis, and only a marginal difference in low back pain. Partly, this might be due to the limited number of USpA patients. It was difficult to collect large samples of USpA patients (e.g. >50 or more) in a short period. Most unexpectedly, although 100% of our familial USpA patients are HLA B27-positive, this is so in only 50% of sporadic USpA. Both are high compared with the 4–9% in our general Taiwan population [22, 23]. The high percentage of HLA B27 in familial USpA is similar to that reported in the French families. For sporadic USpA, the percentages of HLA B27 reported vary from 54% in one Caucasian study [24] to 78% in one Korean study [25]. In both, they are less than the almost 100% in our USpA patients and also in the French familial USpA patients [14]. Our study suggests that, from the genetic point of view, there are two forms of USpA, one of which is HLA B27-positive. In this group, MHC genes play a significant role. However, the HLA B27-negative group does not indicate there are no genetic factors involved. It is worth studying other MHC or non-MHC genes in this group.

Besides reflecting on the genetics of SpA, our results provide several challenges to be considered for future studies of USpA. USpA is a disease that is as common as AS [4, 5, 26, 27]. The long-term prognosis of USpA is less well defined than that of AS. Such information is critical because of the recent availability of TNF blockers for treatment of SpA patients [28–30]. Our study would imply that some sporadic USpA patients might be different from familial USpA patients. However, the two cannot be distinguished by the prevalence of peripheral arthritis or enthesitis. At the moment, assessment of family members and, to a certain extent, HLA B27 is the only helpful parameter. Future studies designed to compare the long-term prognosis of these two groups of USpA patients will be very important.

The authors have declared no conflicts of interest.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 13 October 2004; revised version accepted 14 January 2005.



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