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A strong familiality of Ankylosing Spondylitis through several generations


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To elucidate the familiality of ankylosing spondylitis (AS) in Iceland. The Icelandic genealogy database and population-wide data on all living Icelanders diagnosed as having AS (n=280), who previously had taken part in an epidemiological study on the prevalence of AS in Iceland, were included in the study. Identification of all interpatient relationships in the genealogy database allowed calculation of estimates of the RR for AS in the first-degree relatives (FDRs) to fourth-degree relatives of patients. For each AS proband, 1000 sets of matched Icelandic subjects in the genealogy database were used as controls. FDRs, second-degree and third-degree relatives had RRs of 75.5, 20.2 and 3.5, respectively (all p values <0.0001), indicating a significantly increased risk for relatives of the patients with AS to develop AS, suggesting a strong heritable factor, while the fourth-degree relatives had a RR of 1.04 (p=0.476) for having AS. Patients with AS in Iceland are significantly more related to each other than to randomly sampled control subjects. This is in agreement with previous reports on the familiality of AS, but the present study has more power and extends over larger familiar cohorts than previously reported.
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doi: 10.1136/ard.2009.125914
2010 69: 1346-1348 originally published online May 6, 2010Ann Rheum Dis
Arni Jon Geirsson, Kristleifur Kristjansson and Bjorn Gudbjornsson
through several generations
A strong familiality of ankylosing spondylitis
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Concise report
Ann Rheum Dis 2010;69:1346–1348. doi:10.1136/ard.2009.1259141346
Objective To elucidate the familiality of ankylosing
spondylitis (AS) in Iceland.
Methods The Icelandic genealogy database and
population-wide data on all living Icelanders diagnosed
as having AS (n=280), who previously had taken part
in an epidemiological study on the prevalence of AS in
Iceland, were included in the study. Identifi cation of all
interpatient relationships in the genealogy database
allowed calculation of estimates of the RR for AS in the
rst-degree relatives (FDRs) to fourth-degree relatives
of patients. For each AS proband, 1000 sets of matched
Icelandic subjects in the genealogy database were used
as controls.
Results FDRs, second-degree and third-degree relatives
had RRs of 75.5, 20.2 and 3.5, respectively (all p values
<0.0001), indicating a signifi cantly increased risk for
relatives of the patients with AS to develop AS, suggesting
a strong heritable factor, while the fourth-degree relatives
had a RR of 1.04 (p=0.476) for having AS.
Conclusions Patients with AS in Iceland are signifi cantly
more related to each other than to randomly sampled
control subjects. This is in agreement with previous
reports on the familiality of AS, but the present study has
more power and extends over larger familiar cohorts than
previously reported.
Ankylosing spondylitis (AS) is a chronic infl am-
matory disease, characterised by low back and
buttock pain with morning stiffness of insidious
onset.1 Population-based studies suggest that the
prevalence of AS is between 0.1% and 1.4%1–3 and
we have found the prevalence of AS in Iceland to
be close to 0.13%.4 Clinicians are well aware of
the increased prevalence of AS among siblings of
patients with AS, an observation confi rmed in a
number of studies.5–7
Several studies demonstrate that 6% to 8% of
close relatives of patients with AS have the dis-
ease5–7 in comparison to 0.1% to 1.4% in the gen-
eral population.1–4 The prevalence of AS among
relatives to human leucocyte antigen (HLA)-B27
positive patients with AS is even higher or up to
20%.8 Studies of twins have shown the concor-
dance rate in monozygotic twins to be 40% to
75%,9–11 but 4.3% to 12.5% in dizygotic twins,11
refl ecting that genetic and environmental factors
are important in the pathogenesis of AS. Only two
reports have reported the prevalence of AS among
second-degree relatives (SDRs) and third-degree rel-
atives (TDRs) of patients with AS, respectively.12 13
Several of these studies have had various method-
ological limitations, for example, limited cohort
size, index cases frequently selected from specialty
A strong familiality of ankylosing spondylitis through
several generations
Arni Jon Geirsson,1 Kristleifur Kristjansson,2 Bjorn Gudbjornsson3,4
1Department of Rheumatology,
University Hospital, Reyjavík,
2deCODE Genetics, Reykjavik,
3Centre for Rheumatology
Research, University Hospital,
Reyjavík, Iceland
4University of Iceland, Reykjavik,
Correspondence to
Bjorn Gudbjornsson, Centre
for Rheumatology Research,
Landspitali, Hringbraut –
University Hospital,
Reykjavik 101, Iceland;
Accepted 6 February 2010
clinics, lack of well documented prevalence of AS
in the background population and the ascertain-
ment bias of looking for fi rst-degree relative (FDR)
cases within a family after identifying the index
case, which can result in infl ated λS values, as sug-
gested by Guo.14
To overcome some of these methodological
problems, we have recently identifi ed all known
cases with AS in Iceland4 and by using the Icelandic
genealogy database of deCODE Genetics (Reyk-
javík, Iceland), we are able to calculate the RR for
family members spanning several generations of
individuals with AS.
The study group
The study involved all known patients with AS in
Iceland in 2005. Patients were recruited from three
main sources. The fi rst source was from a database
of individuals participating in genetic studies of
AS and infl ammatory bowel diseases.13 From this
database, 205 individuals were included in the pre-
sent study. The second source was an electronic
registry of patients admitted to the two major hos-
pitals in Iceland (WHO International Classifi cation
of Diseases, 10th edition (ICD-10) codes: M 45,
M 45.5, M45.9, M 46 and M 46.9), Landspitali –
University Hospital in Reykjavík and the University
Hospital in Akureyri. This source yielded an addi-
tional 54 patients with AS. The third source was a
personal call to all private outpatient rheumatology
services in Iceland to report patients to the study,
yielding 64 additional patients with AS.
The above-mentioned 3 sources yielded in total
280 individuals with AS, of which 256 were alive in
December 2005. A detailed description of the inclu-
sion criteria for verifi ed AS according to the modi-
ed New York criteria for classifi cation of AS15 can
be found in our previous work on the prevalence of
AS in Iceland.4
Genealogy database
deCODE Genetics has built a computerised
genealogy database of more than 760 000 indivi-
duals.16 The database contains records of all living
Icelanders, comprising more than 300 000 individ-
uals and a large proportion of all individuals who
have ever lived in the country from the time of the
settlement in the late ninth century. The genealogy
database is essentially complete from the 18th cen-
tury to the present day, allowing distant relation-
ships to be traced accurately.
Use of this database allows the defi nition of all
the relationships between patients with AS, as well
as the degree of the relatedness. It also allows the
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creation of matched control groups for calculation of the relative
risks and their statistical signifi cance. To ensure anonymity of
the patients in the present study, the social security numbers of
participants were encrypted by the Data Protection Commission
of Iceland before being used in the analyses.17 The study proto-
col was approved by the Icelandic Bioethics Committee and the
Icelandic Data Protection Commission.
Assessment of inheritance
The RR for disease in relatives is a measure of the risk of
disease in a relative of an affected person as compared with
the risk in the population as a whole. Obtaining valid esti-
mates of the RR is, however, not straightforward because
many sampling schemes may lead to biased or inaccurate
estimates.14 The use of a population-based group of patients
eliminates some of this potential sampling bias. In addition,
a near-complete genealogy database facilitates identification
of virtually all relationships between patients. It is impor-
tant to note that only probands were used in our analysis,
and no attempt was made to recruit relatives of cases of AS.
This design avoids the potential overestimation of familiar-
ity when secondary cases are recruited through probands, as
described by Guo.14
In the present study, we determined the RR for AS in a previ-
ously described Icelandic population.4 To assess the signifi cance
of the RR obtained for a given group of patients, we compared
their observed values with the RR computed for up to 1000
independently drawn and matched groups of control indivi-
duals.18 Each patient was matched to a single control individ-
ual in each control group. The controls were drawn at random
from the genealogy database and matched for the year of birth,
gender and the number of ancestors recorded in the genealogy
database. Empirical p values can be calculated using the con-
trol groups; thus, a p value of 0.05 for the RR would indicate
that 5% of the matched control groups had values as large as
or larger than that for the patient’s relatives or spouses. The
number of control groups required to obtain a fi xed accuracy of
the empirical p values is inversely proportional to the p value.
We therefore selected the number of control groups generated
adaptively up to a maximum of 1000. When none of the values
computed for the maximum number of control groups were
larger than the observed value for the patient’s relatives and
spouses, we report the p value as being less than 0.001. Using a
variance stabilising square root transform, an approximate 95%
CI may be constructed based on the distribution of RR for con-
trol groups.
Figure 1 shows an example of an ancestral pedigree with 18
patients with AS (in black) spanning 10 generations. In this case,
102 patients were related at or within the distance of only 4
meioses in a total of 45 families. The pedigrees demonstrated
signifi cant clustering of patients with AS. Additional pedigrees
can be obtained from the authors on request.
RR in relatives
The RR estimates for disease in relatives of affected patients
with AS are shown in table 1. The RR for AS were 75.5, 20.2
and 3.5 (all p values<0.0001) among FDRs, SDRs and TDRs of
affected patients, respectively. The RR for the fourth-degree
relatives did not reach signifi cance levels: RR 1.04 (95% CI 0.58
to 1.66), p value=0.476.
If the degree of relatedness includes aunts and uncles, nephews
and nieces, or cousins, the RR is similar to the above- presented
data (further details are presented in table 2).
Sex differences
Calculation of the RR for AS in siblings of affected parents with
AS in relation to whether the they were paternal or maternal
index cases demonstrated a similar RR; paternal siblings had a
RR of 48.2 (95% CI 36.22 to 63.19) and maternal siblings a RR
of 43.1 (95% CI 31.52 to 57.24). In contrast, the father of a case
with AS had a much higher RR than did the mother of the index
case: 167 (95% CI 131 to 194) versus 48.9 (95% CI 24.31 to
Table 1 Relative risk* estimates of ankylosing spondylitis (AS) in
relatives in four generations of affected individuals with verifi ed AS
Degree of relationship RR (95% CI) p Value†
Number of
First-degree relatives 75.49 (60.19 to 93.87) <0.001 112
Second-degree relatives 20.21 (15.15 to 30.20) <0.001 50
Third-degree relatives 3.52 (2.20 to 5.67) <0.001 28
Fourth-degree relatives 1.04 (0.58 to 1.66) <0.476 18
*Risk estimates for AS are the RR (95% CI) for the estimated risk of having the disease
itself (eg, the risk of AS in a relative of a patient with AS) as compared with the risk in
1000 sets of Icelandic control subjects.
†p Values are one sided and indicate the signifi cance of the risk of disease in the
combined relative groupings of all generational levels as compared with matched
control subjects.
Table 2 Relative risk* for having ankylosing spondylitis (AS) for aunts
and uncles, nephews and nieces, or cousins, of affected individuals with
verifi ed AS
Relationship RR (95% CI) p Value†
Number of
Aunts and uncles 18.29 (12.93 to 27.63) <0.001 20
Nephews and nieces 18.12 (12.41 to 27.63) <0.001 20
Cousins 3.66 (2.27 to 5.72) <0.001 26
*Risk estimates for AS are the RR (95% CI) for the estimated risk of having the disease
itself (eg, the risk of AS in a relative of a patient with AS) as compared with the risk in
1000 sets of Icelandic control subjects.
†p Values are one sided and indicate the signifi cance of the risk of disease in the
combined relative groupings of all generational levels as compared with matched
control subjects.
Figure 1 Pedigree of patients with ankylosing spondylitis (AS)
extending over 10 generations. Disease status is known only for the
later generations. This pedigree was created with the use of the deCODE
genetics genealogy database. To protect the anonymity of the families,
some of the unaffected relatives in the pedigree are not shown. The
circles denote female family members and the squares denote male
family members.
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RR in spouses
The RR of spouses of patients was 6.64 (95% CI 0.88 to 12.80),
but this value did not reach signifi cance (p value=0.097). The RR
for spouses of the controls was 0.952.
In the present study, we have used an extensive genealogical
database, extending back to the late ninth century, for evaluat-
ing the relationships of all known patients with AS in Iceland.
The study demonstrates a strong familiality of AS over three
generations, but the risk of developing AS seems to disappear in
the fourth generation of individuals with AS. The present results
are the fi rst to illustrate signifi cant familiality of AS over sev-
eral generations in a population-based cohort. Our study con-
rms results of previous studies of familiality of AS that have
shown an increased prevalence of AS among siblings and FDRs
of patients with AS.5–7 12 13 These studies have illustrated a high
RR of AS in siblings and FDRs of individuals with AS, with a λS
(sibling recurrence RR=λS) of up to 82 and λR2 (SDRs recurrence
RR) of 10, compared to 75 and 20, respectively, in our study.
To our knowledge, only two studies have reported the prev-
alence of AS in SDRs and TDRs of individuals with AS.5 13 In
1961, de Blecourt and coworkers published in the Annals of
Rheumatic Diseases the prevalence of AS among 2862 relatives of
100 patients with AS and reported an 86% inclusion rate among
relatives. They found that the RRs were around 10 for SDRs and
7.0 for TDRs, while we found a RR of 20 and 3.5 in SDRs and
TDRs, respectively. In our study, we identifi ed all known AS
cases in Iceland and therefore were neither dependent on clinical
evaluation of all the relatives of our patients nor on the preva-
lence value of AS in Iceland, which may explain the differences
in our results. We report the RR for FDRs, SDRs and TDRs and
also report that the risk of having AS mostly disappears in the
fourth generations of our 259 index cases (RR 1.04; p=0.476),
which is lower compared to previous report from Iceland on
this issue.13
The observation of a RR of 75 and 20 for FDRs and SDRs,
respectively, to develop AS is far higher than has been observed
using the same methods for rheumatoid arthritis in Iceland, or
4.38 for FDRs and 1.95 for SDRs,19 respectively and also well
higher than we have reported for psoriatic arthritis in Iceland
or 39.2 for FDRs and 12.2 for SDRs.20 Thus, the present results
demonstrate that genetic factors in AS probably play a stron-
ger role in the development of AS than in rheumatoid arthritis
or psoriatic arthritis, but that the genetic effects in all of these
diseases extend over several generations. However, our study
was not designed to elucidate any collective environmental or
immunological factors, for example, HLA-B27, that may play a
role in the pathogenetic processes of AS.
The prevalence of AS is much higher among men than women
(4 to 1). Therefore, we looked at whether the RR of siblings was
dependent on whether their mother or their father had AS. No
signifi cant difference in their RR was found in this respect.
All previous studies on familiality of AS have either presented
only the prevalence value of AS among relatives to patients with
AS or relied on estimates of the population prevalence of AS
when calculating the λ values. In contrast, we based our study
on complete ascertainment of all known cases of AS in Iceland as
we did in our recent population-based study on the prevalence
of AS in Iceland.4 This we believe may alleviate some of the
ascertainment bias that is inherent in studies that collect index
cases and affected relatives for estimation of the familiar-related
RR from specialised outpatient clinics only. These studies are
likely to over-represent patients with more severe disease and
families with more cases, which will infl uence the degree of her-
itability.14 Meanwhile, our study used an unselected nationwide
group of all known patients with verifi ed AS in Iceland.
In conclusion, individuals with AS in Iceland are signifi cantly
more related to each other than randomly sampled Icelandic
subjects for three generations. The present study used large,
unselected family cohorts combined with an extended geneal-
ogy database to avoid the bias of traditional post hoc ascertain-
ment of family members. These fi ndings suggest that genetic
factors play a stronger role in AS in comparison to rheumatoid
arthritis and psoriatic arthritis.
Acknowledgements The authors would like to thank the staff of the Statistics
Department at deCODE Genetics for their assistance with statistical analyses, espe-
cially Valdimar Búi Hauksson.
Funding The study was funded by the research foundations of the University
Hospital in Iceland, the Society for Rheumatology in Iceland and the Wyeth
Rheumatology Foundation in Iceland.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Icelandic
Bioethics Committee and the Icelandic Data Protection Commission.
Provenance and peer review Not commissioned; externally peer reviewed.
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... Since its discovery in families with multiple affected members, HLA-B27 has been established as an important genetic risk factor for axSpA (1,2,(40)(41)(42)(43)(44). However, the genetic risk associated with HLA-B27 status does not completely explain axSpA pathogenesis in the entire population. ...
Full-text available
Axial spondyloarthritis (axSpA) is a chronic, immune-mediated disease characterized by inflammatory axial skeleton involvement and extra-musculoskeletal manifestations. The continuum of axSpA ranges from nonradiographic axSpA (nr-axSpA) to ankylosing spondylitis, also known as radiographic axSpA; the latter is defined by definitive radiographic sacroiliitis. Human leukocyte antigen B27 (HLA-B27) is a genetic marker strongly associated with axSpA; it aids in the diagnosis of axSpA, and its absence leads to delay in diagnosis. For HLA-B27-negative patients, disease pathogenesis is poorly understood, signs and symptoms are frequently underrecognized, and diagnosis and treatment are commonly delayed. The proportion of HLA-B27-negative patients may be higher among non-White patients and those with nr-axSpA, who can face additional diagnostic challenges related to lack of definitive radiographic sacroiliitis. In this narrative review, we discuss the role of HLA-B27 in the diagnosis and pathogenesis of axSpA and highlight various pathways and genes that may be related to axSpA pathogenesis in HLA-B27-negative patients. We also emphasize the need to characterize gut microbial communities in these patients. Adequate understanding of clinical and pathological features underlying HLA-B27-negative patients with axSpA will improve diagnosis, treatment, and outcomes for this complex inflammatory disease.
... D'autres études ont calculé ce risque dans la SA et obtenu des valeurs similaires. Les études de population en Islande ont montré que ce risque au premier degré avait des valeurs allant de 75 à 94 [130,131]. ...
La spondyloarthrite (SpA) est une maladie multifactorielle avec une héritabilité estimée à plus de 90%, principalement en lien avec le HLA-B27. L'ensemble des facteurs de susceptibilité identifiés, incluant HLA-B27, expliquent moins du tiers de l'héritabilité. L'implication de variants rares pourrait expliquer une partie de cette héritabilité manquante. L'objectif de ce travail était d'identifier des variants rares associés à la SpA via une approche combinant analyses familiales et séquençage haut-débit. D'abord, nous avons séquencé une région de 1,4 Mb significativement liée à la SpA en 13q13 chez 71 patients et 21 témoins sains appartenant à des familles avec un score de liaison élevée dans cette région. Nous avons identifié un variant rare dans le gène FREM2 présent chez 9 malades d'une famille fortement liée à la région et non retrouvé dans d'autres familles ou cas isolés de SpA. Nous avons ensuite séquencé l'exome de 48 malades venant de 20 familles multiplex. Malheureusement, nous n'avons pas observé de variants récurrents entre les familles. Puis, nous nous sommes concentrés sur un deuxième pic de liaison génétique, déjà connu, sur le chromosome 9. L'étude de la famille la plus liée à cette région, qui comprend 12 patients, a conduit à l'identification de plusieurs variants rares codants ségrégeant avec la maladie. Cependant les études ultérieures ont montré des fréquences alléliques de ces variants équivalentes entres les cas et les témoins. Enfin, le séquençage du génome entier de 413 patients issus de 76 familles multiplex avec 4 malades ou plus a été réalisé. Nous avons identifié 1203 variants rares, codants et non synonymes et partagés par au moins tous les membres atteints d'une famille. Les analyses de validation génétique et fonctionnelle de ces variants sont en cours, tout comme l'analyse des variants non-codants. En conclusion, ces différentes approches suggèrent une importante hétérogénéité génétique de la SpA et soulignent également la difficulté de confirmer l'implication de variants rares dans les maladies complexes.
... Among patients from the Icelandic genealogy database, risk ratios of first-, second-, and third-degree relatives of individuals with r-axSpA were 75.5, 20.2, and 3.5, respectively (P<.0001 for all comparisons). 16 In a study of all patients diagnosed with r-axSpA in Sweden during a 16-year period, the overall familial odds ratio (OR) for r-axSpA was 19.4 (95% CI, 18.1 to 20.8), and patients with more than 1 family member with r-axSpA had a higher risk for development of the disease (OR, 60.8; 95% CI, 51.3 to 90.1) compared with patients with no known family history. 17 Several genetic risk factors have been associated with the development of axSpA. ...
Full-text available
Axial spondyloarthritis (axSpA) is a chronic, immune-mediated inflammatory disease characterized by inflammatory low back pain, inflammation in peripheral joints and entheses, and other extra-articular or systemic manifestations. Although our understanding of the natural history of axSpA has been limited by incomplete knowledge of disease pathogenesis, axSpA is increasingly understood as a spectrum of axial, peripheral, and extra-articular inflammatory conditions that includes nonradiographic axSpA and radiographic axSpA, also known as ankylosing spondylitis. In this narrative review, we present a road map of this axSpA continuum, highlighting genetic risk factors for the development of axSpA, triggers of disease, and reasons for and implications of diagnostic delay. We present a detailed overview of the spectrum of axSpA clinical manifestations and highlight factors known to influence the risk of disease progression. Finally, we provide some expert commentary on the practical use of this road map to assist health care providers in the identification of axSpA in clinical practice.
... which might have led to an overestimation of the risk (Stolwijk et al., 2016). However, similar ratios were obtained in population-based studies in Iceland with a first-degree RRR ranging from 75 to 94 (Thjodleifsson et al., 2007;Geirsson et al., 2010). In contrast, two register-based case-control studies of AS patients in Sweden reported a substantially lower RRR with a sibling risk between 15 and 20 (Sundquist et al., 2008;Morin et al., 2019). ...
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Spondyloarthritis (SpA) is a chronic inflammatory disorder with a high familial aggregation, emphasizing the existence of genetic susceptibility factors. In the last decades, family-based studies have contributed to better understand the genetic background of SpA, in particular by showing that the most likely model of transmission is oligogenic with multiplicative effects. Coexistence of different SpA subtypes within families also highlighted the complex interplay between all subtypes. Several whole-genome linkage analyses using sib-pairs or multiplex families were performed in the 1990s to try to identify genetic susceptibility factors besides HLA-B27. Unfortunately, no consistent results were obtained and family-based studies have been progressively set aside in favor of case-control designs. In particular, case-control genome-wide association studies allowed the identification of more than 40 susceptibility regions. However, all these loci explain only a small fraction of disease predisposition. Several hypotheses have been advanced to account for this unexplained heritability, including rare variants involvement, leading to a renewed interest in family-based designs, which are probably more powerful in the detection of such variants. In this review, our purpose is to summarize what has been learned to date regarding SpA genetics from family-based studies, with a special focus on recent identification of rare associated variants through next-generation sequencing studies.
... A distinctive feature of SpA is the high familial aggregation. We found a 20-fold increased risk of ankylosing spondylitis (AS) in first-degree relatives of AS patients (17), and even higher estimates have been reported (18)(19)(20). In psoriatic arthritis (PsA), 30-55 times higher risks are reported in first-degree relatives (21)(22)(23)(24). ...
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Objective: To determine whether a family history of spondyloarthritis (SpA) is associated with clinical presentation at the start of tumour necrosis factor inhibitor (TNFi) treatment, or predictive of TNFi drug survival and treatment response in patients with SpA. Method: Family history of SpA in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), and undifferentiated SpA (uSpA) from the Swedish Rheumatology Quality register starting a TNFi as their first biologic in 2006–2018 was assessed through national registers. Clinical characteristics at treatment start were compared by family history status. We used Cox regression to estimate hazard ratios for drug discontinuation, and analysed treatment response at 3 and 12 months with linear regression. Multiple imputation was used to address missing data. Results: We included 9608 patients. Patients with family history had an earlier age at onset and longer disease duration at TNFi treatment start, but did not differ regarding disease activity and presence of SpA manifestations. Hazard ratios for drug discontinuation were 1.08 [95% confidence interval (CI) 0.89–1.31] for AS patients with a family history of AS, 1.02 (95% CI 0.89–1.18) for PsA patients with a family history of PsA, and 1.11 (95% CI 0.85–1.45) for uSpA patients with a family history of uSpA, after adjusting for demographic, socioeconomic, and SpA-related factors. Treatment response at 3 and 12 months was similar between groups. Conclusion: Family history of SpA was not found to be associated with clinical presentation at the start of TNFi treatment, nor was it associated with drug survival or treatment response in SpA patients starting a first TNFi.
... [27] axSpA is a disease of genetic susceptibility. [28][29][30][31] As these contradictory results show, the prevalence of anti-CD74 antibodies may be linked to differences in racial or geographical predilection. Moreover, given the MHC association of this disease, [32] there is no good reason to expect an autoantibody presence; however, this represents an area that needs further investigation. ...
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The European cohort study has indicated about CD74 IgG-autoantibodies as potential marker for axial spondyloarthritis (axSpA) diagnosis. However, multiple studies have questioned the diagnostic value of various disease-specific autoantibodies in different ethnic groups. Here, we have tried to assess the diagnostic value of anti-CD74 IgG and IgA autoantibodies in axSpA patients from Chinese Han population. The anti-CD74 IgG and IgA autoantibodies were analyzed using ELISA assay in a cohort of 97 axSpA patients, including 47 treatment-naïve axSpA patients never treated with steroids or immunosuppressants and 50 treated axSpA patients. The rheumatic disease control (RDC) group consisted of 40 rheumatoid arthritis, 25 systemic lupus erythematosus, 18 psoriatic arthritis patients, and 60 healthy controls (HC). Our data demonstrated the presence of anti-CD74 IgA auto-antibodies in 25.8% of the axSpA patients, 30.1% of the RDC group patients and none in HC. Similarly, anti-CD74 IgG autoantibodies were observed in 23.7% of the axSpA patients, 18.1% of the RDC patients and 18.3% of the HC. The sensitivity, specificity, and accuracy of IgA autoantibodies were 21.3%, 82.5%, & 67.4%, respectively, while for IgG, it was 27.7%, 81.8%, and 68.4%, in treatment-naïve axSpA patients. Furthermore, weak positive relationship between anti-CD74 IgA autoantibodies and bath ankylosing spondylitis disease activity index ( r = 0.253, P = .012) and functional index (bath ankylosing spondylitis functional index; r = 0.257, P = .011) was observed. Overall, our study demonstrated little clinical and predictive value of CD74 autoantibodies in the diagnosis of axSpA and its related manifestations, among Chinese Han population.
Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole genome linkage studies were published in the 1990's, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare-variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease.
Les spondyloarthrites sont des rhumatismes inflammatoires chroniques fréquents et invalidants pouvant amener à des dommages articulaires définitifs difficilement prédictibles. Les mécanismes sous tendant la rupture entre un état sain et le déclenchement de la spondyloarthrite sont à ce jour insuffisamment compris. Les données les plus récentes démontrent que la dysbiose intestinale et l’immunité innée de type 3 occupent une place déterminante dans le développement de cette maladie. Afin d’apprécier cette rupture de tolérance induite par des agents bactériens, nous avons étudié l’arthrite réactionnelle, sous-groupe de spondyloarthrites déclenchées à la suite d’une infection par un agent bactérien spécifique. L’étude du modèle murin SKG d’arthrite réactionnelle induite par Chlamydia nous a permis d’identifier que les macrophages sont à la fois impliqués dans le développement de l’arthrite médiée par le TNF, IL-17 et IL-23 et dans le transport de Chlamydia du tractus génital vers des organes périphériques où l’infection peut persister. Ce travail de thèse met en lumière que l’étude des modèles animaux amène à une meilleure compréhension des mécanismes mis en jeu dans les rhumatismes inflammatoires chroniques. Un des objectifs majeurs des traitements dans la spondyloarthrite est d’améliorer la fonction du patient. Afin de faciliter l’étude de ce paramètre chez le petit animal nous proposons une nouvelle approche innovante qui permet d’évaluer efficacement le retentissement fonctionnel, en limitant les interventions humaines, grâce à des cages digitales connectées.Il est encore difficile à ce jour de discriminer les patients à risque de développer les formes les plus sévères de SpA. L’avenir sera de mieux identifier ces patients afin de proposer une approche thérapeutique personnalisée. Au vu de l’implication de l’immunité innée dans ces rhumatismes inflammatoires, nous avons étudié l’intérêt de la calprotectine sérique (protéine S100A8/A9), alarmine excrétés par les monocytes et neutrophiles. Nous montrons que la calprotectine sérique est un biomarqueur d’activité dans les spondyloarthrites débutantes, preuve indirecte de l’implication des cellules myéloïdes dans cette pathologie. Cependant la calprotectine sérique échoue à identifier les patients à risque de progression structurale. Nous avons ensuite étudié ce biomarqueur dans les vascularites à anticorps anti-cytoplasme (ANCA) des polynucléaires neutrophiles, pathologie médiée par le neutrophile. Il s’avère que l’augmentation des taux de la calprotectine sérique pendant le traitement de maintenance de la rémission est associé au risque de survenue d’un déclin de la fonction rénal suggérant l’intérêt potentiel de ce biomarqueur dans le suivi des patients atteint par une vascularite à ANCA.Outre l’atteinte articulaire, des atteintes cardiaques telles que des valvulopathies aortiques et des atteintes myocardiques sont rapportées dans les spondyloarthrites. A travers un travail de méta-analyse nous avons mis en évidence que la prévalence, en échographie trans-thoracique, des valvulopathies dans les spondyloarthrites axiales est comparable aux sujets sains. Il existe cependant une altération de certains paramètres en faveur d’une dysfonction ventriculaire gauche diastolique dont la signification clinique reste à préciser avant de proposer cet examen en routine. Enfin, en utilisant une approche fondée sur les preuves et un consensus d'experts, nous avons défini un ensemble de variables de base à collecter et à rapporter systématiquement après le diagnostic et pendant le suivi des spondyloarthrites axiales en pratique quotidienne.
Spondyloarthropathies (SpAs) are a debilitating group of chronic autoimmune diseases that affect a considerable proportion of young adults causing medical, social, and economical consequences. The prominent feature of SpAs is positive familial history and presence of HLA-B27 in most patients, which suggests genetic predisposing factors in disease pathogenesis. Ankylosing Spondylitis (AS), being the most prevalent and severe form of SpAs, is generally characterized by inflammatory low back pain accompanied by radiological findings of sacroiliitis. Despite all radiological and laboratory advancements, the complicated manifestations of AS urges for multi-factorial diagnostic criteria evolved during recent years for efficient detection and follow-up of the patients. According to the inflammatory base of SpAs, various anti-inflammatory medications have been used for treating the patients ranging from nonsteroidal anti-inflammatory drugs to Disease-modifying anti-rheumatic drugs, including synthetic and biologic agents. In the present chapter, we provide a general overview of epidemiologic, diagnostic, pathophysiologic, and therapeutic aspects of Spondyloarthropathies.
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Background. Detection of ankylosing spondylitis (AS) in the preclinical stage could help prevent long term morbidity in this patients’ population. The aim of this study was to examine the prevalence of active sacroiliitis in first-degree relatives of AS patients using MRI with clinical and laboratory correlations as these patients may benefit from MRI screening and early treatment. Methods. Seventeen first-degree relatives of AS patients were recruited prospectively. AS screening questionnaires (Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index & Visual Analogue Scale), blood tests (C-Reactive Protein, HLA-B27), and an MRI of the SIJs were taken. Two musculoskeletal radiologists interpreted the MRI scans, and two physiotherapists applied four symptom provocation tests (Gaenslen's test, posterior pelvic pain provocation test, Patrick's Faber (PF) test and palpation of the long dorsal SIJ ligament test), and two functional movement tests (active straight leg raise and Stork test). Results. Seven (41%) of the 17 participants demonstrated MRI evidence of active sacroiliitis. Of the 7 participants with active sacroiliitis, two (29%) had no history of recent low back pain (LBP), two (29%) had negative HLA-B27, and one (14%) participant had neither back pain nor positive HLA-B27. The Cohen's Kappa score for the interobserver agreement between the radiologists was 1.00 (p-value <0.0001). Despite fair to strong between therapist agreement for the physical test outcomes (Kappa 0.26 to 1.00), the physical test results per se did not have any predictive association with a positive MRI. Conclusions. MRI detected active sacroiliitis in 41% of first-degree relatives of AS patients. The lack of a history of prior LBP or positive HLA-B27 in active sacroiliitis participants might suggest that MRI screening for this high-risk population is warranted; however, further larger studies are needed to help elucidate its cost-effectiveness and long-term benefits.
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To determine the prevalence and clinical characteristics of ankylosing spondylitis (AS) in the Icelandic population, which carries a high prevalence of HLA-B27. A nationwide search was performed by screening hospital records and private rheumatology services for cases of AS in association with an on-going genetic study. Individuals diagnosed with AS according to the modified New York criteria were asked to participate in the study by answering a standardised questionnaire and to undergo an interview and clinical evaluation. A total of 256 individuals fulfilled the modified New York classification criteria for AS (169 male, 87 female); 84% of these individuals were HLA-B27 positive vs. 15% in the population (p<10-16). Of those contacted 223 patients (87.1%) answered the standardised questionnaire and were included in the study. The prevalence of AS in Iceland was 0.13% (CI 0.11-0.14%). A highly conservative prevalence number, based only on clinically evaluated patients, gave prevalence of 0.10% (CI 0.09-0.11%). Mean age at onset of symptoms was 24+/-8 years and at diagnosis 32.1+/-10.2 for male and 34.2+/-10.1 for female patients (not significant). Female patients more often had arthritis in peripheral joints and male patients were more often diagnosed with iritis. Prostatitis was experienced by 27% of male patients. AS is less common in the Icelandic population than reported in various Caucasian populations with a similar prevalence of HLA-B27.
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We have studied the prevalence of PsA in Reykjavik, Iceland, in a population-based cohort, and using the Icelandic genealogy database we have estimated the risk ratio (RR) spanning five generations. The national identification numbers of all 220 living Icelanders in Reykjavik known to have PsA were linked with the genealogy database. RRs for developing PsA were estimated in first-degree relatives (FDRs) to fifth-degree relatives of PsA cases. The kinship coefficient (KC) for PsA was also calculated. The control populations were 1000 and 10,000 sets of matched Icelandic subjects for each proband, respectively. FDRs to fourth-degree relatives of patients with PsA had RRs of 39, 12, 3.6 and 2.3, respectively (all P-values < 0.0001), reflecting a strong genetic component, whereas the fifth-degree relatives had an RR of 1.2 (P = 0.236). KCs of 5.0, 3.4, 1.7, 1.3, 1.0, 0.8 and 0.7 were observed for the first seven excluded meioses (all P-values < 0.0001), confirming the familial risk. Patients with PsA in Reykjavik, Iceland, are significantly more related to each other than to randomly sampled control subjects. This is in agreement with previous reports, but the present study examines the inheritance in more distantly related individuals. These findings indicate that in addition to a strong and complex genetic component in PsA, there is an important environmental contribution.
Objective. To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Methods. Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence-specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Results. Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co-twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Conclusion. Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.
Using a standard microcytotoxicity technique of tissue typing, the HL-A 27 antigen was identified in 72 out of 75 patients with classical ankylosing spondylitis and in 3 out of 75 controls. The same antigen was found in 31 out of 60 first-degree relatives.
Clinical, radiological and scintigraphic studies and HLA type assessment were performed in 38 subjects, constituting all the first-degree members of three generations of the families of six patients affected with ankylosing spondylitis (AS). The families included both parents, all siblings and all children of the probands. Definite AS was found in three men and possible AS in another. In another man and in a woman, a diagnosis of asymptomatic bilateral sacroiliitis was made. These six subjects indicate a family prevalence of AS reaching 15.8%. HLA B27 was present in 20 individuals (52.6%), including those with definite and possible AS and the case with asymptomatic sacroiliitis. The woman with asymptomatic sacroiliitis lacked HLA B27 antigen. Our study confirms the familial occurrence of AS, but it shows the occurrence to be lower than that previously reported.
Of the first degree relatives of B27 positive spondylitis probands, 10.2% demonstrated an associated disease, i.e., ankylosing spondylitis, Reiter's syndrome, peripheral arthritis, or acute anterior uveitis; all were B27 positive. Eighteen, i.e., only 13.7% of the B27 positive subjects had sacroiliitis; 4 were asymptomatic. We would therefore caution against the previous over-estimation of disease prevalence in "randomly selected" HLA-B27 positive individuals. None of the B27 negative relatives had any uveitis or spondyloarthropathy.
The present study was performed on 61 HLA-B27 positive first-degree relatives and 40 HLA-B27 negative relatives of 20 HLA-B27 positive probands with ankylosing spondylitis (AS). Of 24 HLA-B27 positive relatives 45 years or older, 21% had AS and 38% sacroiliitis. The HLA-B27 negative relatives did not have features of either disease. In the population study of 2,957 individuals 45 years or older, we found 5 cases of HLA-B27 positive sacroiliitis (according to the New York criteria) and 3 of these fulfilled the New York criteria for diagnosis of AS. In 2 of these 3 individuals, the diagnosis was made on clinical grounds. The phenotype frequency of HLA-B27 in this population is 7.8%, or about 230 HLA-B27 positive individuals in this population sample. Since AS was found in only 3 individuals, 1.3% of the HLA-B27 positive individuals in the population at large have AS; therefore, our data show that among individuals 45 years or older, 21% of HLA-B27 positive relatives of HLA-B27 positive AS patients have AS as compared with 1.3% of the HLA-B27 positive individuals in the population at large. Thus, the risk for AS is 16 times greater in the HLA-B27 positive relatives compared with HLA-B27 positive individuals in the population at large. The discriminatory value of the New York criterion of history of pain or the presence of pain at the dorsolumbar junction or in the lumbar spine was analyzed in the population and family studies and was found to be too nonspecific.
To obtain information on the rate of concordance for ankylosing spondylitis (AS) in a population-based series of twins. AS cases were identified by record linkage of the population-based Finnish Twin Cohort and the nationwide registry for fully reimbursed medications. A clinical examination was performed to establish concordance for AS. There were 6 monozygotic (MZ) pairs and 20 dizygotic (DZ) pairs with at least 1 member affected by AS. Three MZ pairs and 3 DZ pairs were concordant for the disease. All affected subjects were HLA-B27 positive. The pairwise concordance rate was 50% in MZ twins and 20% in HLA-B27 positive DZ twins (95% confidence intervals 11.8-88.2% and 4.3%-48.1%, respectively). These results indicate that AS disease expression is largely, but not entirely, genetically based, with a gene or genes other than B27 probably playing a role.