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Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes.

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ARTHRITIS & RHEUMATISM
Vol. 62, No. 9, September 2010, pp 2688–2695
DOI 10.1002/art.27574
© 2010, American College of Rheumatology
Involvement of Different Risk Factors in
Clinically Severe Large Joint Osteoarthritis According to
the Presence of Hand Interphalangeal Nodes
Ana M. Valdes,1 Daniel McWilliams,2 Nigel K. Arden,3 Sally A. Doherty,2 Margaret Wheeler,2
Kenneth R. Muir,4 Weiya Zhang,2 Cyrus Cooper,3 Rose A. Maciewicz,5 and Michael Doherty2
Objective. To quantify the differences in risk
factors influencing total hip replacement (THR) and
total knee replacement (TKR) based on the presence
versus absence of multiple interphalangeal nodes in 2 or
more rays of the fingers of each hand in patients with
large joint osteoarthritis (OA).
Methods. A group of 3,800 patients with large
joint OA who underwent total joint replacement (1,201
of whom had the nodal phenotype) and 1,906 control
subjects from 2 case–control studies and a populationbased cohort in the UK were studied. Odds ratios (ORs)
and 95% confidence intervals (95% CIs) were calculated
for the risk of total joint replacement in association with
age, sex, body mass index (BMI), height, and prevalence
of the T allele in the GDF5 rs143383 polymorphism.
ORs for total joint replacement were compared between
cases of nodal OA and cases of non-nodal OA and
between patients who underwent TKR and those who
underwent THR.
Results. Age, sex, and BMI had significantly
higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases.
The GDF5 polymorphism was significantly associated
with THR in cases of nodal OA, but not in cases of
non-nodal OA, and increased height was a risk factor
for THR in non-nodal OA cases only. Female sex was a
protective risk factor for TKR in non-nodal OA cases
(OR 0.60, 95% CI 0.52–0.70) but was predisposing for
TKR in the nodal form of OA (OR 1.83, 95% CI
1.49–2.26). The nodal phenotype was associated with a
significantly higher risk of undergoing both THR and
TKR (OR 1.46, 95% CI 1.09–1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI
1.37–2.11), but, paradoxically, was associated with a
lower risk of bilateral THR (OR 0.72, 95% CI 0.56–
0.91).
Conclusion. Nodal and non-nodal forms of large
joint OA have significantly different risk factors and
outcomes, indicating a different etiology for the 2 forms
of OA. With regard to the likelihood of undergoing THR,
this appears to be, at least in part, genetically determined.
Supported by the European Union Seventh Framework Programme (grant 200800), the Medical Research Council (UK), and the
Oxford National Institute for Health Research Musculoskeletal Biomedical Research Unit. AstraZeneca UK funded the Genetics of
Osteoarthritis and Lifestyle (GOAL) study sample and data collection.
The Arthritis Research Council UK funded collection of some of the
Nottingham Osteoarthritis Study cases (grant 17661) and provided
infrastructure support during the Nottingham Osteoarthritis and
GOAL studies (grant 14581).
1
Ana M. Valdes, PhD: King’s College London and St.
Thomas’ Hospital, London, UK; 2Daniel McWilliams, PhD, Sally A.
Doherty, SRN, Margaret Wheeler, BA, PGCE, Weiya Zhang, PhD,
Michael Doherty, MD, FRCP: Nottingham City Hospital, Nottingham, UK; 3Nigel K. Arden, MD, FRCP, Cyrus Cooper, DM, FRCP:
University of Southampton and Southampton General Hospital,
Southampton, and University of Oxford, Oxford, UK; 4Kenneth R.
Muir, PhD: University of Warwick Medical School, Coventry, UK;
5
Rose A. Maciewicz, PhD: AstraZeneca, Loughborough, UK.
Dr. Maciewicz owns stocks or stock options in AstraZeneca.
Address correspondence and reprint requests to Ana M.
Valdes, PhD, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital Campus, London
SE1 7EH, UK. E-mail: ana.valdes@kcl.ac.uk.
Submitted for publication March 16, 2010; accepted in revised
form May 18, 2010.
Severe osteoarthritis (OA) of the hip and the
knee represent 2 of the most significant causes of pain
and physical disability in adults (1). OA is multifactorial,
and patients are most likely affected by a combination of
both genetic and environmental factors, characterized
by a continuous distribution between the extremes of
predominantly genetic and predominantly environmental (2).
Generalized OA refers to the involvement of at
least 3 joints or of a group of joints (e.g., the interphalangeal [IP] joints). Two types of generalized OA have
2688
RISK FACTORS FOR NODAL VERSUS NON-NODAL LARGE JOINT OA
been described: nodal and non-nodal. The nodal type,
characterized by Heberden’s and Bouchard’s nodes
(firm, posterolateral swellings) of multiple distal and
proximal IP joints, is predominant in women and is
associated with underlying radiographic OA of the IP
joints (3). Genetic factors play a role in both the
incidence and, very likely, the outcome of OA. For
instance, the presence of Heberden’s nodes has been
reported to confer a 6-fold increased risk of progression
of knee OA (4). It has been proposed that generalized
OA may be a distinct disease in which systemic (genetic)
predisposition is more important than local environmental (e.g., mechanical) factors (5). Indeed, the presence of
OA in the IP joints of the hand at baseline has been
found to confer an increased risk of future hip OA (6).
The hereditary nature of Heberden’s nodes was
noted as early as the 19th century (7), and by the 1940s,
it was concluded that the phenotype was inherited as a
dominant trait (8). Further studies have established that
nodal OA often occurs in the context of OA at multiple
other joint sites, including the knee and hip, and shows
familial clustering (7). It is thus likely that environmental
and constitutional factors may play a larger role in the
development of the non-nodal form of large joint OA,
whereas genetic factors may have a more prominent role
in large joint OA accompanied by IP nodes or radiographic hand OA.
The most widely reproduced genetic factor found
to be associated with OA is the single-nucleotide polymorphism (SNP) rs143383 in the promoter region of the
growth differentiation factor 5 (GDF5) gene. An association between this SNP and OA of the hip or knee was
reported originally in Japanese and Chinese case–
control cohorts (9). The T allele of this SNP in Asians is
significantly increased in both patients with knee OA
and those with hip OA, and in vitro cell transfection
studies revealed that this allele mediates a significant
reduction in the activity of the GDF5 promoter. A recent
large-scale meta-analysis demonstrated that this SNP is
also strongly and consistently associated with knee OA
in European cohorts (10). However, in patients with hip
OA, very large between-study heterogeneity in this
association was observed, and statistical support for the
involvement of this SNP in hip OA was only borderline
(P ⫽ 0.016). One possible explanation is that there is
substantial genetic heterogeneity between different
forms of hip OA, and the presence of IP nodes may be
one of the factors involved.
The objective of the present study was to investigate possible differences, according to nodal versus
non-nodal status of generalized OA, in some of the
2689
genetic and nongenetic risk factors for the development
of large joint OA of sufficient clinical severity to warrant
total hip replacement (THR) or total knee replacement
(TKR).
PATIENTS AND METHODS
Cohorts. Cases of THR and TKR were recruited from
2 case–control studies in Nottingham, UK, the Nottingham
OA case–control study and the Genetics of Osteoarthritis and
Lifestyle (GOAL) study. In addition, control subjects were
obtained from both of these studies. In order to increase the
sample size, and thus the statistical power, and, more importantly, to include individuals over the age of 60 years who were
representative of the general population, we also included
control subjects from a separate UK population-based cohort,
the Hertfordshire study. (The descriptive characteristics of the
cases and controls from all 3 cohorts, as well as the distribution
of grades of radiographic severity of OA, are available at
http://www.treatoa.eu/publicpdfs/SupplementaryTablesAr-100362.pdf.)
Nottingham OA and GOAL case–control studies. Patients with hip or knee OA were recruited from hospital
orthopaedic surgery lists (current cases as well as those in the
previous 5 years) in the Nottingham area. Some of the
participants for this study were originally recruited as part of a
sibling cohort study (11,12). All participants gave their written
informed consent to take part. Approval for recruitment of
knee and hip OA cases was obtained from the research ethics
committees of Nottingham City Hospital and North Nottinghamshire. In all of the cases in the present study, patients had
symptomatic, clinically severe hip or knee OA and had been
referred to the hospital for joint replacement surgery, and the
majority had undergone unilateral or bilateral THR or TKR
within the previous 5 years.
Preoperative radiographs of the knee or pelvis of
patients with knee or hip OA were examined to confirm the
diagnosis and to grade for changes of OA (11–13). All pelvis
and knee radiographs were scored by a single observer (SAD)
for individual radiographic features of OA according to a
standard atlas, with a grade range of 0–3, using the Kellgren/
Lawrence (K/L) grading system for each knee or each hip joint
(14). Self-reported ethnicity was assessed by a nurseadministered questionnaire, and only individuals of European
descent were included in the genetic study. The presence of IP
nodes in the fingers of each hand was ascertained by trained
metrologists (SAD and MW) in all patients who underwent
total joint replacement. Heberden’s nodes were determined by
clinical inspection and palpation for firm/hard posterolateral
rounded swellings and/or joined dorsal bars, irrespective of any
tenderness or symptom reporting, and classified as present or
absent in each finger of both hands. Bouchard’s nodes were
similarly determined by inspection and palpation, and classified as present or absent. Further details on these clinical
assessments are described elsewhere (3,15). The nodal phenotype was defined as the presence of Heberden’s and/or Bouchard’s nodes that affected at least 2 rays of each hand.
Subjects ages 45–85 years who had undergone intravenous urography (IVU) in the same hospital were recruited as
2690
VALDES ET AL
Table 1. Risk factors for total joint replacement in nodal versus non-nodal large joint osteoarthritis (OA) cases compared with controls from the
3 studies*
THR
Controls
Study of origin, no.
Hertfordshire
327
Nottingham
767
GOAL
812
Total
1,906
Bilateral cases, no. (%)
0
TKR and THR, no. (%)
0
Risk factor
BMI, kg/m2
26.66 ⫾ 4.17
(26.48–26.85)
Age, years
64.74 ⫾ 8.24
(64.38–65.11)
Female, %
54.0
(51.8–56.2)
Height, meters‡
1.667 ⫾ 0.093
(1.662–1.672)
GDF5 T allele, %
62.2
(60.7–63.7)
Nodal OA
0
350
275
625
118 (18.9)
97 (15.5)
27.86 ⫾ 4.89
(27.48–28.25)
70.45 ⫾ 8.06
(69.81–71.08)
72.8
(69.1–76.3)
1.634 ⫾ 0.087
(1.626–1.642)
67.7
(65.0–70.3)
TKR
Non-nodal OA
P
Nodal OA
0
557
697
1,254
298 (23.8)
124 (9.9)
28.90 ⫾ 5.13
(28.61–29.19)
67.81 ⫾ 7.97
(67.37–68.26)
53.7
(50.9–56.4)
1.675 ⫾ 0.092
(1.67–1.681)
62.7
(0.607–0.646)
0
419
254
673
220 (32.7)
97 (14.4)
0.0118†
2.60 ⫻ 10
⫺11
7.00 ⫻ 10⫺16
0.0018†
0.0031
29.89 ⫾ 5.39
(29.48–30.30)
71.49 ⫾ 7.76
(70.91–72.08)
69.4
(65.9–72.9)
1.639 ⫾ 0.093
(1.632–1.647)
67.0
(64.4–69.7)
Non-nodal OA
P
0
819
650
1,469
332 (22.6)
124 (8.4)
30.78 ⫾ 5.54
(30.49–31.07)
68.17 ⫾ 8.30
(67.74–68.59)
45.3
(42.8–47.9)
1.679 ⫾ 0.092
(1.674–1.684)
66.8
(65.1–68.5)
0.0026†
2.30 ⫻ 10⫺17
7.30 ⫻ 10⫺26
0.089†
0.78
* Except where indicated otherwise, values are the mean ⫾ SD (95% confidence interval). GOAL ⫽ Genetics of Osteoarthritis and Lifestyle (study).
P values for comparison between nodal and non-nodal cases were derived by analysis of variance for body mass index (BMI), age, and height, and
by Pearson’s chi-square test for female sex and presence of the GDF5 polymorphism.
† Adjusted for age and sex.
‡ Only a subset of patients had available data on height: for controls, n ⫽ 1,168; for total hip replacement (THR), nodal cases n ⫽ 473 and non-nodal
cases n ⫽ 959; for total knee replacement (TKR), nodal cases n ⫽ 598 and non-nodal cases n ⫽ 1,260.
unrelated controls and underwent clinical examination and
joint radiography. Only individuals with no symptoms and no
clinical evidence of large joint OA (defined as the absence of
swelling, duration of stiffness, if present, ⬍30 minutes, and no
crepitus) or no radiographic evidence of large joint OA were
included as controls. In addition, for some of the proband joint
replacement cases, unaffected siblings who were free from
radiographic OA and whose age was older than 45 years were
considered as controls. A maximum of 1 unaffected sibling per
family was included among the controls. The allele frequencies
between unaffected siblings and unrelated controls were compared, and no differences were detected.
For the GOAL study, patients with clinically severe
knee or hip OA were recruited from joint replacement lists in
an identical manner as that described above for the Nottingham case–control study. Subjects ages 45–85 years who had
undergone IVU in the same hospital and who had no hip or
knee symptoms were recruited as unrelated controls and
underwent clinical examination and joint radiography. Only
control subjects who had no clinical or radiographic signs (in
both hips or both knees) of large joint OA were included in the
present study. Nodal status was again assessed clinically by
trained metrologists for all cases and controls from this cohort.
Medical Research Council (MRC) Hertfordshire cohort
study. The MRC Hertfordshire cohort study is a large
population-based study designed to investigate the relationship
between growth in infancy and the development of adult
disease. Details of the study design have been published
previously (16,17). In brief, 3,000 men and women were
recruited to the MRC Hertfordshire study, which included a
home interview. In addition, a subgroup of patients (498 men
and 468 women) underwent knee radiography. Ethics approval
was obtained from the East and North Hertfordshire ethics
committees, and all participants gave their written informed
consent. Subjects who were taking or had previously taken
bisphosphonate treatment were excluded.
Knee radiographs were graded individually for osteophytes and scleroses using a standard atlas, from which the K/L
score was determined (14). For the present study, only subjects
who had no radiographic evidence of knee OA (K/L grade ⬍2
in both knees) and who had not reported any significant pain
in or around the knees on most days of any given month over
the last year were included as controls. Nodal status was not
available for the Hertfordshire study subjects, but the presence
or absence of Heberden’s or Bouchard’s nodes was reported.
Clinical and laboratory analyses. For all study participants, age at the time of the clinic visit was recorded, and
weight and height (determined with a simple standard tape
measure) were determined to compute the body mass index
(BMI). For 3,096 total joint replacement cases and 1,168
controls, both height and BMI were recorded, but for 827 of
the control subjects (from the Nottingham and GOAL studies)
and 704 of the cases of total joint replacement, only information on BMI was available in the records.
Genomic DNA was extracted from the peripheral
blood leukocytes of patients and control subjects using standard protocols. Genotyping was carried out at Kbioscience in
Hertfordshire, UK. SNPs were genotyped using KASPar
chemistry, which is a competitive, allele-specific polymerase
chain reaction SNP genotyping system that utilizes fluorescence resonance energy transfer quencher cassette oligonucleotides.
RISK FACTORS FOR NODAL VERSUS NON-NODAL LARGE JOINT OA
2691
Table 2. Odds ratios (ORs) for the likelihood of total joint replacement in nodal versus non-nodal large
joint osteoarthritis (OA) cases compared with controls*
OR
(95% CI)
P
P, nodal vs.
non-nodal
OA†
1 ⫻ 10⫺11
4 ⫻ 10⫺49
4 ⫻ 10⫺18
0.36
6 ⫻ 10⫺4
1.77
1.64
1.02
1.20
1.02
(1.62–1.93)
(1.52–1.78)
(0.88–1.18)
(1.06–1.36)
(0.92–1.14)
2 ⫻ 10⫺37
3 ⫻ 10⫺34
0.83
4 ⫻ 10⫺3
0.56
0.015
5 ⫻ 10⫺6
4 ⫻ 10⫺12
0.014
0.013
1 ⫻ 10⫺52
6 ⫻ 10⫺72
1 ⫻ 10⫺8
0.97
2 ⫻ 10⫺3
3.02
1.90
0.60
1.06
1.21
(2.74–3.32)
(1.74–2.07)
(0.52–0.70)
(0.95–1.19)
(1.09–1.35)
2 ⫻ 10⫺111
6 ⫻ 10⫺51
2 ⫻ 10⫺10
0.32
5 ⫻ 10⫺4
0.019
7 ⫻ 10⫺9
2 ⫻ 10⫺16
0.84
0.785
Nodal OA
THR
BMI
Age
Female sex
Height
GDF5
TKR
BMI
Age
Female sex
Height
GDF5
P, THR vs. TKR†
BMI
Age
Female sex
Height
GDF5
OR
(95% CI)
1.48
2.25
2.51
0.92
1.27
(1.32–1.66)
(2.02–2.50)
(2.04–3.10)
(0.78–1.09)
(1.11–1.45)
2.51
2.91
1.83
0.97
1.24
(2.23–2.83)
(2.59–3.27)
(1.49–2.26)
(0.40–2.33)
(1.08–1.42)
Non-nodal OA
P
2.1 ⫻ 10⫺10
0.002
0.035
0.92
0.81
9 ⫻ 10⫺16
0.014
2 ⫻ 10⫺6
0.14
0.028
* ORs with 95% confidence intervals (95% CIs) from the multivariable model with age, height, and body
mass index (BMI) are per standard deviation, while those for the GDF5 polymorphism are per T allele
carried.
† P values represent the Z-statistic comparison between nodal and non-nodal disease or between patients
who underwent total hip replacement (THR) and those who underwent total knee replacement (TKR).
Statistical analysis. For continuous variables, the
mean ⫾ SD values were compared between patients with nodal
OA and patients with non-nodal OA who underwent total joint
replacement, using analysis of variance. The proportions of
each sex and the frequencies of the GDF5 polymorphism
rs143383 (T allele) were computed, and statistically significant
differences were assessed using Pearson’s chi-square test. The
odds ratios (ORs) were calculated for comparisons of the risk
of total joint replacement between cases and controls, with
cases classified according to the nodal OA status, i.e., nodal
versus non-nodal OA. Logistic regression was used to adjust
for confounding factors. Risk factors included in this analysis
were the presence of the GDF5 polymorphism, age, sex, and
BMI. The OR for height, which was derived from a smaller
number of samples (see Table 1), was adjusted for age and sex
only. Given the strong correlation between height and BMI,
the BMI value was not included, to avoid the problem of
multicollinearity.
All analyses were carried out using S-Plus 2000 (Insightful Inc.). To assess the statistical significance of the
difference in ORs between cases of nodal OA and cases of
non-nodal OA or between patients who underwent TKR and
those who underwent THR, the P value for the Z statistic was
computed, as follows: z ⫽ |LnORi ⫺ LnORj|/√(SE2i ⫺ SE2j),
where SEi and SEj denote the standard error of the log OR
(the LnORi and LnORj) for nodal and non-nodal disease,
respectively or for TKR and THR, respectively.
RESULTS
In total, 2,142 patients who underwent TKR (673
nodal OA and 1,469 non-nodal OA cases) and 1,879
patients who underwent THR (625 nodal OA and 1,254
non-nodal OA cases) were studied and compared with
1,906 control subjects. The numbers of samples from
each study are shown in Table 1.
All 5 risk factors considered (BMI, age, sex,
height, and presence of the GDF5 T allele) had significantly different mean values in patients with nodal OA
who underwent THR when compared with patients with
non-nodal OA who underwent THR. In contrast, among
patients who underwent TKR, only age, sex, and BMI
had significantly different mean values between the
nodal and non-nodal forms of the disease (Table 1).
We explored which of these factors influenced
the risk of total joint replacement in patients with nodal
OA and patients with non-nodal OA who underwent
either TKR or THR as compared with that in controls.
The results, as shown in Table 2, indicated differences in
the association of the risk factors with total joint replacement between each form of OA. Age was associated with
total joint replacement in both the nodal and non-nodal
forms of OA, but the association was significantly
greater in patients with nodal OA. Female sex was also
associated with the nodal OA form in those undergoing
total joint replacement, but was not associated with an
increased risk of THR in non-nodal cases. Female sex
was actually a protective factor for TKR in non-nodal
cases. BMI was a strong risk factor for both types of total
2692
joint replacement, but the OR for either form of OA in
TKR was significantly higher than that for either form of
OA in THR, and the OR in patients with the non-nodal
form was significantly higher than that in patients with
nodal disease. Age was a significantly stronger risk factor
for TKR than for THR.
Increased height appeared to significantly increase the risk of non-nodal hip OA, but this did not
appear to be a factor in either the nodal or non-nodal
forms of knee OA. A technical point to consider is the
estimate of effect size for height as a risk factor, which
was not adjusted for BMI to avoid introducing multicollinearity into the model. We observed a difference in
height as a risk factor for THR in patients with the
non-nodal form of OA, but not in those with the nodal
form. The effect size estimates for height were very
similar when BMI was included in the model and when
BMI was not included, for both forms of OA in patients
undergoing THR (P ⬎ 0.35). In fact, the OR for height
as a risk factor for THR was 1.30 (95% confidence
interval [95% CI] 1.15–1.48) in non-nodal OA cases and
0.97 (95% CI 0.82–1.15) in nodal OA cases, when
adjusted for age, sex, and BMI, and the difference
between these 2 estimates was significant (P ⬍ 0.007),
i.e., stronger than when not adjusted for BMI. Thus, the
difference observed is not a statistical artifact due to the
inclusion or exclusion of BMI in the statistical model.
Finally, carriage of the T allele at the rs143383
SNP was a significant risk factor in patients with either
the nodal or non-nodal form of OA who underwent
TKR. However, in patients who underwent THR, this
was only significant in those with the nodal form,
showing no effect on THR in non-nodal OA cases.
Carriage of the T allele was not associated with nodal
status in controls (OR 0.99, 95% CI 0.60–1.61; P ⬍
0.96).
We further investigated whether the nodal and
non-nodal forms of large joint OA had different levels of
severity, as measured by the prevalence of bilateral joint
replacement and by the prevalence of total joint replacement at both the hip and the knee (regardless of
bilateral status). The results, as shown in Figure 1,
indicated that, as expected, patients who underwent
total joint replacement and had the nodal phenotype
were at a higher risk of undergoing both THR and TKR
compared with those with non-nodal OA. Similarly,
patients who underwent TKR and had the nodal form of
the disease were significantly more likely than those with
non-nodal OA to have undergone a bilateral knee
replacement. In contrast, patients who underwent THR
and had the nodal form of OA were significantly less
VALDES ET AL
Figure 1. Risk of undergoing bilateral total hip replacement (THR)
(n ⫽ 1,879), bilateral total knee replacement (TKR) (n ⫽ 2,142), or
multisite joint replacement (hip and knee) (n ⫽ 3,800) among patients
with nodal large joint osteoarthritis (OA), when compared with
patients with non-nodal large joint OA (set at an odds ratio [OR] of
1.00). Bars show the ORs with 95% confidence intervals (95% CIs)
adjusted for age, sex, and body mass index. The size of the squares is
proportional to the sample size available for comparison.
likely than those with non-nodal OA to have undergone
a bilateral hip replacement.
DISCUSSION
Our results indicate that nodal and non-nodal
forms of severe hip OA have different genetic and
nongenetic risk factor profiles and differ in the likelihood of the requirement for bilateral THR. There are
also differences in risk profiles between patients with
nodal OA and patients with non-nodal OA who underwent TKR, but only with respect to age, sex, and BMI.
Our results provide evidence that the nodal phenotype is
associated with a higher prevalence of OA at more than
1 joint, as shown by 1) the higher risk of undergoing both
a hip and a knee replacement in nodal cases of large
joint OA, and 2) the higher risk of bilateral TKR in
nodal cases.
However, some of our findings appear counterintuitive. For example, bilateral THR was associated
more with non-nodal hip OA than with nodal hip OA,
and in spite of the presumed larger genetic component
of nodal OA, both patients with nodal disease undergoing TKR and those with nodal disease undergoing THR
were older at the time of recruitment than their counterparts with non-nodal OA. Such findings suggest that
the relationship between nodal status, severity, and age
at onset is complex. It is possible that the risk of both
bilateral THR and younger age at surgery is also associated with genetic traits, but these traits may differ from
those associated with nodal OA. We speculate that part
of the reason for this observation could be that hip OA
RISK FACTORS FOR NODAL VERSUS NON-NODAL LARGE JOINT OA
is strongly governed by local morphologic characteristics
that result in biomechanical stress (e.g., mild acetabular
dysplasia, nonspherical femoral head shape, neck-shaft
angle) and that the genetic and programming constituents of these parameters are likely to differ from those of
generalized OA, which may reflect more widespread
abnormalities of joint tissue constituents (e.g., bone,
cartilage, muscle). Consistent with this hypothesis, morphologic traits have been implicated in the risk of hip
OA independent of nodal status (18).
Contrary to expectation, we found no differences,
at least for the GDF5 gene, in the risk conferred
between patients with nodal OA and patients with
non-nodal OA who underwent TKR, suggesting that the
non-nodal form of knee OA is affected by genes similar
to those affecting the nodal forms. In addition, our
findings show that height can be a risk factor for some
forms of OA. These data are consistent with results from
a Swedish population-based prospective cohort study in
which height was shown to be a significant risk factor in
hip and knee OA (19). Patients with non-nodal OA were
taller than those with nodal OA. This is not surprising,
given the higher proportion of men and the younger age
among the non-nodal cases. However, in the case of
THR, this difference in height was statistically significant, even after adjusting for age and sex. In addition,
height was a significant risk factor in patients with
non-nodal OA who underwent THR as compared with
that in controls, in spite of the fact that controls were
3.5–5 years younger than the patients with non-nodal
OA who underwent THR. The sex proportions were the
same between the groups. This association with height
further suggests a different etiology from that of other
forms of severe OA.
The main strength of the present study is the
large number of cases that were identified and assessed
in the same way. However, there are some potential
limitations. Not all controls could be excluded on the
basis of radiographic evidence of hip OA and not all
were characterized for nodal status. Nevertheless, this
would seem unlikely to have had an effect on the main
conclusion regarding the differences between nodal and
non-nodal OA. The end point in this study was large
joint OA that was severe enough to require a total joint
arthroplasty, and therefore, in that sense, all controls
were truly free from disease as defined by our inclusion
criteria. Furthermore, such misclassification would have
the effect of underestimating risk factors but would not
have an impact on the differences between nodal and
non-nodal cases, which is the focus of this study. When
the same analyses of the risk of THR were run with
2693
exclusion of controls for whom no assessment of hip
radiographic OA was done, essentially the same results
as those presented herein were obtained. Moreover,
exclusion from the analysis of controls who were siblings
of proband cases and exclusion of all controls with the
nodal phenotype or with no nodal characterization all
yielded the same qualitative results as those presented
herein. Thus, the differences in recruitment criteria for
the various control sets were not a source of bias with
regard to the validity of our conclusions.
A second potential limitation is the choice of
total joint replacement as a clinical end point, which was
used to select a cohort of patients with clinically relevant
OA. Indications for total joint replacement may vary
between centers, doctors, and care settings, but in the
present study, the cases clearly were representative of an
OA population with clinically relevant disease (details
available at http://www.treatoa.eu/publicpdfs/
SupplementaryTablesAr-10-0362.pdf), which is suitable
for the primary analysis of differences between OA cases
with or without the nodal phenotype. Nevertheless, the
fact that the study focused on patients who underwent
total joint replacement may limit the generalizability of
our results. Cases of total joint replacement represent
only a fraction of the overall population with severe,
symptomatic large joint OA. Among subjects over the
age of 60 years in the UK, the prevalence of the need for
total joint replacement (excluding those who actually
receive total joint replacement) is between 12.4% and
16% (20,21), and the prevalence of receipt of total joint
replacement is ⬃6% (20), which, when added to the
prevalence of the need for total joint replacement, yields
a prevalence of total joint replacement with or without
receipt of surgery of between 18.4% and 22%. Thus,
27–33% of individuals who require a total joint replacement receive one.
Our results should be applicable to at least
one-fourth of individuals with severe, symptomatic large
joint OA, which is a high enough proportion of such
cases to be of merit and is consistent with the rates of
transition from hip pain to being listed for total joint
replacement (23%) in primary care patients over a
4-year period in a prospective UK cohort study (22).
Factors such as wealth, education, geographic region,
smoking status, obesity, and sex (21,23) have been
reported to influence rates of access to total joint
replacement, and recent studies have revealed considerable heterogeneity in the radiographic severity, functional disability, and pain in candidates for total joint
replacement (24). Thus, for example, patients undergoing total joint replacement may be generally fitter than
2694
people with both clinically severe large joint OA and
severe comorbidity, and our conclusions may not hold
among nonsurgical severe large joint OA cases. However, it is recommended that comorbidity should not be
a reason to not refer for surgery (25), and advances in
anesthetic technology and perioperative care have resulted in more patients with comorbidity undergoing
surgery. A population-based study with broad inclusion
is required to examine the validity of the results in
nonsurgical severe large joint OA.
A major difference from previous studies is the
large sample size, with 3,800 severe large joint replacement cases being evaluated. As such, it is the first large
study to attempt a detailed comparison of nodal versus
non-nodal severe large joint OA. Nevertheless, a number of smaller studies have tried to describe nodal
generalized OA. Kellgren and Moore were the first to
describe generalized OA, noting its predominance in
middle-aged women and the apparent absence of
marked obesity as a feature (7). The higher prevalence
among women was confirmed herein, but we found that
the age at which patients with nodal OA underwent total
joint replacement was older than that in patients with
non-nodal OA, and that age was a stronger risk factor
for total joint replacement in nodal disease. In the
GOAL study, the average age at first total joint replacement was 66.8 years for nodal OA cases and 64.7 years
for non-nodal OA cases. Furthermore, although BMI is
a strong risk factor for all forms of large joint OA, it is
greater in knee OA than in hip OA and also is a stronger
risk factor in non-nodal cases than in nodal cases.
The fact that nodal and non-nodal large joint OA
may have a different pathogenesis has been suggested by
data showing that chondroitin sulfate disaccharide levels
in synovial fluid are significantly different in patients
who have nodal OA of the hand in addition to knee OA
as compared with those with non-nodal knee OA (26).
However, further studies investigating the differences in
markers of joint damage, inflammation, or other metabolic processes between the 2 forms of OA have not
been reported.
It has been suggested that generalized OA has a
stronger genetic component than other forms of OA
(27). The current data support a different genetic contribution, at least for one genetic variant, for hip OA but
not for knee OA. It is worth noting that radiographic hip
OA has a strong familial aggregation (␭s 4.27–5.07) (12)
and a strong heritability (60%) (28), whereas radiographic knee OA has a weaker familial aggregation (␭s
1.66–2.13) (11) and a weaker heritability (39%) (29). In
spite of this, the strongest genetic associations with large
VALDES ET AL
joint OA reported to date (GDF5, the 7q22 cluster) are
all with knee OA (30), and the reported associations
with hip OA (31) are much more modest. These observations suggest that there may be a considerable amount
of heterogeneity in the hip OA phenotype that is not
captured by simple definitions like total hip replacement
or radiographic grade.
Although the association between hand and knee
OA in people with nodal generalized OA is well accepted, the inclusion of the hip as a target site within the
generalized OA concept is controversial. Kellgren and
Lawrence initially noted that the hip was uncommonly
involved in nodal generalized OA, and several subsequent studies also failed to show a clear association
between the presence of nodes and hip OA (32–35).
However, in contrast, one study has demonstrated an
association between the presence of nodes and hip OA
(36), and 2 studies have shown an association between
radiographic hand OA and hip OA (37,38).
The data presented herein indicate that 2 forms
of severe large joint OA have a different etiology.
Treatment options for severe OA are very limited.
There are no disease-modifying drugs, and use of biochemical markers and imaging to assess progression are
suboptimal. If pharmacologic interventions or monitoring tools are going to work, it is important to understand
that severe large joint OA is not a single disease and that
the pathogenesis, and thus the molecular and environmental factors determining progression, is likely to be
different. Further studies to characterize subsets within
large joint OA seem warranted.
In conclusion, our findings confirm that severe
large joint OA is not a single disease entity, but rather
represents a group of disorders with a similar pathologic
end point. Classification according to nodal status appears to be useful for separating 2 groups with different
risk factor profiles and different clinical outcomes.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Valdes had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Valdes, Arden, Muir, Maciewicz, M.
Doherty.
Acquisition of data. Valdes, Arden, S. A. Doherty, Wheeler, Muir,
Zhang, Cooper, M. Doherty.
Analysis and interpretation of data. Valdes, McWilliams, Arden, S. A.
Doherty, Zhang, M. Doherty.
RISK FACTORS FOR NODAL VERSUS NON-NODAL LARGE JOINT OA
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