Osteoarthritis and Cartilage 23 (2015) 544e549

Clinical phenotypes in patients with knee osteoarthritis: a study in the

Amsterdam osteoarthritis cohort
M. van der Esch y *, J. Knoop y, M. van der Leeden y z x, L.D. Roorda y, W.F. Lems k ¶,
D.L. Knol x #, J. Dekker z x yy
y Amsterdam Rehabilitation Research Center, Reade, Amsterdam, The Netherlands
z VU University Medical Center, Department of Rehabilitation Medicine, Amsterdam, The Netherlands
x VU University Medical Center, EMGO Institute for Health and Care Research, Amsterdam, The Netherlands
k VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands
¶ Reade, Department of Rheumatology, Amsterdam, The Netherlands
# VU University Medical Center, Department of Epidemiology and Biostatistics, Amsterdam, The Netherlands
yy VU University Medical Center, Department of Psychiatry, Amsterdam, The Netherlands

a r t i c l e i n f o s u m m a r y

Article history: Objective: To identify and validate previously established phenotypes of knee osteoarthritis (OA) based
Received 15 August 2014 on similarities in clinical patient characteristics.
Accepted 8 January 2015 Methods: Knee OA patients (N ¼ 551) from the Amsterdam OA (AMS-OA) cohort provided data. Four
clinical patient characteristics were assessed: upper leg muscle strength, body mass index (BMI),
Keywords: radiographic severity (Kellgren/Lawrence [KL] grade), and depressive mood (the Hospital Anxiety and
Osteoarthritis
Depression Scale [HADS] questionnaire). Cluster analysis was performed to identify the optimal number
Knee [Mesh]
of phenotypes. Differences in clinical characteristics between the phenotypes were analyzed with
Muscle strength [Mesh]
Phenotype [Mesh]
ANOVA.
Obesity [Mesh] Results: Cluster analysis identified five phenotypes of knee OA patients: “minimal joint disease pheno-
Depressive disorder [Mesh] type”, “strong muscle strength phenotype”, “severe radiographic OA phenotype”, “obese phenotype”, and
“depressive mood phenotype”.
Conclusions: Among patients with knee OA, five phenotypes were identified based on four clinical
characteristics. To a high degree, the results are a replication of earlier findings in the OA Initiative,
indicating that these five phenotypes seem a stable, valid, and clinically relevant finding.
© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Introduction can identify and manage subgroups of knee OA patients in their

Knee osteoarthritis (OA) is a heterogeneous disease with distinct
characteristics during the various stages of disease progression1,2. It
has been hypothesized that knee OA consists of different subgroups
or phenotypes3. To identify subgroups or phenotypes, several ap-
proaches are available, focusing on etiological and risk factors
(metabolic, traumatic, inflammatory, and subchondral bone turn-
over)4, focusing on genetic factors5, or focusing on clinical charac-
teristics6. The latter approach seems particularly relevant, as the
ultimate goal of identifying clinical phenotypes is that clinicians
* Address correspondence and reprint requests to: M. van der Esch, Amsterdam
Rehabilitation Research Center, Reade, P.O. Box 58271, 1040 HG Amsterdam, The
Netherlands. Tel: 31-20-589-62-91; Fax: 31-20-589-63-16.
E-mail address: m.vd.esch@reade.nl (M. van der Esch).
practices6. There is, however, a paucity of studies identifying clin-
ical, homogenous knee OA subgroups. Most studies focused on a
single clinical characteristics such as pain7, knee malalignment8,
and race and gender9. Only one recent study from our own group
based on data of the OA Initiative (OAI) included several clinical
characteristics at the same time10.
In the last-mentioned study, five clinically relevant phenotypes
were identified with data from the open-population-based “pro-
gression subcohort” of the OAI cohort10. These five phenotypes
were “minimal joint disease phenotype”, “strong muscle pheno-
type”, “non-obese and weak muscle phenotype”, “obese and weak
muscle phenotype”, and “depressive phenotype”. These pheno-
types were based on four patient characteristics i.e., upper leg
muscle strength, body mass index (BMI), radiographic OA, and
depressive mood. The four clinical characteristics are regularly

http://dx.doi.org/10.1016/j.joca.2015.01.006
1063-4584/© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
 M. van der Esch et al. / Osteoarthritis and Cartilage 23 (2015) 544e549 545

assessed and relevant to clinical practice6, and have a major impact
on disease progression and clinical outcome6. In clinical practice,
patients differ highly on these characteristics, necessary for cluster
analysis11.
For reasons of robustness, there is a need to determine whether
the five phenotypes can be replicated in another sample. The pre-
sent study aimed to identify and validate previously established
phenotypes of knee OA based on similarities in clinical patient
characteristics, i.e., upper leg muscle strength, BMI, radiographic
OA, and depressive mood in patients with knee OA from a clinical
population.
Methods
Patients and methods
The Amsterdam OA (AMS-OA) cohort contains patients with OA
of the knee and/or hip who have been referred to a secondary care
outpatient rehabilitation center (Reade, Center for Rehabilitation
and Rheumatology, Amsterdam, the Netherlands)12. The examina-
tion protocol involves assessments by rheumatologists, radiolo-
gists, and rehabilitation physicians. Demographic, clinical,
radiographic, biomechanical, and psychosocial factors related to OA
were assessed. Total knee replacement, rheumatoid arthritis, or any
other form of inflammatory arthritis (i.e., crystal arthropathy or
septic arthritis) were exclusion criteria. In the present study, 551
patients from the AMS-OA cohort with a unilateral or bilateral
diagnosis of knee OA according to the American College of Rheu-
matology (ACR) were included13. The group of patients was defined
as established knee OA due to the combination of confirmed
diagnosis of knee OA according to the ACR criteria and the presence
of knee OA related symptoms making a visit for secondary care
necessary. All patients provided written, informed consent ac-
cording to the Declaration of Helsinki. The study was approved by
the Slotervaart Hospital/Reade Institutional Review Board.
Clustering variables
Muscle strength was used in analyses as the mean score of left
and right lower limb isokinetic muscle strength (quadriceps and
hamstring strength in Newton meters), because the correlation
between left and right muscle strength for extension and flexion
muscle strength was r ¼ .64 and r ¼ .72 (P < .001), respectively14.
BMI was calculated by dividing mass (in kilograms) by squared
height (in meters). Radiographic severity of knee OA (ROA) was
scored by an overall severity grade (Kellgren and Lawrence grade
(KL))15 ranging from 0 to 4, based on weight-bearing fixed-flexion
knee radiograph16. The inter-rater agreement of scoring the
radiographic features was good17. In analysis the most severely
respect to selected variables. Members of the resulting groups are
as similar as possible to others within their group (high within-
group homogeneity) and as different as possible to those in other
groups (low between-group homogeneity). This analysis implicates
that members are permitted to be member of a single group (i.e.,
phenotype)20. The following clinical characteristics were included
in cluster analysis: mean of left and right lower limb muscle
strength (quadriceps and hamstring strength), BMI, KL grade of the
most severely damaged knee, and score on the HADS questionnaire
(depressive mood) (see Table I for more information). Since cluster
analysis techniques are sensitive to outliers, outlier cases should be
identified and removed from the dataset before cluster analysis21.
The FASTCLUS procedure of the SAS package22 was used. An esti-
mation of the optimal number of clusters (between three and eight
clusters) was based on the Calinski and Harabasz pseudo F-statis-
tic23, which is the best performing clustering criterion according to
Milligan and Cooper24. Additionally, a second clustering criterion
was used, as recommended by Milligan and Cooper24. This second
criterion was the Beale's F-ratio, which tests the hypothesis of the
existence of an additional cluster vs the already detected clusters25.
The addition of one cluster in the cluster solution should continue
until the hypothesis e tested by Beale's F ratio e was rejected25.
This analysis was continued till the highest pseudo F value was
found, considering that this was the most adequate number of
clusters.
Spearman's correlation coefficients were computed to examine
the bivariate associations between the four clinical characteristics:
muscle strength, KL grade, BMI and HADS scores. Differences of
muscle strength, KL grade, BMI, and HADS scores between the
clusters (phenotypes) were evaluated with analysis of variance
(ANOVA) and a Bonferroni post-hoc analysis.
Results
No outliers were found and therefore a total of 551 patients
were included in the study. The characteristics of the study group
are displayed in Table I. The mean age was 61.7 (SD ¼ 8.8) years and
68 % of the patients were women. Knee symptoms were present for
more than 5 years in 72% of the patients. Radiographic evidence of
knee OA (i.e., KL grade  2) was found in 63% of the patients. Mean
muscle strength (Nm) and HADS-depressive mood were 70.26
(SD ¼ 35.81) and 4.81 (SD ¼ 3.47), respectively. The mean values of
Table I
Characteristics of study group (mean and standard deviation, unless otherwise
stated)
Characteristic Mean (SD)

damaged knee was used. Depressive mood was based on the Hos- N 551
pital Anxiety and Depression Scale (HADS) questionnaire, which is Age, years 61.7 (8.8)
Gender (% female) 68
one of the most frequently used questionnaires for depressive
Duration of knee symptoms:
mood experiences with very strong psychometric properties18. The Less than 5 years (%) 28
7-item subscale measures depressive mood on a 4-point response More than 5 years (%) 72
scale (from 0, no symptoms, to 3, maximum symptoms), with Bilateral knee pain (% yes) 67
possible scores for the subscale ranging from 0 to 21. The HADS is a Co-occurrence of hip pain (% yes) 15
Number of comorbidities (median and IQR) 2 (1e3)
valid and reliable questionnaire for detecting mood disorder in Muscle strength, Nm 70.3 (35.8)
people with OA19. Body mass index, kg/m2 30.4 (6.2)
Obesity (BMI  30.0) (%) 46
Statistical analysis Radiographic knee OA:
K/L score 0 (%) 5
K/L score 1 (%) 32
Identification of subgroups K/L score 2 (%) 27
K-means (or its equivalent “non-hierarchical”) cluster analysis K/L score 3 (%) 22
was used to identify homogeneous subgroups of knee OA patients K/L score 4 (%) 14
(i.e., phenotypes). Cluster analysis is a data analysis technique HADS depressive mood score 4.8 (3.5)

aimed at grouping entities on the basis of their similarity with IQR ¼ interquartile range.
546 M. van der Esch et al. / Osteoarthritis and Cartilage 23 (2015) 544e549

Table II
Clustering criteria for solution of three or more clusters (five-cluster solution in
bold)
Number of Calinski and Cluster Beale's F
clusters Harabasz F 23 comparison (df*, dfy)25
3 189.23 e e
4 231.00 3 vs 4 1.46 (43, 274)
5 232.42 4 vs 5 1.66 (29, 244)
6 207.13 5 vs 6 0.75 (22, 223)
Bold formatted numbers showed a significant improvement of the model's fit of a
five-cluster solution compared to a four-cluster and a six-cluster solution.
*
numerator degrees of freedom.
y
denominator degrees of freedom.
muscle strength were not significantly different between uni- and
bilateral radiographic OA: mean (SD) 74.48 (38.68) Nm vs 69.16
(35.07), respectively; P ¼ .193. A BMI  30 was found in 46% of the
study group.
Spearman's correlation coefficients of the four clinical charac-
teristics showed weak associations between muscle strength and
depressive mood (r ¼ .17, P < .001) and between KL grade and BMI
(r ¼ .12, P ¼ .006). No significant associations were found between
KL grade and muscle strength (r ¼ .06; P ¼ .172) and KL grade and
depressive mood (r ¼ .07; P ¼ .103). No significant associations were
found between muscle strength and BMI (r ¼ .06; P ¼ .147), and
between BMI and depressive mood (r ¼ .03; P ¼ .441).
The Calinski and Harabasz pseudo F-statistics and Beale's F-ratio
statistics are shown in Table II. Values of both clustering criteria
were the highest in a five-cluster solution. Both F-statistics revealed
that a five-cluster solution showed a significant improvement of
the model's fit compared to a four-cluster solution, while a six-
cluster solution did not show a significant improvement of the
model's fit compared to a five-cluster solution. Therefore, the most
adequate number of phenotypes was five.
The five identified phenotypes were named 1. ”minimal joint
disease phenotype”, 2. “strong muscle strength phenotype”, 3.”se-
vere radiographic OA phenotype”, 4. “obese phenotype”, and
5.”depressive mood phenotype”. The four clinical characteristics
(i.e., upper leg muscle strength, BMI, radiographic severity grade,
and depressive mood) of the five phenotypes and total study group
are shown in Table III.
The differences between the five phenotypes on each clinical
characteristic are presented in Fig. 1 and displayed in Table III. The
between-subgroup differences were significant for muscle
strength, F (4, 539) ¼ 192.87, P < .001. Post-hoc analyses (Bonfer-
roni) showed that muscle strength in phenotype 2 was significantly
greater than in phenotypes 1, 3, 4, and 5. The between-subgroup
Beale's differences were not significant for phenotypes 1, 3, 4, and 5. The
Fp-value26 between-subgroup differences were significant for BMI, F (4,
e 545) ¼ 159.75, P < .001. Post-hoc analysis showed that BMI in
0.040 phenotype 4 was significantly higher than in phenotypes 1, 2, 3, and
0.030
5, while BMI in phenotypes 1, 2, and 5 were not significantly
0.782
different. BMI of phenotype 3 was significantly higher than
phenotype 1, but not higher than BMI of phenotypes 2 and 5. The
between-subgroup differences were significant for KL grade, F (4,
537) ¼ 155.01, P < .001. Post-hoc analyses showed that the KL grade
in phenotype 3 was significantly higher than in phenotypes 1, 2, 4,
and 5. The between-subgroup differences were not significant for
phenotypes 1 and 5 and for phenotypes 2 and 4. The KL grade of
phenotypes 2 and 3 was significantly different from the KL grade of
phenotypes 1 and 5. The between-subgroup differences were sig-
nificant for the HADS score, F (4,514) ¼ 114.07, P < .001. Post-hoc
analysis showed that the HADS score in phenotype 5 was signifi-
cantly higher than in phenotypes 1, 2, 3, and 4. The HADS score in
phenotype 4 was also significantly higher than in phenotypes 1, 2,
and 3, while the HADS scores in phenotypes 1, 2, and 3 were not
significantly different.
Discussion
The aim of the study was to identify phenotypes based on
similarities in four clinical characteristics in a group of patients
with established knee OA. Cluster analysis showed five phenotypes:
“minimal joint disease phenotype”, “strong muscle strength
phenotype”, “severe radiographic OA phenotype”, “obese pheno-
type”, and “depressive mood phenotype”.
We used the same four clinical characteristics (i.e., upper leg
muscle strength, BMI, radiographic severity grade, and depressive
mood) as in our previous study on the OAI data10. These four
characteristics were not associated, except for weak associations
between muscle strength and depressive mood and between KL
grade and BMI. Therefore, the association between clinical char-
acteristics did not add statistical noise to the analysis and did not
corrupt the cluster structure25. The present study revealed a five-
cluster solution, indicating that the optimal number of clusters in
the AMS-OA data as well as in the OAI data was five10. It can be
claimed with more certainty that the finding of five clinical

Table III
Clinical characteristics of five identified phenotypes and total study group in the AMS-OA cohort

1: Minimal joint disease 2: Strong muscle strength 3: Severe radiographic 4: Obese phenotype 5: Depressive Total study group
phenotype phenotype OA phenotype phenotype

n 154 114 116 81 86 551

Isokinetic muscle 57.0 ± 20.8 124.3 ± 23.1* 53.0 ± 22.8 61.2 ± 27.3 55.3 ± 22.8 70.3 ± 35.8
strength, Nm
BMI, kg/m2 27.5 ± 4.0 28.8 ± 3.8 29.6 ± 4.3 41.3 ± 5.0y 28.5 ± 4.4 30.4 ± 6.2
K/L 0e1 69% 22% 0% 31% 56% 37%
K/L 2 31% 35% 0% 35% 37% 27%
K/L 3 0% 31% 55%z 23% 7% 22%
K/L 4 0% 12% 45%z 11% 0% 14%
Depressive mood 3.3 ± 2.0 3.4 ± 2.5 4.0 ± 2.7 5.2 ± 3.4 10.2 ± 2.3x 4.8 ± 3.5
(HADS)

K/L ¼ Kellgren/Lawrence grade for radiographic severity; BMI ¼ body mass index; HADS ¼ Hospital Anxiety and Depression Scale. Bold formatted numbers are significantly
different from other phenotypes and characterize the phenotype.
*
Muscle strength was significantly different from phenotypes 1, 3, 4, 5. No significant difference between phenotypes 1, 3, 4, 5.
y
BMI was significantly different from phenotypes 1, 2, 3 and 5. Phenotype 1, 2 and 5 were not significantly different, phenotype 3 was significantly different from
phenotype 1.
z
KL was significantly different from phenotypes 1, 2, 4 and 5. No significant difference between phenotypes 1 and 5 and between phenotypes 2 and 4.
x
Depressive mood was significantly different form phenotypes 1e4. Phenotype 4 was significantly different from phenotypes 1e3. No significant difference between
phenotypes 1e3.
 M. van der Esch et al. / Osteoarthritis and Cartilage 23 (2015) 544e549 547

Fig. 1. Comparison of the five phenotypes on each clinical characteristic. A. Isokinetic muscle strength (Nm). Phenotype 2 was significantly different (P < .001) from phenotypes 1, 3,
4, and 5. B. BMI. Phenotype 4 was significantly different (P < .001) from phenotypes 1, 2, 3, and 5. Phenotype 3 was significantly different from 1, 2 and 5 (P < .05). C. Radiographic
OA: Kellgren/Lawrence (0e4). Phenotype 3 was significantly different (P < .001) from phenotypes 1, 2, 4, and 5. Phenotypes 2 and 4 were significantly different from 1 to 5 (P < .001).
D. HADS questionnaire: depressive mood). Phenotype 5 was significantly different (P < .001) from phenotypes 1, 2, 3, and 4. Phenotype 4 was significantly different from phenotypes
1, 2, and 3 (P < .05). Phenotypes: 1 ¼ “minimal joint disease”, 2 ¼ “strong muscle strength”, 3 ¼ “severe radiographic OA”, 4 ¼ “obese”, 5 ¼ “depressive mood”. Error bars: 95% CI.

phenotypes, based on the four characteristics, is a valid result: not a
finding by chance, but a definitive, repeatable result.
The clinically heterogeneous population of knee OA patients
seems to exist of five homogeneous subgroups of patients. The
clinical characteristics can be used to interpret these five pheno-
types. The “minimal joint disease” phenotype is a subgroup
without prominent clinical or radiological characteristics, despite
the symptoms necessitating a visit to a second care rehabilitation
center and despite the clinically diagnosed OA. The “strong muscle
strength” phenotype is a subgroup with high muscle strength as
most prominent characteristic, and relatively more radiographic
severity. The “severe radiographic OA” phenotype is a subgroup
with degeneration of cartilage and bone as most prominent char-
acteristic. The “obese” phenotype is a subgroup with high BMI as
most prominent characteristic, and relatively severe radiographic
OA and relatively high depressive mood (HADS). Finally, the
“depressive mood phenotype” is a subgroup with depressive mood
as the most prominent characteristic, irrespective of the other three
characteristics.
The findings are to a large extent similar to what was found by
our research group in the OAI cohort. Both studies had similar
“minimal joint disease”, “strong muscle strength”, and “depressive
mood” phenotypes. In the OAI study, the “severe radiographic OA”
phenotype was named the “non-obese and weak muscle strength”
phenotype, while the “obese” phenotype was named the “obese
and weak muscle strength” phenotype. The renaming of these two
phenotypes (“non-obese and weak muscle strength” into “severe
radiographic OA”, and “obese and weak muscle strength” into
“obese”) was respectively based on the more pronounced appear-
ance of radiographic OA and BMI characteristics in the current
study. The difference in phenotypes might be a real difference, but
could also be explained by a change in interpretation of the data,
primarily based on advancing insight. Taking into account the re-
sults of the current study, the data of the OAI study were re-
analyzed. We noticed that the “non-obese and weak muscle”
phenotype of the OAI study also showed more extent of OA
radiographic severity10, and that in the “obese and weak muscle”
phenotype, muscle strength was not significantly different from the
548 M. van der Esch et al. / Osteoarthritis and Cartilage 23 (2015) 544e549
other phenotypes10. Therefore, these two phenotypes could have
been labeled as “severe radiographic OA” and “obese” phenotype as
well.
In general, knee OA patients will benefit from muscle
strengthening exercises26,27. Based on the results, however, we
believe that segregating patients on four clinical characteristics into
five phenotypes may help in finding the best targeted personalized
care in knee OA. Theoretically, patients within the “minimal joint
disease” phenotype may need a treatment approach including
education, pain coping skill training, and self-management, as has
been used in chronic pain conditions28,29. For patients within the
“strong muscle strength” phenotype, appropriate education and
pain medication might be a targeted solution30e32, and muscle
strengthening exercises would not be the treatment of first choice.
Although the influence of structural degradation in the indication
for surgery in OA is controversial, the “severe radiographic OA”
phenotype might help physicians and surgeons in making decisions
for surgery33. Patients of the “obese” phenotype may need dietary
changes, alongside to exercise therapy34. Additionally, attention for
a slightly increased depressive mood might also be included in the
treatment approach for the “obese” phenotype. Finally, patients of
the “depressive mood” phenotype may benefit from treatment for
their depressive mood, alongside their OA specific manage-
ment35,36. These speculations on targeted personalized care in knee
OA need to be tested in randomized controlled trials in patients
with predefined phenotypes before being applied in clinical care.
The choice of clinical characteristics included in the cluster
analysis may affect the results. We used upper leg muscle strength,
BMI, severe radiographic OA, and depressive mood to identify
clinical phenotypes. Other phenotypes could have been found had
other clinical characteristics been included in the analysis. Biome-
chanical characteristics (e.g., knee alignment, joint stability), bone
involvement, clinical synovitis, or psychosocial characteristics
(anxious mood, self-efficacy) could have been included in cluster
analyses, potentially yielding other phenotypes4. The four included
clinical characteristics, however, are easy to diagnose, with simple
assessment measurements6. In identifying meaningful phenotypes
the compartmental difference between tibiofemoral OA and
patellofemoral OA might also be important37. The KL grading de-
pends on scoring the radiographic features of the tibiofemoral
compartments and not on scoring of the features of the patellofe-
moral compartment. Future phenotype studies should account for
the difference in compartmental grading.
A potential limitation of the study is the cross-sectional design:
longitudinal follow-up of phenotypes is interesting for examining
the stability of the clusters found over time. Longitudinally, patients
might change from phenotype, showing changes in disease tra-
jectories. Knowledge on the change in membership of a phenotype
over time is important for causal reasons and has implications for
personalized care. Therefore, longitudinal studies are needed to test
the stability of the clusters over time and the membership of pa-
tients to these clusters over time. Furthermore, whereas cluster
analysis is an objective means for the subgrouping of patients with
knee OA, its potential shortcomings must be kept in mind. One of
the shortcomings is that no accepted criterion to determine the
number of clusters and the sample size of patients exists. In our
study, however, both the pseudo F-statistic and Beale's F-ratio
statistic indicated that the five-cluster solution was the best solu-
tion. Regarding minimum sample size of patients, there is no
generally accepted rule of thumb. The objective of cluster analysis is
to construct internally homogeneous and clearly distinct clusters.
We used a limited set of four clinical characteristics in a population
of 551 patients: this resulted in internally homogeneous and clearly
distinctable clusters. Finally, a limitation is the setting of patient
recruitment of this cohort in one secondary care rehabilitation
center. Large cohorts, containing detailed information on patients
recruited in multiple settings are costly to establish. An option
could be to merge multiple cohorts obtained in different settings on
comparable clinical characteristics, to ensure representation of
different phenotypes of patients.
In conclusion, among patients with knee OA, five phenotypes
were identified based on four clinical characteristics. To a high
degree, the results are a replication of earlier findings in the OAI.
The five phenotypes seem a stable, valid, and clinically relevant
finding.
Contributors
All authors contributed substantially to the conception and
design of the study and interpreted data. LDR collected data. MvdE,
JK, and DLK analyzed data. MvdE, JK, MvdL, DLK, LDR, WFL, and JD
prepared the first draft of the report. All authors contributed to the
report and approved the final version.
Funding
No funding.
Competing interests
The authors have no conflicts of interest to disclose.
Statement
No commercial party having a direct financial interest in the
results of the research supporting this article has or will confer on
the authors or on any organization with which the authors are
associated.
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