Depression Risk in Patients with Rheumatoid Arthritis in the United Kingdom
Depression Risk in Patients with Rheumatoid Arthritis in the United Kingdom
Louis Jacob . Timo Rockel . Karel Kostev 0 1
0 T. Rockel K. Kostev (&) Epidemiology, QuintilesIMS , Frankfurt , Germany
1 L. Jacob Faculty of Medicine, University of Paris 5 , Paris , France
Introduction: Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases. The goal of this study was to analyze the risk of depression in patients diagnosed with RA and treated by general practitioners in the UK. Methods: The present study included patients first diagnosed with RA between 2000 and 2014 (index date). Individuals were excluded if they had also been diagnosed with depression or if they had received therapy for depression at or prior to the index date. The primary outcome measure was the rate of patients with depression (ICD 10: F32, 33) within 5 years of the RA diagnosis. Demographic data included gender and age. Furthermore, a revised version of the Charlson comorbidity index was used as a generic marker of comorbidity. Results: A total of 4187 patients were included in the study. After 5 years of follow-up, 23.7% of men and 36.5% of women had developed depression (log rank p value \0.001). Women were more likely to develop depression than men (HR 1.61, 95% CI 1.42-1.84). Age and Charlson comorbidity score had no significant impact on the risk of being diagnosed with this psychiatric disorder. Conclusion: Around 30% of RA patients developed depression within 5 years of the RA diagnosis. The depression risk was higher in women than in men. The current findings also indicate that improved detection and treatment of patients with both RA and depression are important.
Depression; Rheumatoid arthritis; Risk factors; United Kingdom
Rheumatoid arthritis (RA) is one of the most
common chronic inflammatory diseases [1, 2].
RA can affect joints, connective tissues,
muscles, tendons, and fibrous tissues . This
disorder has a prevalence of 0.3–1% and is known
to be more common in women and in
developed countries . In the United Kingdom
(UK), at least 1.16% of women and 0.44% of
men were found to be affected by RA .
Rheumatoid arthritis is considered a chronic
condition and has a major impact on the quality
of life of patients , thus underlying the
importance of personalized management and
treatment of people affected by this disease. In
2013, Matcham and colleagues discovered in a
systematic review and meta-analysis that the
prevalence of major depressive disorder was
around 17% in patients diagnosed with RA .
They further estimated that this prevalence was
significantly associated with age, with younger
patients being at a higher risk of developing
depression than older patients. Some have
reported that gender is a risk factor for the development
of depression in individuals diagnosed with RA. In
2005, Ramjeet et al. estimated that women with
recent-onset inflammatory polyarthritis
exhibited higher levels of anxiety and depression than
men . However, Mostafa and Radwan later
found no significant relationship between gender
and depression in RA patients . Finally, a
Taiwanese study showed that women with RA had a
greater risk of depression than men with RA .
Since these findings are controversial, we
decided to analyze the risk of depression in
patients diagnosed with RA and treated by
general practitioners (GPs) in the UK.
The Disease Analyzer database (IMS HEALTH)
compiles drug prescriptions, diagnoses, and
basic medical and demographic data obtained
directly and in anonymous format from
computer systems used in GP practices .
This database recorded multiple patient
characteristics (e.g., age, gender) and
comorbidities (e.g., myocardial infarction, stroke,
cancer, diabetes) with sufficient data to allow
the calculation of the Charlson index, which
examines 22 comorbidities and demographic
factors (see below).
Diagnoses (ICD-10), prescriptions
(Anatomical Therapeutic Chemical (ATC) Classification
System), and the quality of reported data are
monitored by IMS based on a range of criteria
(e.g., completeness of documentation, linkage
between diagnoses, and prescriptions).
In the UK, the sampling methods used to
select physicians’ practices were appropriate to
obtain a representative database of people with
RA . The sampling method for the Disease
Analyzer database is based on statistics from all
doctors in the UK. These statistics are used to
determine the panel composition according to
the following strata: region, community size
category, and age of physician.
Patients who were first diagnosed with RA
(ICD-10: M05, M06) between 2000 and 2014
were included in the present study. The date of
first RA diagnosis documentation by a GP was
considered the index date. Individuals were
excluded if they had also been diagnosed with
depression based on the ICD-10 criteria (F32,
F33) or if they had received therapy for
depression (ATC: N06A) at or prior to the index date.
Formal ethical approval was not required for
this study according to German law (§15 BOA¨ ,
Medical Association’s professional code of
conduct), as the study was based on anonymized
data. It was not possible to identify individual
patients. Therefore, informed consent was not
required (nor could it be received).
Study Outcome Measures
and Independent Variables
The primary outcome measure was the
proportion of patients diagnosed with depression
within 5 years of the diagnosis of RA. Patients
were followed up from January 2010 until June
2016. Demographic data included gender and
age. Furthermore, a revised version of the
Charlson comorbidity index (CCI) was used as a
generic marker of comorbidity . The
Charlson comorbidity index describes 22 comorbid
conditions where each condition is assigned a
score from 1 to 6 depending on the risk of dying
from it. Clinical conditions and associated
scores in the CCI are as follows: myocardial
infarction, congestive heart failure, peripheral
vascular disease, dementia, cerebrovascular
disease, chronic lung disease, connective tissue
disease, ulcer, chronic liver disease, diabetes,
hemiplegia, moderate or severe kidney disease,
diabetes with end-organ damage, tumor,
leukemia, lymphoma, moderate or severe liver
disease, malignant tumor, metastasis, and AIDS
. CCI was included in order to estimate if a
higher RA patient comorbidity status is
associated with a higher risk of depression.
Descriptive analyses were obtained for all
demographic and clinical variables, and the
mean ± SD was calculated for normally
distributed variables. Kaplan–Meier curves were
used to analyze the proportion of RA patients
diagnosed with depression. The Kaplan–Meier
curve is defined as the probability that an event
(for example, diagnosis) will occur within a
given length of time when time is discretized
into many small intervals. It provides a visual
representation of this probability in two or
more groups. The strength of Kaplan–Meier
analysis is that it includes patients who could
not be followed for the complete study duration
(for example, 5 years); these patients are
assumed to have the same event probability as
those who continue to be followed [12, 13].
Finally, a multivariate Cox regression model
was created to determine the impact of
demographic and clinical variables on the risk of
being diagnosed with depression. In a Cox
regression model, the parameter of interest is
the time until the occurrence of an event (for
example, disease). Like Kaplan–Meier analyses,
Cox regression analyses also include patients
who could not be observed throughout the
entire study duration. The Cox regression uses a
proportional hazards model to calculate the
hazard ratio (HR), which shows the ratio of
event probabilities in the two groups .
p values \0.005 were considered statistically
significant. Analyses were carried out using SAS
A total of 4187 patients were included in this
study. The mean age was 59.1 years (SD
17.8 years), and 34.3% were men. The mean
Charlson comorbidity score was 1.4 (SD 1.1).
Figure 1 displays Kaplan–Meier curves for the
time to depression diagnosis by gender, with
23.7% of men and 36.5% of women developing
depression within the 5-year follow-up period
(log rank p value \0.001).
Table 1 displays the results of the multivariate
Cox regression model. Women were more likely
to develop depression than men (HR 1.61, 95%
CI 1.42–1.84). Age and Charlson comorbidity
score had no significant impact on the risk of
being diagnosed with this psychiatric disorder.
In the present retrospective study, around 30%
of patients developed depression within 5 years
of RA diagnosis. We also found a 1.6-fold
increase in the risk of developing depression in
women compared to men.
RA is a chronic condition that has a
substantial impact on health. In 2007, Haroon and
colleagues investigated 136 RA patients and 75
age-matched controls and discovered that
quality of life was compromised in individuals
diagnosed with RA . The authors further
found a significant inverse correlation between
the activity of the disease and the physical and
psychological domains of quality of life. More
recently, a 2013 study performed in Brazil
estimated that moderate to severe RA was
associated with major functional disability and
morbidity, with work and activity impairment
increasing with disease severity .
The impact of RA on depression has been the
focus of several works in the past decade. In
2002, Dickens et al. discovered in a systematic
review and meta-analysis of the literature that
depression was more frequent in individuals
with RA than in healthy individuals . This
may be partially explained by the levels of pain
experienced by RA patients, thus clearly
underlying the importance of personalized
treatments and management for these patients.
In 2013, another meta-analysis of 72 studies
that included 13,189 patients found that the
prevalence of major depression was 16.8% (95%
CI 10–24%) . According to the PHQ-9 test
questionnaire, depression prevalence was even
Women vs men
Age B40 vs [70 years
Age 41–50 vs [70 years
Age 51–60 vs [70 years
Age 61–70 vs [70 years
1.61 (1.42–1.84) \0.001
Fig. 1 Kaplan–Meier curves for time to depression
diagnosis in newly diagnosed RA patients by gender
Table 1 Association of depression with predefined
variables in RA patients: results of the multivariate Cox
Charlson comorbidity index 1.04 (0.97–1.15)
higher and reached 38.8% (95% CI 34–43%).
Finally, the authors showed a significant
relationship between mean age and the rate of
depression, with lower age being associated
with increased rates. In line with these findings,
the present study discovered that
approximately 30% of patients were depressed within
5 years after the diagnosis of RA.
Such results are of particular concern because
depression is known to increase the risk of
mortality in RA patients . The identification
of predictors of depression in this population is
very important and has been the focus of several
recent works [19–21]. In 2006, Covic and
colleagues estimated that 12 variables correctly
classified around 80% of RA individuals into
depressed and nondepressed groups . The
strongest predictors of this psychiatric
condition were high tension, low self-esteem,
and the perceived impact of RA. Interestingly,
fatigue, passive coping, pain, and physical
disability had additional effects on the risk of
developing depression. Later, an American
study of 172 patients found that disease severity
(calculated using the Health Assessment
Questionnaire, HAQ) and ethnicity were
significantly associated with depression . Finally,
Lin and colleagues discovered in 2015 that
women, younger patients, and people with
comorbidities such as stroke, chronic kidney
disease, or cancer were at a particular risk of
depression . The present retrospective study,
which included more than 4000 patients, also
showed that women were more likely to be
diagnosed with depression within the 5 years
following RA diagnosis compared to men.
Recently, the relationship between gender and
depression in RA has been the focus of several
studies. A 2005 UK analysis including 112
individuals affected by recent-onset
inflammatory polyarthritis showed that 36% of the
population was at risk of depressive symptoms .
Furthermore, it was also found that women
displayed higher levels of depression than men,
although gender had no impact on levels of
disability or pain. Later, Mostafa and Radwan
discovered that the prevalence of depression in
an Egyptian population with RA was 15.29% .
The authors notably found positive correlations
between depression and age, disease duration,
and disease activity. In contrast, there was no
significant association with gender. More
recently, it was estimated in a Taiwanese
analysis that included 3698 adults newly diagnosed
with RA that women, the elderly, and patients
with comorbidities were at a higher risk of
developing depression than men, younger
individuals, and patients free of comorbidities
[7, 9]. The association between gender and
depression or anxiety in RA might be explained
by the fact that men tend to adjust better to
their disease than women. Another possibility is
that male RA patients are less likely to reveal
their depressive symptoms to their doctor than
female RA patients. Finally, in the present
study, age and comorbidity had no significant
impact on depression. This difference may be
explained by the fact that the multivariate
regression model was adjusted for
inflammation, which is known to play a key role in both
depression and RA.
In general, retrospective primary care
database analyses are limited by the validity and
completeness of the data on which they are
based. The present study is subject to the
following limitations. The assessment of
diagnoses was based solely on ICD codes entered
by general practitioners, and no information
was available regarding the procedure by
which depression diagnoses were made.
Information about whether depression diagnoses
were made by GPs themselves or by
psychiatrists was unavailable. Data on potential
confounding variables such as socioeconomic
status, marital status, educational level, social
support, psychosocial stressors, and
lifestyle-related risk factors (body mass index,
smoking status, etc.) were also unavailable.
Unfortunately, no data on the severity of
inflammation were available. The strength of
the study is the large number of patients
available for analysis. Another strength is the
use of real-world data in primary care practices
where diagnoses are continuously
documented, allowing for unbiased exposure
assessment (no recall bias).
Around 30% of RA patients developed
depression within 5 years of the diagnosis of RA.
Women had a higher risk of being diagnosed
with depression in the 5 years following the
index date compared to men.
The current findings also indicate that
improved detection and treatment of patients
with RA and depression is needed.
No funding or sponsorship was received for this
study or the publication of this article. All
authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for
authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval to the
version to be published. Professional English
language editing services were provided by
Claudia Jones, MA, Radford, Virginia, United
Disclosures. Louis Jacob, Timo Rockel, and
Karel Kostev have nothing to disclose.
Compliance with Ethics Guidelines. Formal
ethical approval is not required according to
German law (§15 BOA¨ , Medical Association’s
professional code of conduct), as the study is
based on anonymized data. Identification of
individual patients was not possible. Therefore,
informed consent was not required; nor could it
Data Availability. The datasets generated
during and/or analyzed during the current
study are not publicly available due data
protection rules but are available from the
corresponding author on reasonable request.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons license, and
indicate if changes were made.
1. Smolen JS , Aletaha D , McInnes IB . Rheumatoid arthritis . Lancet . 2016 ; 388 ( 10055 ): 2023 - 38 .
WHO. Chronic rheumatic conditions . WHO . 2015 .
http://www.who. int/chp/topics/rheumatic/en/ (cited 2015 Jul 24 ).
3. Glauser TA , Ruderman EM , Kummerle D , Kelly S. Current practice patterns and educational needs of rheumatologists who manage patients with rheumatoid arthritis . Rheumatol Ther . 2014 ; 1 ( 1 ): 31 - 44 .
Symmons D , Turner G , Webb R , Asten P , Barrett E , Lunt M , et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century . Rheumatology . 2002 ; 41 ( 7 ): 793 - 800 .
Matcham F , Scott IC , Rayner L , Hotopf M , Kingsley GH , Norton S , et al. The impact of rheumatoid arthritis on quality-of-life assessed using the SF-36: a systematic review and meta-analysis . Semin Arthritis Rheum . 2014 ; 44 ( 2 ): 123 - 30 .
Matcham F , Rayner L , Steer S , Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis . Rheumatol Oxf Engl . 2013 ; 52 ( 12 ): 2136 - 48 .
Lin M-C , Guo H-R , Lu M-C , Livneh H , Lai N-S , Tsai T-Y. Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study . Clinics . 2015 ; 70 ( 2 ): 91 - 6 .
10. Ogdie A , Langan SM , Parkinson J , Dattani H , Kostev K , Gelfand JM . Medical record databases . In: Strom BL, Kimmel SE , Hennessy S, editors. Pharmacoepidemiology. New York: Wiley-Blackwell ; 2012 . p. 224 - 43 . http://onlinelibrary.wiley.com/doi/10. 1002/9781119959946.ch15/summary (cited 2015 Jun 21).
11. Quan H , Sundararajan V , Halfon P , Fong A , Burnand B , Luthi J-C , et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data . Med Care . 2005 ; 43 ( 11 ): 1130 - 9 .
12. Goel MK , Khanna P , Kishore J. Understanding survival analysis: Kaplan-Meier estimate . Int J Ayurveda Res . 2010 ; 1 ( 4 ): 274 - 8 .
13. Dudley WN , Wickham R , Coombs N. An introduction to survival statistics: Kaplan-Meier analysis . J Adv Pract Oncol . 2016 ; 7 ( 1 ): 91 - 100 .
14. Ressing M , Blettner M , Klug SJ . Data analysis of epidemiological studies: part 11 of a series on evaluation of scientific publications . Dtsch Arzteblatt Int . 2010 ; 107 ( 11 ): 187 - 92 .
15. Haroon N , Aggarwal A , Lawrence A , Agarwal V , Misra R. Impact of rheumatoid arthritis on quality of life . Mod Rheumatol . 2007 ; 17 ( 4 ): 290 - 5 .
16. da Rocha Castelar Pinheiro G , Khandker RK , Sato R , Rose A , Piercy J. Impact of rheumatoid arthritis on quality of life, work productivity and resource utilisation: an observational, cross-sectional study in Brazil . Clin Exp Rheumatol . 2013 ; 31 ( 3 ): 334 - 40 .
17. Dickens C , McGowan L , Clark-Carter D , Creed F. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis . Psychosom Med . 2002 ; 64 ( 1 ): 52 - 60 .
18. Ang DC , Choi H , Kroenke K , Wolfe F. Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis . J Rheumatol . 2005 ; 32 ( 6 ): 1013 - 9 .
19. Covic T , Tyson G , Spencer D , Howe G . Depression in rheumatoid arthritis patients: demographic, clinical, and psychological predictors . J Psychosom Res . 2006 ; 60 ( 5 ): 469 - 76 .
20. Margaretten M , Yelin E , Imboden J , Graf J , Barton J , Katz P , et al. Predictors of depression in a multiethnic cohort of patients with rheumatoid arthritis . Arthritis Rheum . 2009 ; 61 ( 11 ): 1586 - 91 .
21. Iaquinta M , McCrone S. An integrative review of correlates and predictors of depression in patients with rheumatoid arthritis . Arch Psychiatr Nurs . 2015 ; 29 ( 5 ): 265 - 78 .
22. Lin M-C , Guo H-R , Lu M-C , Livneh H , Lai N-S , Tsai T-Y. Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study . Clin Sa˜o Paulo Braz . 2015 ; 70 ( 2 ): 91 - 6 .