Real world long-term impact of intensive treatment on disease activity, disability and health-related quality of life in rheumatoid arthritis

Abstract

Abstract Background The emphasis on treating rheumatoid arthritis (RA) intensively reduces disease activity but its impact in routine care is uncertain. We evaluated temporal changes in disease activities and outcomes in a 10-year prospective observational cohort study of patients in routine care at one unit. Methods The Guy’s and St Thomas’ RA cohort was established in 2005. It involved most RA patients managed in this hospital. Clinical diagnoses of RA were made by rheumatologists. Patients were seen regularly in routine care. Each visit included measurement of disease activity scores for 28 joints (DAS28), health assessment questionnaire scores (HAQ) and EuroQol scores. Patients received intensive treatments targeting DAS28 remission. Results In 1693 RA patients mean DAS28 scores fell from 2005 to 15 by 11% from 4.08 (95% CI: 3.91, 4.25) in 2005 to 3.64 (3.34, 3.78); these falls were highly significant (p 5.1) decreased (25% in 2005; 16% in 2015). In 752 patients seen at least annually for 3 years, persisting remission (68 patients) and intermittent remission (376 patients) were associated with less disability and better health related quality of life. Over time biologic use increased, but they were used infrequently in patients in persistent remission. Conclusions Over 10 years an intensive management strategy in a routine practice setting increased combination DMARD and biologic use: disease activity levels declined; this association is in keeping with a causal relationship. Patients who achieved remission, even transiently, had better functional outcomes than patients never achieving remission.

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R E S E A R C H A R T I C L E Open Access
Real world long-term impact of intensive
treatment on disease activity, disability and
health-related quality of life in rheumatoid
arthritis
Nicola J. Gullick
1*
, Fowzia Ibrahim
2
, Ian C. Scott
3,4,6
, Alexandra Vincent
5
, Andrew P. Cope
5,6
, Toby Garrood
5
,
Gabriel S. Panayi
5
, David L. Scott
2
, Bruce W. Kirkham
5
and On behalf of TITRATE Programme Investigators
Abstract
Background: The emphasis on treating rheumatoid arthritis (RA) intensively reduces disease activity but its
impact in routine care is uncertain. We evaluated temporal changes in disease activities and outcomes in a
10-year prospective observational cohort study of patients in routine care at one unit.
Methods: The Guy’s and St Thomas’RA cohort was established in 2005. It involved most RA patients managed in
this hospital. Clinical diagnoses of RA were made by rheumatologists. Patients were seen regularly in routine care.
Each visit included measurement of disease activity scores for 28 joints (DAS28), health assessment questionnaire
scores (HAQ) and EuroQol scores. Patients received intensive treatments targeting DAS28 remission.
Results: In 1693 RA patients mean DAS28 scores fell from 2005 to 15 by 11% from 4.08 (95% CI: 3.91, 4.25) in 2005 to 3.
64 (3.34, 3.78); these falls were highly significant (p< 0.001). DAS28 components: swollen joint counts fell by 32% and ESR
by 24%; in contrast tender joint counts and patient global assessments showed minimal or no reductions. The reduction
in DAS28 scores was predominantly between 2005 and 2010, with no falls from 2011 onwards. Associated with falls in
mean DAS28s, patients achieving remission increased (18% in 2005; 27% in 2015) and the number with active disease
(DAS28 >5.1) decreased (25% in 2005; 16% in 2015). In 752 patients seen at least annually for 3 years, persisting remission
(68 patients) and intermittent remission (376 patients) were associated with less disability and better health related quality
of life. Over time biologic use increased, but they were used infrequently in patients in persistent remission.
Conclusions: Over 10 years an intensive management strategy in a routine practice setting increased combination
DMARD and biologic use: disease activity levels declined; this associationisinkeepingwithacausal relationship. Patients
who achieved remission, even transiently, had better functional outcomes than patients never achieving remission.
Keywords: Temporal RA change, Intensive treatment, Rheumatoid arthritis
Background
In recent years the management of rheumatoid arthritis
(RA) has been transformed. Methotrexate is used earlier,
access to biologics has increased, and effective combina-
tions of conventional disease modifying anti-rheumatic
drugs (DMARDs) have been identified. National and inter-
national guidelines highlight the value of using these
approaches in early, intensive and effective treatment [1–4].
The treat to target initiative has provided additional support
[5,6]. The overall impact of these innovations on patient
outcomes in routine care settings remains uncertain.
Over 30 years ago, Silman and colleagues [7] suggested
RA severity was declining. Many groups subsequently
reported temporal improvements in RA. Some focussed
on disease activity in early RA [8–12]; others concen-
trated on disease activity in established RA [13–17]. A
few assessed erosive damage [18,19] and joint replace-
ment surgery [20,21]. All studies provide some evidence
* Correspondence: Nicola.Gullick@uhcw.nhs.uk
1
Department of Rheumatology, University Hospitals Coventry and
Warwickshire NHS Trust, Coventry, UK
Full list of author information is available at the end of the article
BMC Rheumatolo
gy
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted 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. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Gullick et al. BMC Rheumatology (2019) 3:6
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of temporal improvements in RA outcomes. Such im-
provements could reflect treatment innovations and im-
plementation of guidelines recommendations. Other
potential influences include earlier referral resulting in
more patients receiving effective therapy during the ini-
tial “window of opportunity”[22], changes in the clinical
phenotype of RA [23] and changes in the relationship of
RA to comorbid conditions [24].
More information is needed on the benefits of imple-
menting intensive treatment strategies in routine clinics
and the potential for further improvements. We exam-
ined both questions in a single-centre prospective obser-
vational study which recorded changes in disease
activity, disability and health related quality of life
(HRQoL) in patients managed intensively between 2005
and 2015.
Methods
Patients
Patients attending the Guy’s and St Thomas’NHS Trust
RA Centre formed a prospective longitudinal observa-
tional cohort study [25]. The majority of RA patients
managed at this hospital were included. All patients had
clinical diagnoses of RA made by experienced rheuma-
tologists. They were seen regularly for routine care and
each visit involved a clinical review and assessment of
key clinical outcomes. Management followed the treat to
target approach with an aim of reaching DAS28 remis-
sion defined as DAS28 < 2.6 [5,25]. The patients were
analysed in two ways: firstly, all patients in whom data
was available; secondly, patients who were followed for
three years or more. Details were collected about age,
disease duration, sex and ethnicity.
Treatments
Patients received treatment with DMARDs and bio-
logics in line with existing English guidance about
these treatments using a goal-directed strategy [26].
They received intensive DMARDs, often given in
combination, and also had biologics when they met
the existing guidelines from the National Institute for
Health and Care Excellence (NICE). These English
guidelines have changed over time and the approach
taken reflected the guidance existing at the time
treatment decisions were made and guidance from
EULAR about treat to target [5,27].
Outcomes
The disease activity score 28 (DAS28), incorporating
swollen and tender joint counts, patient’sglobalas-
sessments, and erythrocyte sedimentation rates (ESR)
evaluated patients’current status [28], and was used
to guide treatment decisions. The Heath Assessment
Questionnaire (HAQ) measured disability [29]. The
EuroQol 5-dimension scale (EQ5D-3 L) measures
health-related quality of life [30]; it can be used to es-
timate health utility and has been widely used in RA.
Flares were also assessed as changes between DAS28
assessments in which there was an increase in score
of 0.60 or more [31].
Data collection
Data were captured in the electronic healthcare records
for inflammatory arthritis patients attending outpatient
clinics at Guy’s and St Thomas’Hospital NHS Founda-
tion Trust (GSST). These records are within the Trust’s
Electronic Patient Records system which provides la-
boratory results and patient demographics. Clinical data
on a patient’s treatment, disease activity, disability level,
and health-related quality of life (HRQoL) were routinely
captured at their clinic appointment and were used for
patients’routine care.
Analyses
Data management and analyses used Stata (version 14.0,
StataCorp, College Station, TX). Descriptive analyses
used numbers of patients and percentages and mean
scores with standard deviations or 95% confidence inter-
vals (CI). We used mixed models to examine the
changes in DAS28 and its components over time. We
also used trend analysis to take into account repeated
measures from the same patient. Subgroups were com-
pared by Chi-Squared analyses or by one-way analysis of
variance.
Ethics approval
Ethics approval for analysis of this routine clinical data
was obtained from the Health Research Authority (IRAS
project ID:209418).
Results
Patients studied
All patients
Between 2005 and 2015 1693 RA patients were entered
into the database. Most were female (1262, 75%) and
Caucasian (1134, 67%). Their mean age was 55 years and
mean disease duration was 11 years. The median time
between assessments was 3 (IQR: 2–6) months and the
mean was 5.3 (SD 6.6) months. Details of the patients
are shown in Table 1. Numbers of patients with data in
each calendar year are shown in Additional file 1: Table
S1. Out of the total sample 337/1693 (19%) had at least
one missing DAS28 during follow up. Similar propor-
tions of HAQ and EQ5D data were missing (22 and 20%
respectively).
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Patients followed over three or more years
Seven hundred fifty-two patients were seen at least an-
nually over three years or more. Their baseline features
were similar to those of the overall group (Table 1). The
median time between assessments was 3.5 (IQR 1–5)
months and mean was 5.0 (SD: 5.5) months.
Changes in DAS28
All patients
There were 10,773 measures of DAS28 in the 1693
patients. DAS28 scores fell when assessed as mean
changes by calendar years (Fig. 1). The mean DAS28
scores fell by 11% from 4.08 (95% CI: 3.91, 4.25) in
2005 to 3.64 (3.34, 3.78) in 2015. A mixed effects
maximum likelihood regression model showed the co-
efficient was −0.033 (95% CI -0.044, −0.023) and
these falls in DAS28 were highly significant (p<
0.001). The reduction in DAS28 scores was predomin-
antly between 2005 and 2010; there were no falls
from 2011 onwards. Associated with these falls in
mean DAS28 scores was an increase in the number
of patients in remission (18% in 2005; 27% in 2015)
and the number with active disease (DAS28 > 5.1) de-
creased (25% in 2005; 16% in 2015).
Patients followed over three or more years
There were 4345 annual measures of DAS28 in the 752
patients with at least three annual clinic visits. Their
mean DAS28 scores showed similar falls over time
(Fig. 1). The mean DAS28 scores fell 12% from 3.95
(95% CI 3.73, 4.17) to 3.48 (95% CI 3.22, 3.74). Trend
analysis, which takes into account repeated measures,
showed similar changes (Additional file 2:TableS2).
The number of patients in remission also increased
(20% in 2005; 29% in 2015) and the number with active
disease decreased (21% in 2005; 14% in 2015).
Changes in DAS28 components
All patients
Changes in the components of DAS28 showed varied pat-
terns of change over time in all patients (Fig. 2). Swollen
joint counts fell by 32% from 3.1 (95% CI 2.7, 3.5) in 2005
to 2.1 (95% CI 1.7, 2.5) in 2015. The ESR showed similar
Table 1 Baseline Characteristics Of Patients Studied: Number (%) or Mean (SD) Values Are Shown
All
Patients
Patients Followed Over Three Or More
Years
Patients Followed Less Than Three
Years
(n = 1693) (n = 752) (n = 941)
Gender, n (%) Female 1262
(75%)
579 (77%) 683 (73%)
Male 412 (24%) 165 (22%) 247 (26%)
Missing 19 (1%) 8 (1%) 11 (1%)
Ethnicity, n (%) Caucasian 1134
(67%)
540 (72%) 594 (63%)
Black African/
Caribbean
209 (12%) 100 (13%) 109 (11%)
Asian/other
background
128 (8%) 52 (7%) 76 (8%)
Not Stated 79 (5%) 27 (4%) 52 (6%)
Missing 143 (8%) 33 (4%) 110 (12%)
Age (years) 55 (16) 55 (15) 55 (14.7)
Disease Duration (years) 11 (10) 10 (10) 10 (9.7)
Tender Joint Counts (28 joints) 5.0 (6.6) 4.8 (6.0) 5.2 (6.5)
Swollen joint Counts (28 joints) 2.9 (4.7) 3.2 (3.9) 3.3 (4.3)
Erythrocyte Sedimentation Rate
(mm/hr)
22 (21) 22 (21) 21.5 (22)
Patient Global Assessment (mm) 46 (28) 44 (27) 45 (28)
DAS28 3.83
(1.63)
3.79 (1.50) 3.85 (1.62)
Health Assessment Questionnaire 1.18
(0.83)
1.22 (0.86) 1.18 (0.83)
EQ5D-3 L 0.53
(0.34)
0.52 (0.33) 0.53 (0.34)
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falls of 24% from 25 (95% CI 22, 27) in 2005 to 19 (95% CI
16, 20) in 2005. In contrast tender joint counts fell by only
10% from 5.0 (95% CI 4.4, 5.7) to 4.5 (95% CI 3.7, 5.2) and
patient global assessments increased by 9% from 43 (95%
CI 40, 46) to 47 (95% CI 44, 50).
Patients followed over three or more years
These patients showed a similar pattern of change (re-
sults not shown). Swollen joint counts fell by 49%, ESR
by 25% and tender joint counts by 17%; but patient glo-
bal increased by 8%.
Remission status in patients followed over three or more
years
Disease activity groups and remission status
Based on the presence of remission the patients were
subdivided into 3 sub-groups: 68 (9%) were always in re-
mission, 376 (50%) had one or more episodes of remis-
sion without being sustained, and 308 never achieved
remission. There were substantial differences between
these groups (Table 2). In addition 16% had sustained
low disease activity or remission and 58% had point low
disease activity or remission at one or more time-points
without being sustained.
Fig. 1 Changes in DAS28 (Means with 95% Confidence Intervals) and Percent Patients in Remission and with Active Disease
Fig. 2 Changes in Components of DAS28 in All Patients (Mean With 95% Confidence Intervals)
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In the relatively small group of 68 patients always in
remission, there were fewer females (50%), more patients
with Caucasian ethnicity (85%) and shorter mean initial
disease duration (5 years). The other two groups had
similar numbers of females (80%) and similar initial dis-
ease durations (10 and 12 years). Patients with intermit-
tent remission included more patients with Caucasian
ethnicity (76%) and fewer with Black African/Caribbean
Ethnicity (10%) than those without remission (63 and
20% respectively).
By definition overall mean DAS28 scores were low-
est in those patients who were always in remission
and highest in patients with no remission. Flares
(increase in DAS28 ≥0.6 between consecutive assess-
ments) occurred in 40% of patients always in remis-
sion and 71 and 63% of the other patient groups.
Overall mean EQ5D-3 L scores were highest (better)
in patients always in remission and lowest in patients
with no remission.
Patients who never achieved remission included 14 pa-
tients who always had high disease activity (DAS28 >
5.1). All 14 patients were females with longer initial dis-
ease durations (17 years); only 8 (57%) had Caucasian
ethnicity. They had very low overall mean EQ5D-3 L
scores (0.07).
Changes in DAS28 scores and remission status
The 3 subgroups showed differences in DAS28 scores from
2005 to 2015 (Fig. 3). There were no temporal changes in
patients always in remission and patients who never had
remission. By contrast in patients with one or more remis-
sions, DAS28 scores fell by 25% from 3.75 (95% CI 3.46,
4.03) to 2.80 (95% CI 2.54, 3.07).
Changes in treatment and remission status
The use of DMARD monotherapies, combination
DMARDs and biologics changed over time (Fig. 4).
Initially 55% of patients were taking DMARD mono-
therapies and 19% biologics. DMARD monotherapy fell
progressively, with increasing use of biologic therapies;
by 2015 this had changed to 35% of patients taking
DMARD monotherapies and 42% biologics. Similar
changes in biologics use were seen in patients followed
over three or more years (Additional file 3:TableS3).
Patients always in remission received fewer DMARD
monotherapies and biologics compared to patients
with some or no remissions. There was strong evi-
dence of increasing intensity of care in line with the
intensive treatment strategy; in particular patients
with initial moderate disease had increased biologic
use rising from under one quarter in 2005 to over
one half by 2015 irrespective of remission status
(Additional file 4:FigureS2).
Disability and remission status
Overall mean HAQ scores were lowest in the patients
always in remission. 85% of these patients had HAQ
scores below 0.50 on one or more occasions. Overall
mean HAQ scores were highest in patients with no re-
missions and only 18% had HAQ scores below 0.50 on
one or more occasions.
In all three subgroups there was a relationship be-
tween low HAQ scores and low patient global scores
(Fig. 5). This analysis shows that irrespective of remis-
sion status, those patients who had overall mean patient
global scores under 30 were significantly more likely to
have HAQ scores below 0.5, regardless of their remis-
sion status. This difference was significant in all three
Table 2 Disease Activity Sub-Groups In Patients Followed Over Three Or More Years
Always Remission Some Remission No Remission Significance
(n = 68) (n = 376) (n = 308)
Females (%) 34 (50%) 299 (80%) 246 (80%) P< 0.001*
Caucasian Ethnicity (%) 58 (85%) 287 (76%) 195 (63%) P< 0.001*
Black African/Caribbean Ethnicity (%) 1 (2%) 37 (10%) 62 (20%) P< 0.001*
Initial Mean Age In Years (SD) 54 (16) 55 (15) 56 (14) NS**
Initial Disease Duration In Years (SD) 5 (5) 10 (9) 12 (11) P= 0.003**
Initial Mean DAS28 (SD) 1.65 (0.65) 3.48 (1.32) 4.65 (1.19) P< 0.001**
Overall Mean DAS28 (SD) 1.57 (0.45) 3.06 (0.71) 4.47 (0.82) P< 0.001**
Any Flares (%) 27 (40%) 266 (71%) 194 (63%) P< 0.001*
Overall Mean EQ5D-3 L (SD) 0.77 (0.17) 0.58 (0.24) 0.38 (0.28) P< 0.001**
Initial Mean HAQ (SD) 0.31 (0.50) 1.06 (0.81) 1.58 (0.81) P< 0.001**
Overall Mean HAQ (SD) 0.31 (0.45) 1.03 (0.70) 1.66 (0.67) P< 0.001**
HAQ Below 0.50 On One Or More Occasion (%) 58 (85%) 180 (48%) 56 (18%) P< 0.001*
*Chi-Squared Testing **One Way Analysis Of Variance
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subgroups (Chi Squared analyses showed that in patients
always in remission the significance level of the differ-
ence was 0.013; in both other groups it was < 0.001).
Finally in the subgroup with some remission, 62/110
(56%) who had no flares (increase in DAS28 ≥0.60) had
one or more HAQ scores < 0.5 compared with 118/266
(44%) of patients who had one or more flares. This dif-
ference was significant (Chi-Squared with continuity cor-
rection 4.02; DF 1; p= 0.034). Flares were unrelated to
low HAQ scores in the other remission groups.
Impact of flares
Patients who had more flares had overall higher mean
HAQ scores and higher end-point HAQ scores (Table 3).
When patients who were always in remission were ex-
cluded, the end-point HAQ remained significantly differ-
ent between remission groups (P= 0.043 on one way
analysis of variance) but the overall mean HAQ was no
longer significantly different.
Impact of disease duration
Dividing patients followed for three years or more into those
with disease durations of less than 5 years and those with
more than 5 years showed no evidence that DAS28 scores
were different over time between them (Additional file 5:
Figure S1) However, there two differences between them (a)
sustained remission was more frequently seen in patients
with less than 5 years duration (12% versus 3%; Chi-squared
Fig. 3 Changes in DAS28 in Three Sub-Groups of Patients Followed Over Three or More Years
Fig. 4 Changes in Treatment Strategies in Three Sub-Groups of Patients in Patients Followed for Three or More Years
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10.8; DF = 1; P= 0.001); (b) flares were more frequently seen
in patients with more than 5 years duration (78% versus
62%; Chi-squared 11.9; DF = 1; P= 0.001).
Discussion
Our long-term real world observational study shows both
the potential benefits and limitations of a goal directed, in-
tensive treatment strategy for patients with established
RA. A preliminary cross sectional analysis of goal directed
therapy in these patients compared to a matched group
receiving less intensive approaches has previously estab-
lished the benefit of this approach [25].
During the decade of follow-up reported here, treat-
ment intensities increased, mean disease activity fell and
there were more remissions. Patients who achieved one
or more remissions had lower levels of disability and
higher health related quality of life. However, not all pa-
tients responded to intensive treatment and a small
minority had persistently active disease with high dis-
ability levels and low health related quality of life.
The presence of intermittent and persistent remissions
had a substantial relationship with both treatment and
disease outcomes. Patients with remissions were more
likely to be male and Caucasian with shorter disease
duration, which reflects previous experience predicting
RA outcomes [32–34]. There were also differences in
treatment intensity with patients in persisting remission
having less intensive treatment and, in particular, fewer
biologics. It is possible patients in sustained remission
had any biologic treatment tapered and stopped.
ReducedDAS28scoresovertimewereonlyseenin
those patients who had intermittent remission. In
addition, we found strong relationships between dis-
ease activity, disability and health related quality of life.
Patients with persistent remissions had the lowest
HAQ and highest (best) EQ5D scores and patients who
never had a remission had the highest HAQ and lowest
EQ5D scores. An extensive body of clinical evidence
from observational studies has previously highlighted
these relationships, including reports from Alemo et al.
[35] and Radner et al. [36,37]. There is also evidence
that with conventional non-intensive treatment, dis-
ability increased with disease duration and over time
relationships between disease activity and disability
change [38]. These findings highlight the importance
for patients of controlling active disease. Overall in our
patients DAS28 remission frequencies increased from
an average of 18% in 2005 to 27% in 2015 in our pa-
tients. These remission rates are similar to those
Fig. 5 Low HAQ scores are associated with Low Patient Global regardless of remission status
Table 3 Relationship Between Flares And Disability
Number of
Flares
Number Of Patients Overall HAQ
Mean (95% CI)
Final HAQ
Mean (95% CI)
0 260 1.08 (0.98, 1.18) 1.19 (1.08, 1.31)
1 290 1.29 (1.20, 1.38) 1.23 (1.13, 1.33)
2 127 1.21 (1.08, 1.35) 1.32 (1.16, 1.48)
3 47 1.50 (1.33, 1.66) 1.53 (1.28, 1.78)
4 14 1.43 (1.11, 1.75) 1.73 (1.27, 2.20)
One Way
Analysis Of
Variance
P= 0.002 P= 0.029
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reported in trials of biologics in established RA. For ex-
ample, Kivitz et al. [39] reported 32% remission rates
adding tocilizumab to methotrexate and Smolen et al.
reported 23% remission rates adding certolizumab to
methotrexate in established RA [40]. The DAS28 re-
mission rates were relatively static in a long-term ex-
tension study [41].
The decreases in disease activity we observed over
time reflect the previous evidence that RA is becoming
less severe over time [7–21]. Interestingly we found that
some aspects of disease activity, in particular swollen
joint counts and the ESR, improved more than others, in
particular patient’s global assessments. We also noted
patient global assessments were most closely associated
with disability scores, reflecting our previous findings in
clinical trials [42]. This is of potential clinical importance
as it implies need for treatment of aspects of RA beyond
inflammatory synovitis to reduce patient global assess-
ments and improve disability in all patient groups.
Long-term assessments from the BARFOT study have
shown that whilst disease activity has declined over time,
disability and pain have not [43]. One explanation for
this finding is that some features of RA are not directly
driven by synovial inflammation; and may represent
“fibromyalgic RA”[44]. Such patients have more pain
[45], often fail to achieve remission when treated inten-
sively [46] and have less evidence of active synovitis [47].
It is possible that other drug treatments or non-drug
treatments such as psychological support [48] or exer-
cise [49] may be beneficial in these patients. The impli-
cation is that intensive drug treatment alone is not
sufficient and the use of other approaches to manage
established RA needs to be extended. It is also possible
there is a lower level of DAS28 which can be achieved
by current drug treatments as international comparisons
in the QUEST-RA study found no country achieved
mean DAS28 scores below 3.0 [50]. In addition the tim-
ing of NICE and other guidance may have influenced
clinical practice, though we have not found any definite
evidence to support this contention. The main strength
of our study is that it presents findings from a single
centre in which clinical staff followed an agreed manage-
ment approach for RA based on goal-directed, intensive
management approaches and used standardised clinical
assessments. It also has several limitations. The principal
weakness, inherent in all observational studies, is that
we recruited consecutive patients irrespective of their
disease severity or activity. It is therefore difficult to be
certain how much secular trends in the severity of RA
have contributed towards our findings, though recent
analysis of early RA patients from England since 1990
does not suggest this has occurred to any great extent
[24]. A second limitation is that patients were seen as re-
quired rather than in any standardised manner, reflecting
current clinical practice. As patients with active disease
are likely to be seen more frequently than patients in re-
mission, this approach may over-estimate the relative
frequency of active disease, particularly in the final years
of the study. A third limitation is that patients were not
followed-up if they left the clinic, which is in line with
routine clinical practice. Consequently we cannot ex-
clude impacts from censoring or informativeness of the
follow-up process. A fourth limitation is that our treat-
ments with biologics were influenced by NICE criteria;
greater use of biologics might have improved outcomes
even more. A fifth limitation is the definition of flares;
other definitions were all developed some time after our
study started and are difficult to apply retrospectively. A
sixth limitation is that many patients did not remain
under follow-up for over three years. The reasons for
this are likely to be complex; death is one factor; London
has a highly mobile population and patients frequently
move within London or outside the capital; RA patients
often have comorbid diseases and these can result in
their moving to other hospitals for their care; and
patients may stop attending specialist units, with histor-
ical studies suggest nearly half of RA patients may not
be under specialist care receiving DMARDs during the
course of their disease [51,52] Finally, our cohort pre-
dominantly included patients with established disease ra-
ther than new referrals with early RA. Whilst this most
closely reflects routine practice, it means caution must
be used when comparing our findings with those from
inception cohorts of early RA patients, which will in-
clude patients with mild disease who may not require
follow up in specialist clinics.
Conclusions
We conclude intensive management regimens have been
associated with progressive improvement in disease activ-
ity and more remissions over the last 10–15 years. When
patients achieve intermittent or sustained remission their
function and quality of life improve. Our treat-to-target,
goal-directed therapy strategy, using DAS28 as the meas-
ure, was used as a guide to medical therapy, with reduc-
tions in swollen joint count and ESR. Although we did not
assess longitudinal radiographs in our population, it is
likely that improvement in these disease attributes, also
noted in other populations, most likely accounts for the
substantial reduction in radiographic progression now
seen in people with RA [53]. This is a significant achieve-
ment, as progressive joint damage was previously com-
mon in RA. However, tender joint counts and patient
global assessments have improved less and may need al-
ternative or additional treatment approaches. A minority
of patients have continued high disease activity with sub-
stantial disability and reduced quality of life. Individualised
Gullick et al. BMC Rheumatology (2019) 3:6 Page 8 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

strategies may be required for this group including novel
therapies or psychological interventions.
Additional files
Additional file 1: Table S1. Patients seen in each calendar year
(DOCX 36 kb)
Additional file 2: Table S2. Changes In DAS28 In Patients Followed
For Three Or More Years Using Trend Analysis To Take Into Account
Repeated Measures (DOCX 43 kb)
Additional file 3: Table S3. Treatments Used Over Time (DOCX 56 kb)
Additional file 4: Figure S2. Biologic Use In Patients With Initial
Moderate Disease Activity And Remission Status (DOC 66 kb)
Additional file 5: Figure S1. Changes In Mean DAS28 Over Time In
Patients Seen Within Five Years Of RA Onset Or Later (DOC 66 kb)
Acknowledgements
We acknowledge support from the NIHR Biomedical Research Centre at
Guy’s and St Thomas’NHS Foundation Trust in partnership with King’s
College London.
On behalf of TITRATE Programme Investigators.
Work Stream A: Heidi Lempp, Jackie Sturt, Sofia Georgopoulou and Louise
Prothero;
Work Stream B: Naomi Martin, Richard Jenner, Isabel Neatrour, Rhiannon
Baggott, Fowzia Ibrahim, Brian Tom, Allan Wailoo, Jonathan Tosh, James
Galloway, Gabrielle Kingsley and David Scott;
Work Stream C: Brian Tom, Fowzia Ibrahim, Yujie Zhong, Aneela Mian, James
Galloway & David L Scott.
Funding
The paper presents independent research funded by the National Institute
for Health Research (NIHR) as one of its Programme Grants For Applied
Research (Grant Reference Number: RP-PG-0610-10066; Programme Title:
Treatment Intensities and Targets in Rheumatoid Arthritis Therapy:
Integrating Patients’And Clinicians’Views –The TITRATE Programme). The
views expressed are those of the authors and not necessarily those of the
NHS, the NIHR or the Department of Health and Social care. Additional
funding was received from Abbvie as a partnership project supporting ana-
lysis of RA Centre data. Dr. Nicola Gullick and Dr. Ian Scott were supported
by NIHR Clinical Lectureships.
Availability of data and materials
The dataset used for this manuscript is kept at Guy’s & St Thomas’Hospitals
(Dr Bruce Kirkham). The dataset is not publicly available to protect study
participants’confidentiality. Ethical approval to share the study data with
third parties has not been obtained.
Authors’contributions
NJG, DLS, GSP and BK conceived the study. NJG, AV, APC, TG, GSP, and BK
collected the data. FI and ICS analyzed the data. NG, FI, DLS and BK wrote
the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethics approval for analysis of routine clinical data was obtained from the
Health Research Authority (IRAS project ID:209418). The need for consent
was waived due to the use of of previously collected, de-identified data, and
complies with the Helsinki Declaration.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Rheumatology, University Hospitals Coventry and
Warwickshire NHS Trust, Coventry, UK.
2
Department of Rheumatology, 3rd
Floor, Weston Education Centre, King’s College London, Cutcombe Road,
London, UK.
3
Research Institute for Primary Care & Health Sciences, Primary
Care Sciences, Keele University, Keele, Staffordshire, UK.
4
Department of
Rheumatology, Haywood Hospital, High Lane, Burslem, Staffordshire, UK.
5
Department of Rheumatology, Guy’s and St Thomas’NHS Trust, 4th Floor,
Tower Wing, Guy’s Hospital, Great Maze Pond, London, UK.
6
Academic
Department of Rheumatology, Centre for Molecular and Cellular Biology of
Inflammation, 1st Floor, New Hunt’s House, Guy’s Campus, King’s College
London, Great Maze Pond, London, UK.
Received: 6 August 2018 Accepted: 25 January 2019
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