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Treat-to-target (T2T) recommendations for gout

  • Rheumazentrum Ruhrgebiet, Herne, Germany


Objectives: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. Methods: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. Results: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. Conclusions: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.
Treat-to-target (T2T) recommendations for gout
U Kiltz,
J Smolen,
T Bardin,
A Cohen Solal,
N Dalbeth,
M Doherty,
B Engel,
C Flader,
M Matsuoka,
F Perez-Ruiz,
G da Rocha Castelar-Pinheiro,
K Saag,
A So,
J Vazquez Mellado,
M Weisman,
T H Westhoff,
H Yamanaka,
J Braun
Objectives The treat-to-target (T2T) concept has been
applied successfully in several inammatory rheumatic
diseases. Gout is a chronic disease with a high burden
of pain and inammation. Because the pathogenesis of
gout is strongly related to serum urate levels, gout may
be an ideal disease in which to apply a T2T approach.
Our aim was to develop international T2T
recommendations for patients with gout.
Methods A committee of experts with experience in
gout agreed upon potential targets and outcomes,
which was the basis for the systematic literature search.
Eleven rheumatologists, one cardiologist, one
nephrologist, one general practitioner and one patient
met in October 2015 to develop T2T recommendations
based on the available scientic evidence. Levels of
evidence, strength of recommendations and levels of
agreement were derived.
Results Although no randomised trial was identied in
which a comparison with standard treatment or an
evaluation of a T2T approach had been performed in
patients with gout, indirect evidence was provided to
focus on targets such as normalisation of serum urate
levels. The expert group developed four overarching
principles and nine T2T recommendations. They
considered dissolution of crystals and prevention of ares
to be fundamental; patient education, ensuring
adherence to medications and monitoring of serum urate
levels were also considered to be of major importance.
Conclusions This is the rst application of the T2T
approach developed for gout. Since no publication
reports a trial comparing treatment strategies for gout,
highly credible overarching principles and level D expert
recommendations were created and agreed upon.
Gout is caused by deposition of monosodium urate
(MSU) crystals within joints in the setting of
chronic hyperuricaemia.
It affects 1%2% of
adults in developed countries and is the most
common type of inammatory arthritis worldwide.
Epidemiological data are consistent with a rise in
the prevalence and incidence of gout.
and genetic polymorphisms of renal transporters of
urate and other genes seem to be the main causal
factors of primary gout. Gout and hyperuricaemia
are associated with hypertension, diabetes mellitus,
metabolic syndrome and renal and cardiovascular
There is a strong link between gout
and increased risk of death from all causes and
cardiovascular diseases.
The economic burden of
gout is considerable.
Gout is a common clinical problem encountered
by both general and specialist clinicians. The key
principles of gout management include establishing
adenitive diagnosis, treating acute attacks
promptly and using urate-lowering therapies (ULTs)
appropriately to dissolve MSU crystals to eventually
prevent further attacks and joint damage. When
serum urate concentrations are lowered below the
saturation point of MSU, new crystal formation is
prevented, existing crystals dissolve and gout can
be cured. The gold standarddiagnostic test for
gout remains the identication of MSU crystals by
polarised light microscopy in synovial uid cells or
in a tophus.
Non-steroidal anti-inammatory drugs (NSAIDs)
and colchicine remain the most widely recom-
mended systemic drugs to treat acute attacks.
some patients, especially those with comorbidities
that preclude NSAID use, oral glucocorticoids
(GCs) may represent an alternative. Joint aspiration
and injection of GC is recommended where feas-
ible, as in most hospital settings.
Patient educa-
tion, appropriate advice regarding lifestyle and
treatment of comorbidities are important in the
management of patients with gout.
Many different recommendations on the man-
agement of gout have been published over the last
1113 1518
However, major questions, as
discussed below, remain.
In many areas of medicine, such as diabetes care
or cardiology, clear therapeutic targets have been
dened and the continuous effort to reach these
targets is standard practice.
More recently,
treatment targets have also been advocated for
rheumatoid arthritis (RA), spondyloarthritides
(SpA) including psoriatic arthritis (PsA) and sys-
temic lupus erythematosus, namely remission or
low disease activity.
29 30
These recommendations
have been based on insights gained from systematic
literature reviews (SLRs) of clinical trials.
31 32
successful application of a treat-to-target (T2T)
strategy in a rheumatologic disease was rst
reported in RA and subsequently in PsA.
33 34
Much less information is currently available
regarding the value of dening therapeutic targets
for gout. Despite recently published treatment
1113 15 17 18
and some scientic
and therapeutic advances, such as the approval of
the rst selective urate transporter inhibitor, a
variety of challenges, such as preventing recurrence
To cite: Kiltz U, Smolen J,
Bardin T, et al. Ann Rheum
Dis 2017;76:632–638.
Handling editor Tore K Kvien
Additional material is
published online only. To view
please visit the journal online
For numbered affiliations see
end of article.
Correspondence to
Professor Juergen
Braun, Rheumazentrum
Ruhrgebiet, Herne D-44652,
Germany; juergen.braun@
Received 1 March 2016
Revised 26 August 2016
Accepted 27 August 2016
Published Online First
632 Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
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of attacks, remain when considering the current management of
patients with gout. These challenges exist, in part, because a
clear therapeutic target and strategies to reach such a target have
not yet been dened optimally. To improve the management of
gout in clinical practice, a core group was convened to discuss
and develop consensus recommendations aimed at dening a
treatment target and initiate a T2T programme for gout.
Five rheumatologists from Europe and North America with
expertise in gout met in Athens in April 2014 and agreed on the
need to develop T2T recommendations for gout. A steering
committee was established, comprised of rheumatologists who
were identied based upon their expertise in gout, experience in
developing treatment recommendations, publication record and
participation in clinical trials of novel therapies for gout.
Through face-to-face discussions and email communications,
they agreed to use a four-step methodology:
(i) dene treatment targets and outcomes
(ii) perform a systematic literature review (SLR)
(iii) evaluate the ndings of the SLR within the steering
(iv) develop nal recommendations for T2T for gout with a
larger task force.
Denition of target and outcomes: The steering committee
determined potential targets and outcomes by email communi-
cation. There was no limitation to the number of targets and
outcomes that could be proposed. Each target and outcome was
then voted upon by email communication using a Delphi
method; those that were supported by at least 75% of the
members were accepted.
Systematic literature review: Search terms for the SLR were for-
mulated based on the PICO (participant intervention, control,
outcome) system, taking into account the targets and outcomes
(see online supplementary table S1). Authors UK and CF per-
formed the SLR using Medline, EMBASE and Cochrane, focus-
ing on strategy trials in which therapeutic adjustments were
made according to prespecied timelines and/or prespecied
endpoints. Detailed inclusion and exclusion criteria and the list
of search strings are shown in online supplementary tables
S1 and S2. All English language human studies were evaluated
based on an iterative process with screening of titles, followed
by screening of abstract and completed by a full-text review. The
results of the SLR were graded for the level of evidence pro-
vided by the Oxford Centre for Evidence-Based Medicine on a
scale of 15.
We did not exclude studies based on quality.
Evaluation: The ndings of the SLR were presented to the steer-
ing committee at a meeting in Herne, Germany, in June 2015.
On this basis, the steering committee formulated a provisional
set of recommendations according to European League Against
Rheumatism standardised operating procedures fullling the
AGREE criteria.
36 37
The level of evidence and strength of each
recommendation were determined and categorised as A
(highest) to D (lowest) on the basis of the SLR. The preliminary
recommendations were distributed to the international task
force, which consisted of gout experts from North America,
South America, Europe, Oceania (New Zealand) and Asia; a
nephrologist, a cardiologist, a general practitioner and a patient
with gout.
Development of nal recommendations: The international mul-
tispecialty task force met in Herne, Germany, in October 2015,
to discuss the T2T approach in detail and develop the nal
recommendations. The background of the T2T approach was
discussed and the preliminary recommendations developed by
the steering committee were presented. These were reformu-
lated and reordered, until each recommendation received a
majority of at least 75% of the votes by using a nominal consen-
sus technique. After the face-to-face meeting, the nal recom-
mendations were circulated by email to the entire task force for
nal comments. Only suggestions intended to improve the
clarity of wording or to address redundancies were considered;
no changes to the content were allowed at this point. The task
force then voted by email on the level of agreement with each
recommendation using a numerical rating scale of 010, with
the highest value indicating the greatest level of agreement.
Denition of target and outcomes: Six possible treatment
targets and ve possible outcome domains were identied by
the steering committee (table 1). The nal list includes four
targets and three outcomes about which a SLR should be
Systematic literature review: Of the initial 761 papers retrieved,
55 were selected for full-text review. No randomised trial was
identied in which a T2T approach had been evaluated in com-
parison with standard treatment (ow chart in online supple-
mentary gure S1 illustrates the selection process). However,
there was indirect evidence that optimal therapeutic approaches
help to control the disease.
The investigators showed that
control of serum uric acid levels (SUA) is optimised by providing
patient education, enhanced telephone access to expert advice,
upward titration of allopurinol, febuxostat or benzbromarone
and increased frequency of visits until the target SUA concentra-
tion was achieved.
Other urate-lowering agents, such as lesi-
nurad, might also be used but strategy trials employing these
drugs were not identied in the SLR. Successful reduction of
SUA levels by upward titration of ULT, but without prescheduled
therapeutic adaptation processes, has been demonstrated in
many other trials.
3840 43 44
Patients with gout exhibited a
higher velocity of tophus size reduction when reaching a serum
urate concentration below the saturation point of MSU early
and maintaining that level.
39 45 46
Table 1 Voting on treatment targets and outcomes
Agreement* (%) Accept
Treatment targets
Serum urate level 90 Yes
Time to resolution of inflammation 40 No
Amount/reduction/absence of tophi
(burden of deposition)
90 Yes
Pain reduction 90 Yes
Prevention/absence of attacks 100 Yes
Adherence to medication 60 No
Clinical: Pain, joint count, number of attacks/year 100 Yes
Laboratory: Serum urate level, CRP, ESR, serum
90 Yes
Functional: SF-36 (physical component score) 60 No
Imaging: Radiographs (specific signs), ultrasound
(tophi), dual energy CT (urate deposition)
60 No
PRO: QoL, SF-36, work status, productivity, work
days off, absenteeism/presenteeism
80 Yes
*10 members of the steering committee voted.
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PRO, patient-reported
outcomes; QoL, quality of life; SF-36, short-form 36.
Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
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Signicant discussion also focused on asymptomatic hyperuri-
caemia. Although intervention to treat severe asymptomatic
hyperuricaemia has been recommended in Japan,
there is
inadequate evidence to support its appropriateness. The task
force members agreed that it could be valuable to develop an
appropriate strategic approach to the treatment of asymptomatic
hyperuricaemia. However, they concurred that there is no evi-
dence to suggest that the treatment target for asymptomatic
hyperuricaemia should be any different than that for gout.
Evaluation: Based on the SLR, preliminary recommendations
(three overarching principles and eight recommendations) were
formulated by the steering committee.
Recommendations: The preliminary recommendations were
reformulated and reordered by the task force during a meeting
in October 2015, yielding four overarching principles and nine
recommendations. The nal consensus recommendations are
listed in table 2 and discussed in detail below.
Overarching principles
Since gout is a potentially curable disease, the central guiding
principles are to reduce serum urate levels and to maintain a
target serum urate level. To achieve these goals, patients must be
educated completely about the disease and should participate in
the decision-making process. The overarching principles, which
are listed in table 2, address the following aspects:
A. Gout as a chronic and serious disease that can be treated
B. The importance of reducing and maintaining serum urate
below a dened target.
C. The requirement for patient education about all aspects of
the disease and for shared decision-making with the
D. The need for long-term adherence to urate-lowering therapy.
The main points discussed were as follows:
(i) Both providers and patients should be educated about the
disease and its treatment.
(ii) Patients and healthcare providers should make treatment
decisions together.
(iii) The primary treatment approach is to reduce and maintain
serum urate at a level sufcient to effect dissolution of MSU
(iv) Modifying lifestyle and monitoring renal function are
It was decided to not differentiate between acuteand
chronicgout, since both belong to the spectrum of a single
All recommendations are presented in table 2 together with the
level of supporting evidence, the strength of the recommendation
and the level of agreement. Of note and in line with the SLR, the
level of evidence was low (D) for most of the recommendations.
This lack of evidence supporting how best to treat gout likely is
one of the main reasons why it is often difcult to treat the disease
successfully and especially to maintain patients free of disease
activity over the long term. In the presence of comorbidities, such
as renal impairment, the aim of low disease activity is much more
complicated to reach which was the basis to recommend assess-
ment of renal function on a regular basis. It also provides the basis
for the research agenda, since much more information is needed
to develop highly valid treatment recommendations.
Interestingly and despite the low level of evidence, there was
a very high level of agreement among task force members, with
six of the nine recommendations achieving agreement levels of
9.5 or more on a 10-point scale. This suggests that the experts
from different elds and the patient with gout on the task force
were quite convinced of the validity of the statements. Only rec-
ommendation #5, which deals with prophylaxis, had a lower
level of agreement (8.3). This lower level of agreement was due
to the absence of prospectively acquired data regarding the
appropriate duration of prophylaxis.
A research agenda was also developed (table 3). It was
decided to re-evaluate the current proposals at a future meeting
attended by several stakeholders, including more patients.
Therefore, the present recommendations should be regarded as
a basis for further discussion and amendment.
Table 2 Recommendations to treat-to-target gout
Overarching principles
A Gout is a chronic and serious disease with impaired quality of life and reduced life expectancy that can be treated effectively. 9.5±0.9
B Reducing and maintaining serum urate below a defined target is mandatory to eliminate urate crystals and improve patient outcomes. –– 9.8±0.7
C Successful management of gout requires education about all aspects of the disease and full involvement of the patient in shared
–– 9.7±0.7
D Long-term adherence to urate-lowering therapy is essential for an optimal outcome. –– 9.4±0.8
1 Serum urate must be measured regularly and urate-lowering therapy should be adjusted to attain the therapeutic target. 2 B 9.8±0.6
2 A serum urate level <6 mg/dL (<360 mmol/L) should be targeted and maintained in all patients with gout 1 A 9.5±0.9
3 In patients with severe gout, such as those with tophi or frequent attacks, the target should be a serum urate level <5 mg/dL (<300 mmol/L)
until clinical remission is achieved
5 D 9.2±1.5
4 Acute attacks should be treated promptly with anti-inflammatory medications, taking safety issues into consideration 5 D 9.9±0.5
5 Prophylaxis against attacks should be initiated and continued for at least 6 months after starting urate-lowering therapy. 5 D 8.3±1.7
6 In all patients with gout, renal function should be assessed at the time of diagnosis and then monitored regularly. 5 D 9.6±0.7
7 Comorbidities associated with gout may influence therapy and outcomes and should be assessed regularly and managed 5 D 9.5±0.8
8 Modifiable risk factors should be addressed primarily through patient education and support. 5 D 9.2±1.5
9 Information about gout and its management should be made readily available to patients by their healthcare professionals. 5 D 9.7±0.7
SoR on a 010 scale with 0=no agreement at all and 10=very strong agreement.
GoR, grade of recommendation; LoE, level of evidence; SoR, strength of recommendation.
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This is the rst initiative to propose overarching principles and
recommendations for the management of gout using a T2T strat-
egy. Since this approach has been applied to several other rheum-
atic diseases,
29 30
we considered it important to employ this
successful concept in gouta disease for which a major target can
be dened easily and in which outcomes depend upon
maintenance of the serum urate concentration at a low level.
However, the scope of the recommendations is focusing on tar-
geted treatment options and on a broader concept including
recommendations for prophylaxis against attacks and monitoring
of comorbidities. This rationale is based on the fact that aiming for
low serum urate concentrations must be supported by anti-
inammatory strategies and/or prevention of comorbidities.
Table 3 Research agenda
No Research question Comment with respect to a T2T approach
1 What is the optimal target serum urate level to manage gout? SUA level of <6 mg/dL (<360 mmol/L) or <5 mg/dL (<300 mmol/L) are not data
driven, a valid and reliable cut-off will facilitate a targeted approach.
2 Is the current recommended target serum urate level a valid endpoint? This important question should be addressed by taking the scientific evidence and
the patient point of view into account. A laboratory parameter might not
adequately reflect the signs and symptoms of the patient.
3 How often should the serum urate level be measured to optimally control disease? Definition of time intervals to measure SUA is mandatory to adapt therapy based
on the treatment target.
4 How does frequency of serum urate measurement impact on the management of
patients with gout?
Frequency of measurements should be feasible and aim to avoid overassessment
and underestimation. No trial exists at all to address impact of measurement on
the management of patients with gout.
5 Are very low serum urate levels dangerous (such as by causing neuropsychiatric
disease, eg, dementia)?
The knowledge about valid upper and lower thresholds of SUA is mandatory to
follow a T2T approach.
6 What are the consequences of lowering serum urate levels? A T2T approach in patients with gout must address potential harmful consequences
(like occurrence of acute attacks while initiating ULT).
7 Is it possible to develop a composite disease activity measure that might serve as
a better target for management of gout disease activity in clinical practice?
(GDAI=gout disease activity index).
More than the SUA level influences disease activity in patients with gout.
Therefore, it seems likely that a composite instrument is addressing the patients
need more accurate.
8 Does an elevated serum urate level cause chronic kidney disease? The relationship between gout and chronic kidney disease is bidirectional and
whether it is a causal relation or an association is still a matter of debate. It still
has to be shown that lowering of SUA prevents renal function from further
deterioration (and vice versa).
9 How often should renal function be measured? Frequency of measurements should be feasible and aim to avoid overassessment
and underestimation.
10 What is the optimal management of gout in patients with multiple comorbidities? Determination of treatment target and strategy to adapt the therapy depends on
occurrence of many factors, that is comorbidities. Multidisciplinary management
should agree upon an achievable treatment target.
11 Is there any diagnostic utility to aspirating joints in patients with intercritical gout? The absence of crystals in the synovial fluid is one of the targets that are linked to
lowering SUA. Serial joint aspiration studies confirmed the disappearance of
crystals with effective ULT. The value of this laboratory finding in patients with
absent of gout attacks is questionable.
12 Should monitoring by ultrasound or CT be used in gout? Diagnostic utility of imaging procedure has been studied to diagnose but has not
been extensively studied to monitor the disease. Since deposition of MSU crystals
in the tissue is a consequence of increased levels of SUA imaging procedure might
serve as a surrogate marker in the management of gout.
13 How is the treatment of both acute and chronic manifestations of gout best
integrated into a T2T strategy?
Whether the artificial partition between acute and chronic stages is helpful in
treating patients with gout is still a matter of debate. However, research on
implementations strategies focused on setting a target and adapting the treatment
accordingly is strongly needed.
14 What is the optimal timing of initiating treatment for acute gout attacks? The start of the treatment and prescheduled adaptation process within the
treatment strategy is a crucial point that is not yet well defined in studies.
Especially, initiating ULT during an acute gout attack remains a matter of debate.
15 What is the optimal strategy to eliminate tophi? The outcome size and number of tophiis difficult to assess. There is no consensus
about the optimal tool to assess this outcome reliable and sensitive to change.
However, assessment of tophi is crucial to assess adaptation process within the
treatment strategy.
16 Should urate lowering therapy be initiated after the first gout attack? Whether ULT therapy should be initiated after the first gout attack or after a
subsequent attack remains controversial. Studies should be conducted to address
this question, so as to optimise treatment
17 Is there any effect of treating asymptomatic hyperuricaemia? Studies are warranted to assess whether T2T approach is also applicable for
patients with asymptomatic hyperuricaemia.
18 What is the role of surgery in the treatment of tophi? Pharmacological interventions are the cornerstone in the T2T approach, but the
value of surgical procedures has not been investigated.
19 Does a T2T approach improve the adherence of patients to their treatment? Adherence to treatment is low in patients with gout. In a T2T approach, patients
do have increased visits at least in the beginning of their disease. One important
question is whether this approach is increasing the adherence of patients to their
MSU, monosodium urate; SUA, serum uric acid levels; T2T, target-to-target; ULT, using urate-lowering therapy.
Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
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After discussion about asymptomatic hyperuricaemia, the
group decided not to make recommendations regarding treat-
ment of hyperuricaemia in the absence of musculoskeletal symp-
toms because of inadequate evidence. One major concern,
which was raised during this discussion, was that treatment
targets for asymptomatic hyperuricaemia need to be dened.
Further research on this topic is warranted and should be con-
ducted in collaboration with cardiologists and nephrologists.
A T2T approach is based on assessing disease activity or sever-
ity. Neither is dened for patients with gout. The term severity
is inexact when referring to patients with gout and reects a
variety of parameters, such as frequency of attacks, number of
swollen joints, number and size of tophi and presence of
comorbidities. No threshold has been dened to differentiate
between severe and mild disease states. Some progress has been
made in establishing disease activity scores for gout. Recently,
the KING study group proposed a new disease activity score for
gout including are, SUA, pain, global activity assessment, joint
count and measure of tophi.
However, assessment of outcome domains is not yet standar-
dised in trials with gout patients. Several processes have been
implemented within OMERACT to endorse measures of
outcome. Pain, joint count and patient global assessment are the
recommended outcome measures for patients with acute gout,
whereas these three outcome measures with the addition of
activity limitation are the outcome measures recommended for
patients with chronic gout.
49 50
There is sufcient evidence to
support measures of pain, joint tenderness and swelling as ful-
lling the requirements of the OMERACT lter.
almost no appreciable impact of the OMERACT-proposed
domains could be detected in our SLR.
Initially, we discussed possible treatment targets that should
be able to reect when patients are in remission. The nal target
list includes pain and SUA levels, as well as the absence of
attacks and tophi, as potential parameters to dene remission in
patients with gout. Remission as a separate variable was not
included in our list of treatment targets because no formal deci-
sion has yet been made about the set of variables proposed by
OMERACT in 2014 to dene remission. The publication of pre-
liminary remission criteria for gout in 2016 supports the
OMERACT groups recommendation of variables to dene
Because of the lack of strategy trials in gout, existing thera-
peutic recommendations are rather vague. For example, clini-
cians need guidance regarding the strategic use of
anti-inammatory medications to balance potentially benecially
and harmful effects in patients with acute attacks. However,
T2T recommendations are primarily generic in nature and do
not provide detailed management recommendations or focus on
specic drugs. Although some drugs are mentioned as examples,
the current recommendations do not endorse one drug over
others. With respect to the use of anti-inammatory medica-
tions, our task force was not able to propose a specic sequence
of anti-inammatory medications because trials to address this
question were never performed. Therefore, we propose a
research agenda to stimulate investigation into the unmet needs
in this area, including evaluation of the validity of a T2T strat-
egy in gout. This research agenda includes those questions that
were considered to be most important by the task force, but the
list obviously could be expanded in many areas, including
molecular aspects of pathophysiology and patient and physician
This represents the rst initiative to characterise gout as a
disease that should be managed by dening, achieving and
maintaining a treatment target to provide patients with the best
possible outcome. Its strengths are the inclusion of experts from
different areas of medicine and a gout patient representative on
the task force and the very high level of agreement that was
achieved for most of the recommendations. However, the
present activity was limited by the absence of published clinical
trials of strategies to treat gout. Thus, recommendations had to
be developed based solely upon expert opinion. Another limita-
tion of our approach might be our having limited our SLR to
only articles written in the English language. The prevalence of
gout and the need for a targeted therapeutic approach is also
increasing in less developed countries, such as those in Latin
America and in parts of Asia.
Further research is needed to apply our T2T recommenda-
tions in a clinical trial, comparing target-directed therapy with
routine care. The research agenda addresses many practical
questions, such as determining the frequency with which critical
blood tests should be performed, assessing the impact of
comorbidities and developing a gout disease activity index.
Given the low adherence to medication by patients with gout,
strategy trials, in which therapeutic adjustments are made
according to a prespecied timeline and/or prespecied end-
points, should address this critical issue. Presumably, strategy
trials will be able to include an adequate approach to control
for non-adherence.
A treatment strategy study will be import-
ant to improve the management of patients with gout and
should be initiated in the near future.
Author afliations
Rheumazentrum Ruhrgebiet, and Ruhr University Bochum, Herne, Germany
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna,
Vienna, Austria
Assisitance Publique Hôpitaux de Paris Rheumatology Department, Lariboisière
Hospital, University Paris Diderot, Sorbonne Paris-Cité and INSERM, UMR 1132,
Paris, France
Research Medical Unit INSERM, Université Paris VIIDenis Diderot Assistance
PubliqueHôpitaux de Paris, Service de Cardiologie, Hôpital Lariboisière, Paris,
University of Auckland and Auckland District Health Board, Auckland, New Zealand
University of Nottingham, Nottingham, UK
Medical Faculty, Institute of General Practice and Family Medicine, University Bonn,
Bonn, Germany
UMass Memorial Medical Center and University of Massachusetts Medical School,
Worcester, Massachusetts, USA
Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
Rheumatology Division, Hospital de Cruces, Baracaldo, Vizcaya, Spain
Discipline of Rheumatology, Rio de Janeiro State University, Rio de Janeiro, Brazil
University of Alabama at Birmingham, Birmingham, Alabama, USA
Service de Rhumatologie, Centre Hospitalier Universitaire Vaudois and University of
Lausanne, Lausanne, Switzerland
Servicio de Reumatología, Hospital General de México, México City, México
Division of Rheumatology, Cedars-Sinai Medical Center, David Geffen School of
Medicine at UCLA, Los Angeles, USA
Medical Department I, Marien Hospital Herne, Ruhr-University of Bochum, Herne,
Tokyo Womens Medical University, Tokyo, Japan
Contributors All authors were fully involved in the T2T project. All authors
participated in the voting rounds, meetings and evaluation process. Authors UK and
CF did the SLR with judgement by JB. All authors actively participated in writing and
revising the paper.
Funding Financial support was requested and obtained from four companies
(Novartis, Berlin-Chemie Menarini, Astra-Zeneca and Ardea Bioscience).
Competing interests JS, MM, BE, JVM, TW, CF have no competing interests in
respect to this work. UK has received grant and research support and consultancy
fees from AbbVie, Chugai, MSD, Novartis, Pzer, Roche and UCB. JB has received
honoraria for talks, advisory boards, paid consultancies and grants from studies from
Berlin-Chemie Menarini and Novartis. HY has received honoraria for talks, advisory
boards and grants from Abbvie, Astellas, AstraZeneca, BMS, Chugai,
Mitsubishi-Tanabe, Pzer, Takeda, Teijin and UCB. GRCP has received honoraria for
consultancies from: AbbVie, AstraZeneca, BMS Hospira, Janssen, Pzer, Roche,
636 Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
on 2 September 2018 by guest. Protected by copyright. Rheum Dis: first published as 10.1136/annrheumdis-2016-209467 on 22 September 2016. Downloaded from
RuiYi, and Sano-Aventis. ND has received consulting fees, speaker fees or grants
from the following companies: Takeda, Menarini, Teijin, Pzer, Crealta, Cymabay,
Fonterra, Ardea Biosciences and AstraZeneca. MD has received honoraria for ad hoc
advisory boards for Ardea Biosciences, AstraZeneca, and Nordic Biosciences. Roche,
and AstraZeneca are funding a Nottingham University Investigator-led non-drug
study on gout. JK has received research funding paid to the University of
Massachusetts Medical School from Ardea Biosciences and consulting fees from
AstraZeneca; Novartis Pharmaceuticals Corporation; and Regeneron Pharmaceuticals.
KS has received consulting fees and served as a study investigator from Ardea/Astra,
Crealta, Takeda. TB has received consulting fees, speaker fees or grants from the
following companies: Ipsen Pharma, Menarini, Astrazeneca, Novartis, Sobi and
Provenance and peer review Not commissioned; externally peer reviewed.
1 Richette P, Bardin T. Gout. Lancet 2010;375:31828.
2 Kuo CF, Grainge MJ, Zhang W, et al. Global epidemiology of gout: prevalence,
incidence and risk factors. Nat Rev Rheumatol 2015;11:64962.
3 Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: results from the UK
General Practice Research Database, 19901999. Ann Rheum Dis
4 Kuo CF, Grainge MJ, Mallen C, et al. Comorbidities in patients with gout prior to
and following diagnosis: case-control study. Ann Rheum Dis 2016;75:21017.
5 Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany:
prevalence, comorbidities and management in general practice 20002005.
Ann Rheum Dis 2008;67:9606.
6 Kuo CF, See LC, Luo SF, et al. Gout: an independent risk factor for all-cause and
cardiovascular mortality. Rheumatology (Oxford) 2010;49:1416.
7 Shields GE, Beard SM. A Systematic Review of the Economic and Humanistic
Burden of Gout. Pharmacoeconomics 2015;33:102947.
8 Pascual E, Sivera F, Andrés M. Synovial uid analysis for crystals. Curr Opin
Rheumatol 2011;23:1619.
9 van Durme CM, Wechalekar MD, Buchbinder R, et al. Non-steroidal
anti-inammatory drugs for acute gout. Cochrane Database Syst Rev 2014;(9):
10 van Echteld I, Wechalekar MD, Schlesinger N, et al. Colchicine for acute gout.
Cochrane Database Syst Rev 2014;(8):CD006190.
11 Khanna D, Khanna PP, Fitzgerald JD, et al, American College of Rheumatology.
2012 American College of Rheumatology guidelines for management of gout. Part
2: therapy and antiinammatory prophylaxis of acute gouty arthritis. Arthritis Care
Res (Hoboken) 2012;64:144761.
12 Zhang W, Doherty M, Bardin T, et al, EULAR Standing Committee for International
Clinical Studies Including. EULAR evidence based recommendations for gout. Part II:
Management. Report of a task force of the EULAR Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
13 Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and
British Health Professionals in Rheumatology guideline for the management of gout.
Rheumatology (Oxford) 2007;46:13724.
14 Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if
informed appropriately: proof-of-concept observational study. Ann Rheum Dis
15 Khanna D, Fitzgerald JD, Khanna PP, et al, American College of Rheumatology.
2012 American College of Rheumatology guidelines for management of gout. Part
1: systematic nonpharmacologic and pharmacologic therapeutic approaches to
hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:143146.
16 Zhang W, Doherty M, Pascual E, et al, EULAR Standing Committee for International
Clinical Studies Including. EULAR evidence based recommendations for gout. Part I:
Diagnosis. Report of a task force of the Standing Committee for International
Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
17 Engel B, Prautzsch H. Management of gout. ZFA 2014;90:712.
18 Sivera F, Andrés M, Carmona L, et al. Multinational evidence-based
recommendations for the diagnosis and management of gout: integrating systematic
literature review and expert opinion of a broad panel of rheumatologists in the 3e
initiative. Ann Rheum Dis 2014;73:32835.
19 Wise E, Khanna PP. The impact of gout guidelines. Curr Opin Rheumatol
20 Doherty M, Bardin T, Pascual E. International survey on the diagnosis and
management of gout. Ann Rheum Dis 2007;66:16856.
21 Khanna PP, FitzGerald J. Evolution of management of gout: a comparison of recent
guidelines. Curr Opin Rheumatol 2015;27:13946.
22 Bardin T, Doherty M. Can we make gout crystal clear? Introduction. Rheumatology
(Oxford) 2009;48(Suppl 2):ii1.
23 Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal
cardiovascular disease in Europe: the SCORE project. Eur Heart J
24 Warram JH, Manson JE, Krolewski AS. Glycosylated hemoglobin and the risk of
retinopathy in insulin-dependent diabetes mellitus. N Engl J Med
25 Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic
blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:114352.
26 The effect of intensive treatment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus.
The Diabetes Control and Complications Trial Research Group. N Engl J Med
27 Egan BM, Lackland DT, Cutler NE. Awareness, knowledge, and attitudes of older
Americans about high blood pressure: implications for health care policy, education,
and research. Arch Intern Med 2003;163:6817.
28 Rachmani R, Slavacheski I, Berla M, et al. Treatment of high-risk patients with
diabetes: motivation and teaching intervention: a randomized, prospective 8-year
follow-up study. J Am Soc Nephrol 2005;16(Suppl 1):S226.
29 Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target:
recommendations of an international task force. Ann Rheum Dis 2010;69:6317.
30 Smolen JS, Braun J, Dougados M, et al. Treating spondyloarthritis, including
ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an
international task force. Ann Rheum Dis 2014;73:616.
31 Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to
target: results of a systematic literature search. Ann Rheum Dis 2010;69:63843.
32 Schoels MM, Braun J, Dougados M, et al. Treating axial and peripheral
spondyloarthritis, including psoriatic arthritis, to target: results of a systematic
literature search to support an international treat-to-target recommendation in
spondyloarthritis. Ann Rheum Dis 2014;73:23842.
33 Coates LC, Moverley AR, McParland L, et al. Effect of tight control of inammation
in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised
controlled trial. Lancet 2015;386:248998.
34 Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control
for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled
trial. Lancet 2004;364:2639.
35 Medicine OCfE-b. Levels of Evidence (cited 28 January 2016).
36 van der Heijde D, Aletaha D, Carmona L, et al. 2014 Update of the EULAR
standardised operating procedures for EULAR-endorsed recommendations.
Ann Rheum Dis 2015;74:813.
37 Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing guideline
development, reporting and evaluation in health care. J Clin Epidemiol
38 Lim AY, Shen L, Tan CH, et al. Achieving treat to target in gout: a clinical practice
improvement project. Scand J Rheumatol 2012;41:4507.
39 Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the
velocity of size reduction of tophi in chronic gout. Arthritis Rheum
40 Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial
uid after successful hypouricaemic treatment relates to the duration of gout.
Ann Rheum Dis 2007;66:10568.
41 Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al.Efcacy of allopurinol and
benzbromarone for the control of hyperuricaemia. A pathogenic approach to the
treatment of primary chronic gout. Ann Rheum Dis 1998;57:5459.
42 Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, et al. Treatment of chronic gout in
patients with renal function impairment: an open, randomized, actively controlled
study. J Clin Rheumatol 1999;5:4955.
43 Mitha E, Schumacher HR, Fouche L, et al. Rilonacept for gout are prevention
during initiation of uric acid-lowering therapy: results from the PRESURGE-2
international, phase 3, randomized, placebo-controlled trial. Rheumatology (Oxford)
44 Stamp LK, ODonnell JL, Zhang M, et al. Using allopurinol above the dose based on
creatinine clearance is effective and safe in patients with chronic gout, including
those with renal impairment. Arthritis Rheum 2011;63:41221.
45 Sundy JS, Baraf HS, Yood RA, et al.Efcacy and tolerability of pegloticase for the
treatment of chronic gout in patients refractory to conventional treatment: two
randomized controlled trials. JAMA 2011;306:71120.
46 Strand V, Khanna D, Singh JA, et al. Improved health-related quality of life and
physical function in patients with refractory chronic gout following treatment with
pegloticase: evidence from phase III randomized controlled trials. J Rheumatol
47 Yamanaka H, Japanese Society of Gout Nucleic Acid Metabolism. Japanese
guideline for the management of hyperuricemia and gout: second edition.
Nucleosides Nucleotides Nucleic Acids 2011;30:101829.
48 Scire CA, Carrara G, Viroli C, et al. Development and rst validation of a disease
activity score for gout. Arthritis Care Res (Hoboken) 2016; [epub ahead of print 27
Jan 2016]. doi:10.1002/acr.22844.
Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
on 2 September 2018 by guest. Protected by copyright. Rheum Dis: first published as 10.1136/annrheumdis-2016-209467 on 22 September 2016. Downloaded from
49 Singh JA, Taylor WJ, Simon LS, et al. Patient-reported outcomes in chronic gout:
a report from OMERACT 10. J Rheumatol 2011;38:14527.
50 Singh JA, Taylor WJ, Dalbeth N, et al. OMERACT endorsement of
measures of outcome for studies of acute gout. J Rheumatol 2014;41:
51 Taylor WJ, Redden D, Dalbeth N, et al. Application of the OMERACT lter to
measures of core outcome domains in recent clinical studies of acute gout.
J Rheumatol 2014;41:57480.
52 Araujo F, Cordeiro I, Ramiro S, et al. Outcomes assessed in trials of gout and
accordance with OMERACT-proposed domains: a systematic literature review.
Rheumatology (Oxford) 2015;54:98193.
53 de Lautour H, Taylor WJ, Adebajo A, et al. Development of Preliminary Remission
Criteria for Gout Using Delphi and 1000Minds Consensus Exercises. Arthritis Care
Res (Hoboken) 2016;68:66772.
54 McGowan B, Bennett K, Silke C, et al. Adherence and persistence to urate-lowering
therapies in the Irish setting. Clin Rheumatol 2016;35:71521.
638 Kiltz U, et al. Ann Rheum Dis 2017;76:632–638. doi:10.1136/annrheumdis-2016-209467
on 2 September 2018 by guest. Protected by copyright. Rheum Dis: first published as 10.1136/annrheumdis-2016-209467 on 22 September 2016. Downloaded from
... The management of gout can be challenging for multiple reasons [14]. To ascertain the diagnosis of gout, the current gold standard is the detection of uric acid crystals in the synovial fluid, in periarticular tissues, or directly in tophi. ...
... Imaging techniques such as arthrosonography have been shown to potentially support a diagnosis of gout since the detection of the so-called double contour phenomenon at the articular cartilage as well as topheous deposits and/or bony erosions, preferentially located peri-or intraarticularly-so-called punched-out lesions are suggestive of being caused by gout [8]. Another, relatively new imaging technique, dual-energy computed tomography (DECT), is a diagnostic tool that can detect uric acid crystals based on their specific X-ray absorption behavior [14][15][16]. ...
... The initial therapeutic strategies comprise non-steroid anti-inflammatory drugs (NSAIDs) and glucocorticoids usually lead to rapid improvement of symptoms. However, since the other targeted therapeutic strategies differ substantially a solid confirmation of the diagnosis is mandatory and much wanted by the responsible rheumatologist and/or general practitioner [14,21]. ...
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Gout often presents as acute arthritis but may also present with chronic joint inflammation. For the diagnosis of an acute gout attack with its typical symptoms, the differentiation towards a bacterial joint infection is critical and mandatory. The detection of intracellular uric acid crystals in the synovial fluid of affected joints is important for the initial diagnosis of gout. In the case of a chronic course with polyarticular joint involvement, the differentiation from other inflammatory rheumatic diseases such as rheumatoid arthritis (RA) can be challenging. The case presented here is of interest because the patient initially had characteristic clinical symptoms of tophaceous gout including a typical medical history—even though rheumatoid factor and anti-citrullinated protein antibodies (anti-CCP) were positive. The course of the disease and the critical evaluation of all findings also, and most interestingly, including histological results finally suggested a main diagnosis of RA.
... Treatment targets have already been defined in several areas of rheumatology, including rheumatoid arthritis (RA), spondyloarthritis (SpA), gout and systemic lupus erythematosus (SLE). [13][14][15][16][17] Moreover, studies have demonstrated that a targeted management approach yields superior outcomes than conventional care in terms of clinical course, long-term damage and functional status. [18][19][20][21] Up to now, T2T is not a recognised treatment approach in GCA and PMR, and to this point there has not been a systematic evaluation and consensus finding process on this topic. ...
... The task force notes that an evidenced-based definition of remission is absent, which is in contrast to the situation in many other rheumatic diseases. [13][14][15][16] There is an ongoing ACR/EULAR project to develop response criteria in GCA and in addition, OMERACT projects are currently underway to develop definitions of remission in GCA and PMR. Another important uncertainty is the role of imaging. ...
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Objectives To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). Methods A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously. Results Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment. Conclusion These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.
... The T2T strategy has been applied in several trials in adult patients with rheumatoid arthritis (RA), and recommendations for the implementation of the T2T have been promulgated for RA, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, giant cell arteritis, polymyalgia rheumatica, and gout [31][32][33][34][35][36][37][38][39][40]. ...
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Purpose of Review To summarize the current evidence on the adoption of the treat-to-target (T2T) strategy in pediatric rheumatic diseases (PRD). Recent Findings The recent advances in the management of PRD have markedly increased the ability to achieve disease remission. Complete disease quiescence is regarded as the ideal therapeutic goal because its attainment leads to lesser long-term damage and physical disability, and to optimization of quality of life. Studies in adult rheumatic diseases have shown that patient outcomes are improved if complete suppression of the inflammatory process is aimed for by frequent adjustments of therapy according to quantitative indices. This approach, which underlies the T2T concept, has been applied in strategic trials in rheumatoid arthritis (RA). Furthermore, recommendations for the T2T have been issued for RA and other adult rheumatic diseases. There is currently a growing interest for the introduction of T2T in PRD, and recommendations for treating juvenile idiopathic arthritis (JIA) to target were promulgated. A similar initiative has been undertaken for childhood-onset systemic lupus erythematosus. Preliminary therapeutic studies have explored the T2T design in JIA. Summary The T2T strategy is a modern therapeutic approach that holds the promise of improving the outcomes in patients with PRD.
... One example of solid data is that published by Perez Ruiz and colleagues [110]; in their survival analysis of an inception gout cohort, the authors found that not achieving the urate target (below 6 mg/dL) was independently associated with a 2.39-fold higher risk of subsequent all-cause mortality, and a 2.37-fold higher risk of cardiovascular mortality. While more research using robust data is needed, their findings reinforce the importance of treating gout with a defined target [111], as well as for cardiovascular purposes. ...
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Gout is intimately associated with cardiovascular disease—especially in cases of an atherosclerosis origin, but also with others such as heart failure, atrial fibrillation, or aortic valve stenosis. Besides the common presence of vascular comorbidities in gout sufferers, the disease is—in itself—an independent cardiovascular risk factor, with disease events and mortality attributable to having this condition. This review aims to update the current knowledge regarding several grey areas of the gout–cardiovascular disease spectrum—particularly in terms of risk variations across sex or ancestries, potential monosodium urate crystal deposition in the artery tree as a pathogenic pathway, the efforts undertaken to assess risk estimations in the gout population, and recent controversies surrounding the effects of gout therapies on cardiovascular disease.
... Tophi is a speci c sign of chronic gout, which not only causes changes in body structure and joint movement restrictions [33] but also exerts negative effects on psychological and social participation, and increases the burden to health care systems [31] . Treatment to target (T2T) is an effective way to prevent and reduce tophi [34] . Therefore, the implementation of standard treatment should be considered in the management of gout patients. ...
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Background The health-related quality of life (HRQoL) of gout patients is poor, and studies have shown that providing psychosocial behaviors interventions can improve the HRQoL of gout patients, but there is no cross-sectional study on whether psychosocial behaviors affect the HRQoL of gout patients. Methods For this cross-sectional study, 225 male patients with gout were enrolled. HRQoL was assessed using the gout impact scale, and the gout knowledge questionnaire was used to assess patients´ degree of knowledge about the disease. The positive psycap questionnaire was used to assess positive psychological capacity and finally, the gout patient self-management assessment scale was used to assess self-management behaviors. Multiple linear regression was used to analyze the factors affecting HRQoL in gout patients. Results The overall mean gout impact scale score was 52.7 (maximum possible = 100). Factors associated with the total gout impact scale score were tophi (β = 4.746), pain intensity (β = 1.294), and resiliency (β=-0.559). In addition, demographic characteristics (education level, smoking and marital status), clinical characteristics (tophi, pain intensity, number of attacks over 6 months, and number of affected joints) and psychosocial behavior variables (resiliency, hope, disease treatment management, diet management) were associated with several dimensions of the gout impact scale. Conclusions The HRQoL of male gout patients in Southwest China was assessed as at a medium level. We found that clinical characteristics and psychosocial behaviors are important factors affecting the HRQoL in men with gout, and should be the focus for interventions.
... Целевое лечение, или «лечение до достижения цели» (treat-to-target, T2T), -это известная концепция лечения хронических заболеваний, направленная на предотвращение повреждения органов и сохранение их функции при условии достижения определенных целевых характеристик. Концепция T2T была испытана и подтверждена при многих хронических терапевтических заболеваниях и состояниях, таких как гиперлипидемия, сахарный диабет, артериальная гипертензия и разнообразная ревматологическая патология [20]. ...
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In recent decades, there has been a steady increase in the incidence of ulcerative colitis worldwide. The purpose of the work was to analyze the literature data on modern features of the treatment of ulcerative colitis, as well as to present our own results and cases from practice. Mesalazine remains the mainstay of remission and often its induction in patients with ulcerative colitis. Currently, the nature of the treatment of ulcerative colitis is determined by the target level of remission. The fact of the onset of endoscopic remission is known to occur much later than subjective clinical improvement. In recent years, this provision has been supplemented by evidence of a delay in histological, laboratory (fecal calprotectin) and transmural remission from endoscopic. There is increasing evidence that the duration and quality of remission depends on the depth of remission. When using ultrasound, it is not difficult to urgently assess the activity and prevalence of inflammation by the parameters of the intestinal wall. Together with the level of fecal calprotectin, this information may be key to the choice of induction, escalation, maintenance or de-escalation treatment options. Of course, endoscopic examination with colon biopsy remains a necessary planned component of the management of a patient with ulcerative colitis. There are 3 cases from practice in which the achievement of transmural remission was carried out during the treatment with mesalazine. The possibility of monitoring the activity of the inflammatory process and its prevalence in the colon with the help of ultrasound examination of the intestinal wall has been clearly demonstrated. According to the results of our study, it was found that with a high activity of the disease according to the scale of Doppler mapping of the colon wall (Limberg 4), an erosive-ulcerative process was recorded in all patients according to the results of endoscopic examination (Mayo 3). Detection of the normal intestinal wall on the echogram in all cases was accompanied by the absence of endoscopic activity (Mayo 0) or its minimal manifestations (Mayo 1).
... In this treat-to-target (T2T) approach, serum urate is lowered by increasing the dose or combining ULT until the target of <0.36mmol/l (6mg/dl) or even <0.30mmol/l (5mg/dl) in patients with tophi, severe polyarticular gout and/or erosions is reached [3][4][5][6] and maintained at target. Although globally rheumatologists strongly believe in a continued T2T approach [7], an alternative strategy also commonly used in daily practice is a treat-to-avoidsymptoms (T2S) approach [8]. ...
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Background Long-term gout treatment is based on reducing serum urate levels using urate-lowering therapy (ULT). Most guidelines recommend using a lifelong continuation treat-to-target (T2T) strategy, in which ULT is dosed or combined until a serum urate target has been reached and maintained. However, a frequently used alternative strategy in clinical practice is a treat-to-avoid-symptoms (T2S) ULT discontinuation strategy, with the possibility of restarting the medication. This latter strategy aims at an acceptable symptom state, regardless of serum urate levels. High-quality evidence to support either strategy for patients in prolonged remission while using ULT is lacking. Methods We developed an investigator-driven pragmatic, open-label, multicentre, randomized, superiority treatment strategy trial (GO TEST Finale). At least 278 gout patients using ULT who are in remission (>12 months, preliminary gout remission criteria) will be randomized 1:1 to a continued T2T strategy (treatment target serum urate < 0.36 mmol/l) or switched to a T2S discontinuation strategy in which ULT is tapered to stop and restarted in case of (persistent or recurrent) flaring. The primary outcome is the between-group difference in the proportion of patients not in remission during the last 6 months of 24 months follow-up and will be analyzed using a two proportion z test. Secondary outcomes are group differences in gout flare incidence, reintroduction or adaptation of ULT, use of anti-inflammatory drugs, serum urate changes, occurrence of adverse events (with a special interest in cardiovascular and renal events), and cost-effectiveness. Discussion This study will be the first clinical trial comparing two ULT treatment strategies in patients with gout in remission. It will contribute to more specific and unambiguous guideline recommendations and improved cost-effectiveness of long-term gout treatment. It also paves the way (exploratory) to individualized long-term ULT treatment. In this article, we elaborate on some of our trial design choices and their clinical and methodological consequences. Trial registration International Clinical Trial Registry Platform (ICTRP) NL9245. Registered on 2 February 2021 (METC Oost-Nederland NL74350.091.20); EudraCT EUCTR2020-005730-15-NL. Registered on 11 January 2021.
Zusammenfassung Ziel Gicht und Adipositas sind miteinander assoziiert und oft mit einem schlechten Gesundheitszustand verbunden. Es wird der aktuelle Stand der Diagnostik, Therapie und Prophylaxe der Gicht unter besonderer Berücksichtigung der Kontroversen dargestellt. Methodik Selektive Literatursuche und Zusammenfassung von Leitlinienempfehlungen. Ergebnisse Für den akuten Gichtanfall können unter Berücksichtigung von Komorbidität NSAR, Prednisolon oder Colchicin empfohlen werden. Für die Prophylaxe werden harnsäuresenkende Medikamente und Lebensstilmaßnahmen empfohlen. Schlussfolgerungen Die Evidenz für die Therapie und Prophylaxe der Gicht beruht auf nur wenigen Studien. Empfehlungen basieren oft vorwiegend auf empirischen Überlegungen. Für die Gicht und Adipositas werden ähnliche Lebensstilmaßnahmen empfohlen. Hier sind Public Health Ansätze sind vermutlich erfolgsversprechender als individualmedizinische Ansätze.
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Background: Gout is a common and debilitating condition that is associated with significant morbidity and mortality. Despite advances in medical treatment, the global burden of gout continues to increase, particularly in high-sociodemographic index (SDI) regions. Objective: To address the aforementioned issue, we used age-period-cohort (APC) modeling to analyze global trends in gout incidence and prevalence from 1990 to 2019. Methods: Data were extracted from the Global Burden of Disease Study 2019 to assess all-age prevalence and age-standardized prevalence rates, as well as years lived with disability rates, for 204 countries and territories. APC effects were also examined in relation to gout prevalence. Future burden prediction was carried out using the Nordpred APC prediction of future incidence cases and the Bayesian APC model. Results: The global gout incidence has increased by 63.44% over the past 2 decades, with a corresponding increase of 51.12% in global years lived with disability. The sex ratio remained consistent at 3:1 (male to female), but the global gout incidence increased in both sexes over time. Notably, the prevalence and incidence of gout were the highest in high-SDI regions (95% uncertainty interval 14.19-20.62), with a growth rate of 94.3%. Gout prevalence increases steadily with age, and the prevalence increases rapidly in high-SDI quantiles for the period effect. Finally, the cohort effect showed that gout prevalence increases steadily, with the risk of morbidity increasing in younger birth cohorts. The prediction model suggests that the gout incidence rate will continue to increase globally. Conclusions: Our study provides important insights into the global burden of gout and highlights the need for effective management and prophylaxis of this condition. The APC model used in our analysis provides a novel approach to understanding the complex trends in gout prevalence and incidence, and our findings can inform the development of targeted interventions to address this growing health issue.
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Background Healthy individuals with normal level of serum uric acid (SUA) may not be truly at the lowest risk of cardiovascular disease (CVD). This study aimed to assess the association of SUA levels with CVD and its subtypes in people without CVD risk factors and determine a suitable target of SUA to prevent CVD. Methods and Results We enrolled 25 284 participants who were free of CVD, absent of CVD risk factors, and with an SUA level between 180 and 359 μmol/L (3–6 mg/dL) at baseline from the Kailuan study. Cox proportional hazards models were applied to calculated adjusted hazard ratio (HR) and 95% CI for the risk of CVD and its subtypes. During a median follow‐up of 12.97 years (interquartile range, 12.68–13.16 years), we identified 1007 cases of CVD. There was an increase in the risk of incident CVD with increasing SUA levels ( P trend =0.0011). Compared with participants with SUA levels of 180 to 239 μmol/L (3–4 mg/dL), the HR of CVD was 1.12 (95% CI, 0.96–1.31) and 1.28 (95% CI, 1.08–1.52) for SUA levels of 240 to 299 μmol/L (4–5 mg/dL) and 300 to 359 μmol/L (5–6 mg/dL), respectively. A multivariable‐adjusted spline regression model showed a J‐shaped association between SUA and the risk of CVD. Similar results were observed for stroke and myocardial infarction. Conclusions The risk of incident CVD increased with elevating SUA levels among individuals without hyperuricemia or other traditional CVD risk factors. These findings highlighted the importance of primordial prevention for SUA level increase along with other traditional CVD risk factors.
Summary Background Early intervention and tight control of inflammation optimise outcomes in rheumatoid arthritis but these approaches have not yet been studied in psoriatic arthritis. We aimed to assess the effect of tight control on early psoriatic arthritis using a treat-to-target approach. Methods For this open-label multicentre randomised controlled trial, adult patients (aged ≥18 years) with early psoriatic arthritis ( vs polyarticular). The randomisation procedure was done through a central 24-h automated telephone system based at the Leeds Institute of Clinical Trials Research (Leeds, UK). This was an open-label study in which patients and clinicians were aware of treatment group assignment. Clinical outcomes were recorded by a masked assessor every 12 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology (ACR) 20% (ACR20) response at 48 weeks, analysed by intention to treat with multiple imputation for missing ACR components. Cost-effectiveness was also assessed. This trial is registered with, number NCT01106079, and the ISCRCTN registry, number ISCRCTN30147736. Findings Between May 28, 2008, and March 21, 2012, 206 eligible patients were enrolled and randomly assigned to receive tight control (n=101) or standard care (n=105). In the intention-to-treat patient population, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control group than in the standard care group (odds ratio 1·91, 95% CI 1·03–3·55; p=0·0392). Serious adverse events were reported by 20 (10%) patients (25 events in 14 [14%] patients in the tight control group and eight events in six [6%] patients in the standard care group) during the course of the study. No unexpected serious adverse events or deaths occurred. Interpretation Tight control of psoriatic arthritis disease activity through a treat-to-target approach significantly improves joint outcomes for newly diagnosed patients, with no unexpected serious adverse events reported. Funding Arthritis Research UK and Pfizer.
Objective: To develop a new composite disease activity score for gout and provide its first validation. Methods: Disease activity has been defined as ongoing presence of urate deposits that lead to acute arthritis and joint damage. Every measure for each OMERACT core domain was considered. A three-step approach (factor analysis, linear discriminant analysis and linear regression) was applied to derive the gout activity score (GAS). Decision to change treatment or 6-month flare count were used as surrogate criterion of high disease activity. Baseline and 12-month follow-up data of 446 patients included in the Kick-off of the Italian Network for Gout (KING) cohort were used. Construct and criterion-related validity were tested. External validation on an independent sample is reported. Results: Factor analysis identified 5 factors: patient-reported outcomes, joint examination, flares, tophi and serum uric acid (sUA). Discriminant function analysis resulted in a correct classification of 79%. Linear regression analysis identified a first candidate GAS including: 12 month flare count, sUA, visual analogue scale (VAS) of pain, VAS global activity assessment, swollen and tender joint count and cumulative measure of tophi. Alternative scores were also developed. The developed GAS demonstrated a good correlation with functional disability (criterion validity) and discrimination between patient- and physician-reported measures of active disease (construct validity). The results were reproduced in the external sample. Conclusion: This study developed and validated composite measure of disease activity in gout. Further testing is required to confirm its generalisability, responsiveness and usefulness in assisting with clinical decisions. This article is protected by copyright. All rights reserved.
Three hundred and eighty male hypertensive patients with diastolic blood pressures averaging 90 to 114 mm Hg were randomly assigned to either active antihypertensive agents or placebos. The estimated risk of developing a morbid event over a five-year period was reduced from 55% to 18% by treatment. Terminating morbid events occurred in 35 patients of the control group as compared to 9 patients in the treated group. Nineteen deaths related to hypertension or atherosclerosis occurred in the control group and 8 in the actively treated group. In addition to morbid events, 20 control patients developed persistent diastolic levels of 125 mm Hg or higher. Treatment was more effective in preventing congestive heart failure and stroke than in preventing the complications of coronary artery disease. The degree of benefit was related to the level of prerandomization blood pressure.
Objectives: The aim of this study was to establish consensus for potential remission criteria for use in clinical trials of gout. Methods: Experts (n=88) in gout from multiple countries were invited to participate in a web-based questionnaire study. Three rounds of Delphi consensus exercises were conducted using SurveyMonkey® followed by a discrete choice experiment using 1000Minds®. The exercises focused on identifying domains, definitions for each domain and the timeframe over which remission should be defined. Results: There were 49 respondents (56% response) to the initial survey with subsequent response rates ranging from 57% to 90%. Consensus was reached for the inclusion of serum urate (98% agreement), flares (96%), tophi (92%), pain (83%) and patient global assessment (93%) of disease activity as measurement domains in remission criteria. Consensus was also reached for domain definitions including serum urate (< 0.36mM), pain (<2 on a 10-point scale) and patient global assessment (<2 on a 10-point scale), all of which should be measured at least twice over a set time interval. Consensus was not achieved in the Delphi exercise for the timeframe for remission with equal responses for six months (51%) and one year (49%). In the discrete choice experiment, there was a preference towards 12 months as a timeframe for remission. Conclusion: These consensus exercises have identified domains and provisional definitions for gout remission criteria. Based on the results of these exercises, preliminary remission criteria are proposed with domains of serum urate, acute flares, tophus, pain and patient global assessment. These preliminary criteria now require testing in clinical datasets. This article is protected by copyright. All rights reserved.
Gout is a crystal-deposition disease that results from chronic elevation of uric acid levels above the saturation point for monosodium urate (MSU) crystal formation. Initial presentation is mainly severely painful episodes of peripheral joint synovitis (acute self-limiting 'attacks') but joint damage and deformity, chronic usage-related pain and subcutaneous tophus deposition can eventually develop. The global burden of gout is substantial and seems to be increasing in many parts of the world over the past 50 years. However, methodological differences impair the comparison of gout epidemiology between countries. In this comprehensive Review, data from epidemiological studies from diverse regions of the world are synthesized to depict the geographic variation in gout prevalence and incidence. Key advances in the understanding of factors associated with increased risk of gout are also summarized. The collected data indicate that the distribution of gout is uneven across the globe, with prevalence being highest in Pacific countries. Developed countries tend to have a higher burden of gout than developing countries, and seem to have increasing prevalence and incidence of the disease. Some ethnic groups are particularly susceptible to gout, supporting the importance of genetic predisposition. Socioeconomic and dietary factors, as well as comorbidities and medications that can influence uric acid levels and/or facilitate MSU crystal formation, are also important in determining the risk of developing clinically evident gout.
Gout is a chronic and inflammatory form of arthritis that is often overlooked despite the associated pain caused by acute flares and associated joint damage caused by the development of debilitating tophi. The increasing burden of gout, due to an aging population and the increased prevalence of known risk factors for hyperuricaemia, means that there is a continued need for new and effective urate-lowering treatments. The evaluation of these treatments will require a comprehensive and comparative evidence base describing the economic and humanistic burden of gout, taken from the perspective of patients, the healthcare system, and wider society. The objective of this study is to review and summarise the current evidence of the disease burden related to chronic gout, assessed in terms of both cost and health-related quality of life (HRQL), and to identify key factors correlated with an increased burden. The overall aim is to support the economic evaluation of new treatments for gout, and to highlight key data gaps that may need further study and exploration. Relevant literature dating from January 2000 to July 2014 was sourced through searches of the MEDLINE database via PubMed and The Cochrane Library. Articles published in English and reporting either the economic burden (cost) or the humanistic burden (HRQL/utility) of gout were identified, and key data were extracted and summarised, with key themes and data gaps identified and discussed. Of the 323 studies identified, 39 met the inclusion criteria, of which 17 and 26 were relevant to the economic and humanistic burden, respectively. The economic burden of gout varied according to numerous factors, most notably serum urate acid levels and number of flares and tophi, resulting in higher healthcare resource use most often attributed to hospitalisation and inpatient stay. The incremental direct cost of gout has been suggested in the range of US$3165 to US$5515 (2004 and 2005 values, respectively) climbing to US$10,222 to US$21,467 (2008 values) per annum where patients are experiencing regular acute flares and have tophi present. The humanistic burden of gout was largely due to physical disability and pain resulting from chronic clinical manifestations. Short Form 6 dimensions (SF-6D) assessed utility weights are estimated at 0.53 for a patient with severe gout (≥3 flares/year and tophi) compared with 0.73 for an asymptomatic gout patient with serum acid levels <6 mg/dl. The evidence confirms that gout has a growing overall prevalence and represents a significant burden in terms of both direct healthcare cost and HRQL outcomes. In light of this, effective urate-lowering treatments are likely to be valued if they can be clearly demonstrated to be both clinically effective and cost effective. Published data to support healthcare decision making in non-US countries with regards to treatments for gout are currently limited, which is a key limitation of the current evidence base. More research is also required to extend our understanding of the impact of gout on indirect costs, and a need also exists to develop a more comprehensive set of comparative HRQL utility assessments.
This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care.
There have been several guidelines on the management of gout over the last decade; however, inconsistencies between them create confusion for practitioners. This review highlights areas of agreement between guidelines and discusses data where disagreements exist. For acute gout, the guidelines agree that anti-inflammatory treatment should start as soon as possible, preferably within 24 hours. Older guidelines preferred NSAIDs or colchicine over steroids, but newer ones leave the choice of agent to the physician. For colchicine, all guidelines recommend using low dose. Intra-articular, oral or intramuscular steroids are all described as effective. For management of hyperuricemia, indications for initiating urate-lowering therapy (ULT) have become more inclusive over the years by requiring lower burden of disease severity or including patient comorbidities. Probenecid has fallen out of favour with most guidelines favouring allopurinol over febuxostat. Although there is a disagreement about timing of initiation for ULT, guidelines recommend treating to target of serum urate (sUA) less than 6 mg/dl, and less than 5 mg/dl for patients with more severe disease. Concurrent anti-inflammatory prophylaxis has gained strong support over the years. Most guidelines are in agreement with recommendations for management of gout and most changes have been directional and evolutionary.