Gout is the most common form of inflammatory arthritis, and the
incidence and prevalence are rising. The key pathological
mechanism in developing gout is characterised by the deposition of monosodium urate crystals in tissues and fluids which is created by a continuously elevated serum urate (SU) concentration in the
blood. Gout is characterized by a sudden onset of acute arthritis
and if untreated, recurrent episodes of arthritis (gout flares) can
occur. Advanced gout characterised by tophi and/or chronic
arthritis will occur in some individuals.
This PhD consists of three research areas in gout:
Part A: Biomarkers and surrogate outcomes (Paper I, II, IV).
We wanted to validate Serum Urate (SU) as a surrogate outcome for
clinical patient centred outcomes in gout. This was done using
systematic review and meta-analysis and then assessing whether
serum urate would pass the Biomarker Surrogate Evaluation Schema (BSES). The meta-regression analysis did not support serum urate as a surrogate outcome measure for gout flares. The validation of serum urate using the BSES was likewise unsuccessful due to incomplete statistical proof. In Paper IV the data from Paper II and additional evidence from the Stamp et al. study1 using individual patient data were presented at the Outcome Measures in
Rheumatology (OMERACT) Special Interest Group (SIG) meeting.
Agreement among OMERACT SIG meeting participants on the
relevancy of validating SU was obtained. Furthermore, participants
agreed that there was sufficient data to accept SU as a valid surrogate outcome.
Part B: Core Outcome Set (Paper III, V).
In Paper III (sub-analysis of paper II) we address the difficulties
regarding reporting in clinical trials of urate-lowering therapy. We
proposed a minimum reporting set for SU and gout flares in long
term urate lowering therapy trials in gout. In Paper V, we
conducted a systematic review, to assess the reporting of the
OMERACT core outcome domains in RCT studies of acute and
chronic gout. The OMERACT core outcome set in gout clinical trials
is not completed and there is low adherence with the intended
mandatory core outcome domains for acute and chronic studies
which represents a poor uptake of the global OMERACT efforts.
Part C: Gout and comorbidities. (Paper/protocol VI).
The URICORI trial was designed to be executed with the
incorporation of surrogate outcomes (Part A), the core outcome domains and the minimum reporting requirements we proposed in
Part B of this thesis. This planned trial was entitled “A
Multifactorial ‘Urica Cor Intervention’ to Prevent Cardiovascular
Disease in People with Gout: A Multicentre, Randomised
Controlled, Blinded Endpoint URICORI Trial”. The objective of the
URICORI trial was to evaluate the effectiveness of a one-year,
intervention of modifiable risk factors for cardiovascular disease
administered in a rheumatology outpatient setting, compared with
conventional treatment in primary care of modifiable risk factors
for cardiovascular disease in people with gout. We wanted to
perform a clinical study addressing how an intervention strategy
(URICORI) would affect surrogate outcomes after one year and
clinical outcomes after 5 years. After postponing the URICORI trial
due to COVID-19 we included the first patient in November 2020.
Unfortunately, inclusion in the “URICORI” study did not proceed at
a satisfactory rate and despite three inclusion centres being up
running, we had to close the trial. A large part of the work of this
PhD project was done during the Covid-19 pandemic with varying
degrees of lockdown and challenges in the health sector.
In the international setting of the OMERACT Biomarker surrogate
outcome group, data from this PhD has contributed to the process
of validating serum urate as a surrogate outcome for patient centred outcomes (gout flares) in clinical trials of gout. The data
has been presented the international OMERACT meeting and a
stakeholder agreement of the relevancy of validating SU as a surrogate was obtained as well as an OMERACT consensus-based agreement of serum urate as a surrogate outcome measure for gout
flares in clinical gout trials. Furthermore, we have shown that the
core outcome set for gout is not completed and adherence to the
core outcome domains is poor. Further effort to ensure the underreported patient reported outcomes in clinical trials of gout
should be reinforced.
The URICORI trial was closed prematurely and the challenges regarding design of the study, the study protocol, obtaining permissions and the conduction of a multicentre RCT (during COVID-19)
has been very educational.