Crystal arthropathies
RMD Open: first published as 10.1136/rmdopen-2023-003586 on 21 September 2023. Downloaded from http://rmdopen.bmj.com/ on October 4, 2023 by guest. Protected by copyright.
To cite: Shi M, Luo J, Ding L,
et al. Spontaneous resolution
of acute gout: mechanisms and
therapeutic targets. RMD Open
2023;9:e003586. doi:10.1136/
rmdopen-2023-003586
MS and JL contributed equally.
MS and JL are joint first authors. However, the underlying mechanism for spontaneous
Received 6 August 2023
Accepted 6 September 2023
© Author(s) (or their
employer(s)) 2023. Re-­use
permitted under CC BY.
Published by BMJ.
1
Medical College of Nanchang
University, Nanchang, China
2
Department of Rheumatology
and Clinical Immunology, Jiangxi
Provincial People's Hospital,
The First Affiliated Hospital of
Nanchang Medical College,
Nanchang, China
3 remission of gout attacks that will aid the
Jiangxi Provincial Clinical
Research Center for Rheumatic
and Immunologic Diseases,
Nanchang, People's Republic
of China
4
Key Laboratory of
Rheumatology and Immunology,
Health Commission of Jiangxi
Province, Nanchang, People's
Republic of China
Correspondence to
Dr Lihua Duan;
​lh-​duan@​163.​com
VIEWPOINT
Spontaneous resolution of acute gout:
mechanisms and therapeutic targets
Meiling Shi ‍ ‍,1,2,3,4 Jiao Luo,2,3,4 Liting Ding,2,3,4 Lihua Duan ‍ ‍1,2,3,4
ABSTRACT
Gout is a common inflammatory arthritis that has been
increasing in both prevalence and incidence. Consequently,
management of refractory and chronic gout has been
gaining attention. Onset of gout is related to the deposition
of monosodium urate crystals under hyperuricaemia.
Interestingly, acute gout attacks often resolve
spontaneously within 7–10 days, and many studies have
confirmed the notion that gout flares can be self-­relieved.
remission of gout requires further elucidation. In this
article, we summarise the roles and mechanisms related
to spontaneous remission of gout, which are essential for
understanding its pathogenesis and developing potential
targeted therapies.
Gout caused by chronic deposition of mono-
sodium urate (MSU) crystals is the most
common inflammatory arthritis in adults.
Gout flares are usually self-­limiting inflam-
matory reactions that exhibit disappearance
of redness, swelling and severe pain in the
joints within 7–10 days, and may be associated
with rapid induction of anti-­ inflammatory
factors like Transforming growth factor beta
1 (TGFβ1), interleukin (IL)-­10 and soluble
tumour necrosis factor (TNF) receptors as
well as intracellular cytokine negative regu-
lators like cytokine inducible SH2-­containing
protein and regulatory immune cells.1 Never-
theless, the prevalence and incidence of
refractory and chronic gout have continued
to increase. Consequently, the question arises
as to what can be learnt from the spontaneous
management of patients with refractory and
chronic gout.
Research has shown that neutrophils are
involved in not only the production of acute
inflammation but also its self-­ remission.
After phagocytosis of MSU crystals, neutro-
phils undergo the formation of neutrophil
extracellular traps (NETs), a process known
as NETosis, and release inflammatory cyto-
kines. It is worth noting that neutrophils
reach a threshold and that large DNA/MSU
Shi M, et al. RMD Open 2023;9:e003586. doi:10.1136/rmdopen-2023-003586
crystal structures, designated aggregation
neutrophil extracellular traps (aggNETs),
are subsequently formed. AggNETs sequester
proinflammatory cytokines and chemokines
for degradation by serine proteases, resulting
in the relief of gout attacks.2 In 2021, CIT-­
013, which binds to citrullinated histones
H2A and H4, was tested in a phase 1 clinical
trial as a first-­in-­class humanised therapeutic
antibody targeting NET formation and clear-
ance. CIT-­013 may be further developed for
treatment of gout.3 Activated neutrophils that
engulf dying neutrophils by phagocytosis in
the late stages of gout attacks can promote
the production of TGFβ1 and eliminate the
inflammatory response.4 Furthermore, non-­
inflammatory phagocytosis of dying neutro-
phils by macrophages is associated with
spontaneous remission of gout flares.5 Mean-
while, although studies of TGFβ1 in the treat-
ment of autoimmune diseases have failed due
to tumour development, single or a few doses
may be beneficial for acute gout therapy.
IL-­1β is an inflammatory cytokine secreted
by macrophages that also plays a crucial role
in gout. Canakinumab was found to be effec-
tive and well-­ tolerated for the short-­ term
control of acute gouty arthritis in several
clinical trials.6 Uptake of MSU crystals by
macrophages induces activation of NOD-­
like receptor thermal protein domain asso-
ciated protein 3 (NLRP3) inflammasomes,
which in turn leads to activation of caspase-­1
precursor (procaspase 1) that converts pro-­
IL-­1β to biologically active IL-­ 1β. In the
clinic, colchicine relieves gout inflammation
by inhibiting MSU crystal activation in the
NLRP3 inflammasome, thereby blocking
the release of IL-­1β.7 Anakinra, a recombi-
nant human IL-­ 1Ra, is the first biological
agent approved for treatment of rheumatoid
arthritis. It acts by blocking the biological
activity of IL-­1 through competitive inhibition
of the binding between IL-­1 and interleukin-­1
type I receptor (IL-­1RI). Interestingly, syno-
vial fluid (SF) from patients with acute gout
   1
RMD Open

contains significantly higher levels of IL-­1Ra than SF from
patients with osteoarthritis. Furthermore, IL-­1Ra is posi-
tively correlated with serum uric acid and inflammatory
markers, and two randomised controlled trials reported
the use of anakinra to treat gout flares.8 9
Patients with gout have significantly elevated levels of
TNF-α. Furthermore, the combination of TNF-α and
MSU causes significant induction of precursor IL-­ 1β
RMD Open: first published as 10.1136/rmdopen-2023-003586 on 21 September 2023. Downloaded from http://rmdopen.bmj.com/ on October 4, 2023 by guest. Protected by copyright.
expression in neutrophils, while MSU stimulation alone
fails to induce precursor IL-­ 1β expression and IL-­1β
secretion by neutrophils.10 In addition, MSU can indi-
rectly promote pro-­IL-­1β production through local cell
necroptosis, leading to release of damage-­ associated
molecular patterns (DAMPs) that stimulate macrophage
or dendritic cell production of TNF-α.11 During the
development of gout inflammation, the levels of soluble

Figure 1 Summary diagram for the mechanisms of gout attacks and their self-­remission. Phagocytosis of crystals by
parenchymal cells activates immune cells surrounding parenchymal cells by inducing necroptosis leading to the release
of DAMPs. Activated immune cells produce pro-­inflammatory cytokines, such as pro-­IL-­1β and TNF-α. TNF-α can also
induce necroptosis and promote the production of pro-­IL-­1β via TNFR1. The auto-­amplification loop between cell death and
inflammation can be blocked by using a soluble TNFR1-­hIgG1 fusion protein etanercept. MSU crystals enter cells mainly
through CD14, activate NLRP3 inflammasome and promote pro-­IL-­1β maturation. Elevated IL-­33, IL-­37, aggNETs, IL-­1Ra, and
TGFβ1 during inflammation relieve gout flares by inhibiting the action of the IL-­1β pathway. These negative regulatory cytokines
are potential targeted therapeutic drugs. In addition, anti-­CD14 antibody (IC14) that blocks MSU uptake and colchicine that
inhibits NLRP3 inflammasome activation, and anti-­histone antibody (CIT-­013) that inhibits NETs formation are also targeted
therapies. aggNETs, aggregation neutrophil extracellular traps; DAMPs, damage-­associated molecular patterns; IL, interleukin;
mCD14, membrane-­bound CD14; MSU, monosodium urate; NETs, neutrophil extracellular traps; NLRP3, NOD-­like receptor
thermal protein domain associated protein 3; TGFβ1,Transforming growth factor beta 1; TNF, tumour necrosis factor; TNFR-­I,
TNF receptor I.

2 Shi M, et al. RMD Open 2023;9:e003586. doi:10.1136/rmdopen-2023-003586


TNF receptor I (sTNFRI) and II (sTNFRII) are signifi-
cantly elevated in the SF. A case report indicated that the
TNF-α antagonist etanercept combined with febuxostat
showed efficacy for refractory gout. In addition to treat-
ment of rheumatoid arthritis and ankylosing spondylitis,
etanercept is currently in clinical use for acute refractory
gout attacks.12 13
CD14 is a proximal point in the innate immune response
to MSU crystal uptake, caspase-­1 activation and IL-­1β
production in macrophages. Remarkably reduced MSU
uptake is observed in CD14 knockout mice.14 Membrane-­
bound CD14 (mCD14) and soluble CD14 (sCD14) coop-
erate with Toll-­like receptors (TLRs) to facilitate innate
immune responses.15 We found that mCD14 expression
on peripheral blood mononuclear cells is significantly
reduced in patients with gout. Furthermore, serum
sCD14 levels are significantly reduced and have a posi-
tive correlation with C-­ reactive protein levels. CD14
expression is also directly reduced after MSU stimulation
of monocytes/macrophages from healthy volunteers.
Therefore, reduced CD14 production in MSU-­induced
inflammation may contribute to spontaneous remis-
sion,16 and blockade of CD14 function may be useful for
refractory gout. In fact, IC14, a chimeric monoclonal
antibody, is a potential anti-­CD14 therapeutic agent that
has been investigated in COVID-­19 patients.17 Thus, IC14
may also be useful for treatment of gout by blocking the
interactions of CD14, DAMPs and MSU, thereby attenu-
ating the NLRP3/IL-­1β pathway.
The IL-­1 family members IL-­33 and IL-­37 are known
to be negative regulators of IL-­1β signalling, and their
anti-­
inflammatory properties have been demonstrated
in numerous disease models. We previously showed
that IL-­33 is increased in patients with gout and that
exogenous IL-­ 33 reduces neutrophil recruitment and
IL-­1β production in MSU-­ induced acute inflamma-
tion,18 although IL-­33 can attenuate sepsis by enhancing
neutrophil influx to infection sites in experimental sepsis
induced by cecal ligation and puncture.19 The IL-­ 37
levels in patients with tophaceous gout are significantly
increased, and patients who are carriers of distinct rare
IL37 variants affecting the IL-­37 protein structure and
consequently its anti-­inflammatory function experience
either onset of gout at a younger age or a more severe
disease phenotype. Moreover, administration of recom-
binant IL-­37 can dampen the inflammation induced by
MSU crystals.20 In addition to TGFβ1, these regulatory
cytokines may be potential therapeutic agents for refrac-
tory gout.
CONCLUSION
At present, the number of patients with refractory gout
is continuing to increase, and the question of how to
control acute attacks in patients with refractory gout
is a clinical problem that requires urgent resolution.
Treatment of acute gout inflammation mainly relies on
non-­ inflammatory drugs, colchicine and
steroidal anti-­
Shi M, et al. RMD Open 2023;9:e003586. doi:10.1136/rmdopen-2023-003586
Crystal arthropathies
RMD Open: first published as 10.1136/rmdopen-2023-003586 on 21 September 2023. Downloaded from http://rmdopen.bmj.com/ on October 4, 2023 by guest. Protected by copyright.
glucocorticoids; however, refractory gout is a persistence
of clinical manifestations characterised by the inability
to reduce the serum urate acid concentration below the
target 6.0 mg/dL, increased MSU deposition and tophi
formation, and chronic inflammatory arthritis, ongoing
symptoms of recurrent flares. Patients with refractory
gout often do not respond well to these drugs or have
contraindications. Targeted therapy, including biologics
and targeted synthetic small molecule drugs, has been
widely used in other inflammatory arthritis diseases, such
as rheumatoid arthritis and ankylosing spondylitis, with
promising results. We hope that patients with refractory
gout can receive similar targeted therapies to patients
with rheumatoid arthritis and ankylosing spondylitis. We
have discovered many potential therapeutic targets by
elucidating the pathogenesis and self-­remission mecha-
nisms of gout (figure 1). Fortunately, some drugs have
either received approval or are currently in clinical trials.
We believe that targeted therapy for gout is coming soon,
providing welcome relief for patients with refractory
gout.
Contributors MS and JL reviewed the literature and wrote the first draft. MS and
LDi reviewed the literature and finalised the manuscript. MS, LDi and LDu revised
the manuscript. All authors have read and approved the final manuscript. MS and
JL contribute equally to this work.
Funding This work was supported by the National Natural Science Foundation of
China (82371773, 82260112, 62363028 and 81960296), Jiangxi Provincial Natural
Science Foundation (20232BBG70026, 20202ACBL206011 and 20192BBG70028),
Jiangxi Province Medical Leading Discipline Construction Project (Rheumatology),
Provincial and Municipal Joint Construction Projects of Medical Disciplines in
Jiangxi Province (Rheumatology), and Aifengshi-­Qingxin Foundation of Chinese
Rheumatology Association.
Competing interests None declared.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made. See: https://creativecommons.org/​
licenses/by/4.0/.
ORCID iDs
Meiling Shi http://orcid.org/0009-0000-1739-3056
Lihua Duan http://orcid.org/0000-0002-1631-4675
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