GOUT: new revelations
about a very old disease
GEORGE V [GEORDIE] LAWRY MD
CHIEF, RHEUMATOLOGY, UC IRVINE
NOVEMBER 18, 2014
GOUT: clinical
expression of
pathologic MSU
crystal deposition
in a variety of
tissues of the
body
GOUT: uric acid from childhood to adulthood
(normal physiologic changes)
• Childhood:
and
uric acid ~ 3-4 mg%
• Puberty:
have a ~ 1-2 mg%  in uric acid
have no change
• Midlife:
have a slow  in uric acid
have no change
• Menopause:
approach
uric acid levels rise,
levels
GOUT HISTORY: pattern recognition
attacks typically progress
from:
to:
infrequent
frequent
explosive
smoldering
monoarticular
oligo/polyarticular
lower extremity
upper extremity
non-tophaceous
tophaceous
nearly always
remains asymmetric
MONOARTHRITIS
OLIGOARTHRITIS
POLYARTHRITIS
GOUT:
The FRUCTOSE Connection
NEW INSIGHTS
Gout: the FRUCTOSE Connection
BACKGROUND:
• Diet in GOUT: Restriction of purine and alcohol intake
No restriction of sugar sweetened soft drinks
• Sugar-sweetened soft drinks contain: low levels of purine (GOOD)
large amounts of fructose (SO WHAT?)
• FRUCTOSE is:
the only carbohydrate known to
uric acid levels
• Rapid
•
in serum uric acid through:
accentuated degradation of purine nucleotides
increased purine synthesis
found to be exaggerated in individuals with:
hyperuricemia
history of gout
BMJ. 2008 Feb 9;336(7639):309-12. Epub 2008 Jan 31
Gout: the FRUCTOSE Connection
FRUCTOSE induces ↑ uric acid production
by ↑ ATP degradation to AMP, a precursor
of uric acid.
Fructose phosphorylation in the liver uses
ATP and phosphate, limiting regeneration
of ATP from ADP. ADP in turn is substrate
for catabolic pathway to uric acid
formation.
Minutes after IV fructose, plasma
(later, urinary) uric acid concentrations ↑
In conjunction with purine nucleotide
depletion, rates of de novo purine
synthesis are accelerated, thus
potentiating uric acid production.
In contrast, glucose and other simple
sugars do not have the same effect.
Gout: the FRUCTOSE Connection
RESEARCH QUESTION:
Unknown if this FRUCTOSE-INDUCED ACUTE
ELEVATION IN SERUM URIC ACID LEVELS is
sustained on a long term basis and could eventually
translate into an INCREASED RISK OF GOUT ?
BMJ. 2008 Feb 9;336(7639):309-12. Epub 2008 Jan 31
SOFT DRINKS, FRUCTOSE CONSUMPTION, AND THE RISK OF GOUT IN MEN:
A PROSPECTIVE COHORT STUDY
HYON K CHOI, ASSOCIATE PROFESSOR OF MEDICINE, GARY CURHAN, ASSOCIATE PROFESSOR OF MEDICINE
BMJ 2008
• Objective: To examine the relation between intake of sugarsweetened soft drinks and fructose and risk of incident gout in men
• Design: Prospective cohort over 12 years
• Setting: Health professionals follow-up study, an ongoing longitudinal
study of 51,529 male dentists, optometrists, osteopaths, pharmacists,
podiatrists, and veterinarians. Men were predominantly white (91%) and
were aged 40 to 75 years in 1986.
• Participants: 46,393 men with no history of gout at baseline who
provided information on intake of soft drinks and fructose through validated
food frequency questionnaires in 1986 and updated every 4 years hence
• Main outcome measure: Incident cases of GOUT meeting the
American College of Rheumatology survey criteria for gout.
WHAT ARE GLUCOSE, FRUCTOSE, AND SUCROSE ?
Glucose is a simple monosaccharide found in
plants and animals. It is absorbed directly into
the bloodstream during digestion
Fructose, or fruit sugar, is a simple
monosaccharide found in many plants,
where it is often bonded to glucose to form the
disaccharide sucrose; FRUCTOSE is one of the
three dietary monosaccharides, along with
GLUCOSE and GALACTOSE, that are absorbed
directly into the bloodstream during digestion
Sucrose is a sugar, commonly known as
table sugar, cane sugar, beet sugar or,
usually, just sugar. The molecule is a
disaccharide composed of the
monosaccharides glucose and fructose
HIGH FRUCTOSE CORN SYRUP:
“biological novelty” for the human body
HIGH FRUCTOSE CORN SYRUP
Sugar sweetened vs diet soft drinks and incident gout:
Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout (table 2)
Compared with the reference consumption level of <1 serving a month, the mv RR of gout for
5-6 servings a week = 1.29 (95% CI 1.00 to 1.68), for one serving a day = 1.45 (1.02 to 2.08), and for
2 or more servings a day = 1.85 (1.08 to 3.16; P for trend 0.002).
In contrast, diet soft drinks = no association with risk of gout (P for trend 0.99).
Sugar sweetened vs diet soft drinks and incident gout:
Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout (table 2)
Compared with the reference consumption level of less than one serving a month, the mv RR of gout for
5-6 servings a week = 1.29 (95% CI 1.00 to 1.68), for one serving a day = 1.45 (1.02 to 2.08), and for
2 or more servings a day = 1.85 (1.08 to 3.16; P for trend 0.002).
In contrast, diet soft drinks = no association with risk of gout (P for trend 0.99).
ICONOCLASIA:
ICONOCLASIA:
may
your risk of gout !”
if that’s not bad enough …
EVEN the
“PAUSE THAT REFRESHES”…
Sugar sweetened vs diet soft drinks and incident gout:
Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout (table 2)
Compared with the reference consumption level of less than one serving a month, the mv RR of gout for
5-6 servings a week = 1.29 (95% CI 1.00 to 1.68), for one serving a day = 1.45 (1.02 to 2.08), and for
2 or more servings a day = 1.85 (1.08 to 3.16; P for trend 0.002).
In contrast, diet soft drinks = no association with risk of gout (P for trend 0.99).
diet soft drinks
X
risk of gout !!
Fructose intake and incident gout:
increasing fructose intake was associated with increasing risk of gout (table 3).
Compared with men in the lowest fifth of free fructose intake, the mv RR of gout in the highest fifth when
substituting fructose for the equivalent energy from fat = 1.81 (95% CI 1.38 to 2.38; P for trend <0.001).
Fructose-rich foods & beverages and incident gout:
Total fruit juice intake was associated with risk of gout (table 4) Compared with men who consumed <1 glass of
fruit juice a month, the mv RR for gout in those consuming 2 or more glasses a day = 1.81 (95% CI = 1.12 to 2.93).
The corresponding mv RR for orange juice or apple juice = 1.82 (1.11 to 3.00).
Similarly, intake of oranges or
apples was associated with risk of gout. Compared with men who consumed <1apple or orange/month,
the mv RR of gout in those who consumed 1 apple or orange/day = 1.64 (1.05 to 2.56)
Fructose-rich foods & beverages and incident gout:
Total fruit juice intake was associated with risk of gout (table 4) Compared with men who consumed <1 glass of
fruit juice a month, the mv RR for gout in those consuming 2 or more glasses a day = 1.81 (95% CI = 1.12 to 2.93).
The corresponding mv RR for orange juice or apple juice = 1.82 (1.11 to 3.00).
Similarly, intake of oranges or
apples was associated with risk of gout. Compared with men who consumed <1apple or orange/month,
the mv RR of gout in those who consumed 1 apple or orange/day = 1.64 (1.05 to 2.56)
ICONOCLASIA:
“An apple a day …………
may
your risk of gout !”
GOUT:
The NETosis Connection
NEW INSIGHTS
What the Heck is a “NET”
?
Gout: the NETosis Connection
RESEARCH QUESTION:
GOUT: acute inflammatory reaction with accumulation of
neutrophils in response to MSU crystals
Inflammation can resolve spontaneously within a few
days, although MSU crystals can still be detected in SF
and tissues
What mechanisms mediate RAPID CONTROL AND
TERMINATION OF MSU-TRIGGERED INFLAMMATION ?
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Objective: to examine the possible anti-inflammatory role of neutrophil
extracellular traps (NETs) in terminating MSU-triggered inflammation
Conclusions:
• PMNs recruited to sites of inflammation undergo oxidative burst and form
neutrophil extracellular traps (NETs)
• At low PMN densities, MSU crystals induced ROS-dependent
NET formation accompanied by cytokine and chemokine release
• Under high PMN densities, these NETs aggregate and degrade cytokines
and chemokines via serine proteases
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
NETosis what is it?
NEUTROPHIL EXTRACELLULAR TRAPS
Pro-inflammatory response
of neutrophils to immobilize
and kill extracellular pathogens
• PMNs stimulated by ________
• Profound ultrastructural
alterations (preparation for a
self-sacrificing, host-protecting
evisceration)
• Release of cellular contents
DNA-backbone, “decorated”
with histones, neutrophil granular
and cytoplasmic proteins (NETs)
which ensnare (trap) and kill
microorganisms
• PMNs, now dying/dead,
phagocytized by macrophages
http://jcb.rupress.org/content/198/5/773/F3.large.jpg
NETosis what is it?
YOUTUBE VIDEO:
NETosis
https://www.youtube.com/watch?v=TIFmtnSdolM
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
MSU crystals induce NETosis and aggregation of NETs
• Observations from subjects with gout prompted further examination of
whether MSU crystals can induce NETosis
• Analyzing in vitro interaction of DNA-stained human neutrophils with MSU
crystals by video microscopy revealed:
rearrangement of the neutrophils’ nuclear structures
rapid cellular disintegration
independent of phagocytosis of MSU crystals
• During the disintegration process, chromatin was externalized, forming
NETs comparable to those induced by microorganisms and cytokines
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Figure 1 Characterization of MSU-induced NETs in tophi and synovial fluid from subjects with gout
• Representative immunofluorescence images of DAPI-stained [DNA stain]
and NE-stained [neutrophil elastase] cytospins from synovial fluid of patients
with gout (containing MSU crystals)
and MSU-free arthritis (rheumatoid arthritis)
• White arrows show spread NETs in gout samples
• Blue arrows indicate diffused NETs / aggregated NETs
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Aggregated NETs degrade neutrophil-derived
inflammatory mediators
• Analyzed the inflammatory mediators released during
MSU-induced NETosis and aggregation of NETs
• Cytokines and chemokines were in HIGH concentrations
in supernatants from low-density PMN cultures, however,
Cytokine and chemokine concentrations were LOW in
supernatants from high-density PMN cultures
• Observed a time-dependent decrease in concentration of
cytokines and chemokines in media containing aggNETs,
not observed in the absence of aggNETs
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Figure 2 MSU crystals trigger NETosis and aggregation of NETs in cultured human neutrophils
• Representative fluorescence microscopy images of:
MSU-treated
Untreated
human neutrophils cultured at different concentrations and stained for DNA
(DAPI) and neutrophil elastase (NE)
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Gouty tophi share characteristics with NETs
• Clinically overt gouty tophi in humans detected by DECT during a highly
inflammatory phase persist during a clinically silent (intercritical gout) phase
• NETs, extranuclear DNA structures co-localizing with material from neutrophil
granules, can be found in human tissue sections of subjects with acute gout
and tophus control individuals
• Extranuclear DNA co-localization with NE [neutrophil elastase] was abundant
in the tophus, whereas in the non-tophus areas and in MSU-negative synovitis
(RA), neutrophils were sparse, and DNA exhibited a predominantly nuclear
appearance
• Quantification of fluorescent-labelled DNA indicated large stretches of diluted
extracellular DNA spread over tophi [suggesting NETs] as compared to a
more regular nuclear morphology in adjacent tissues and in non-gouty
synovitis
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
• MSU crystals can induce NETosis AND aggregation of NETs
• Tophi in chronic gout, share characteristics with aggregated NETs
[low inflammatory profile: “traps become tarps” – gvl]
• In individuals with impaired NETosis, MSU crystals induce uncontrolled
production of inflammatory mediators from neutrophils and persistent
inflammation
• NETosis-deficient mice develop exacerbated and chronic inflammatory
disease that can be reduced by adoptive transfer of aggregated NETs
AGGREGATED NETS PROMOTE THE RESOLUTION OF
NEUTROPHILIC INFLAMMATION BY DEGRADING CYTOKINES
AND CHEMOKINES AND DISRUPTING NEUTROPHIL
RECRUITMENT AND ACTIVATION
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
AGGREGATED NEUTROPHIL EXTRACELLULAR TRAPS LIMIT INFLAMMATION
BY DEGRADING CYTOKINES AND CHEMOKINES
CHRISTINE SCHAUER, CHRISTINA JANKO, LUIS E MUNOZ, ET AL
NATURE MEDICINE
Clearance of neutrophils by mononuclear phagocytes is
important for the resolution of inflammation in tissues with
high amounts of infiltrating leukocytes
• Inflammation can be attenuated by the action of aggregated NET
structures formed under conditions of high neutrophil density.
• MSU crystal–triggered aggNETs trap and proteolytically degrade
neutrophil-derived cytokines and chemokines, reducing
inflammation
• This mechanism may account for the ENIGMATIC SPONTANEOUS
REMISSION OF ACUTE INFLAMMATORY ATTACKS elicited by
MSU crystals in individuals with gout
[and may be of importance in other forms of neutrophilic inflammation as well]
Nat Med 2014 May;20(5):511-7. Epub 2014 Apr 28.
GOUT:
The COMPLIANCE Connection
NEW INSIGHTS
FIRE & GARBAGE
Initial Management:
“putting out the fire”
• NSAIDs and STEROIDS say: “Hey Macrophages, PMNs,
and synoviocytes, take a chill pill, we got enough people
trying to clean up this party, no need to use inflammatory
mediators to call any more friends”
• COLCHICINE, the cop, says: “Hey inflammatory
cells/tubulin, FREEZE, no more eating crystals and you are
not going anywhere, and if you try to replicate and divide you
will die”
Long-Term: “treating the garbage problem”



check the serum uric acid level ~q month
adjust the dose of urate lowering drug until the patient
is attack-free [NO FIRES] and uric acid level is
4-5 mg% or even lower, 3-4 mg% in tophaceous
patients
[REDUCE GARBAGE LEVEL]
continue the anti-inflammatory until reaching the
desired level of uric acid, then stop the antiinflammatory [LOW GRADE FIRE HOSE SPRAY ON
DUMP TO PREVENT RECURRENT FIRES]
GOUT:
The TAKE HOME Points
WHAT 3 NEW THINGS DID YOU LEARN FROM
THIS TIME TOGETHER?
SO WHAT?