Gout

Recent criteria and guidelines for management

By/ Shrouk Ayman Mohammed
Resident in rheumatology department, Sohag university
Contents
• Introduction
• Epidemiology
• Pathogenesis
• Diagnosis
• 2015 ACR-EULAR classification criteria
• Treatment
• 2020 ACR guideline for management
Introduction
• Gout is the most common form of inflammatory
arthritis .
• It is caused by deposition of monosodium urate
crystals due to long standing hyperuricemia.
• Usually begins as intermittent acute mono or
oligoarthritis, especially in the first MTP.
• Flares typically become more frequent and
involve more joints with time.
• Extraarticular manifestations include
subcutaneous tophi and renal stone.
Epidemiology
• Gout is the most common inflammatory arthritis
globally, affecting ~ (3.9%) in the US.
• Prevalence of gout increases with age and is
more common in males than females
• Gout in premenopausal women is rare due to
uricosuric effect of estrogen.
• Rarely, it may happen in children and young
adults in some rare inborn errors of purine
metabolism. These enzymatic defects result in
increased SUA with consequent production of
UA crystals in kidneys and joints
 Pathogeneis
Pathogenesis of hyperuricemia:
• Urate is the ionized form of uric acid present in the
body.
• Uratecrystals deposition in tissues starts to occur when
serum uric acid level rises above the normal threshold.
Pathological threshold of hyperuricemia is defined as
6.8 mg/dL.
• Some factors may affect the solubility of uric acid in
the joint. These include synovial fluid pH, water
concentration, electrolytes level.
• Factors affecting SUA levels include age and gender.
• SUA level in the body is determined by the
balance between its production either from
purine intake in diet or endogenous
production by cellular turnover and its
excretion by the kidneys and GIT. Increased
production of UA is responsible for only
10% of cases of gout while the remaining
90% are caused by its renal under-excretion
Pathogenesis of acute gouty arthritis:
• The pathogenesis of gouty arthritis involves initial activation of monocytes
and mast cells followed by neutrophils.
• Less-differentiated monocytes produce abundant amounts of TNF, IL-1, IL-
6 and IL-8 along with endothelial activation following phagocytosis of
urate crystals. Also, mast cells are key players in inducing the acute gouty
attack by producing histamine and IL-1. This results in increasing vascular
permeability and vasodilatation.
• The chemotactic factors produced by monocytes and mast cells and the
local vasodilatation stimulates neutrophilic chemotaxis. Also, endothelial
cells activation further aggravates the inflammatory response and migration
of neutrophils. This leads to an influx of neutrophils locally .
Pathogenesis of chronic gouty arthritis:
• Chronic gout manifests by chronic synovitis, bony erosions,
cartilage damage and tophi formation.
• This can be explained by different mechanisms. Presence of
urate crystals in the synovium leads to stimulation of
chondrocytes to produce inflammatory cytokines resulting in
cartilage damage.
• On the bone level osteoblasts release pro-inflammatory
cytokines leading to erosions and bone destruction in addition
to compromising their own bone formation function.
 Diagnosis
Symptoms and signs:
Gout undergoes 4 stages during its course :
Asymptomatic hyperuriceamia
• In this stage, patients have no symptoms or signs and are
usually accidentally discovered when measuring SUA (serum
level greater than 7 mg/dL).
Acute gouty attack
• Acute gouty attack is usually monoarthritic that peaks within hours to
severely inflamed joint with cardinal signs of inflammation.
• Gout has a predilection for lower extremities such as the first MTP, which
is the commonest site for acute gout known as podagra . Other joints that
can be affected are the tarsal and metatarsal joints, ankles, knees, wrists,
MCPs as well as interphalangeal joints of the hands. Rarely, hip and
shoulder joints can be involved. Vertebral column involvement is extremely
rare.
• Arthritis of more than one joint at the same time is not very rare. It is more
common in long-term untreated gout or in postmenopausal women.
• Constitutional symptoms such as fever, headache, and malaise can be
present. In such case, the joint has to be managed as septic arthritis until
proven otherwise.
Erythema and swelling can be
seen in the area of the first
metatarsophalangeal joint (MTPJ)
of this patient's left foot.
Intercritical period
• When the acute attack settles down within hours to days
following the introduction of colchicine or NSAIDs, patients
enter into a remission phase.
• This period is characterized by the absence of symptoms. This
quiescent stage can be prolonged after the first attack.
• Without proper treatment, however, attacks become more
frequent and more severe
Chronic tophaceous gout
• As disease progress, the patient enters the stage of chronic gouty arthritis.as
a result of macrophage response .
• It usually develops 10 years of acute intermittent arthritis .
• It is when the intercritical periods are no longer symptom free and the
affected joints now are persistently uncomfortable.
• Also it progresses into destruction of joints with formation of palpable
tophi.
• A tophus is a mass formed of large amounts of accumulated crystals. It can
be present around the joints in the ears, the subcutaneous tissue or the skin.
It is a manifestation of chronicity and uncontrolled disease.
Macroscopically, tophi contain a white chalky material.
• Bony erosions may also occur as growing tophi extend to the bone
 Chronic tophaceous gout: (a) hands, (b) ankle,
(c) left greater toe
Lab :
• Serum urate:
• Should be checked when pt is not on any ULT and at least 4 weeks after the last flare
• Most pts have elevated serum uric acid level (>6.8)
• however, diagnosis of gout based on hyperuricemia is a common misconcept among
non-rheumatologists.
• Hyperuriceamia is usually asymptomatic and does not necessitate the diagnosis of
gout.
• Among patients with SUA levels between 7 and 7.9 mg/dL only 0.09% will develop
gout every year. As for patients with SUA between 8 and 8.9 mg/dl, 0.4% out of them
may develop gout. With hyperuriceamia above 9 mg/dl, only 0.5% of patients may get
gout

• Also it should be noted that during gouty attacks, SUA might drop to normal levels.
Hyperuricemia is a weak marker for gout diagnosis and the disease might still be
• CBC : leuckocytosis with neutrophilia (during
attack)
• ESR, CRP: elevated (during attack)
• 24hr urinary uric acid: not required in all
patients. It is useful in assessing the etiology of
hyperuriceamia in gout patients. Urinary uric acid
of more than 800 mg/24 h indicates that such
patients have increased production of uric acid,
thus they excrete a large amount of uric acid. They
require a drug that prevents uric acid production
such as xanthine oxidase inhibitors rather than a
uricosuric agent.
• Synovial fluid analysis:
• Analysis of synovial fluid should include leukocytic
count, chemistry, culture and sensitivity.
• In acute gout, synovial fluid leukocytic count 5000-
80000 cells/µL in some cases mostly polymorphs.
• Chemistry reveals normal glucose levels contrary to
septic arthritis, in which bacteria consume glucose
leading to low levels.
• Care should be taken to exclude septic arthritis in gouty
cases, as both may be present in the same joint. So,
culture and sensitivity along with gram stain is crucial to
confirm the diagnosis
• Identification of MSU crystals:
• The gold standard of diagnosis is the identification of MSU crystals in synovial
fluid aspirate using polarized light microscopy.
• MSU crystals are found in the synovial fluid in all stages of the disease; during
attacks, in the intercritical period or in chronic tophaceous gout.
• Samples should be examined as soon as possible; better within 6 h. Though, they
can be examined within 24 h if kept refrigerated at 4 °C. This is to avoid cellular
dissolution and disappearance of crystals.
• Using simple light microscopy, UA crystals are needle-like in shape, with different
sizes. These can be easily distinguished from pseudogout (CPPD) crystal, which
are usually rhomboidal in shape.
Radiological :

X-Ray: in early stages of the disease it is not very helpful . Radiographic changes
may be missed for a minimum of 10 years after the first gouty attack.

In chronic tophaceous gout, the main radiographic features are:

(a) Tophi which are articular or periarticular soft tissue dense nodules.

(b) MSU deposits in the cartilaginous part

(c) Joint space narrowing in advanced disease.

(d) Bone erosions are characteristic. They are well circumscribed intraarticular or
juxtarticular lesions with overhanging margins. They result from the growth of tophi
into the bone, hence are usually seen near tophi.
characteristic erosions with "overhanging"
edges seen in gout (white arrows).
These have been characterized as appearing
like "rat-bites."
U/S: In gout US features can be either nonspecific or specific.
Nonspecific features include:
(1) Synovial fluid
Synovial fluid varies from being totally anechoic to containing
aggregates of variable echogenicity. Aggregates of MSU
microcrystals can be detected as hyperechoic spots or bright
stippled foci. They tend to float in the joint space sometimes
giving a snow-storm appearance when applying gentle pressure
on the skin surface.
(2) Synovial proliferation and hypervascularization
(3)Bone erosions
Specific US features in gout include:
1. Articular cartilage “double contour Sign” (DCS):
DCS is very specific for gout. It is defined as abnormal hyperechoic band
over the superficial margin of the articular hyaline cartilage.
2. MSU deposits (Tophi and Aggregates):
A tophus is a circumscribed, inhomogeneous, hyperechoic, and/or
hypoechoic aggregation (that may or may not generate posterior acoustic
shadow), which may be surrounded by a small anechoic rim .Tophi have
been also described by US as “wet sugar clumps” with an oval or irregular
shape.
Three examples of Ultrasonography in gout. (a)
Intraarticular tophus, metatarsophalangeal
joint; (b) Double contour sign; (c) Longitudinal
image of extensor digitorum longus (EDL)
tendon showing markedly distended sheath
with synovial effusion, synovial hypertrophy
and crystal aggregates (arrows)
Dual-Energy CT (DECT):
• New imaging technique that allows the differentiation of deposits based on their
different X-ray spectra.
• It is superior to all other available imaging technologies in its ability to identify all
urate deposition in the area imaged DECT can offer a quick, non-invasive method
to visualize MSU crystals, soft tissue changes, and early erosions at high-resolution.
• DECT is not widely available, which limits its application for clinical and research
purposes. Its costs are equivalent or higher than CCT and it entails radiation
exposure.
 DECT of a gouty patient showing two views of
MSU deposits (in red) in the tibialis posterior
tendon
2015 ACR- EULAR
classification criteria
Treatment
1. Management of flares:

Gout flare medications include colchicine, Non-Steroidal anti-

inflammatory Drugs (NSAIDs) and steroids, which can be taken
together in severe cases and are most efficient when taken early
after the flare onset
Colchicine:
• Better taken within 12 h after flare onset
• 1.8 mg (1.2 mg then 0.6 mg one hour later)
• Has a narrow therapeutic toxicity window and can be very toxic when used
inappropriately. Gastrointestinal intolerance (diarrhea, nausea, or vomiting) is
usually the first feature of colchicine toxicity Further toxicity includes neutropenia
and multi-organ failure, which can be lethal.
• The maximum daily dose has been recently reduced to 2 mg (in divided doses)
• In pts with CKD : Doses should be limited to 0.5–0.6 mg/d in patients with
moderate renal insufficiency (eGFR from 30 to 60 mL/min) and to 0.5–0.6 mg
every 2 or 3 days in those with eGFR from 15 to 30 mL/min. Colchicine is contra-
indicated in CKD stage 5 patients (eGFR < 15 mL/min or dialysis).
• In pts with hepatic failure:Doses should also be reduced, as the drug is
predominantly eliminated through the hepato-biliary system.
NSAIDS
• NSAIDs or COXIBs are used at the maximum authorized
dose, with proton inhibitors when indicated.
Steroids
• Oral prednisone, at a daily dose of 30 mg/d for 7 days
• Best indicated in patients contra indicated for NSAIDs or
colchicine (i.e. CKD patients). Co-prescription of a small
dose (0.5–1 mg/d) of colchicine, when not
contraindicated, may avoid rare inflammation relapses
after steroid cessation
• Intra-articular steroid injections appear as very efficient in
the management of mono or pauci-articular flares.
IL-1 antagonist:

• IL-1 receptor antagonist anakinra used in

patients resistant or contraindicated to NSAIDs,
colchicine and steroids.
• Current infection is a contraindication
2. Management of chronic gout and prevention of flares
Patient education
• Patient education is key to gout management success.
• Information should be given on the pathophysiology
of the disease, its relationship with uricemia, its
curable nature, uricemic targets to be reached, the
life-long nature of urate-lowering treatment, the
importance to treat flares early, the mechanisms of
ULD-induced flares and ways to prevent them.
Patient education takes time and must frequently be
repeated, but it is a mandatory tool to achieve success
in long-term gout management.
Life style modification :
• weight loss in obese patients
• avoidance of beer (including non-alcoholic), spirit,
and sugar sodas.
• restriction of meat and seafood intake; and increased
intake of skimmed-milk products,
• enhanced physical activity .
• Diet modification appears to be less effective than
ULD to control hyperuricemia. However, combining
both is very successful in management of chronic
gout.
Cessation of hyperuricemic drugs:
• Attempts should be made to stop drugs that increase
uricemia. This is mainly the case with antihypertensive
drugs. Thiazide and loop diuretics increase uricemia by
an average of 0.65 and 0.96 mg/dL respectively .
• Beta-blockers, non-losartan ARBs and ACE inhibitors
have also been associated with an increased risk of gout
and increased uricemia.
• Calcium channel inhibitors and losartan should be
privileged.
• In cardiac failure, spironolactone, which has no effect on
uric acid can be advised when possible
Urate lowering drugs (ULDs):
• The initiation of ULDs is associated with an
increased risk of gout flares due to crystal
mobilization: when they start to dissolve, deposits
become more fragile and crystals can shed into
the joint space and trigger inflammation. This
should be explained to the patient and the risk
should be reduced by progressive titration of
ULDs and prescription of low dose (0.5–1 mg/d)
of colchicine or NSAID as a prophylaxis against
ULD-induced gout flares in patients with no
contraindications to these drugs.
Allopurinol:
• oral xanthine oxidase inhibitor
• The maximal approved daily dose of allopurinol is
800 or 900 mg/d
• It is important to start allopurinol at a low dose (50-
100 mg/d) to be progressively increased every 2–4
weeks until the targeted uricemia is obtained, as
recommended by the EULAR
• Excretion of oxypurinol is mainly through the
kidney and is decreased by renal failure and
increased by uricosurics.
Febuxostat:
• Febuxostat is an oral, once a day, non-purine
xanthine oxidase inhibitor, which is available as 40
and 80 mg tablets in the USA and 80 and 120 mg
tablets in Europe.
• At the doses of 80 and 120 mg/d, the maximum
doses approved in the USA and Europe respectively,
febuxostat is a more potent ULD than allopurinol 300
mg/d.
• Because of its mixed renal and hepatic metabolism,
the drug can be prescribed with no dose reduction in
patients with moderate renal failure.
Uricosurics:
• Uricosurics lower uricemia by increasing uric acid
output in the urine. Therefore they expose the patients to
the risk of uric acid stone, which is worse at the onset of
treatment.
• They should not be administered as a monotherapy in
patients with a history of uric acid stone or hyperuricuria
and should be taken with abundant water intake.
• They are now most often used in combination with
xanthine oxidase inhibitors, when these fail to obtain the
uricemia targets.
• Probenecid , Sulfinpyrazone, Benzbromarone
Urate oxidases
• Pegloticase is a PEGylated uricase which has been approved, in the
USA and Europe, for the management of severe gout, refractory to
oral ULDs.
• The drug is administered by IV infusions of 8 mg every 2 weeks and
has been shown to be very effective .
• Antibodies develop at high titers in about half of the patients, leading
to loss of uricemia response and to an increased risk of serious
infusion reactions.
• It is therefore recommended to measure uricemia in the 24 h
preceding every planned reinfusion and to stop the drug if uricemia is
not decreased.
• No other ULD should be prescribed concomitantly to keep this
warning signal
 2020 ACR guidelines for
management
• The 2012 American College of Rheumatology ACR)
Guidelines for the Management of Gout recommend treat-to-
target strategies with use of urate-lowering therapy (ULT).
• Despite these recommendations, over the past 2 decades there
has been no increase in ULT utilization. Adherence to ULT
remains poor.
• The prior 2012 ACR Guidelines for the Management of Gout
have been criticized due to low quality of evidence
supporting.
• Since the 2012 ACR Guidelines for the Management of Gout
were published, several clinical trials have been conducted
that provide additional evidence regarding the management of
gout, leading the ACR Guidelines Subcommittee to determine
Recommendations :
Forty-two recommendations (including 16 strong
recommendations) were generated.
Indications for ULT:
• Initiating ULT is strongly recommended for gout
patients with any of the following: ≥1 subcutaneous
tophi; evidence of radiographic damage (any
modality) attributable to gout; OR frequent gout
flares, with frequent being defined as ≥2 annually.
• Initiating ULT is conditionally recommended for
patients who have previously experienced >1 flare
but have infrequent flares (<2/year)
• Initiating ULT is conditionally recommended
for patients with comorbid moderate-to severe
CKD (stage ≥3), SU concentration >9 mg/dl, or
urolithiasis.
• Initiating ULT is conditionally recommended
against in patients with gout experiencing their
first gout flare.
• Initiating ULT is conditionally recommended
against in patients with asymptomatic
hyperuricemia.
Recommendations for choice of initial ULT
for
patients with gout :
• Treatment with allopurinol as the preferred first-
line agent, over all other ULTs, is strongly
recommended for all patients, including those
with moderate-to-severeCKD (stage ≥3).
• The choice of either allopurinol or febuxostat
over probenecid is strongly recommended for
patients with moderate-to-severeCKD (stage
≥3).
• The choice of pegloticase as a first-line therapy
is strongly recommended against.
• Starting treatment with low-dose allopurinol
(≤100 mg/day and lower in patients with CKD
[stage ≥3]) and febuxostat (≤40 mg/day) with
subsequent dose titration over starting at a
higher dose is strongly recommended.
• Starting treatment with low-dose probenecid
( 500 mg once to twice daily) with subsequent
dose titration over starting at a higher dose is
conditionally recommended.
• Administering concomitant anti-inflammatory
prophylaxis therapy (e.g., colchicine,
nonsteroidal antiinflammatory drugs [NSAIDs],
prednisone/ prednisolone) over no anti-
infLammatory prophylaxis therapy is strongly
recommended.
• Continuing concomitant anti-inflammatory
prophylaxis therapy for 3–6 months over
<3months, with ongoing evaluation and
continued prophylaxis as needed if the patient
continues to experience gout flares, is strongly
recommended
Timing of ULT initiation
• When the decision is made that ULT is indicated while
the patient is experiencing a gout flare,starting ULT
during the gout flare over starting ULT after the gout
flare has resolved is conditionally recommended.
• A treat-to-target management strategy that includes
ULT dose titration and subsequent dosing guided by
serial SU measurements to achieve a target SU, over a
fixed-dose ULT strategy, is strongly recommended for
all patients receiving ULT.
• Achieving and maintaining an SU target of <6mg/dl
over the use of no target is strongly recommended for
all patients receiving ULT.
• Delivery of an augmented protocol of ULT dose
management by non physician providers to
optimize the treat-to-target strategy that includes
patient education, shared decision-making, and
treat-to-target protocol is conditionally
recommended for all patients receiving ULT.
Duration of ULT
• Continuing ULT indefinitely over stopping ULT
is conditionally recommended
Recommendations for patients receiving ULTmedications:
Allopurinol
• Testing for the HLA–B*5801 allele prior to starting allopurinol
is conditionally recommended for patients of Southeast Asian
descent (e.g.Han Chinese, Korean, Thai) and for African
American patients, over not testing for the HLA–B*5801
allele.
• Universal testing for the HLA–B*5801 allele prior to starting
allopurinol is conditionally recommended against in patients
of other ethnic or racial background over testing for the HLA–
B*5801 allele.
• As noted above, starting allopurinol in daily doses of ≤100 mg
(and lower doses in patients with CKD) is strongly
recommended over starting at a higher dose.
• Allopurinol desensitization is conditionally
recommended for patients with a prior allergic
response to allopurinol who cannot be treated
with other oral ULT agents.
Febuxostat
• Switching to an alternative oral ULT agent, if
available and consistent with other
recommendations in this guideline, is
conditionally recommended for patients taking
febuxostat with a history of CVD or a new
CVD-related event.
Uricosurics
• Checking urinary uric acid is conditionally recommend against
for patients considered for or receiving uricosuric treatment.
• Alkalinizing the urine is conditionally recommended against for
patients receiving uricosuric treatment
When to consider changing ULT strategy
• Switching to a second XOI over adding a uricosuric agent is
conditionally recommended for patients taking their first XOI,
who have persistently high SU concentrations (>6 mg/dl) despite
maximum-tolerated or FDA-indicated XOI dose, and who have
continued frequent gout flares (>2 flares/year) OR who have non
resolving subcutaneous tophi.
• Switching to pegloticase over continuing current
ULT is strongly recommended for patients with gout
for whom XOI treatment, uricosurics,and other
interventions have failed to achieve the SU target,
and who continue to have frequent gout
flares(≥2flares/year) OR who have nonresolving
subcutaneous tophi.
• Switching to pegloticase over continuing current
ULT is strongly recommended against for patients
with gout for whom XOI treatment, uricosurics, and
other interventions have failed to achieve the SU
target, but who have infrequent gout flares (<2
flares/year) AND no tophi.
Gout flare management
• Using colchicine, NSAIDs, or glucocorticoids
(oral,intraarticular, or intramuscular) as
appropriate first-line therapy for gout flares over
IL-1 inhibitors or adrenocorticotropic hormone
(ACTH) is strongly recommended for patients
experiencing a gout flare.
• Given similar efficacy and a lower risk of
adverse effects, low-dose colchicine over high-
dose colchicine is strongly recommended when
colchicine is the chosen agent.
• Using topical ice as an adjuvant treatment over
no adjuvant treatment is conditionally
recommended for patients experiencing a gout
flare.
• Using an IL-1 inhibitor over no therapy (beyond
supportive /analgesic treatment) is conditionally
recommended for patients experiencing a gout
flare for whom the above anti inflammatory
therapies are either ineffective, poorly tolerated,
or contraindicated.
• Treatment with glucocorticoids (intramuscular,
intravenous, or intraarticular) over IL-1
inhibitors or ACTH is strongly recommended
for patients who are unable to take oral
medications.
Management of lifestyle factors
• Limiting alcohol intake is conditionally recommended for patients with
gout, regardless of disease activity.
• Limiting purine intake is conditionally recommended for patients with
gout, regardless of disease activity.
• Limiting high-fructose corn syrup intake is conditionally recommended for
patients with gout, regardless of disease activity.
• Using a weight loss program is conditionally recommended for those
patients with gout who are overweight/ obese, regardless of disease activity.
• Adding vitamin C supplementation is conditionally recommended against
for patients with gout, regardless of disease activity.
Management of concurrent medications
• Switching hydrochlorothiazide to an alternate antihypertensive
when feasible is conditionally recommended for patients with
gout, regardless of disease activity.
• Choosing losartan preferentially as an antihypertensive agent
when feasible is conditionally recommended for patients with
gout, regardless of disease activity.
• Stopping low-dose aspirin (for patients taking this medication
for appropriate indications) is conditionally recommended
against for patients with gout, regardless of disease activity.