JOMO KENYATTA UNIVERSITY OF

AGRICULTURE AND TECHNOLOGY

B.Sc. CLINICAL MEDICINE 4.1

ICM: 240

ORTHOPAEDICS AND
TRAUMATOLOGY 3

GROUP 3
GROUP MEMBERS

 MAURINE NJOROGE – HSM 211-0543/2021

 ABDIRIZAK MOHAMED – HSM211-0353/2021
 JOSEPH GICHUHI – HSM211-0066/2021
 FLORENCE ABALA – HSM2110103/2021
 PRUDENCE WANJIRU – HSM211-0480/2021
 NKALOS WELSH –HSM211- 0131/2020
 ALEX KARIUKI – HSM211-0059/2021
 EPHRAIM KARIUKI – HSM211- 0190/2020
 DAVE GITUMA – HSM11-0451/2020
 IBRAE ADANO – HSM211-0491/2020
GOUT
Introduction GOUT
Gout, once known as the "disease of kings and king of diseases," is among the most prevalent
etiologies of chronic inflammatory arthritis in the United States, characterized by monosodium
urate (MSU) monohydrate crystals deposition within tissues. Hippocrates first described gout in
ancient Greece; hence, it is the most understood and manageable disease among all rheumatic
diseases.

Gout is characterized biochemically by extracellular fluid urate saturation, which is reflected by

hyperuricemia in the blood, with plasma or serum urate concentrations exceeding 6.8 mg/dL
(approximately 400 µmol/L); this level is the approximate limit of urate solubility. The clinical
manifestations of gout may include:

• Acute gout flare (recurrent flares of inflammatory arthritis)

• Chronic gouty arthropathy
• Accumulation of urate crystals in the form of tophaceous deposits
• Uric acid nephrolithiasis
• Chronic nephropathy

Risk Factors of Hyperuricemia and Gout

Modifiable risk factors Nonmodifiable risk factors
Hypertension Age
Obesity Genetic variants
Hyperlipidemia Gender
Diabetes mellitus Ethnicity
Cardiovascular disease

Alcohol

Medications altering urate balance

Chronic kidney disease

Dietary factors
Cause of Gout

Gout happens when urate, a substance in your body, builds up and forms needle-shaped crystals
in your joints. This leads to pain, swelling, redness, and changes in the movement and use of the
affected joint. However, not everyone with high urate levels develops gout.
Urate comes from purines, which are found in your body’s tissues and many foods. When
purines break down, they become urate. Normally, urate passes out of your body in urine.
However, when too much is made or too little is removed, urate builds up in your blood and
needle-shaped crystals form in your joints, causing inflammation that is experienced as gout
flares that cause pain and swelling.

Researchers continue to study how genes and environmental factors contribute to a buildup of
urate in your blood. However, certain factors may increase your chances of developing gout,
including:

• Having high urate levels.

• Having a family history of gout.

• Being male.

• Having menopause.

• Increasing age.

• Drinking alcohol.

• Drinking sugar-sweetened beverages, such as soda.

• Having an unhealthy diet and eating foods that are rich in purines (usually from animal
sources), a substance that breaks down into urate.

Some health conditions may increase your risk of developing gout, such as:

• Overweight or obesity.

• Metabolic syndrome, a name for a group of conditions that include high blood pressure,
high blood sugar, abnormal cholesterol levels, and excess body fat around the waist.

• Chronic kidney disease, a condition that develops when your kidneys are damaged and
cannot filter blood the way they should.

• High blood pressure.

• Conditions that cause your cells to turn over rapidly, such as psoriasis or some cancers.

• Rare genetic conditions (Kelley-Seegmiller syndrome or Lesch-Nyhan syndrome) that

lead to increased urate.
Some medications can increase your risk of developing gout, such as:

• Diuretics, which help your body eliminate excess fluid.

• Low-dose aspirin.

• Niacin, a vitamin, when taken in large amounts.

• Cyclosporine, which is an immunosuppressant for people who have organ transplants and
is approved to treat some autoimmune diseases.

Gout is of two types: primary and secondary.

• In primary gout an inborn enzymatic defect leads to hyperuricaemia.

• Secondary gout refers to a state where some other primary disorder leads to the increase
of uric acid leve

Over 90% of the hyperuricaemia patients are males; women suffering from this disorder are
usually post- menopausal.

Primary Gout

Any disorder in which purine (de novo) synthesis is increased, causes enhanced production of
purine nucleotides. Since purine nucleotides cannot be stored in human body, increased
production is regulated by increased degradation. This results in enhanced uric acid production.

Some of the enzymatic defects leading to increased purine synthesis are as below:

Increased activity of PRPP synthetase: Some variants of this enzyme have altered kinetic
properties, such as increased Vmax or low Km for ribose 5-phosphate, or resistance to feedback
inhibition. These properties permit this enzyme to bring about increased transformation of ribose
phosphate to PRPP, leading to enhanced purine biosynthesis.

Note: The PRPP synthetase overactivity is inherited as an X-linked trait.

Glucose 6-phosphatase deficiency: The condition is called von Gierke’s disease. Deficiency of
this enzyme leads to intracellular accumulation of glucose 6-phosphate that forms pentose
(ribose) phosphate through the stage II of hexose monophosphate pathway. Increased
intracellular concentration of ribose phosphate leads to increased rate of purine synthesis.
Deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT): It is a purine salvage
enzyme; its defIciency is inherited as an X-linked trait causing Lesch-Nyhan syndrome. It is
associated with increased purine synthesis by a 3-fold mechanism.

• Firstly, recycling of the substrate bases (hypoxanthine and guanine) is impaired, they are
metabolized to uric acid.

• Secondly,accumulationofthePRPP,theothersubstrate for HGPRT, occurs, which is channeled

into the de novo purine biosynthetic pathway. The pathway is stimulated because of
feedforward activation effect of PRPP.

• Finally, the defect in the salvage pathway leads to decreased levels of AMP and GMP, which
decreases the feedback inhibition of the rate-limiting enzyme, PRPP amidotransferase (Fig.
20.11). This further speeds up purine biosynthesis.

Most cases of primary gout, however, fall into a less defined category in which the specific
defect and the mode of inheritance is not known.

Secondary Gout

It refers to a state where hyperuricaemia is consequence of some other primary disorder as noted
earlier. Haematologic maliganancies such as leukaemia and multiple myeloma lead to increased
cell turnover, which is accompanied by increased degradation of excess nucleic acids to uric
acid. Chronic renal failure is associated with an impaired excretion of uric acid with consequent
retention of abnormally large amounts of this com- pound. Various drugs, particularly diuretics
and alcohol also minimize the excretion of uric acid in urine, thus leading to hyperuricaemia
(Case 20.1). Urinary excretion of uric acid falls in starvation as well.

Uric Acid Pool in Gout

The miscible uric acid pool has been estimated to be around 1200mg in normal subjects. It is
increased to 3000mg or more in patients suffering from gout. Uric acid may exist in the
dissociated form (i.e. ionized form called urate) or the undissociated form (called uric acid). At
pH of 5.75, only about half of the total molecules are in urate form (since pK’ of the most acidic
group of uric acid is 5.75). At body pH of 7.4, almost all molecules are in the urate form because
the body pH exceeds the pK’ value. Therefore, in all body fluids and blood, the urate
predominates while uric acid accounts for a small proportion. In urine, where pH may fall below

5.75, the predominant form is uric acid. The solubility of these two forms differs vastly: uric acid
is about 13 times less soluble than urate. Solubility of the sodium salt of the latter is still lower.

Solubility of uric acid 15 mg/dL Solubility of urate 150–200 mg/dL Solubility of sodium urate 7
mg/dL
Low Solubility: The Offending Factor in Gout

The low solubility and consequent precipitation of uric acid crystals is the cause of gouty
arthritis and uric acid nephropathy. When concentration of serum urate is increased, its sodium
salt (sodium urate) readily forms in the body. Its precipitation is a constant risk since lim- its of
solubility (7 mg/dL) are exceeded with even moder- ate rise of serum urate level (normal serum
urate is 3–7mg/dL). Focal deposits of these precipitates, called tophi, are asymptomatic initially,
but may lead to arthri- tis or nephropathy.

Gauty arthritis: Accumulation of trophi in joints triggers the inflammatory response of gouty
arthritis by the

following mechanism: the crystals are first ingested by leukocytes. These cells subsequently
rupture, releasing the lysosomal enzymes that degrade articular tissue and induce the
inflammatory response.

The crystals can be deposited in subcutaneous tissues also, most commonly in the external ear,
over the knees and elbows, and along the tendons. However, a sustained hyperuricaemia for
several years is required to bring about such deposition of tophi.

Nephropathy: Sodium urate or uric acid may precipitate in kidneys and ureters also to cause
renal damage, termed uric acid nephropathy. As noted, formation of uric acid from urate is
favoured as the pH falls. Therefore, with acidification of urine in renal tubules uric acid is gener-
ated. Being of limited solubility, it tends to crystallize as urinary stones. Sharp abdominal pain,
obstruction to urine flow and damage to organ are the consequences.

INVESTIGATIONS Synovial Fluid Analysis

Monosodium urate crystal identification remains the gold standard for diagnosing gout.[80] Gout
flares are marked by MSU crystals in synovial fluid obtained from affected joints of bursas,
visualized through direct examination of a fluid sample using compensated polarized light
microscopy. The crystals are often intracellular, indicating active phagocytosis. This technique
can also identify uric acid crystals from tophaceous deposits and joints during the intercritical
period.During a gout flare-up, synovial fluid is usually yellow and cloudy, containing crystals
and white blood cells (WBCs) with neutrophil predominance.

In patients with septic arthritis, the synovial fluid will be more opaque, with a yellow-green
appearance. Microscopic examination reveals a higher WBC count (>50000/microL) with a
predominance of neutrophils. However, there is considerable overlap in WBC counts and
neutrophil percentages between patients with acute gouty arthritis and septic arthritis, making
these parameters unreliable for diagnosis. Positive synovial fluid gram stains and cultures, along
with low synovial fluid glucose levels, are common findings in septic arthritis. It is essential to
note that the presence of crystals in synovial fluid analysis does not rule out septic arthritis, as
both conditions can coexist.

Under polarizing microscopy, synovial fluid or tophus aspiration analysis reveals needle-
shaped, negatively birefringent crystals. Arthrocentesis is essential to confirm the diagnosis and
differentiate it from other conditions such as septic arthritis, Lyme disease, or pseudogout
(caused by calcium pyrophosphate crystals).

Laboratory Study

The examination usually reveals elevations in the WBC, erythrocyte sedimentation rate (ESR),
and C-reactive protein (CRP) during acute gouty arthritis. These features are nonspecific and do
not confirm or differentiate the diagnosis from septic arthritis.

During acute gouty arthritis, the serum urate level may be high, normal, or low. About 50% of
patients with acute gouty arthritis will not have an elevated serum uric acid. Serum uric acid
measurement during an acute attack is of no diagnostic value; it is most useful when checked
after the resolution of the flare. Hyperuricemia is helpful in the clinical diagnosis of gout in
symptomatic patients, but hyperuricemia alone does not confirm the diagnosis. Asymptomatic
hyperuricemia is not uncommon in the general population. Persistently low serum uric acid
concentrations make the diagnosis of gout unlikely. In patients suspected of gout based on
clinical features, an elevated serum uric acid level (>6.8 mg/dL) can support the diagnosis but is
neither diagnostic nor required to establish the diagnosis. The most accurate time to assess serum
urate level to establish a baseline value is 2 weeks or more after a gout flare has subsided.

Urinary fractional excretion of uric acid can be measured, especially in young populations with
nonspecific causes of hyperuricemia. The measurement can help differentiate between
overproduction or underexcretion of uric acid and can guide therapy.

Imaging

Although not routinely used, ultrasonography and dual-energy CT (DECT) can assist in
diagnosing gout. On ultrasound, MSU deposition appears as a hyperechoic enhancement over the
cartilage, known as the double contour sign. DECT can identify urate deposits based on the
beam attenuation after exposure to 2 different X-ray spectra. In a pooled analysis, the ultrasound
double contour sign had a sensitivity of 83% and a specificity of 76%, while DECT had a
sensitivity of 87% and a specificity of 84% for diagnosing gout. A meta-analysis of ultrasound's
diagnostic accuracy, which included features like the double contour sign, tophus, or bony
erosion, showed a sensitivity of 65.1% and specificity of 89% for a diagnosis of gout.

Treatment / Management
Specific goals guide the treatment of gout. During acute flares, the primary objective is to
alleviate inflammation and symptoms. In the long term, the goal shifts toward reducing serum
urate levels to suppress flare-ups and regression of tophi.
General Principles of Therapy

• Early on, introducing treatment for a gout flare leads to a more rapid resolution of
symptoms.
• The duration of gout flare therapy ranges from a few days to several weeks, depending on
the timing of treatment initiation.
• Anti-inflammatory gout flare prophylaxis should generally be continued during the early
months (up to 6 months) of ULT.
• For patients receiving ULT at the time of gout flare, the urate-lowering medication
should be continued without interruption as there is no benefit to temporary
discontinuation.
• The presence of tophi indicates initiating long-term ULT either during or following the
resolution of a gout flare to reverse or prevent joint damage and chronic gouty arthritis.
Acute Gout Flare

The management of acute flares of gouty arthritis aims to decrease inflammation and resulting
pain. Treatment should commence within the first 24 hours of onset to reduce the severity and
duration of the flare-up if possible.Nonpharmacological management, such as rest with topical
application of ice packs can be combined with medications that reduce inflammation. First-line
treatments for gout flares are nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or
systemic glucocorticoids. The length of treatment should be at least 7 to 10 days to prevent
rebound flare-ups. Early initiation of NSAIDs may lead to the resolution of the attack with a
single dose.

NSAIDs

NSAIDs are most effective when therapy is initiated within 48 hours of the onset of gout
symptoms. Indomethacin and naproxen are the more potent NSAIDs for gout, although many
other commonly used NSAIDs exist. NSAID names and dosing are as follows:

• Indomethacin 50 mg 3 times daily

• Naproxen 500 mg twice daily
• Naproxen 500 mg twice daily
• Ibuprofen 800 mg 3 times daily
• Diclofenac 50 mg 2 to 3 times daily
• Celecoxib 200 mg twice daily
Typically, NSAID treatment for gout flare lasts for 5 to 7 days. There is no significant preference
for one NSAID over another, but high-dose, fast-acting NSAIDs such as naproxen or diclofenac
are options. Indomethacin is not preferable due to its toxicity profile. NSAIDs are usually given
in full doses for the first 3 days and then tapered according to the clinical improvement. COX2
selective inhibitors like celecoxib can be used to reduce adverse GI effects.

Contraindications for the use of NSAIDs include active duodenal or gastric ulcer, cardiovascular
disease (uncontrolled HTN or CHF), NSAID allergy, and CKD with creatinine clearance (CrCl)
of less than 60 ml/minute per 1.73 square meters. Aspirin is not recommended for treating gout
flares due to the paradoxical effects of salicylic acid on serum urate levels.This paradoxical
effect results from uricosuria at higher doses and renal uric acid retention at lower doses (less
than 2 to 3 g/day).

Oral Glucocorticoids

Glucocorticoids are recommended for gout patients with contraindications to NSAIDs and
colchicine, and they are also preferred for patients with renal insufficiency. The initial dose for a
gout flare is:

• Prednisolone or prednisone 30 to 40 mg once daily or divided into twice-daily doses until

resolution begins. Taper the dose over the next 5 to 10 days.
This has been proven to be at least comparable to NSAID efficacy. High starting doses of
systemic steroids (>0.5 mg/kg body weight) are required for acute gout, especially in patients
with a polyarticular presentation. A depot preparation for triamcinolone (60mg once) or
methylprednisolone has been reported to be effective. However, the dose may need to be
repeated at intervals of 48 hours to achieve resolution of the flare. Glucocorticoids can be
administered intra-articularly for a monoarticular gout flare-up or orally for polyarticular
flareups. The efficacy of glucocorticoids is similar to or superior to other agents and has no
greater risk of adverse effects in most patients.

In patients with an unclear diagnosis of an acute gout flare, arthrocentesis and synovial fluid
analysis should be performed, and oral and intra-articular glucocorticoids should be avoided
until the results are available. Initiation of other agents, such as NSAIDs or colchicine, should be
considered. Frequent adverse effects of moderate- to high-dose, short-term glucocorticoid use
include hyperglycemia, fluid retention, increased blood pressure, and mood changes. Repeated
and regular courses of glucocorticoids should be avoided to limit adverse effects.

In patients with concomitant or suspected infections, uncontrolled diabetes mellitus, prior

glucocorticoid intolerance, and post-operative status, glucocorticoids may heighten the risk of
impaired wound healing. Careful consideration of these factors is crucial when determining the
appropriate course of treatment for patients with gout flares.

Parenteral Glucocorticoids

Intravenous or intramuscular glucocorticoids are suggested for patients who are not candidates
for intraarticular glucocorticoid injection or cannot take oral medications. A typical
methylprednisolone dose is 20 mg intravenously twice daily, with a stepwise reduction and rapid
transition to oral prednisone when improvement begins. Adrenocorticotropic hormone (ACTH)
is also efficacious for treating gout flare, but limited availability and high cost restrict its use.
Colchicine

Colchicine, derived from the Colchicum autumnale plant and with a history spanning over 3500
years, has proven comparable in efficacy to other agents when taken within 24 hours of gout
flare onset. In a randomized control trial, colchicine reduced pain by over 50% at 24 hours
compared to a placebo. The lipophilic nature of colchicine makes it readily bioavailable for
cellular uptake after oral administration. The primary target of colchicine is tubulin, and it is
metabolized through hepatic elimination.

Colchicine acts by binding tightly to unpolymerised tubulin and forms a colchicine-tubulin

complex that regulates microtubule and cytoskeletal function. This regulation extends to diverse
cellular processes, including cell proliferation, gene expression, signal transduction, chemotaxis,
and neutrophil secretion of granule contents. Furthermore, colchicine decreases neutrophil
adhesion by suppressing E-selectin redistribution in the endothelial membrane.

EULAR consensus guidelines recommend a maximum of 3 doses of 0.5mg of colchicine daily

for treating acute gout. The total colchicine dose should not exceed 1.8 mg on day 1, 1.2 mg for
the first dose followed by 0.6 mg an hour later [US Food and Drug Administration (FDA)
approved dose] or 0.6 mg 3 times on the first day. On subsequent days, colchicine should be
taken once or twice daily until the gout flare resolves.

A reduced dose of colchicine may be required for patients with diminished hepatic or renal
function or those at risk of potential drug interactions. Colchicine toxicity can occur with
ABCB1 inhibitors like cyclosporin and clarithromycin; neuromyopathy may develop weeks after
initiating cyclosporin. High-dose colchicine regimens should be avoided due to their high
toxicity. Adverse effects of colchicine include gastrointestinal (GI) symptoms like nausea and
diarrhea, myotoxicity, and myelosuppression (leukopenia, thrombocytopenia, and aplastic
anemia).The most common adverse effects are abdominal cramping and diarrhea. Intravenous
colchicine is strongly discouraged due to serious adverse effects, including death, and it is no
longer approved by the FDA in the US.

Colchicine dosing adjustments for certain high-risk groups of patients should follow the
guidelines outlined in the manufacturer's FDA-approved information. Typically, a maximum of
0.3 mg dose is administered on the day of a gout flare, and the dose is not repeated for at least 3
to 7 days or longer in such patients. The high-risk groups include:

• Individuals who have used colchicine prophylaxis in the last 14 days possess normal
hepatic and renal function and have taken a medication that inhibits P-glycoprotein or is a
potent inhibitor of CYP3A4 within the previous 14 days.
• Individuals who have used colchicine prophylaxis in the last 14 days, regardless of
hepatic and renal status, and have taken a medication that is a moderate CYP3A4
inhibitor within the same timeframe.
 • Individuals with advanced hepatic or renal impairment (Child-Pugh C cirrhosis or
equivalent CrCl of <30 mL/min), regardless of recent colchicine use.
Colchicine exhibits interesting effects beyond treating and preventing gouty arthritis flares.
Research suggests it has a beneficial effect on cardiovascular events. A population study linked
colchicine use in patients with gout to reduced cardiovascular events and all-cause mortality. In a
randomized, double-blind trial involving post-MI patients within 30 days (n = 4,745), low-dose
colchicine use lowered the risk of cardiovascular events (resuscitated cardiac arrest, MI, stroke,
and angina leading to revascularization) compared to placebo: 5.5% with colchicine versus 7.1%
with placebo; HR 0.77 (95% CI 0.61-0.96; P=0.02). While colchicine did not affect outcomes
like death from cardiovascular causes, resuscitated cardiac arrest, or MI, it notably reduced
stroke and angina, leading to coronary revascularization.

Prophylaxis For Acute Gout

The subclinical joint inflammation in gout justifies colchicine prophylaxis, as acute gout flares
are ULT's most common adverse effect. For prophylaxis, low-dose colchicine therapy is the
first choice. It is commenced 1 or 2 weeks before using urate-lowering drugs and continues for
up to 6 months after normalizing uric acid levels or until the clinically visible tophi are
resolved. Low-dose NSAIDs and low-dose corticosteroids can be used but carry more
toxicity.The recommended colchicine dosage is 0.6 mg once or twice daily without renal or
hepatobiliary compromise. In patients with renal impairment, the colchicine dose may be
reduced to 0.3 mg daily or 0.6 mg every other day.

Interleukin-1 Inhibition

IL-1 antagonists have shown efficacy in refractory cases of gouty arthritis. Anakinra, a
soluble IL1 receptor antagonist, is administered at 100 mg/day subcutaneously for 3 days or a
single dose of IL-1 beta monoclonal antibody, canakinumab. The subcutaneous dose of 150
mg canakinumab was more effective than a single-dose intramuscular (IM) dose of
triamcinolone acetonide, although the risk-benefit ratio is uncertain.

Urate lowering therapy (ULT) Non-pharmacologic treatment

Gout is associated with several comorbidities, including obesity. In a study examining the
association between obesity and gout, adults aged 40 to 75 years (n = 11,079) in NHANES
2007 to 2014 were categorized into 4 groups: stable obese, weight gain, weight loss, and those
maintaining a normal BMI over time (reference group). Among those with stable obesity, the
risk of gout was the highest, with an HR of 1.84 (95% CI 1.08-3.14). Patients who gained
weight as adults also exhibited an increased risk of gout with HR of 1.65 (95% CI 1.19-2.29).

Diet can affect serum uric acid levels. Weight loss and dietary adjustments can reduce serum uric
acid by 1 to 2 mg/dL. Foods high in purines, such as organ meats, shellfish, and beer, can elevate
uric acid levels. Soft drinks containing high-fructose corn syrup are associated with an increased
risk of gout; therefore, reducing their intake can help reduce serum uric acid. The DASH diet has
been proven to lower serum uric acid compared to a standard Western diet, making it beneficial
for gout management. Consuming at least 500 mg daily of vitamin C has also been shown to
decrease serum uric acid levels and lower the risk of incident gout. Studies have shown that
higher doses of vitamin C correspond to reduced risk of gout in men. Cherry consumption has
also been linked to lowered serum uric acid levels and a decreased risk of recurrent gout attacks.

Pharmacologic

The 2020 American College of Rheumatology Guideline for managing

gout advises against initiating ULT after the first episode of acute gouty arthritis. ULT should
not be initiated in patients with asymptomatic hyperuricemia. The guidelines provide specific
criteria for initiating ULT, including the following:

• Frequent or disabling gout flares (≥2 yearly) that are difficult to treat
• Gout with chronic kidney disease (stage 3 or higher)
• Tophus diagnosis on physical examination or imaging
• Past urolithiasis
• Chronic tophaceous gout
The decision to initiate ULT should be individualized. For instance, in a younger patient with
their first gout attack with elevated serum uric acid levels, the likelihood of future gout
attacks and progressive joint damage with tophi is higher, making it prudent to start ULT.
Conversely, in an elderly patient with gout, multiple comorbidities, and taking multiple
medications, the decision to treat may be more nuanced, and careful consideration should be
given in this scenario. It is essential to note that the guidelines are to provide guidance but not
dictate therapy.

ULT is started at a low dose to monitor the side effects and treatment response. Dose
adjustments are made every 2 to 6 weeks to achieve serum urate levels of less than 6 mg/dL or 5
mg/dL in patients with tophi. The 2020 American College of Rheumatology Guideline
conditionally recommends starting ULT during acute gout flares, with some evidence supporting
its safety with medications like allopurinol and febuxostat. However, initiating therapy during
an acute attack might pose challenges regarding patient compliance, especially considering that
patients experiencing acute flares are often hospitalized for the first time.

During the initiation of ULT, there is an increased risk of gout flare-ups. As a prophylactic
measure, colchicine is recommended for 3 months after achieving the serum urate goal in
patients without tophi or 6 months in those with tophi. This strategy helps to minimize the risk of
flare-ups during this critical period.

ULT can be categorized into 3 classes based on their mechanisms:

Xanthine oxidase inhibitors (XOI)

XOIs work by inhibiting uric acid synthesis. This class includes allopurinol and febuxostat.
Allopurinol is the recommended first-line pharmacologic ULT in gout. Physicians should
regularly monitor liver enzymes, renal function, and blood count. Adverse effects from
allopurinol can range from skin rashes to life-threatening severe allopurinol hypersensitivity,
especially in HLA-B*5801-positive patients.

Allopurinol

Allopurinol is converted to its active metabolite oxypurinol in the liver and has a half-life of 24
hours. The initial allopurinol dose is 100 mg daily in patients with CrCl more significant than 60
mL/min and is titrated upward by 100 mg every 2 to 4 weeks. A daily dose of 300 mg of
allopurinol reduces serum urate levels in 33% of the population. Allopurinol can be increased
above 300 mg daily to achieve the target serum uric acid.

Allopurinol is taken once daily. Medications like allopurinol and oxypurinol lower the serum
urate by a dual action of inhibiting xanthine oxidase inhibitor and by competing with
phosphoribosylpyrophosphate in the salvage pathway and through suppressive effects of drug
nucleotides on aminotransferase activity. Allopurinol also nonselectively inhibits pyrimidine
metabolism. In patients with stage 3 or greater CKD, the starting dose of allopurinol should be
50 mg daily.

Adverse effects associated with allopurinol include the potential to trigger gout flares, pruritic
and maculopapular rashes, leukopenia, thrombocytopenia, diarrhea, and severe cutaneous
adverse reactions. Bone marrow suppression is uncommon but may occur at very high doses or
in patients with CKD. Allopurinol can lead to a drug reaction with eosinophilia and systemic
symptoms (DRESS) syndrome, a life-threatening reaction to allopurinol.

Major hypersensitivity reactions like Steven-Johnson syndrome or toxic epidermal necrolysis

may occur in major allopurinol hypersensitivity syndrome (AHS). The highest risk for AHS
occurs in the first 60 days after initiating allopurinol therapy. Patients who carry the
HLAB*5801 allele are at increased risk for developing severe hypersensitivity reactions, which
are more common in people of Han Chinese, Korean, or Thai descent. Testing for this allele is
advisable in high-risk patients. Starting at a low dose and gradually increasing it can decrease the
risk of adverse reactions. The recommended starting dose is 1.5 mg per unit of estimated GFR.
Interestingly, allopurinol can be safely increased above 300 mg daily, even in patients with
CKD, to achieve the target serum uric acid.

Allopurinol can enhance the cytolytic and immunosuppressive effects of azathioprine and
6mercaptopurine (6-MP), as these drugs are partially metabolized by xanthine oxidase.
Therefore, allopurinol should be avoided in patients undergoing treatment with these agents.
Additionally, in patients on warfarin, their anticoagulation status must be carefully monitored
when allopurinol is prescribed.

Febuxostat

Febuxostat is a selective XOI that occupies the access channel to the molybdenum-pterin active
site of the enzyme. Renal elimination plays a minor role in febuxostat pharmacokinetics. FDA
approval for febuxostat in treating patients with gout and hyperuricemia includes initial daily
doses of 40 mg. If the urate levels do not normalize within 2 weeks, the dosage is increased to 80
mg daily. Studies have demonstrated the superior effectiveness of febuxostat over allopurinol
(maximum dose of 300 mg daily).However, febuxostat may be more common with allopurinol
than cardiovascular and hepatic abnormalities. In patients with CKD, febuxostat exhibits a more
potent urate-lowering than allopurinol. Febuxostat has a distinct chemical structure, making it an
option for patients who have experienced hypersensitivity reactions to allopurinol. Patients
taking azathioprine, 6-MP, and theophylline are considered contraindications for the use of
febuxostat.

In the CARES trial, which focused on cardiovascular safety in patients with gout and a history of
cardiovascular disease, febuxostat and allopurinol were compared.The primary endpoint, a
composite of cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina requiring
revascularization, showed no significant difference between the 2 drugs. However, febuxostat
was associated with an increased risk of cardiovascular death (HR of 1.34, 95% CI 1.03-1.73,
P=0.03) and higher all-cause mortality (HR of 1.22, 95% CI 1.01-1.47, P=0.04). Some
population studies have also shown an increased risk of cardiovascular events and death.
However, some studies do not show an increased risk of cardiovascular events, including a
randomized, open-label noninferiority study, 2 population studies, and a systematic review. In a
follow-up investigation of the CARES trial, patients who discontinued ULT experienced
increased cardiovascular events and deaths at 30 days and 6 months.

Allopurinol and febuxostat are similarly effective, although some data suggest that febuxostat
may be more effective in patients with CKD. In a comparative noninferiority trial of allopurinol
and febuxostat, where at least 33% of patients had stage 3 CKD, both drugs showed similar
efficacy in managing flares and reducing serum uric acid levels to the target range.

XOIs have demonstrated various effects, particularly in population studies focusing on

cardiovascular disease. The theory is that chronic hyperuricemia and MSU deposition result in
chronic inflammation, thereby enhancing the progression of atherosclerosis. Notably,
allopurinol has been associated with a modest reduction in all-cause mortality among patients
with gout. A case-matched cohort study conducted in Taiwan revealed that patients with gout
faced an increased risk of cardiovascular and all-cause mortality. However, ULT treatment was
linked to a reduced risk of cardiovascular (HR 0.29, 95% CI 0.11-0.80) and all-cause mortality
(HR 0.47, 95% CI 0.29-0.79). Allopurinol use was correlated with a lower risk of developing
incident atrial fibrillation.

ULT may also slow the progression of CKD,and allopurinol is associated with a lower risk of
incident renal disease in elderly patients compared to febuxostat.Literature suggests that ULT in
gout patients might affect outcomes, including dementia, erectile dysfunction, and other
comorbidities. While some controlled trials have explored the effect of allopurinol on the
incident rate of cardiovascular events, renal disease, and DM, these studies were performed in
atrisk patients, not specifically in those with gout. Therefore, the relevance of these findings to
patients with gout remains unclear.

Uricosuric Drugs

The uricosuric agents work by increasing renal urate clearance.Patients with low or normal
urinary uric acid excretion in the presence of hyperuricemia are potential candidates for
uricosuric therapy. Drugs in this class include probenecid and lesinurad (withdrawn from the US
market). These agents inhibit URAT1 at the apical membrane of the renal proximal tubule
epithelial cell. However, they are ineffective as monotherapy in patients with low creatinine
clearance (<30 ml/min) and contraindicated in patients with a history of nephrolithiasis.

Probenecid, the only agent approved as a monotherapy, is initiated at 250 mg twice daily.
Dose adjustments are made according to the serum urate concentration level, with increments
every few weeks. The usual maintenance dose ranges from 500 to 1000 mg (taken 2 to 3 times
daily), aiming to achieve target urate levels of less than 6 mg/dL (<357 µmol/L).

The significant side effects of uricosuric drugs are the precipitation of a gout flare, uric acid
urolithiasis, gastrointestinal intolerance, and rash. Uricosuric agents are not appropriate for
patients with CKD and a creatinine clearance of less than 60 mL/min. Patients with tophi are best
treated with XOIs or pegloticase.

Uricase Pegloticase (urate oxidase)

Uricase is present in nonprimates and lower primates. Pegloticase, a pegylated recombinant form
of uricase, is a potent agent that rapidly reduces serum urate levels by directly degrading uric
acid into highly soluble allantoin. Polyethylene glycol (PEG) molecules are attached to the
recombinant porcine-baboon uricase in a process known as PEGylation.This process extends the
PEG molecule's half-life to days or weeks and decreases but does not eliminate immunogenicity.

Pegloticase is reserved for patients with refractory gout, usually those with a high tophaceous
burden. Patients must discontinue ULT while starting this medication because antibodies against
pegloticase may develop. Pegloticase is administered as intravenous infusions every 2 weeks,
and before each infusion, serum urate levels should be monitored to confirm urate-lowering
efficacy. If the serum uric acid rises above 4 mg/dL, the infusions should be stopped, indicating
that the patient is developing antibodies to pegloticase, which could lead to infusion reactions.

Pegloticase has effectively lowered serum uric acid in patients with refractory gout, as evidenced
by short and long-term clinical trials. Phase 3 studies revealed complete resolution of 1 or more
tophi in 20% of patients by 13 weeks and lowered uric acid levels to less than 6 mg/dl in 42% of
subjects within 6 months.During the initial 6 months of pegloticase therapy, all patients should
receive gout flare prophylaxis.

Due to the risk of severe hemolytic anemia, pegloticase is contraindicated in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency. Acute gout flares are observed in 80%
of patients during the first few months of pegloticase therapy, even with prophylactic measures
in place. Moderate infusion reactions like flushing, urticaria, and hypotension are expected, with
2% of patients experiencing severe reactions like anaphylaxis. Some reactions, such as severe
muscle pain and cramping, occur due to unknown mechanisms. Efforts to reduce the
immunogenicity of pegloticase with concomitant use of methotrexate or mycophenolate mofetil
have been effective, although infusion reactions remain a major issue.

Rasburicase, a nonpegylated recombinant uricase, has not received FDA approval for gout
treatment. It prevents acute uric acid nephropathy due to tumor lysis syndrome in patients with
high-risk leukemia and lymphoma.

Other Drugs With an Effect on Serum Uric Acid

Several drugs used to treat conditions like hypertension, type 2 DM, and HLD can affect the
serum uric acid (see Table. Urate-Lowering Drugs and Mechanisms and Table. Urate-Increasing
Drugs and Mechanisms). The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are
particularly noteworthy. Studies have demonstrated their effectiveness in lowering serum uric
acid levels.In an investigation on the effect of empagliflozin therapy on heart failure, significant
interactions were observed between empagliflozin treatment and baseline serum uric acid levels,
affecting cardiovascular and all-cause mortality. Additionally, SGLT2 inhibitors have been
shown to reduce the risk of developing incident gout and acute flares of gouty arthritis.

Differential Diagnosis
The differential diagnosis for an acute gout flare includes the following:

• Calcium pyrophosphate crystal deposition disease

• Basic calcium phosphate crystal disease
• Septic arthritis (crystal arthritis and septic arthritis may coexist) [92]
• OA
• Psoriatic arthritis
• Cellulitis
• Trauma
The differential diagnosis for tophaceous gout includes:

• Dactylitis
• Rheumatoid arthritis
• Osteomyelitis

Complications

Complications of gout are diverse and may encompass various systemic issues, including the
following:[169]
Skeletal Complications

• Tophi
• Joint deformity
• OA
• Bone loss
Urological Complications

• Urate nephropathy
• Nephrolithiasis
Ocular Complications

• Conjunctivitis
• Uveitis
• Scleritis

Pseudogout
Pseudogout is a form of arthritis that causes sudden episodes of pain and swelling in your joints.

Pseudogout is arthritis that causes sudden flares of pain, swelling and stiffness in your joints. It’s
called pseudogout because it causes similar symptoms that come and go just like gout. But it’s a
different condition. Gout happens when there’s too much uric acid in your blood. A buildup of
calcium pyrophosphate dihydrate (CPP) causes pseudogout.
Pseudogout can affect any joint in your body, but it’s most common in:
• Knees.
• Hands and wrists.
• Shoulders.
• Hips and pelvis.
• Elbows.
• Ankles.
Healthcare providers also call pseudogout other names, including:

• Calcium pyrophosphate deposition (CPPD).

• Calcium pyrophosphate arthritis.
• Chondrocalcinosis.

All of these names refer to the same condition.

What is the difference between pseudogout vs. gout?

Gout and pseudogout (also called calcium pyrophosphate deposition disease, or CPPD) are forms
of arthritis which cause sudden and extremely painful attacks in one or more joints of the body.

Gout often affects the big toe first, along with the elbow, wrist, and finger joints. Pseudogout, on
the other hand, generally affects larger joints such as the knee or wrist. During both conditions
sharp crystals form in the joint causing irritation, swelling, redness, and pain. However, gout and
pseudogout have very different caues.

Causes of Gout

In gout, the crystals causing irritation are formed due to a build-up of uric acid in the blood. This
can happen if you produce too much uric acid, or if your kidneys fail to filter out enough uric
acid from your body.

High levels of uric acid in the blood can be a consequence of your genetics, and one in five
people with gout also have a close family member with the condition. Dietary factors, such as
eating red meat, seafood, consuming sugary drinks, or drinking alcohol, also increase your level
of uric acid.

Many health-related factors that have been associated with the development of gout include:
obesity, high cholesterol, heart disease, insulin resistance, kidney disease, and hyperthyroidism.
Some medications can also increase your uric acid levels and risk of gout, including: diuretics,
high blood pressure medication, blood thinners, chemotherapy medicines, and cyclosporine (a
medication given to patients after an organ transplant).

Causes of Pseudogout

Pseudogout, in contrast, occurs when calcium pyrophosphate dihydrate crystals form in a joint.
Many people will form these crystals throughout their life, including nearly half of those aged
over 85 years. However, most of them do not develop pseudogout. It is unclear why only some
people suffer with pseudogout, but research suggests it is not caused by diet or medication.

Symptoms

The most common pseudogout symptoms include:

• Sudden, intense joint pain.

• Skin discoloration or redness.

• Swelling.
 • Stiffness.
• A feeling of heat or warmth in or around a joint.

Pseudogout symptoms come and go (recur) in episodes called flares or attacks. Pseudogout
attacks can happen suddenly. You’ll usually notice symptoms all at once, rather than feeling
them slowly building up over time. A flare of pseudogout symptoms can last anywhere from a
few days to a few weeks (or longer).

Causes pseudogout

A buildup of calcium pyrophosphate (CPP) in your affected joints causes pseudogout. The extra
CPP forms small crystals that build up in the cartilage and fluid-filled synovial membranes
cushioning your joints. Eventually, the CPP crystals clump together inside your joints and cause
a flare of pseudogout symptoms.

Experts aren’t sure what causes your body to make extra CPP. Some studies have found that it
might be hereditary, meaning that parents can pass the risk of developing pseudogout to their
biological children. Some people develop it after experiencing trauma or an injury that damages
a joint. Experts think certain metabolic or endocrine conditions can cause pseudogout.

Risk factors

Anyone can develop pseudogout, but it’s much more common among people older than 65.
Having certain health conditions can increase your pseudogout risk, including:

• Hypomagnesemia.

• Hyperparathyroidism.

• Thyroid disease.

• Hemochromatosis (iron overload).

• Hypophosphatasia.

• Osteopenia.

• Chronic kidney disease (CKD).

People with other types of arthritis may be more likely to develop pseudogout, too, including:

• Gout.

• Osteoarthritis.

• Rheumatoid arthritis.

• Post-traumatic arthritis.
Diagnosis and Tests

A healthcare provider will diagnose pseudogout with a physical exam and some tests. Your
provider will examine your joints and ask about the symptoms you’re experiencing. Tell your
provider:

• When you first noticed symptoms.

• If the symptoms seem to come and go.
• If any activities or times of day seem to make the symptoms worse (or better).

Your provider may do a joint aspiration (arthrocentesis) to confirm that you have extra CPP
crystals in your joint fluid. They’ll insert a needle into your joint, withdraw some fluid and send
the sample to a lab. A lab technician will look at the sample of your joint fluid using a
microscope. Finding excess CPP crystals in your joint fluid after an aspiration is usually the best
way to confirm pseudogout.

A joint aspiration can hurt, especially if you’re experiencing severe symptoms in that joint. Your
provider can give you numbing medication so you feel less pain during the aspiration.

Your provider may also use imaging tests to look for chondrocalcinosis (signs of CPP buildup).
Your provider might take pictures of your joints and the tissue around them with:

• X-rays.

• CT scan .

• MRI .

• Ultrasound.

Management and Treatment

Your provider will suggest treatments to manage the symptoms you’re experiencing and reduce
how often you have pseudogout attacks. The most common treatments are medications,
including:

• NSAIDs: Over-the-counter NSAIDs (nonsteroidal anti-inflammatory drugs) like

ibuprofen or naproxen relieve pain and reduce inflammation. It’s not safe for everyone to
take NSAIDs — especially if you have certain health conditions. Talk to your provider
before starting NSAIDs, and before taking them for more than 10 days in a row.
• Corticosteroids: Corticosteroids are prescription anti-inflammatory medications. Your
provider may give you pills you take orally (by mouth) or inject a cortisone shot directly
into your affected joint.
• Colchicine: Colchicine is a prescription medication that reduces inflammation and pain.
It’s especially effective if you take it within 24 hours of a pseudogout attack starting.
Your provider may suggest taking a low dose for a longer period of time to reduce how
often you have symptom flares.
• Biologic injections: Your provider may suggest anakinra or canakinumab injections to
manage pseudogout attacks. These prescription medications work in a similar way to
colchicine. They’re approved by the U.S. Food and Drug Administration (FDA) to treat
other types of arthritis, but they haven’t yet been FDA-approved to treat pseudogout.
This means your insurance may not cover them, and they might be more expensive than
other treatment options.