CRYSTAL-INDUCED

ARTHRITIS
 CRYSTAL-INDUCED INFLAMMATION
• Supersaturation of body fluids with a variety
of solutes may result in the deposition of
different forms of crystals and calculi.
– Monosodium salt of uric acid (MSU)
– Calcium pyrophosphate dihydrate [CPPD]
– Hydroxyapatite [HA]
– Oxalate crystal deposition, calcium oxalate (CaOx)
 Musculoskeletal Manifestations of Crystal-Induced Arthritis

Acute mono- or polyarthritis Destructive arthropathies

Bursitis Pseudo-rheumatoid arthritis

Tendinitis Pseudo-ankylosing spondylitis

Enthesitis Spinal stenosis

Tophaceous deposits Crown dens syndrome

Peculiar type of osteoarthritis Carpal tunnel syndrome

Synovial osteochondromatosis Tendon rupture

Monosodium salt of
uric acid (MSU)
Gout
 GOUT
The term gout is derived
from the Latin gutta ,
which means a drop.

In the 13th century, it

was thought that gout
resulted from a drop of
evil humor affecting a
vulnerable joint.
 GOUT AND HYPERURICEMIA
• Gout is a clinical disease associated with
hyperuricemia and caused by the deposition
of monosodium urate (MSU) crystals in and
around the tissues of joints.
– Inflammatory arthritis
– Chronic destructive arthropathy
– Soft tissue accumulation of MSU crystals (tophi)
– Renal disease involving glomerular, tubular, and
interstitial tissues and blood vessels
– Uric acid nephrolithiasis
 Uric Acid Metabolism
• Uric acid is the final breakdown product of purine
degradation in humans.

• It is a weak acid with pKas of 5.75 and 10.3.

• Urates, the ionized forms of uric acid, predominate in

plasma extracellular fluid and synovial fluid, with
~98% existing as monosodium urate at pH 7.4.
 Uric Acid Metabolism
• Plasma is saturated with monosodium urate at a
concentration of 415 mol/L (6.8 mg/dL) at 37°C.
• Urine, pH 5.0, saturated with uric acid at 360–900
mol/L
• Urine, pH 7.0, saturation reached at 9480 and 12,000
mol/L

• Clinical point: urine alkalization is important in renal

uric acid excretion in uric acid overload .
Uric Acid Metabolism
 Uric Acid Metabolism

• About one-third of the body

uric acid pool is derived from
dietary sources and two-thirds
from endogenous purine
metabolism.
• The concentration of uric acid
in body fluids depends on the
balance between endogenous
synthesis, and elimination by
the kidneys (two-thirds) and
gut (one-third).
 URATE HANDLING IN THE NEPHRON
Glomerular Filtration: Normally ~99%

Bidirectional
*
Urate Movement
in Proximal Tubule Reabsorption
Secretion

Reabsorption Fine Tuning

? Na+/H+
antiporter,
OATS
Excretion:
Normally ~10%
of Filtered Load

*
Pharmacogenomics and URAT1:
Probenecid, Pyrazinamide, Benzbromarone Fail to Alter
Renal Urate Clearance in subjects with Defective URAT1
 Uric Acid Metabolism
renal handling of
urate/uric acid
1. glomerular
filtration
2. tubular
Urte transporter 1 (URAT1) reabsorption
3. Secretion
4. postsecretory
reabsorption

Organic anion
transporters (OATs)

Uricosuric compounds inhibit URAT1 on the apical side of the tubular cell.
 Classification of Hyperuricemia by Pathophysiology
Urate Overproduction Decreased Uric Acid Excretion 90%
• Primary idiopathic • Primary idiopathic
• HPRT deficiency • Renal insufficiency
• PRPP synthetase overactivity • Polycystic kidney disease
• Hemolytic processes • Diabetes insipidus
Lymphoproliferative diseases • Hypertension
• Myeloproliferative diseases • Acidosis
• Polycythemia vera • Lactic acidosis
• Diabetic ketoacidosis
• Psoriasis
• Starvation ketosis
• Paget's disease
• Berylliosis
• Glycogenosis III, V, and VII • Sarcoidosis
• Rhabdomyolysis • Lead intoxication
• Exercise • Hyperparathyroidism
• Alcohol • Hypothyroidism
• Obesity • Toxemia of pregnancy
• Purine-rich diet • Bartter's syndrome
• Down syndrome
 Classification of Hyperuricemia by Pathophysiology

Combined Mechanism Decreased Uric Acid Excretion

• Glucose-6-phosphatase • Drug ingestion CAN’T

deficiency LEAP
• Fructose-1-phosphate
– C yclosporine
• aldolase deficiency
• Alcohol – A lcohol
• Shock – N icotinic acid
– T hiazides
– L asix (furosemide)
(and other loop
diuretics)
– E thambutol
– A spirin (low dose)
– P yrazinamide
 Medications with Uricosuric
Activity
• Acetohexamide ACTH Ascorbic acid
Azauridine Benzbromarone Calcitonin
Chlorprothixene Citrate Dicumarol Diflunisal
Estrogens Fenofibrate Glucocorticoids
Glyceryl guaiacolate Glycopyrrolate Halofenate
Losartan Meclofenamate
Phenolsulfonphthalein Phenylbutazone Probenecid
Radiographic contrast agents
Salicylates (>2 g/d) Sulfinpyrazone
Tetracycline that is outdated Zoxazolamine
 Factors affecting the balance of crystal
formation and tissue concentration.
• There must be sufficient
concentration of the chemical
components (ionic product), but
whether a crystal then forms
depends on the balance of tissue
factors that promote and inhibit
crystal nucleation and growth.

• Many tissues are supersaturated

for the various products but
depend on natural inhibitors to
prevent crystallisation.
• Crystals can paradoxically reside
in cartilage or tendon for years
without causing inflammation or
symptoms, and it is only when
they are released that they
trigger inflammation.

• This may occur spontaneously

but can also result from local
trauma, changes in the
concentration of the
components that form crystals,
or be part of an acute phase
response due to intercurrent
illness or surgery.
 Pathogenesis of acute gout

Shedding of crystals leads to leukocyte activation and the release of inflammatory

mediators. IgG, immunoglobulin G; PMN, polymorphonuclear leukocyte.
 GOUT - Definition
• The course of classic gout passes through three
distinct stages:
– Asymptomatic hyperuricemia
– Acute intermittent gout
• Acute gout
• Intercritical gout
– Advanced gout
• Hyperuricemia is defined as a serum uric acid
level greater than 7.0 mg/dL in adult men and
6.0 mg/dL in premenopausal women.
 EPIDEMIOLOGY
• Hyperuricemia is fairly common, 2.6% and 47.2%
• Factors associated with high serum urate concentrations in adults
– Serum creatinine
– Urea nitrogen levels
– Body weight
– Height
– Age
– Blood pressure
– Alcohol intake
• Gout prevalence less than 1% to 15.3%
 ENVIRONMENTAL FACTORS
Increased risk for gout Not increased risk for gout
• Alcohol consumption (Beer) • Oatmeal
• Meat 41% higher risk • purine-rich vegetables
• Seafood 51% higher risk (e.g., peas, mushrooms,
lentils, spinach, and
cauliflower)
• The consumption of milk
one or more times a day or
yogurt consumption at
least once every other day
is associated with lower
serum urate levels
 CLINICAL FEATURES
Gout passes through three stages STAGES OF CLASSIC GOUT
1. Asymptomatic
hyperuricemia
2. Episodes of acute gouty
arthritis separated by
asymptomatic intervals
(termed intercritical or
interval gout)
3. Chronic gouty arthritis,
the period when tophi
often become apparent.
 ASYMPTOMATIC HYPERURICEMIA
• Asymptomatic hyperuricemia is a condition in
which the serum urate level is high, but gout—
manifested by arthritis or uric acid
nephrolithiasis—has not yet occurred.
• This occurs at least 20 years of sustained
hyperuricemia.
• The phase of asymptomatic hyperuricemia
ends with the first attack of gouty arthritis or
urolithiasis.
 ACUTE GOUTY ARTHRITIS
• First attack of acute gouty arthritis
– Between age 40 and 60 years in men
– After age 60 in women
– Before age 25 the possibility unusual form of gout,
• A specific enzymatic defect that causes marked purine
overproduction,
• An inherited renal disorder
• The use of cyclosporine.
 ACUTE GOUTY ARTHRITIS
• A single joint 85% to 90% of first attacks, 1th MTP
• The initial attack is polyarticular in 3% to 14%.
• Acute gout is predominantly a disease of the lower extremities
• Ninety percent (90%) of patients experience acute attacks in the great toe,
next in order of frequency are the insteps, ankles, heels, knees, wrists,
fingers, and elbows.
• Acute attacks rarely affect the shoulders, hips, spine, sacroiliac joints,
sternoclavicular joints, acromioclavicular joints, or temporomandibular
joints.
• Acute gouty bursitis, tendinitis, or tenosynovitis can also occur.
• Early attacks tend to subside spontaneously within 3–10 days
 ACUTE GOUTY ARTHRITIS
Events may precipitate acute
gouty arthritis Podagra
• Dietary excess
• Trauma
• Surgery
• Excessive ethanol ingestion,
• Hypouricemic therapy
• Serious medical illnesses
– myocardial infarction, stroke.
ACUTE GOUTY ARTHRITIS
 INTERCRITICAL GOUT
• The periods between gouty attacks
• Some patients never have a second attack.
• Most patients suffer a second attack within 6 months
to 2 years
• The frequency of gout attacks usually increases over
time in untreated patients.
• Later attacks have a less explosive onset, are
polyarticular, become more severe, last longer, and
abate more slowly.
• Nevertheless, recovery is complete.
 CHRONIC GOUTY ARTHRITIS
Tophaceous gout
• Eventually, the patient
may enter a phase of
chronic polyarticular gout
with no pain-free
intercritical periods
• Tophaceous gout is the
consequence of the
chronic inability to
eliminate urate as rapidly
as it is produced.
CHRONIC GOUTY ARTHRITIS
Tophaceous gout
Radiologic Finding
Radiologic Finding
 Diagnosis
Needle aspiration Extracellular and intracellular
• Synovial fluid cell counts are monosodium urate crystals
elevated from 2000 to 60,000/L.
• Effusions appear cloudy due to
the increased numbers of
leukocytes.
– strongly birefringent needle-
shaped MSU crystals with
negative elongation are
typically seen both
intracellularly and
extracellularly
Serum uric acid levels can be normal or low at the time of the acute attack
Extracellular and intracellular monosodium urate crystals
 Differential Diagnosis
Acute gouty arthritis Chronic tophaceous gout
• Acute septic arthritis • Rheumatoid Arthritis
• The other crystalline-
associated arthropathies
• Palindromic rheumatism
• Psoriatic arthritis
 Patient Evaluation
1. History of risk factors and physical Examination
2. Coexistent condition (obesity, hyperlipidemia,
alcoholism, and, especially, hypertension)
3. Joint and Tophus examination
4. Uric acid level (serial control)
5. Renal function and urinary uric acid (serum Cr
and uric acid and 24 hours Cr, uric acid)
6. Renal stone
 Patient Evaluation
Blood Pressure Alcohol intake
 Patient Evaluation
Obesity High purine diet
 TREATMENT OF GOUT
The therapeutic aims in gout are as follows:
1. To terminate the acute attack as promptly and
gently as possible
2. To prevent recurrences of acute gouty arthritis
3. To prevent or reverse complications of the disease
resulting from the deposition of sodium urate or
uric acid crystals in joints, kidneys, or other sites
4. To prevent or reverse associated features of the
illness that are deleterious, such as obesity,
hypertriglyceridemia, and hypertension
 TREATMENT OF GOUT
Nonpharmacologic
• General recommendation
– Ideal BMI
– Healthy diet
– Exercise
– Smoking cessation
– Hydration
• Diet recommendation
– Avoid
• Organ meat – high fructose beverage or food – Alcohol overuse -
– Limit
• Red meat – seafood (Sardine, Shellfish) – salt – sauces – gravy - alcohol
– Encourage
• Low fat or non fat dairy products – vegetables
 TREATMENT OF GOUT
1. Management of Acute Gouty Attack
– NSAIDs
– Colchicine, oral
– Intraarticular steroids
– Systemic steroid therapy
– Adrenocorticotropic Hormone
2. Management of Intercritical and Chronic Gout
3. Non–Urate-Lowering Prophylactic Therapy
4. Lifestyle Modifications and Education
5. Treatment of Hyperuricemia in Patients Without Gout
 TREATMENT OF GOUT
1. Management of Acute Gouty Attack
2. Management of Intercritical and Chronic Gout
– Urate-Lowering Therapy
• Uricostatic Therapy (Allopurinol and febuxostat are XO Inhibitors)
• Uricosuric Therapy (probenecid )
• Uricolytic Therapy (Pegloticase, Rasburicase)
3. Non–Urate-Lowering Prophylactic Therapy
4. Lifestyle Modifications and Education
5. Treatment of Hyperuricemia in Patients Without Gout
 TREATMENT OF GOUT
1. Management of Acute Gouty Attack
2. Management of Intercritical and Chronic Gout
3. Non–Urate-Lowering Prophylactic Therapy
– Low-dose colchicine or NSAIDs
4. Lifestyle Modifications and Education
5. Treatment of Hyperuricemia in Patients Without Gout
 TREATMENT OF GOUT
1. Management of Acute Gouty Attack
2. Management of Intercritical and Chronic Gout
3. Non–Urate-Lowering Prophylactic Therapy
4. Lifestyle Modifications and Education
– Risk factors and associated illnesses such as obesity,
hypertension, and hyperlipidemia
– Decreased consumption of high-purine foods
– Drugs: diuretics
5. Treatment of Hyperuricemia in Patients Without Gout
 TREATMENT OF GOUT
1. Management of Acute Gouty Attack
2. Management of Intercritical and Chronic Gout
3. Non–Urate-Lowering Prophylactic Therapy
4. Lifestyle Modifications and Education
5. Treatment of Hyperuricemia in Patients Without Gout
– There is no evidence to support their use for the
routine treatment of asymptomatic hyperuricemia
– Cancer chemotherapy
 Calcium
Pyrophosphate
Dihydrate (CPPD)
Deposition Disease
 Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease
• It is characterized by the presence of
intraarticular CPPD crystals.
• These crystals are deposited primarily in the
cartilage.
 Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease
• CPPD deposition disease typically affects the elderly
population.

• Up to 50% of individuals older than 85 years of age

have radiographic evidence of CPPD crystal
accumulation in cartilage (chondrocalcinosis), but
most are asymptomatic.

• The most commonly involved joints are the knee

menisci and the triangular fibrocartilage of the wrist.
Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease
Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease
 Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease The clinical course:
• Asymptomatic disease may be an incidental finding on
radiographs showing chondrocalcinosis.
• Pseudogout is an acute monoarthritis similar in presentation
to the acute gouty attack.
• A chronic symmetric polyarticular arthritis pattern resembling
rheumatoid arthritis and a severe destructive arthropathy
that mimics neuropathic arthritis on radiographs may be seen.
• The most common clinical manifestation, (>50% ) is a peculiar
type of osteoarthritis called pseudo-osteoarthritis; it is a
noninflammatory arthritis involving joints not typically
affected by osteoarthritis, such as the wrist, shoulder, ankle,
and metacarpophalangeal joints.
Calcium Pyrophosphate Dihydrate
(CPPD)Deposition Disease
Apatite-Associated
Arthropathy
 Apatite-Associated Arthropathy
(Basic Calcium Phosphate, or BCP)
• Abnormal accumulation of apatite may occur in
hypercalcemic states and other illnesses.

• BCP crystals are not identifiable by polarized microscopy

and can be seen only by electron microscopy.

• The most common apatite-associated condition is

calcific periarthritis, which typically occurs in the
shoulder.
Apatite-Associated Arthropathy
(Basic Calcium Phosphate, or BCP)
• Calcific periarthritis
• Calcific deposits in tendons, bursae, joint capsules
• Acute calcific periarthritis
• BCP arthropathy
• Acute synovitis
• Destructive arthropathy

• Subcutaneous/soft tissue calcifications

• Connective tissue diseases: SLE, SSC, MCTD, dermatomyositis
• Metastatic calcifications: chronic renal failure with high calcium–
phosphorus product (>70)
• Tumoral calcinosis
Apatite-Associated Arthropathy
(Basic Calcium Phosphate, or BCP)
 Calcium Oxalate
Deposition Disease
 Calcium Oxalate Deposition Disease

• In calcium oxalate deposition disease, or

oxalosis, calcium oxalate crystals are
deposited in tissue.
 Calcium Oxalate Deposition Disease

• In primary oxalosis, a hereditary metabolic

disorder, this deposition leads to
nephrocalcinosis, renal failure, and early
mortality.
• Secondary oxalosis complicates long-term
hemodialysis or peritoneal dialysis; crystals
are deposited in bone, cartilage, synovium,
and periarticular tissue.
 Calcium Oxalate Deposition Disease

• Crystal shedding into the joint space may

result in inflammatory arthritis of peripheral
joints.
• Chondrocalcinosis or soft tissue calcifications
can be seen on plain radiographs.