Crystal arthropathies - PowerPoint Presentation

Slide1

Crystal arthropathies

Gout

Slide2

it is a group of diseases characterized by hyperuricaemia and uric acid crystal formation. These clinical syndromes include gouty arthritis, tophaceous

gout, uric acid

nephrolithiasis

, and gouty nephropathy. In its more narrow and perhaps more commonly used definition, gout refers to arthritis caused by uric acid crystals

.

Risk

factors for primary gout

Male gender

Age >40 years

Obesity

Family history

Alcohol use

Renal insufficiency

Hypertension

Slide3

Purine metabolism

Slide4

Mechanisms of hyperuricaemia

in primary gout

Primary gout is simply defined by the absence of any identifiable underlying disease causing

hyperuricaemia

. This criterion defines the largest group of patients with gout.

Most

of these patients are older men and 80–85 per cent are

hyperuricaemic

on the basis of

underexcretion

of uric acid.

There

is no difference in rates of intestinal

uricolysis

in patients with primary gout compared with controls. Thus, the site of the abnormality in patients with primary gout who

underexcrete

is most likely to be at the kidney.

Slide5

most patients with primary gout have low fractional uric acid excretion rates. The mechanism of underexcretion remains to be elucidated but is most likely a defect in secretion or

reabsorption

rather than in filtration.

A minority of patients with primary gout have high urinary uric acid levels and excessive de novo

purine

synthesis.

The best evidence to date supports a role for increased PRPP availability or decreased

purine

nucleotide concentrations (thus diminishing feedback inhibition of the synthetic enzymes) in patients with primary gout who overproduce uric acid

Slide6

H G PT deficiency produces hyperuricaemia

by increasing de novo synthesis of

purine

nucleotides through increased availability of the substrate PRPP, which stimulates synthesis

.

In

its most complete form

,

H

GP

T

deficiency results in the

Lesch–Nyhan

syndrome. This syndrome presents in early childhood with severe mental retardation, self-mutilation,

choreoathetosis

, spasticity,

hyperuricaemia

, and premature gout. Although it is linked to the X chromosome, there are two reported cases in girls

.

Slide7

Partial defects of HGP T result in

hyperuricaemia

alone without the severe neurological consequences of complete

H

G

P T

deficiency.

The diagnosis of

H

G

P T

deficiency can be made by documenting low

H

G

P T

activity in erythrocytes. Numerous different genetic mutations have been described

in

H

G

P T

deficiency

Slide8

Mechanism through wich MSU crystal cause

inflamation

Slide9

Clinical features

Articular

gout is often divided into four clinical stages. The first stage is defined by asymptomatic

hyperuricaemia

. This is followed by acute gouty arthritis and then by another asymptomatic phase termed

intercritical

gout. When allowed to proceed untreated, some patients will go on to develop chronic

tophaceous

gout.

Acute gout

The first clinical symptom of gout is usually an acute, self-limited,

monoarticular

inflammatory arthritis affecting the joints of the lower extremities. Gout has a predilection for the first

metatarsophalangeal

joint(

Podagra

). As many as 50–70 per cent of first gout attacks occur in the big toe. Other frequently involved joints include those of the foot, ankle, knee, wrist, elbow, and the small joints of the hands. The large axial joints and those of the spine are uncommon sites for early acute gout attacks.

Slide10

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The onset of an attack occurs suddenly and often late at night or early in the morning. Patients will describe very severe pain, associated with swelling, extreme tenderness, and redness overlying the joint. Without intervention, the attack will usually subside within 5–7 days. Low-grade fever, malaise, and anorexia may occur. The attack may be preceded by brief twinges of pain (petit attacks) in the affected joint.

Common precipitants of acute attacks include excess alcohol intake,

intercurrent

illness, surgery, starvation, trauma, and the initiation of drugs that alter

urate

metabolism. All of these precipitants alter serum

urate

levels.

Slide12

Physical examination shows signs of inflammation with erythema, warmth, and swelling over the joint, often extending to the overlying skin. There is exquisite tenderness over the affected joint.

Not infrequently, an overlying

cellulitis

or accompanying

tenosynovitis

occurs. The skin may desquamate in the later days of an attack.

Acute gout can also occur in bursas, and gout is a common cause of acute inflammatory

olecranon

bursitis.

After the attack resolves, the patient will be completely asymptomatic. This phase is referred to as

intercritical

gout. Most patients will go on to have an additional attack within 2 years of the first attack.

Slide13

In one study, 78 per cent had recurrent attacks within 2 years, and after 10 years, 93 per cent had had more than one attack .Untreated, the intercritical

phases become shorter. Interestingly, they still present an opportunity for diagnosis, as many joints will still have

urate

crystals in the synovial fluid during the

intercritical

phase if they were involved in a previous attack, and

urate

-lowering therapy has not been initiated

Slide14

Chronic tophaceous gout

In the later stages of untreated disease, clinical manifestations characteristically change. Acute attacks are more often

polyarticular

. The

intercritical

stage shortens, and repeated joint damage results in permanent deformities, loss of motion, chronic pain, and

tophi

.

Polyarticular

gout occurs in late-stage disease, although some patients present earlier with

polyarticular

attacks.

Intercritical

stages are short or non-existent and involvement of atypical sites including the upper extremities, the spine, and axial joints may ensue. After repeated attacks in a single joint, deformity and loss of motion may occur.

Slide15

Tophi are deposits of urate embedded in a matrix composed of amorphous

urates

, lipids, proteins, and

calcific

debris .

Tophi

are usually subcutaneous, but they rarely occur in bone and other organs including the heart valves and the eye.

Classic sites include the

pinna

of the ear, bursas around elbows and knees, the dorsal surfaces of the

metacarpophalangeal

joints, and the Achilles tendon.

Tophi

are not distinguishable on physical examination from rheumatoid nodules or other subcutaneous nodules. There is no accompanying inflammation and they are usually painless. The overlying skin may be taut and shiny. A thick white or whitish-yellow

exudate

is seen if the skin integrity is compromised.

Slide16

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Tophi or chronic polyarthritis may occur as early as 3 years or as late as 42 years after the first acute attack. In the pre-treatment era, 50 per cent of patients with gout had

tophi

after 10 years of disease . Currently, about 5 per cent of patients with gout will have

tophi

.

Their occurrence is directly correlated with serum

urate

levels, and they identify a group of patients with severe and prolonged

hyperuricaemia

.

Another group at risk of developing

tophi

and

polyarticular

gout are elderly women with primary nodal osteoarthritis on diuretic therapy

Slide18

Urate nephropathy The pathological changes that define

urate

nephropathy are common. MSU crystals in the renal medulla are associated with a giant-cell inflammatory reaction. The clinical significance of these pathological findings, however, remains unclear.

Renal insufficiency is unequivocally common in patients with gout, but controversy exists as to the

aetiology

of this renal dysfunction. Current dogma states that

urate

crystals themselves produce only a minor amount of renal damage.

Slide19

Most of the renal disease associated with gout is secondary to inadequately controlled hypertension, non-steroidal anti-inflammatory drug (NSAID) use, and other comorbidities Uric acid

nephrolithiasis

the risk factor is high serum

urate

&low

urin

PH.

Slide20

Laboratory investigation

Synovial fluid analysis remains the single most important diagnostic study in the patient with suspected gout. Synovial fluid is usually easily obtained from a large joint, while often only a drop of fluid or blood from the joint or adjacent tissues is necessary to provide a sample for definitive diagnosis of gout in a small joint. Synovial fluid is typically inflammatory with a mean white cell count of 20 000 cells/mm

3

.

Most cells are

polymorphonuclear

leucocytes. Viscosity is often poor. A definite diagnosis can be made if typical, negatively

birefringent

, needle-shaped crystals are seen in the fluid with a polarizing light microscope .

They may be extra- or intracellular. Rarely one may see spherules of uric acid in acute gout.

Slide21

Few other laboratory studies are of significant clinical utility in diagnosing acute gout. Serum uric acid levels during the acute attack may not reflect pre-attack levels and cannot be used to make a diagnosis of gout in the absence of urate

crystals in the synovial fluid.

One may see a peripheral

leucocytosis

, an elevated erythrocyte sedimentation rate, and increased levels of other acute-phase reactants during an acute attack. Synovial fluid cultures and Gram stains may help rule out concurrent infection.

Radiographs are often normal during early episodes of gout. They may be useful to differentiate other problems such as fracture or infection from acute gout. Often, soft tissue swelling is the sole radiographic finding in early gout.

Slide22

Diagnosis

definitive diagnosis of gout can only be made by the identification of

urate

crystals in the synovial fluid of an affected joint. Identification of

urate

crystals in

tophi

also allows a definitive diagnosis to be made.

In the absence of these findings, other clinical criteria may be used to make a putative diagnosis of gout

As crystals may be present in the

intercritical

phase, one may aspirate an asymptomatic but previously affected joint to establish a definite diagnosis. Many clinical conditions can mimic acute gout

These include infectious arthritis, other crystal-associated

arthropathies

such as

pseudogout

or BCP-associated

periarthritis

, or trauma.

Slide23

Patients with palindromic rheumatism may give a similar history of self-limited monoarticular

attacks associated with exquisite pain, tenderness, and

erythema

near the affected joint.

Rarely, other causes of

polyarticular

inflammatory arthritis, particularly psoriatic arthritis or Reiter's syndrome, may present with

monoarticular

self-limited attacks of the lower extremities that may be confused with gout.

Once

tophi

and deformities occur, gout can be misdiagnosed as rheumatoid arthritis. As many as 30 per cent of patients with gout will have positive serum rheumatoid factors .

Slide24

Clinical conditions that mimic gouty arthritis CPPD disease (

pseudogout

) *Psoriatic arthritis

BCP arthritis *Rheumatoid arthritis

Cellulitis

Erythema

nodosum

arthritis

Trauma

Palindromic

rheumatism

Reiter's syndrome

Slide25

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Slide27

Management of gouty arthritis

divided into three phases: treatment of acute gout, treatment of chronic or

tophaceous

gout, and preventive measures

Management of acute gout

Traditional therapies for acute gout include NSAIDs,

colchicine

, and steroids. Rest and splinting of the affected joint may be helpful adjuncts to any pharmacological therapy.

Colchicine

Colchicine

tends to be much more effective in the early hours of an attack and loses efficacy with time. The mechanism of action of

colchicine

is unknown. It inhibits

polymorphonuclear

leucocyte

function through its action on microtubules, but may also have very specific effects on crystal-induced inflammation .

Colchicine

can be given in intravenous and oral forms.

Slide28

A dose of 1–3 mg diluted in 20 ml of normal saline can be slowly instilled into a large vein. Another 1-mg dose can be given 6 h later if the clinical response is incomplete. The maximum dose is 4 mg in 24 h. No additional doses should be given for 7 days after the initial dose. Intravenous

colchicine

is particularly useful for patients unable to take oral medications. Now that

parenteral

forms of NSAIDs are available, its use may decline further.

Absolute contraindications to the use of intravenous

colchicine

include significant renal or hepatic compromise, bone marrow suppression, or sepsis. It should be used with great caution in patients with mild renal or hepatic disease, or those on daily oral

colchicine

prophylaxis.

Slide29

Side-effects range from venous sclerosis or tissue damage from extravasation of

colchicine

, to fatal bone marrow failure. Other side-effects include renal or hepatic failure, disseminated intravascular coagulation, and neuromuscular toxicity. Deaths from misuse of intravenous

colchicine

have been reported

Corticosteroids

Regimens for acute gout include intramuscular ACTH, intramuscular

triamcinolone

, and oral steroids .

These regimens are safe and well tolerated. Their efficacy remains to be proven. They may be particularly useful for patients in whom NSAIDs and

colchicine

are contraindicated. The use of intra-

articular

steroids is less controversial. Although no studies of the efficacy of intra-

articular

steroids have been published, they remain a mainstay of therapy in patients unable to tolerate more traditional therapies.

Slide30

Allopurinol Allopurinol

is the drug most commonly used for the prevention of acute gout and the treatment of chronic

tophaceous

gout .It is a

xanthine

oxidase

inhibitor and thus decreases uric acid production. It may also have other actions .

It is very effective in lowering serum uric acid levels and is the drug of choice for patients with renal insufficiency, a history of

nephrolithiasis

, or

tophi

.

It is also indicated in patients who clearly overproduce uric acid such as those with

tumour

lysis

syndrome or primary metabolic defects.

Allopurinol

is usually given as a once daily dose of 300 mg.

Slide31

The most common side-effects include a hypersensitivity syndrome of rash and fever. Life-threatening reactions, including fulminant hepatitis, interstitial nephritis, and toxic epidermal

necrolysis

, are even more unusual. Patients with renal disease may have a greater incidence of drug allergy.

Allopurinol

can be given cautiously to an allergic patient using available desensitization regimens .

Slide32

Uricosurics Probenecid

and

sulfinpyrazone

are the most commonly used

uricosuric

drugs. They interfere with the renal handling of

urate

by altering organic anion transport, thus increasing

urate

excretion.

Uricosurics

are contraindicated in patients with

nephrolithiasis

and ineffective in patients with significant renal compromise, or those using acetylsalicylates. Side-effects include rare hypersensitivity reactions, rashes, gastrointestinal complaints, and

nephrotic

syndrome.

Benzbromarone

is a

uricosuric

drug available in Europe. Unlike other commonly used

uricosuric

drugs, it is effective in patients with renal insufficiency

Slide33

Less potent uricosuric agents include the angiotensin 1 receptor antagonist

losartan

, and the lipid-lowering agents

atorvastatin

and

fenofibrate

.

New

urate

lowering agent as

Febuxostat

, which inhibits

xanthine

oxidase

through a different mechanism than

allopurinol

and

oxypurinol

, blocks substrate access to

xanthine

oxidase

by occupying a channel in the enzyme leading to the active site.

Slide34

Gout & food