Crystalline Arthropathies

Question 1

What are the three main crystal types in arthropathies?

Answer 1

basic calcium phosphate (BCP)

calcium pyrophosphate dihydrate (CPPD)

monosodium urate (gout)

Question 2

What is BCP? Where does it deposit?

Answer 2

aka calcium hydroxyapatite - calcium-containing mineral found in bone

deposit in:

• soft tissues (Acute calcific periarthritis) - first MTP in young men (pseudo-podagra)
• joints (BCP arthropathy) - Milwaukee Shoulder Syndrome
• tendons (calcific tendinitis) - shoulder, most commonly in supraspinatous tendon

Question 3

acute calcific periarthritis

Answer 3

BCP crystals shed from calcific deposit - intense local inflammation, looks like gout on exam, but in “wrong type” of patients

comes on quickly, near the joint, not in the joint

Question 4

BCP arthropathy

Answer 4

Milwaukee Shoulder Syndrome

inflammation leading to severe degenerative arthritis of the shoulder joint

destruction of rotator cuff, cannot abduct arm, huge swelling

BCP crystals identified

common in women >70

bilateral involvement common but can affect other joints such as knees, hips, and fingers (Philadelphia finger)

Question 5

calcific tendinitis

Answer 5

most commonly seen in the shoulder

up to 5% of shoulder x-rays

usually in the muscles that abducts and stabilizes the shoulder

bursitis, impingement syndrome

hand, wrist, hip, knee, foot and neck

Question 6

What are the features of BCP histology?

Answer 6

shiny choins on ordinary light microscopy

not birefringent, not seen on polarized light microscopy

joint aspirate staned for alizarin red

electron microscopy diagnostic

Question 7

ABCs of BCP

Answer 7

A - Acte calcific periarthritis, Alizarin red stain, Atypical gout

B - BCP arthropathy, not Birefringent, Beer (Milwaukee Shoulder Syndrome)

C - Calcific tendinitis, Cuff (supraspinatous), Coints “shiny” on light microscope

Question 8

Calcium Pyrophosphate Dihydrate (CPPD) Crystal Disease

Answer 8

results from pyrophosphate dihydrate salts depositing

in cartilage appears as chondrocalcinosis on radiographs

in joint space as pseudogout, pseudo-rheumatoid arthritis

spectrum of presentations

Crowned Dens syndrome - calcific deposit on the top of the dens

Question 9

What is the spectrum of presentation in CPPD?

Answer 9

asymptomatic (lanthanic) - most common

30% population has chondrocalcinosis on x-rays by 90 years of age

pseudogout

polyarticular arthritis

osteoarthritis with superimposed atacks of pseudogout (Crowned Dens Syndrome)

overlap between various forms

Question 10

pseudogout

Answer 10

fever, malaise

acute onset of joint pain, swelling with effusion, erythema over joint, tenderness, warmth

usually less painful than gout and takes longer to peak intensity

large joints affected mostly

diagnosis - aspirate, inflammatory, crystals within PMNs

knee and wrist are the most common joints

Question 11

What are factors associated with secondary CPPD?

Answer 11

advanced age (>50)

OA

long-term consequences of mechanical knee joint trauma

familial (manifests third and fourth decades)

associated with systemic metabolic disease such as hyperparathyroidism, dialysis-dependent renal failure

hemochromatosis

hypomagnesemia

ochronosis

Question 12

ochronosis

Answer 12

genetic lack of homogenistic oxidase enzyme, leading ot increased levels of endogenous phenols and hydroxyapatite

Question 13

treatment of BCP and CPPD

Answer 13

NSAIDs

intraarticular steroid injections

anakinra (IL-1 inhibitor), inhibits the inflammasone

glucocorticoids

can only treat acute attack, no prevention

Question 14

What is the epidemiology of gout?

Answer 14

prevalence increases with age

more men than women (3/4:1) - disappears after menopause (1:1)

estrogen has uricosuric effects

Question 15

risk factors for gout

Answer 15

obesity, metabolic syndrome, insulin resistance

diet (rich in purines: meat, shellfish, ethanol (esp. beer), soft drinks and high fructose syrup)

drugs - thiazide cyclosporine, low dose ASA (<1g/day)

renal insufficiency

organ transplantation

inborn errors of metabolism: Lesch Nyhan, PRPP syndrome

Question 16

hyperuricemia

Answer 16

due to overproduction or underexretion - taking in too many purines, increased cell production such as malignancy

occurs when concentration >6.8 mg/dL

treatment goal < 6.0 mg/dL for both

many people are hyperuricemic and never develop gout

Question 17

What are the general methods of uric acid accumulation?

Answer 17

most people are both udnerexcretor and overproducer

others are underexcretors, which require higher serum urate level for renal excretion

overpreoducers are rare except for cancer where there is increased cell turnover

Question 18

How does urine concentrations reflect the mechanism of uric acid build-up?

Answer 18

can get 24 hour collection for uric acid and creatinine

if >1000 mg then overproducer

if <1000 mg then underexcretor

Question 19

What are the four stages of gout?

Answer 19

asymptomatic hyperuricemia - only 15% of hyperuricemic people develop gout

acute gouty arthritis - monoarticular acute inflammatory arthritis

intercritical gout - asymptomatic intervals between acute attacks

chronic tophaceous gout - uric acid deposits accumulate in the soft tissues

Question 20

acute gout treatment

Answer 20

NSAIDs

Colchiciene 0.6 mg - inhibitor of mitotic spindle fibers

intraarticular steroid injections

Anakinra (IL-1 inhibitor)

glucocorticoids

next generation IL-1 inhibitors coming up - Canakinumab, Rilonacept

Question 21

What are the methods of prevention for chronic gout?

Answer 21

xanthine oxidase inhibitors - Allopurinol and Febuxostat (Uloric) block hypoxanthine into xanthine and xanthine into uric acid

uricosurics - Probenecid (not used a lot now because need to take 4 times a day)

Uricases - Pegloticase/Krystexxa (humans don’t produce uricase, but most creatures do)

Question 22

When should preventative gout therapy be initiated?

Answer 22

patients with hyperuricemia:

• >/= 2 acute gout attacks
• presence of tophi
• coexisting illness (nephrolithiasis)

patient preference

start 2-4 weeks after resolution of acute gout attack

Question 23

allopurinol

Answer 23

purine analog xanthin oxidase inhibitor

metabolized to oxypurinol

lowers srum urate in the order of 20%

not to be started or stopped during acute attacks

rash in 2% - can attempt oral desensitization

Allopurinol Hypersensitivity Syndrome

GI intolerance a problem

can cause vasculitis

Question 24

Febuxostate (Uloric)

Answer 24

non-purine analog xanthine oxidase inhibitor

decreases production of uric acid

can lead to paradoxical gout flares like allopurinol

more cardiovascular events

in HD and CHF - transaminitis in 2-3%

superior to allopurinol for safety (rash)

Question 25

When should Febuxostate be taken?

Answer 25

should be considered in patients:

• intolerant to allopurinol
• uncontrolled gout with other available therapies
• renal insufficiency (crt cl>30mL/min)
• tried before alopurinol desensitization
• with nephrolithiasis before uricosuric drugs

Question 26

Pegloticase (Krystexa)

Answer 26

pepylated uricase

rapidly lowers serum uric acid and dissolves tophi

very expensive

immunogenicity

reports

Question 27

What is the treatment schema for gout?

Answer 27

don’t start allopurinol or beuxostat during acute attack

during accute attacks:

• colchicine - need to dose according to creatinine clearance
• NSAIDs, steroids, ACTH
• prophylax with NSAIDs or colchicine for 6 months after starting ULT
• opinion: avoid febuxostat in patients with IHD and CHF until results of open label study available

consider uricases for refractory cases

Question 28

rilonacept

Answer 28

IL-1 trap, a dimeric fusion protein consisting of the extracellular domain of human Il-1 receptor and the FC domain of human IgG1 that binds and neutralizes IL-1

in patients with gout, ongoing treatment with rilonacept reduced gout flares during urate-lowering therapy

if administered withint 72 hours of onset of a flare, the drug did not provide any pain relief