Crystal Induced Arthropathy

Crystal Induced Arthropathy

Update on Crystal Related


John W. Pendleton, M.D.

What’s New in Crystal Related




Unique characteristics of gout in older patients

The role of hyperuricemia in related conditions and

should it be treated

Treatment of gout

Calcium Pyrophospahte Dihydrate Deposition



Multiple presentations and evaluation



A disorder related to monosodium urate crystal

(MSU) deposition in tissues and characterized by

Hyperuricemia –At levels ≥ 6.8 –7 mg./dl., MSU is

supersaturated in plasma and begins to deposit in

synovium and soft tissues

Arthritis –acute and chronic


Potential for renal dysfunction



BUT ‐ Eighty percent of people with uric acid

over 7 mg/dl do not develop gout.

Risk of gout related to level of uric acid in 2046

men followed for 14.9 years

UA level 5 year incidence of gout *

7 –7.9 2%

8 –8.9 4.1%

9 – 9.9 29.8%

> 10 30.5%

Hyperuricemia appears to lead to similar risk of

gout in women as in men

Amer J Med 1987;82:421-26

Gout ‐ Diagnosis

Typically acute monoarthritis

Serum uric acid may be misleading –

Normal in up to 40% at time of attack

Frequently elevated without symptoms or with

musculoskeletal symptoms unrelated to gout

Best diagnostic clues

Sensitivity Specificity*

Podagra 96 97

Tophi 30 99

Urate crystals in

Synovial fluid 84 100

Arthrocentesis ‐ best way to confirm

Negatively birefringent crystals

YUPA ‐ yellow urate parallel axis

*Adapted from Am Fam Phy 2007;2007:801

Acute Podagra

Compensated polarized microscopy - YUPA

Gout in the Older Patient

Incidence is increasing

65 –74 ≥ 75

1990 21 to 24/1000 21/1000

1999 31/1000 41/1000

Women are 40 % of new cases

Prevalence after age 80 –M 9%, W 6%

Unusual joints –DIP, PIP, shoulder

Presentation may be atypical

Polyarticular, more chronic joint problems

Develop tophi more quickly, unusual locations

J Rheum 2004;31:1582-7

Gout in the Older Patient

Incidence is increasing

65 –74 ≥ 75

1990 21 to 24/1000 21/1000

1999 31/1000 41/1000

Presentation may be atypical

Polyarticular, more chronic joint problems

Develop tophi more quickly, in unusual locations

Women are 40 % of new cases

Prevalence after age 80 –M 9%, W 6%

Unusual joints –DIP, PIP, shoulder

J Rheum 2004;31:1582-7

Hyperuricemia & Related



U.A. increased in 25‐60% of adults, 90% of adolescents

Myocardial Infarction

MRFIT ‐ OR 1.1 ( 1.08 –1.15) p< .001, ↑ of 1 mg/dl of uric

acid, ↑ risk of MI by 4%

Rotterdam study ‐ ↑ MI & CVA

Metabolic Syndrome

insulin inhibits uric acid excretion

serum uric acid is strong predictor of development, thus

hyperuricemia may be an early marker

Gout & Related Conditions


NHANES III – 69% w/ gout vs. 30% control

Myocardial Infarction

MRFIT –OR* 1.26 ( 1.14 –1.40) p < .001

Similar data from HPFS – fatal & non‐fatal

Metabolic Syndrome

NHANES III –63% vs 25%

first gout attack precedes features of metabolic syndrome

*OR – odds ratio

Gout & Related Conditions


HPFS – prevalence of gout ↑ with ↑ BMI

Type 2 Diabetes Mellitus

MRFIT –RR of developing 1.34 (1.09‐1.64)

NHANES III –OR 2.55 of having FBS > 110

Hyperuricemia – A Cause of or

Marker for These Diseases

Is hyperuricemia an independent risk factor and

should it be treated as such?

Evidence for causal relationship

Uric acid causes endothelial dysfunction in animal models

Induced hyperuricemia in mice leads to arteriolar disease

and hypertension

Degree of hypertension related to degree of


Can be reversed with uric acid lowering meds

Hyperuricemia – Cause or


Problems with evidence of causal relationship

Human data is essentially all observational

No RCT trials that demonstrate lowering uric acid

impacts on the incidence or outcome of any of these


The adverse drug events associated with the uric acid

lowering drugs require clear indication prior to using

So What Should We Do?

Should we treat asymptomatic hyperuricemia

To prevent gout ‐ Not at this time

To impact related diseases –Not at this time

But in a patient with asymptomatic


Look for remedial causes of the hyperuricemia –

obesity, alcohol, medications

Look for evidence of risk factors of or presence of

related disorders that need to be addressed

In patients with gout and related disorder

• Early and effective uric acid lowering treatment

Gout – Treatment of Acute Attack

Educational points for patients –

The earlier an attack is treated, the more quickly it


If on uric acid lowering agent and an acute attack occurs,

continue the uric acid lowering agent


All effective, shorter t1/2 preferred

Would avoid in older patients and those with congestive

heart failure, chronic renal insufficiency, or peptic ulcer


Gout – Treatment of

Acute Attack


GI side effects limit use

Lower dose may be effective with less GI problems

1.2 mg. as initial dose, then 0.6 mg in 1 hour

better tolerated and as effective than 0.6 mg q hour for 7 hours*

Most effective if used within 12 hours of onset of


Would not give with CrCl < 10, patients on dialysis, or with

obstructive jaundice

*Arth & Rheum 2008;58:S879, abstract 1944

Gout ‐ Treatment

Acute Attack


Oral prednisone 40 to 60 mg/day or prednisilone 35 mg

with taper over 7 to 10 days

Intraarticular injection for single joint

Intravenous if NPO

Consider with chronic renal failure

Concomitant colchicine 0.6 mg a day may help prevent

rebound, may need to reduce dose of colchicine with CRF,

i.e. every other day

*Lancet 2008;371:1854

Gout ‐ Treatment

Acute Attack

ACTH 40 units* or Cosyntrophin 0.25 mg

May repeat in 12 and 24 hours

Would consider in patients with

Renal insufficiency




May allow you to use lower dose of prednisone

* J of Rheum 1994;31:803-5

Gout – Uric Acid Lowering


Goal ‐ serum uric acid < 6 mg. /dl.

Agents available

Uricosurics –

Probenecid – need 24 hour urine, not as effective with CrCl < 60

Xanthine Oxidase inhibitors

Allopurinol and Febuxostat, no 24 hour urine needed, effective in both

underexcretors and over producers

Treatment may precipitate an attack in about 25% of patients

warn patient

If an acute attacks occurs while on uric acid lowering agent, treat the

attack but continue the drug

treatment with prophylactic colchicine or NSAID prevents 85% of these



Dose –

Initial ‐ 100 to 300 mg/day, single dose

FDA approves up to 800 mg a day, ? upper limit

Recent studies suggest only 20‐25% of patients reach

uric acid level of < 6 mg/dl on 100 to 300 mg of

allopurinol *

Inhibits the metabolism of azathioprine, 6‐MP so dose

of these drugs must be reduced by 50%

Removed by dialysis, give dose after dialysis if needed

*Arth & Rheum ( Art Care & Res) 2008;59:1535

Allopurinol Use with Chronic Renal


Half life of allopurinol and oxypurinol increased with

decrease in renal function

Initial dose should be reduced based on Cr. Cl.

Goal for uric acid is still < 6 mg./dl.

If level not achieved, trial of Febuxostat

If Febuxostat not effective or available, consider

slowly increasing allopurinol dose, i.e. 50 mg every 3

to 4 weeks, with careful monitoring of


Uric acid

Liver enzymes.

Allopurinol Hypersensitivity


Typically begins 4 to 6 weeks after beginning


Fever, skin rash (palpable purpura),

adenopathy, hepatomegaly

Leukocytosis w/ eosinophilia, abnl LFTs, renal


Treatment ‐ STOP drug

Fatal in up to 20% of patients if not recognized


Non purine xanthine oxidase inhibitor

Potential advantages over allopurinol

More selective & potent XO inhibitor

Metabolized in liver

< 10% of active drug or active metabolite excreted by


Effectiveness of doses ‐ U.A. < 6.0 *

80 mg –48 to 53%

120 mg –62 to 65%

240 mg – 69%

*Arth & Rheum (Art Care & Res) 2008;59:1535


Approved in U.S. for 40 or 80 mg. and in Europe at

120 mg. but in Europe not recommended for

patients with ischemic heart disease or CHF

No apparent safety advantage over allopurinol

Short term studies suggest dose does not need to

be adjusted with Cr Cl of 10 –29 cc./min.*, but no

patients with creatinine ≥ 2.0 mg./dl. included any

of the studies to date.

Appears safe with mild hepatic dysfunction*

*Therapuetics and Risk Manag 2008;4:1209-20

Other Ways to Reduce Risk of


Patient Education

Emphasize long term medicine compliance

Weight loss

Dietary ‐ Foods to avoid *

Red meat, seafood, and organ foods

High fructose corn syrup –soft drinks

Dietary ‐ Helpful foods*

Low fat dairy products are uricosuric

High protein diets and high purine vegetables (legumes) do not

increase uric acid

Diet with moderate caloric restriction, ↑ complex carbohydrates, ↓

saturated fats ↓ uric acid by 1.7 mg/dl. and decrease in frequency

of gouty attacks


Other Ways to Reduce Risk of


Patient Education

Alcohol avoidance *

Interferes with excretion and increases production of


Beer > liquor, wine minimal effect –2 to 4 glasses a

week no increase risk of gout

Risk increased with heavy intake and binges

Modify medication regimen

Consider drugs that decrease uric acid levels

Losartin, Fenofibrate, Diflunisal, vitamin C

*Lancet 2004;363:127781

Other Ways to Reduce Risk of


Modify medication regimen

Avoid or use lowest dose possible of diuretics

To minimize hyperuricemic effect of diuretics,

combine with ACE inhibitor or ARB if additional drug


Treatments on the Horizon

Acute attacks

Interleukin‐1 beta inhibition


Pegylated uricase

Urate transporter 1 (URAT 1) inhibitors

Calcium Pyrophosphate Dihydrate

Deposition Disease (CPPD)

A group of syndromes associated with the

deposition of calcium pyrophosphate in hyaline or

fibrocartilage, synovium, joint capsule, or tendons

Asymptomatic x‐ray finding – chondrocalcinosis

Most common manifestation

Prevalence increases with age

Age 65 ‐74 ‐15%, 75‐84 ‐ 36%, > 84 ≈ 50%

Most typical locations

Wrist, Shoulder, knee, and symphysis pubis

Calcium Pyrophosphate Dihydrate

Deposition Disease (CPPD)

Clinical syndromes –


Pseudo osteoarthritis

Less common – pseudo rheumatoid arthritis, pseudo

neuropathic joint

With significant joint damage, chondrocalcinosis may

not be evident x‐ray

CPPD may be maker for underlying metabolic

disorders, especially if occurs in a younger


Disease Associations

Idiopathic most common ‐↑ PPi production

Previous trauma or surgery

• Hemochromatosis

Considerations in younger patients


Hyperparathyroidism, hypomagnesemia, and


Probably related



Hypocalcuric hypercalcemia

Clincal Clues to Diagnosis


Most common cause of acute monoathropathy in elderly

Knee is most common site –50% of cases

Cluster attacks in 2 to 5 joints

Petite attacks – mild swelling and inflammation

Pseudo osteoarthritis

OA picture with atypical joints

MCPs, wrists, elbows, or shoulders

OA with acute or petite flares

Pseudo rheumatoid arthritis

Chronic polyarticular arthritis

No erosions on x‐rays

Crystals in synovial fluid

CPPD ‐ Diagnosis

Demonstration of positively birefringent

crystals and typical cartilage or joint capsule

calcifications on x‐ray

Synovial fluid

Crystals – smaller, weakly birefringent

Synovial fluid –WBC typically 15‐30,000

Joints to survey for chondrocalcinosis

Shoulder, wrist, knee, symphysis pubis

CPPD ‐ Diagnosis

Other suggestive findings on X‐ray

Hook like osteophytes on MCPs

Severe patellofemoral joint narrowing or


Isolated radiocarpal joint narrowing

From Krey PR & Lazaro DM. Analysis of Synovial Fluid Ciba-Geigy, 1992


From the ACR

slide collection


From the ACR slide collection


CPPD ‐ Treatment


Aspiration and corticosteroid injection is preferred if


NSAIDs or prednisone as in gout if needed

Colchicine or NSAID as prophylaxis if needed

Other syndromes –

Symptomatic and as in osteoarthritis

Daily colchicine may prevent acute flares

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