Crystal Induced Arthropathy

Update on Crystal Related
Arthritis
John W. Pendleton, M.D.

What’s New in Crystal Related
Arthritis?
Gout
Diagnosis
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
Disease
Diagnosis
Multiple presentations and evaluation
Treatment

Gout
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
Tophi
Potential for renal dysfunction
Nephrolithiasis

Gout
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
Conditions
Hypertension
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
Hypertension
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
Obesity
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
hyperuricemia
Can be reversed with uric acid lowering meds

Hyperuricemia – Cause or
Marker
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
disorders
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
hyperuricemia
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
responds
If on uric acid lowering agent and an acute attack occurs,
continue the uric acid lowering agent
NSAIDs
All effective, shorter t1/2 preferred
Would avoid in older patients and those with congestive
heart failure, chronic renal insufficiency, or peptic ulcer
disease

Gout – Treatment of
Acute Attack
Colchicine
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
symptoms
Would not give with CrCl < 10, patients on dialysis, or with
obstructive jaundice
*Arth & Rheum 2008;58:S879, abstract 1944

Gout ‐ Treatment
Acute Attack
Corticosteroids*
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
DM
PUD
NPO
May allow you to use lower dose of prednisone
* J of Rheum 1994;31:803-5

Gout – Uric Acid Lowering
Agents
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
flares

Allopurinol
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
Failure
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
Creatinine
Uric acid
Liver enzymes.

Allopurinol Hypersensitivity
Syndrome
Typically begins 4 to 6 weeks after beginning
treatment
Fever, skin rash (palpable purpura),
adenopathy, hepatomegaly
Leukocytosis w/ eosinophilia, abnl LFTs, renal
failure
Treatment ‐ STOP drug
Fatal in up to 20% of patients if not recognized

Febuxostat
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
kidney
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

Febuxostat
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
Gout
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
*NEJM2004;350:1093-103

Other Ways to Reduce Risk of
Gout
Patient Education
Alcohol avoidance *
Interferes with excretion and increases production of
purines
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
Gout
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
needed

Treatments on the Horizon
Acute attacks
Interleukin‐1 beta inhibition
Hyperuricemia
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 –
Pseudogout
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
patient

Disease Associations
Idiopathic most common ‐↑ PPi production
Previous trauma or surgery
• Hemochromatosis
Considerations in younger patients
Familial
Hyperparathyroidism, hypomagnesemia, and
hypophosphatasia
Probably related
Gout
Hypothyroidism
Hypocalcuric hypercalcemia

Clincal Clues to Diagnosis
Pseudogout
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
degeneration
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
Psuedogout
Aspiration and corticosteroid injection is preferred if
feasible
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