This document discusses calcium pyrophosphate deposition (CPPD) disease, also known as pseudogout. It begins by noting that CPPD disease is underrecognized and can present in varied ways, from acute pseudogout attacks to chronic polyarticular arthritis. It then covers the pathophysiology of CPP crystal deposition, risk factors for acute pseudogout, associated medical conditions, diagnostic findings on imaging and arthrocentesis, and treatment approaches which are all off-label and based on small studies or expert opinion.

1. Crystal-Induced
Arthritis

2. Gout

3. Acute Gout

4. Flare: Classic Description
The victim goes to bed and sleeps in good health. About two o’clock in
the morning he is awakened by a severe pain in the great toe; more
rarely in the heel, ankle, or instep. The pain is like that of a dislocation,
and yet the parts feel as if cold water were poured over them . . . Now it
is a violent stretching and tearing of the ligaments – now it is a gnawing
pain, and now a pressure of tightening. So exquisite and lively
meanwhile is the feeling of the part affected, that it cannot bear the
weight of the bedclothes nor the jar of a person walking in the room. The
night is spent in torture.
Sydenham, 1683
Sydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc. 1850 (translation)

5. Pathogenesis of Gout

7. Mechanism of Inflammation in Gout
Neogi, T, NEJM 2011;364:443-452

8. Common Sites of Acute Flares
Midfoot
Gout can occur
in bursae, tendons,
and joints
Olecranon Bursa
Elbow
Wrist
Knee
Ankle
Subtalar
1st MTP
(eventually affected in ~90%
of individuals with gout)
Fingers

9. Classic Gout vs Atypical Gout
Chronic form can be
misdiagnosed as rheumatoid
arthritis or osteoarthritis: acute
flare-ups can be misdiagnosed as
cellulitis or infection
Can be misdiagnosed as cellulitis
or infection
Chronic but can have acute flare-
ups
Acute
Tophi common at presentationTophi rare at presentation
Any joint, upper or lower extremityUsually in lower extremity
Symmetric or asymmetricAsymmetric
PolyarthritisMonarthritis
Diagnosed in as many women as
men
Predominantly men
Observed in elderly patientsCan present at any age, including
patients older than 60 years
Atypical GoutClassic Gout

10. NSAIDS CONTRAINDICATED?
Renal Disease
CHF
Anticoagulants
GI Intolerance
STEROIDS CONTRAINDICATED? CORTICOSTEROIDS
NSAIDS
# of Joints
PO or
IA Steroids
IA
SteroidsColchicineAnakinra
> 1
1
Yes
No
NoYesYes

11. 0
10
20
30
40
50
60
70
80
90
100
Female,72yrsold
Male,70yrsold
Female,72yrsold
Male,72yrsold
Male,51yrsold
Male,40yrsold
Male,76yrsold
Male,70yrsold
Male,53yrsold
Male,38yrsold
Patients
Paientassessmentof
Improvementinpain(%)
Response to IL-1 receptor antagonist:
Anakinra 100 mg daily SQ x 3 days
Mean 79%" response"
in a pilot analysis
So A, D T, Revaz S, Tschopp J. Arthritis Res Ther. 2007 Mar 12;9(2):R28

12. DNA
Purine Bases
(Adenosine, Inosine)
Hypoxanthine
Xanthine
Uric Acid
Allantoin
(Avians, most mammals, not primates)
Xanthine-oxydase
Uricase
pKa 5.4
pKa 7.4
Metabolism of Purines

13. Choi, H. K. et. al. Ann Intern Med 2005;143:499-516
Uric Acid Homeostasis

14. Protein Consumption and Relative Risk
of Gout
Variable Relative Risk 95% CI
Total Protein 1.07 .84-1.36
Animal Protein .98 .74-1.23
Vegetable Protein .73 .56-.96
Dairy Protein .52 .40-.69
Non-Dairy Animal
rotein
1.18 .90-1.53
47,150 male participants (the Health Professionals Follow-up
Study [HPFS], 730 incident gout cases) with no history of gout at
baseline
Choi, HK et al NEJM 2004

15. Alcoholic Intake and Relative Risk of
Incident Gout
Variable RR 95%CI
Total Alcohol Intake (per
10 g daily)
1.17 1.11-1.22
Beer
(per 12 oz daily)
1.49 1.32-1.70
Liquor (per
shot daily)
1.15 1.04-1.28
Wine (per
4 oz glass daily)
1.04 .88-1.22
Choi, HK et al Lancet 2004
47,150 male participants (the Health Professionals
Follow-up Study [HPFS], 730 incident gout cases) with no
history of gout at baseline

16. Stages of Gout

17. Acute Gout

18. Definitive diagnosis is established by joint aspiration and identification of
negatively birefringent intracellular crystals by polarized microscopy.

19. Gouty Tophi

20. Radiology of Gout

21. Management Strategies in Patients with
Hyperuricemia
Neogi, T, NEJM 2011;364:443-452

22. Correctable Factors
Contributing to Hyperuricemia
• Obesity
• Hyperlipdemia
• ETOH
• Diuretic Therapy
• High Fructose Corn Syrup
• Poorly controlled hypertension
• High purine consumption
• Decreased urine flow (<1 ml per minute)

23. Xanthine Oxidase Inhibitors
Allopurinol
•Start low eg: 50-100 mg qd
•Increase by 50-100mg every 2-3 weeks according to symptoms and
measured SUA
•“Average” dose 300 mg daily
– lower dose if renal/hepatic insufficiency but can push to target
– higher dose in non-responders.
•Treat to Target
• Usually UA < 6mg/dL , but 5mg/dL if Tophi
Febuxistat
•40-80 mg daily
•Theoretically safer in pts with renal insufficiency, but increased overall
mortality
For patients with gout and CVD, febuxostat and allopurinol had a similar overall
cardiovascular safety profile, but febuxostat was associated with greater risks for all-cause
and cardiovascular mortality. Despite febuxostat's known advantage over allopurinol in
lowering uric acid levels, its cost and mortality disadvantages suggest that it be reserved for
patients who have allergic reactions to, or do not benefit from allopurinol. N Engl J
Gore, J Med 2018 Mar 12;

24. New Agents
• Lesinurad (Zurampic)
• Blocks URAT1 and OAT4 transporters in kidney, blocking uric acid
reabsorption
• Used in conjunction with Xanthine Oxidase Inhibitors
• 200mg dosing in pts who have not reached target levels of UA on XOI’s
• Pegloticase (Krystexxa)
• Pegylated Uricase
• IV every 2weeks
• 30% risk of infusion reactions
• Cannot be used in pts w/ G6PD deficiencies

25. ACP vs ACR/EULAR Rx
Recommendations

26. Control of Hyperuricemia
• Differing opinions regarding initiation esp. around 1st
attack.
• Clear evidence if:
• erosions + on X-ray / chronic tophaceous gout
• >2 gout attacks per year.
• May decrease risk of CVD and CRI

27. LASSO Trial
Max Dose
Allopurinol
% of Pts Duration of Rx
(days)
Treatment
Emergent Events
< 300 mg 14.4% 155.5 15.2%
300 mg 65.4% 152 9.5%
>300 mg 20% 159.7 11.4%
6 month safety trial
1732/1735 pts received >1 dose Allopurinol
Treatment Emergent Events: Rash < 1.5 %
No cases of Allopurinol Hypersensitivity Sydrome
Becker M et al Seminars in A&R 2017 45; 2: 174-183

28. Allopurinol Hypersensitivity Syndrome
• < 0.1% pts w/ mortality rate approx. 27%
• Risk Factors
• Genetics
• HLA B 5801
• Renal Function
• Diuretic Use
• Recent start of Allopurinol
• Starting dose of Allopurinol
• Recommendations:
• HLA testing in high risk individuals; ie. Han Chinese, Koreans, Thai, AA(?)
• Starting dose <1.5mg/mL/min eGFR
• Not > 100mg for normal
• 50 mg fo rpts w/ eGFR < 60 mL/min
Stamp L et al Joint, Bone & Spine 2016;1:19-24

29. Gout Flares with Treatment
Becker MA et al, NEJM 2005;2450-2461

31. CPPD Disease Under-recognized
• CPPD disease: Prevalence 4-7%, based on radiographic criteria
(chondrocalcinosis)
• Unusual in patients under 60-years-old
• Considered an arthritis of aging
• CPPD disease is underdiagnosed
• 29-43% TKRs have CPP crystals (not previously diagnosed with CPPD disease)
• CPPD disease includes a broad range of clinical presentations
• Acute presentation = “pseudogout”
• Chronic CPP crystal inflammatory arthritis

33. Varied Clinical Presentations
• Classic: Acute gout-like arthritis
• Acute pain, swelling, warmth (synovitis) of knee or wrist
• Caused by calcium pyrophosphate (CPP) crystals
• Chronic CPP arthritis (chronic pseudogout)
• Polyarticular involvement
• Symptoms lasting weeks-months

34. CPP Deposition
(Pseudogout)
• Gout• Pseudogout
Weakly positively birefringent
Rhomboid-shaped crystals
(Blue when parallel to polarizer)
Calcium pyrophosphate
dihydrate
Gout
(Monosodium urate)
Strongly negatively
birefringent
Needle-shaped crystals
(Yellow when parallel to
Gout

35. Chronic CPP arthritis:
AKA “Chronic pseudogout”
• Chronic large joint effusions (knees, shoulders) lasting weeks-months
• Polyarticular arthritis involving knee, wrist, elbow, shoulder (glenohumeral
joint), MCPs of hand
• Difficult-to-treat osteoarthritis suggests underlying CPPD disease
• If chronic joint effusion, consider diagnostic arthrocentesis
• Chroninc CPP arthritis may mimic rheumatoid arthritis
• Chronic CPP arthritis can present with symmetric synovitis of the MCP joints
of the hands
• Seronegative inflammatory arthritis (RF, CCP negative)
• CPPD disease may cause erosive disease in severe cases, though erosions are
much less common in CPPD disease than in RA
• Older age of onset than rheumatoid arthritis

36. Xray Findings: Hand MCP Joint Arthritis
• Osteoarthritis (joint space narrowing) does not typically involve the
metacarpal phalangeal (MCP) joint of the hand
• Suggests other arthritis such as CPPD disease or rheumatoid arthritis
• “Hook-like” osteophytes

37. CPPD Disease:
Associated Conditions
• Hereditary hemochromatosis
• Hyperparathyroidism (OR 3.03%) (primary or secondary)
• Hypomagnesemia
• Magnesium is a cofactor for pyrophosphatases
• Magnesium increases solubility of CPP crystals
• Gitelman syndrome (autosomal recessive)
• Hypophosphatasia (rare congenital disease)
• Chronic kidney disease, Stage V
• Particularly acute CPP arthritis

38. Risk Factors for Acute CPP Arthritis
(Pseudogout)
• Age (strongest known risk factor)
• Prior joint trauma, h/o meniscectomy, OA
• Post-operative period
• Post-parathyroidectomy (may be related to hypomagnesemia)
• Post-hip fracture repair
• Loop diuretic use
• Not seen with thiazides
• May be related to hypomagnesemia

39. Factors Not Associated
with CPP Deposition Disease
• Calcium supplementation does not increase risk of CPPD disease
• No dietary factors (unlike gout)
• Rheumatoid arthritis
• Thyroid disease
• Diabetes

40. Screening for Associated Conditions
• Consider screening if:
• CPPD disease with polyarticular involvement
• Younger than 60-years-old
Check:
• Iron studies
• Iron, transferrin, % Saturation, ferritin
• Serum calcium
• Parathyroid hormone
• Magnesium
• Alkaline phosphatase
• Family history of similar symptoms
• Treatment of the associated disease does not necessarily improve CPPD
disease

41. Calcium Pyrophosphate Deposition
(CPPD) Disease: Treatment Overview
• Acute calcium pyrophosphate (CPP) arthritis (“pseudogout”)
• Chronic CPP arthritis
• All treatments are off-label
• Small RCTs, retrospective studies, or expert opinion
o Methotrexate
o Colchicine
o HCQ
o Low dose Prednisone
o NSAID’s
o Chronic Anakinra
• Asymptomatic chrondrocalcinosis does not require treatment
No treatments reduce CPP crystal load
No disease modifying drugs for CPPD disease

42. Chronic CPP Arthritis: Treatment
• Oral NSAID with gastroprotection
• Colchicine 0.6 mg daily or BID
• Caution with liver or renal insufficiency
• Glucocorticocoids, low dose
• Prednisone 5 mg daily
• Hydroxychloroquine (plaquenil) 200-400 mg daily
• Methotrexate (5-20 mg once per week) with daily folic acid
supplementation
• Caution with liver or renal insufficiency
• Interleukin-1β inhibitors: anakinra (Kineret) daily injection
• May be used with CKD
• Combine low doses of several different therapies
• Treatment often dictated by comorbidities
Zhang W, Doherty M, Pascual

43. Thank you!