1. Pseudogout: Real Stories of a Misunderstood Crystal
Justin Gan, MD
Division of Rheumatology
December 23, 2016
Calcium Pyrophosphate Deposition Disease

2. Disclosures I have no financial relationships to disclose
I will discuss off label use and/or investigational use of medications in my presentation

3. Classic “Pseudogout” Classic: Acute gout-like arthritis
Acute pain, swelling, warmth (synovitis) of knee or wrist
Not caused by monosodium urate, but rather a calcium-based crystal:
Calcium pyrophosphate dihydrate (CPP)
Pseudogout includes a broad range of clinical presentations
Acute presentation = “pseudogout”
Chronic “pseudogout”
1961: McCarty and colleagues first identified CPP crystals from knee synovial fluid of patients with acute synovitis and chondrocalcinosis (dense narrow band following the countour of the epiphysis), introducing the term “calcium pyrophosphate dihydrate crystals”
Mono or oligoarticular. PIC: Swollen knee, chondrocalcinosis

4. Pseudogout: Renaming a Classic Arthritis
CPP crystals: calcium pyrophosphate dihydrate cystals
Chondrocalcinosis: cartilage calcification seen on X-ray
CPPD: Calcium pyrophosphate deposition
Refers to presence of CPP crystals
CPPD disease encompasses all related clinical presentations:
Acute CPP crystal arthritis = “Pseudogout”
Acute pain and swelling, usually monoarticular
Chronic CPP crystal inflammatory arthritis
Chronic CPP arthritis (chronic pseudogout)
Zhang W, et al. EULAR CPPD Part I: terminology and diagnosis. Ann Rheum Dis 2011; 70: PIC: CPP Crystal

5. Learning Objectives
Articulate the clinical manifestations of acute and chronic CPPD disease
Describe the systemic diseases that are associated with CPPD disease (pseudogout)
List the treatment options for CPPD disease (pseudogout)
To give it the credit it deserves

6. 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
Prevalence data uses chondrocalcinosis / radiographic findings which are inaccurate in diagnosis of CPPD disease. Likely underestimates true prevalence.

8. Rhomboid, birefringent calcium pyrophosphate (CPP) crystals are seen under polarizing light microscopy in this
sample of synovial fluid that was obtained from a patient with acute CPP crystal arthritis of the wrist (Panel A). The
hands of an elderly patient with CPPD disease show swelling in the left wrist and the third proximal interphalangeal
joint of the left hand (Panel B).

11. 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

12. Chronic CPP arthritis: “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
Patient >70 years old, with significant shoulder GH OA suggests crystal arthritis.

13. CPP Deposition Disease: Diagnosis
Acute CPP crystal arthritis (pseudogout)
Need diagnostic arthrocentesis for confirmation of calcium pyrophosphate (CPP) crystals
Consider sending synovial fluid Gram stain and culture even when crystals are present (especially with other co-morbidities or risk factors for infection)
Differential includes gout and septic arthritis
Radiographic findings are suggestive but not diagnostic

14. CPP Deposition (Pseudogout)
Calcium pyrophosphate dihydrate
Gout
(Monosodium urate)
Gout
Pseudogout
Pseudogout, Calcium pyrophosphate dihydrate crystals: Positively weakly birefringent rhomboid shaped crystals
By convention, negative / positive birefringence is defined by the orientation to the polarizing lens. Positive bireferingence is defined by crystals are blue when parallel to polarizer.
Weakly positively birefringent
Rhomboid-shaped crystals
(Blue when parallel to polarizer)
Strongly negatively birefringent
Needle-shaped crystals
(Yellow when parallel to polarizer)

15. “Pseudogout” vs Gout CPP Deposition Disease (Pseudogout) Gout
Joint distribution
Knee, wrist, MCPs of hands (podagra is rare)
Podagra, midfoot ankle, knee (with tophi)
Duration
Weeks-months
Days, 1-2 weeks
Crystals
Calcium pyrophosphate dihydrate
Monosodium urate
Radiographic findings
Chondrocalcinosis
Erosions
PIC microscope
PIC knee, wrist

16. Chondrocalcinosis Radiographic term
Calcium-containing crystals detected as radiodensities in articular cartilage
Typically we see chondrocalcinosis on xrays

17. 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
PIC Hand xray MCP OA, hook like osteophytes

18. Role of Imaging in Diagnosis
X-ray findings are suggestive but not diagnostic
Chondrocalcinosis: knees, wrists, hips, pubic symphysis, sternoclavicular joint
Knees: patellofemoral joint space narrowing
Wrists: Radiocarpal narrowing
Hand MCPs: joint space narrowing and hook-like osteophytes
Shoulders: Severe glenohumeral osteoarthritis
Spine: Annulus fibrosus calcification
CT: C1-C2 “crowned dens syndrome”

19. Role of Imaging in Diagnosis
CT is more sensitive than X-ray for chondrocalcinosis
Dual-energy CT useful for monosodium urate crystals (gout), but not CPPD disease (difficulty distinguishing CPP crystals from other calcified structures)
MRI does not visualize chondrocalcinosis well
Ultrasound may be useful
Operator-dependent

20. Chondrocalcinosis: A Radiographic Finding
Chondrocalcinosis ¹ clinical CPPD disease
Chondrocalcinosis is not diagnostic of CPPD disease
Asymptomatic chondrocalcinosis is not CPPD disease
40%-80% of patients with clinical CPPD disease have chondrocalcinosis
44% of patients older than 84 yo had chondrocalcinosis on x-rays (not necessarily clinical CPPD disease)
Prior trauma is a risk factor for chondrocalcinosis
Seen in 20% of those with history of meniscal surgery (meniscectomy)
Only seen in 4% of contralateral knees of same patients
Chondrocalcinosis on xrays: Pre-clinical CPPD disease?
Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med Jun 30;374(26):
Low sensitivity, low specificity. Even prior trauma is a RF for chondrocalcinosis. We don’t know if chondrocalcinosis a pre-clinical finding that may imply future CPPD disease.
We do not have good data on the proportion of people that have chondrocalcinosis without clinical arthritis, either CPPD or even OA?

21. Do CPP Crystals Cause Osteoarthritis?
CPPD disease and osteoarthritis are considered arthritides of aging
20% TKRs have CPP crystals (not previously diagnosed with CPPD disease)
Early osteoarthritis is particularly evident in rare familial forms of CPPD disease with widespread CPP deposition / chondrocalcinosis
Is there a relationship between presence of CPP crystals and development of osteoarthritis?
Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med Jun 30;374(26):
Even more important question is…
Epidemiologic studies suggest systemic CPP deposition is likely.

22. How do CPP crystals form?
Produced within cartilage by chondrocytes
Vesicles from chondrocytes are the sites of inorganic phosphate and crystal formation
Extracellular pyrophosphate (PPi; from ATP) excreted from chondrocytes and vesicles
Inorganic phosphate complexes with calcium to form calcium pyrophosphate dihydrate salt (Ca2P2O2 2H2O)

23. Pathophys
Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med Jun 30;374(26):
PIC: Severe OA, chondrocalcinosis
-Overproduction of extracellular inorganic pyrophosphate (Ppi) contributes
-Chondrocytes from CPPD-containing cartilage produces more extracellular pyrophosphate than normal and OA control cartilages
-Matrix vesicles can produce CPPD crystals in vivo
-Synovial hypertrophy, then PG and cytokines. Chondrocyte activation by crystals. Then damage of matrix

24. Factors Influencing Extracellular Pyrophosphate
Intracellular pyrophosphate and ATP efflux via transmembrane transport protein encoded by ANKH gene
ANKH: Gain-of-function mutation = Familial chondrocalcinosis (rare form of CPPD)
Genetic factors in sporadic CPPD disease are not as clear
Pyrophosphate degraded to inorganic phosphate by alkaline phosphatase
Low alkaline phosphatase  Hypophosphatasia
SNPs on ANKH gene: CCAL2 chrom 5p (regulates Ppi out of cells), CCAL1 chrom 8q

25. CPP Crystals and Inflammation
CPP crystals induce inflammasome formation
CPP crystals have biomechanical effects on cartilage matrix via production of:
Prostaglandin E2
Matrix metalloproteinase
Inflammatory infiltrate, remodeling of cartilage
CPPD formed in areas of abnormal pericellular matrix but not normal matrix

26. Osteoarthritis Associates with CPPD Disease
Knee osteoarthritis associates with chondrocalcinosis at multiple sites (wrists, hips, knees)
Association between osteoarthritis and chondrocalcinosis is independent of age
Prevalence of chondrocalcinosis increases with severity of OA
OA associates with chondrocalcinosis and CPPD disease, independent of age
Chondrocalcinosis may be a consequence of OA
Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin N Am. 2014;
In a large case control study, knee OA associated with CC at wrists, hips, knees- whereas hip OA did not associate with CC at any joint. (Abhishek A, Doherty S, Maciewicz R, et al. Arthritis Care Res (Hoboken) 2013;65:
Association between osteoarthritis and chondrocalcinosis is independent of age (Neame RL, et al. UK prevalence of knee CC. Ann Rheum Dis 2003;62:513-8.) (Sanmarti R, et al. Ann Rheum Dis 1996;55:30-3.)
CC in Knee OA 8-33% (hospital-based), 30-53% in end-stage knee OA.

27. Osteoarthritis Associates with CPPD Disease
It is unclear if CPPD disease is associated with osteoarthritis progression
Evidence regarding CPPD and osteophyte development is conflicting
Chondrocalcinosis (CC) did not associate with knee OA progression in larger prospective community-based studies
Epidemiologic data is deficient due to inability to identify symptomatic CPPD disease
Abhishek A. Calcium pyrophosphate deposition disease: a review of epidemiologic findings. Curr Opin Rheum. 2016; 28 (2):
Although it seems osteoarthritis associates with CPPD Disease, an important distinction, and truly a more important question – it is unclear if CPPD disease is…
Larger prospective community-based studies CC does not associate with knee OA progression
CC does not associate with incident OA
Effect on progression remains unclear

28. Hemochromatosis and CPPD Disease
Hereditary hemochromatosis
Iron inhibits pyrophosphatases
Chondrocalcinosis only in H63D variant (not C282Y)
Other factors in hemochromatosis other than iron overload that may predispose to CPPD disease
Arthritis not improved by phlebotomy

29. 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
Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin N Am. 2014;
Nephrolithiasis?
Gitelman’s: AR disorder, loss of function mutation of the thiazide sensitive sodium chloride symporter of DCT= hypokalemic metabolic alkalosis, hypocalciuria, hypoMag
Hypophosphatasia: tissue non-specific alkaline phosphatase (TNSALP), Osteomalacia  stress fractures

30. CPPD Disease: Associated Conditions
Hypomagnesemia: acquired causes
Diuretic therapy (loop diuretics)
Short bowel syndrome
Malabsorption
Proton pump inhibitors
Cyclosporine
Tacrolimus

31. 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
Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin N Am. 2014;
Nephrolithiasis?
Gitelman’s: AR disorder, loss of function mutation of the thiazide sensitive sodium chloride symporter of DCT= hypokalemic metabolic alkalosis, hypocalciuria, hypoMag
Hypophosphatasia: tissue non-specific alkaline phosphatase (TNSALP), Osteomalacia  stress fractures

32. 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

33. 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
Rheumatoid arthritis: 11% have CPP crystals

34. 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
Abhishek A. Calcium pyrophosphate deposition disease: a review of epidemiologic findings. Curr Opin Rheum. 2016; 28 (2):

35. Calcium Pyrophosphate Deposition (CPPD) Disease: Treatment Overview
Acute calcium pyrophosphate (CPP) arthritis (“pseudogout”)
Chronic CPP arthritis
Asymptomatic chrondrocalcinosis does not require treatment
All treatments are off-label
Small RCTs, retrospective studies, or expert opinion
No treatments reduce CPP crystal load
Treatments are aimed at reducing the inflammatory response to CPP crystals
Allopurinol reduces urate crystal load in gout; no equivalent for CPP crystals in CPPD disease / pseudogout
No disease modifying drugs for CPPD disease
EULAR recommendations 2011
Treatment of CPPD disease is independent of any associated conditions

36. Acute CPP Arthritis (Pseudogout): Treatment
NSAIDs with gastroprotection
Joint aspiration with intra-articular glucocorticoid injection
Ice, temporary rest
If no improvement, consider:
Colchicine 0.6 mg daily or BID
Oral steroids, short tapering course
Prednisone mg daily tapered over 3-7 days
Treatment often dictated by comorbidities
Expected response time: Days
Zhang W, Doherty M, Pascual E, et al. Ann Rheum Dis 2011; 70:

37. Chronic CPP Arthritis: Treatment
Prevent acute CPP arthritis episodes
Reduce frequency and intensity of episodes
Manage chronic polyarticular synovitis
May involve wrists, knees, hands (MCPs)
No treatments reduce crystal load
Treatments are aimed at reducing inflammatory response to CPP crystals
No disease modifying drugs
Trial-and-error approach for treatment of chronic CPPD disease
Zhang W, Doherty M, Pascual E, et al. Ann Rheum Dis 2011; 70:

38. 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) mg daily
Methotrexate (5-20 mg once per week) with daily folic acid supplementation
Interleukin-1β inhibitors: anakinra (Kineret) daily injection
May be used with CKD
Combine low doses of several different therapies
Treatment often dictated by comorbidities
Trial-and-error approach for treatment of chronic CPPD disease
HCQ, MTX may take weeks-months to see prophylaxis effect
Zhang W, Doherty M, Pascual E, et al. Ann Rheum Dis 2011; 70:

39. Chronic CPP Arthritis: Treatment
Osteoarthritis with chronic CPPD disease
Consider trial of colchicine, plaquenil, or corticosteroids
May be useful if other therapies are contraindicated due to comorbidities
Treatment of associated conditions may not improve symptoms of CPPD disease
Hyperparathyroidism, hemochromatosis, hypomagnesemia
Anticoagulation,

40. Calcium Pyrophosphate Deposition (CPPD) Disease: Summary
Clinical presentations include both classic acute CPP arthritis (“Pseudogout,” with acute joint synovitis of knees and/or wrists) and chronic CPP arthritis (“chronic pseudogout,” also involving hands/MCPs, elbows, and shoulder glenohumeral joints)
Age < 60: Consider screening for conditions associated with CPPD disease
Iron studies (% Saturation) (Hereditary hemochromatosis)
Serum calcium, parathyroid hormone (Hyperparathyroidism)
Magnesium (Hypomagnesemia)
Alkaline phosphatase (Hypophosphatasia, rare congenital disease)
Treatment of associated conditions may not improve CPPD disease (except magnesium)
Treatment of acute CPP arthritis (pseudogout) includes ice, temporary rest, NSAIDs, joint aspiration +/- corticosteroid injection
For chronic CPP arthritis, also consider colchicine, low-dose oral corticosteroids (prednisone 5-10 mg daily), plaquenil, methotrexate (weekly low-dose), or combination therapy

41. References
Abhishek A. Calcium pyrophosphate deposition disease: a review of epidemiologic findings. Curr Opin Rheum. 2016; 28 (2):
Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin N Am. 2014;
Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med Jun 30;374(26):
Zhang W, Doherty M, T Bardin, et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis 2011; 70:
Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition Part II: Management. Ann Rheum Dis 2011; 70:

42. Thank you
Happy holidays and happy New Year!